Random urine electrolytes were obtained after the patient was admitted to the PICU

Posted on November 29, 2023 by hemp2022

The classic triad of findings in rhabdomyolysis is muscle pain, weakness, and dark urine. Patients with rhabdomyolysis usually have some combination of highly elevated creatine kinase, myoglobinuria, hyperkalemia, hyperphosphatemia, acute kidney injury, hypocalcemia, and metabolic acidosis with or without an anion gap.In this patient’s case, there was no clear inciting event, and her symptoms were episodic with spontaneous resolution. Additionally, she did not complain of focal pain or weakness as would be expected in compartment syndrome. Although she did have an elevated creatine kinase, the elevation was not significant and the expected laboratory findings of hyperkalemia and hyperphosphatemia were not present. I felt that compartment syndrome and rhabdomyolysis were unlikely. In this young adult patient with episodic weakness and hypokalemia, hypokalemic periodic paralysis was immediately considered as part of the differential diagnosis. This condition is characterized by attacks of weakness with a normal neurologic exam in between, as seen in this patient. Primary hypokalemic periodic paralysis follows an autosomal dominant inheritance pattern, and notably this patient had no known family history of the same. Bulbar and respiratory functions are preserved and between attacks, patients will also present with normal plasma potassium. Triggers include stress, exercise, and carbohydrates. The condition also presents with arrhythmias.There are, however, other conditions that can cause non-familial hypokalemic paralysis, including RTA.All three sub-types of RTA are characterized by an inability to acidify the urine. As a result of this, RTAs present with an increased urine anion gap, but this information was not provided in the case history. In distal or type 1 RTA,pipp grow racks there is impaired hydrogen ion secretion in the distal tubule of the nephron. In proximal or type 2 RTA, there is impaired bicarbonate reabsorption in the proximal tubule of the nephron. In type 4 RTA, there is decreased aldosterone secretion or aldosterone resistance.

As a result of this, type 4 RTA is associated with serum hyperkalemia while the other two types of RTA result in hypokalemia.8 Due to the serum potassium levels, which were not suggestive of aldosterone resistance, I eliminated type 4 RTA from my list of possibilities. The types of hypokalemic RTAs are differentiated by examining the potential of hydrogen of the patient’s urine. In type 2 RTA, urine pH is initially high, then decreases to < 5.5. The urine pH remains above 5.5 in type 1 RTA.This patient had a urine pH of 7.0, suggesting either a type 1 RTA or an early type 2 RTA. Type 1 RTA can be hereditary or be caused by autoimmune diseases such as Sjögren’s syndrome, or as a complication of chemotherapy or toluene use. The causes of type 2 RTA include genetic abnormalities, Fanconi syndrome, monoclonal gammopathy, and carbonic anhydrase inhibitor use.There was no mention of chemotherapy or carbonic anhydrase inhibitors with the patient’s presentation. The patient had no family history of similar issues, and it would stand to reason that a genetic abnormality would have come to light before age 19 years. As such, I feel type 1 RTA is more likely than type 2 RTA. The Agency for Toxic Substances and Disease Registry notes that toluene is a solvent found in paints, nail polish, paint thinners, and adhesives, among other substances. It can have toxic effects if ingested or inhaled.The findings of acute toluene use include a hypokalemic paralysis and a metabolic acidosis. Patients are also often found to have liver injury and rhabdomyolysis, and may present with altered mentation, renal failure, and acidemia.This patient’s presentation is most consistent with type 1 RTA due to toluene use. She denied any illicit drug use but did admit to a history of alcohol ingestion and marijuana use, raising the question of whether there could be toxic alcohols or other coingestions. Unfortunately, there is no diagnostic test for toluene use. However, proximal and distal RTA can be differentiated by calculating the urinary ammonium ion concentration from the measured urine anion gap and osmolar gap. Therefore, my test of choice would be a urine electrolyte panel to calculate the anion gap and osmolar gap.

Additionally, I would consult nephrology to assist in management of this patient.The patient developed bigeminy while in the ED but remained hemodynamically stable and did not have a change in her mental status. Her electrolytes were replaced with oral and intravenous potassium, with improvement of her arrythmia and symptoms. She declined central line placement for more rapid replacement. The patient was admitted to the pediatric intensive care unit for further management and evaluation. Nephrology was consulted because these results demonstrated an elevated urine anion gap suggestive of RTA. The patient’s symptoms completely resolved once her electrolytes were repleted. She was found to have positive antinuclear and anti–Sjögren’s-syndrome-related antigen A autoantibodies, leading to the diagnosis of Sjögren’s syndrome, despite a lack of phenotypic features. The patient’s urine anion gap was indeterminate for the etiology of her non-anion gap metabolic acidosis; however, her urine osmolar gap of less than 150 milliosmoles per kilogram suggested type 1 or type 4 RTA as the etiology. This coupled with laboratory findings suggestive of autoimmune disease led to the diagnosis of type 1 RTA. Her RTA was treated with potassium supplementation and alkali therapy to achieve a normal serum bicarbonate concentration. Unfortunately, the patient has not been compliant with her home therapy and has required multiple hospitalizations since her original presentation. Her presentation and urine anion gap strongly suggest toluene toxicity, but the patient repeatedly denied insufflating glue and there is no diagnostic test for toluene.Hyperchloremic, hypokalemic metabolic acidosis is a condition all emergency providers should be prepared to diagnose and manage. In this case, the patient presented with a cardiac arrhythmia due to severe hypokalemia. The underlying etiology of the hypokalemia should be sought while simultaneously treating the condition. The initial ED evaluation includes obtaining a basic metabolic panel and a urinalysis. Once it is determined that the patient does not have a serum anion gap, the clinician should consider three broad categories of non-anion gap acidosis and their etiologies: increased acid production; loss of bicarbonate; and decreased renal excretion of acid .

Type 1 or distal RTA is a primary problem of urine acidification due to impaired hydrogen ion secretion in the distal convoluted tubules. The underlying etiology in adults is usually autoimmune diseases such as Sjögren’s syndrome or rheumatoid arthritis.In pediatrics, the cause is usually a hereditary gene mutation for either the basolateral chloridebicarbonate exchanger or the apical hydrogenadenosine triphosphatase gene. Lastly, a distal RTA can be iatrogenic due to ifosfamide, a chemotherapeutic analog of cyclophosphamide.Type 2 or proximal RTA is a primary problem of impaired bicarbonate reabsorption leading to increased bicarbonate loss.In adults, the underlying etiology is most commonly proximal tubular toxicity from increased exertion of monoclonal immunoglobulin light chains as seen in multiple myeloma.Type 2 RTAs are seen in Fanconi syndrome , and in patients prescribed carbonic anhydrase inhibitors .In pediatric patients, type 2 RTAs are usually idiopathic, but they can be due to a complication from chemotherapy, cystinosis , or inherited mutations in the KCNJ15 and SLC4A4 genes.The term “type 3 RTA” is rarely used as it is now considered a combination of types 1 and 2. Type 4 RTA is beyond the scope of this discussion. The test of choice when evaluating for a RTA is urine electrolytes so that the clinician can calculate how much ammonium is being excreted.18 Ammonium excretion will be decreased in a true RTA and normal/increased if the acidosis is due to toluene use or chronic diarrhea. Unfortunately, ammonium excretion is rarely measured directly. Urine ammonium excretion can be estimated by using the urine anion gap or urine osmolar gap.20The misuse of opiates is a serious problem worldwide, is increasing in young adults, and has substantial individual and societal consequences. In 2014 in the United States alone, approximately 1.9 million people had an opiate use disorder, including 586,000 heroin users. Neuroimaging in opiate dependence indicates both altered brain structure, particularly in the anterior cingulate cortex , and brain function involving dorsolateral prefrontal cortex and ACC. Magnetic resonance spectroscopy allows the non-invasive quantitation of brain metabolites that provide information on the neurophysiologic integrity of brain tissue. The few 1H MRS studies in opiate dependence to date revealed lower concentration of N-acetylaspartate , a marker of neuronal integrity, in the medial frontal cortex, including the ACC, as well as lower glutamate , a primary excitatory neurotransmitter,motel grow racks or glutamate+glutamine concentration in some but not all studies. The discrepant MRS findings may relate to differences among study participants regarding the prevalence and severity of comorbid substance use , the type, dose and duration of replacement therapy for heroin users , and/or participant age.

The ACC, DLPFC and orbitofrontal cortex are important components of the brain reward/executive oversight system, a neural network critically involved in the development and maintenance of addictive disorders. Structural brain imaging in opiate dependence revealed generally lower gray matter volume or density in frontal regions, including the DLPFC, with thinner frontal cortices related to longer duration of opiate misuse. Functional MR imaging showed that the DLPFC, OFC and ACC are involved in decision making, and in opiate dependent individuals, lower task-based fMRI activity in the ACC related to compromised behavioural control of cognitive interference. Furthermore, smaller frontal gray matter volume in opiate dependence related to higher impulsivity on the Barratt Impulsivity Scale . Correspondingly, opiate dependence is associated with cognitive deficits, primarily in executive functioning and self-regulation . Thus, the neuroimaging literature in opiate dependence suggests altered frontal brain structure as well as compromised neuronal integrity and glutamatergic metabolism. Few if any studies however investigated their relationships to opioid and other substance use behaviour or cognition. Further research into specific regional brain effects and their potential cognitive and behavioural correlates may inform better targeted treatment of individuals with opioid use disorders. We measured in opiate dependent individuals’ metabolite concentrations from the ACC and previously unexplored DLPFC and OFC and related them to quantitative measures of neurocognition, self-regulation, and substance use. Specifically, we compared opiate dependent individuals on buprenorphine maintenance to controls . We also included another control group, a substance-dependent ‘control’ group of 3 week abstinent alcohol dependent individuals , a commonly investigated treatment-seeking group to differentiate opiate dependence from not only control individuals but also individuals with a substance dependence . Our primary hypotheses were that: OD have lower NAA and Glu concentrations than CON in ACC, DLPFC, and OFC, these frontal cortical NAA and Glu deficits are associated with the level of opiate use and cigarette-smoking severity, the frontal NAA and Glu deficits in OD relate to higher impulsivity, poorer executive function, and lower decision making skills, and OD have more pronounced metabolite concentration deficits than ALC. The results of this study will contribute to a better understanding of the neurobiology and neuropsychology in OD, helping to identify novel targets for the treatment of opiate dependence. All participants provided informed consent according to the Declaration of Helsinki and underwent procedures approved by the University of California, San Francisco and San Francisco VA Medical Center 00000068. Twenty-one chronic cigarette smoking OD, stable on buprenorphine maintenance therapy for at least 3 months, met DSM-IV criteria for dependence on opiates; they were allowed to meet DSMIV criteria for current abuse or dependence on cocaine, amphetamines, and/or cannabis, but dependence on alcohol or benzodiazepines was exclusionary. OD was part of a buprenorphine treatment program focusing on smoking cessation and they were studied before smoking cessation. For group comparisons of metabolite concentrations specifically in the ACC, DLPFC, and POC and when correlated with neuropsychological variables, there were data from thirty-five cigarette smoking ALC recruited from local treatment programs of the VA and Kaiser Permanente and 28 cigarette smoking CON recruited from the community. The ALC group met DSM-IV criteria for alcohol dependence and was abstinent from alcohol for 21 ± 11 days at time of study. For group comparisons of metabolite concentrations in the OFC and when correlated with neuropsychological variables , smokers and non-smokers were included in the ALC and CON groups: 21 ALC and 19 CON due to a lack of sufficient data in smokers. All participants were studied with structural MRI, 1H MRS, and neuropsychological testing, all were fluent in English and they were allowed to smoke ad libitum before assessment and during breaks. Table 1 contains demographics, tobacco and alcohol use variables, mood measures, and laboratory variables for the three groups.

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Life expectancy for persons living with HIV is now similar to the general population

Posted on November 28, 2023 by hemp2022

In contrast, both groups showed comparable performance on a DD task that that involved making choices about hypothetical rewards provided in the more distant future. These findings point to key alterations in how people with schizophrenia value different types of rewards.Due to the advent of anti-retroviral therapy in the mid-1990s, HIV is now considered a chronic medical condition rather than a devastating terminal illness. Currently, over 50% of PWH in the United States are over the age of 50, with aging trends projected to continue . As such, researching aging with HIV is critical to better understand the impact of HIV on the aging process and how it may differ from the general population. Aging with HIV is associated with an increased risk of HIV-associated neurocognitive disorders , the current research term to describe neurocognitive impairments associated with HIV disease, with some evidence of accelerated brain aging . Given the potentially compounding effects of HIV and aging on the brain, the rapidly growing population of aging PWH may be at increased risk for Alzheimer’s disease and its precursor, amnestic mild cognitive impairment . As such, there is an urgent public health need to identify clinical tools to accurately identify older PWH on the AD trajectory and understand biological mechanisms that may put PWH at higher risk of aMCI/AD. To clarify, in the HIV literature, “older” PWH usually refers to PWH aged 50 and over; however, in the aging literature, “older” usually refers to people aged 65 and older, and “middle-age” refers to people aged 45 to 64. To rectify this discrepancy in terminology, the aging literature terminology will be used when discussing both the HIV literature and the aging literature.HAND remains prevalent in the ART era . While the pathogenesis of HAND is not entirely clear, HAND is thought to be the result of the neurotoxic cascade initiated by HIV .

The majority of neurocognitive deficits associated with HAND are in the mild range and do not significantly impact everyday functioning ,cannabis grow system and executive functioning, learning, and memory deficits are most common . Importantly, longitudinal studies have shown that HAND is usually non-progressive . AD is a neurodegenerative disease associated with progressive cognitive and functional impairment . AD is the most common cause of dementia, and it affects 10% of persons without HIV over the age of 65 and 17% between the ages of 75-84 . AD is characterized by the accumulation amyloid plaques and tau tangles in the brain, that start in the medial temporal lobe and result in initial atrophy of the medial temporal lobe and later more widespread atrophy . These brain changes start years to decades before clinical symptoms appear . On neuropsychological testing, AD typically presents initially with impairment in memory, which progresses to global impairment and loss of independent functioning . Mild cognitive impairment is defined as the transitional stage between cognitively normal and major neurocognitive impairment in which persons have observable cognitive deficits but these deficits are not yet significantly impacting everyday functioning. MCI can be further divided into amnestic and non-amnestic MCI sub-types, with aMCI being more associated with AD . While participants are often dichotomized as “MCI” or “cognitively unimpaired,” cognitive decline associated with AD is insidious; therefore, even milder deficits in memory in participants classified as cognitively unimpaired are associated with underlying AD pathology such as amyloid accumulation or medial temporal lobe atrophy . Due to the overlap in cognitive presentation , middle-aged and older PWH are at risk of erroneously being classified as HAND, due to HIV diagnosis, when they may instead be on an AD trajectory. Given that aMCI is associated with progressive cognitive and functional impairment, as opposed to HAND, which is more stable, it is imperative that the etiology of the cognitive impairment is correctly identified .

While there is currently no cure for AD, a misdiagnosis of HAND when a person with HIV has aMCI limits the opportunity for early intervention when interventions may be most beneficial . For example, early identification of AD allows more time for life planning and the acquisition of compensation strategies, which may prolong independent functioning, and, by extension, sustain quality of life . Furthermore, accurate diagnosis is important to allay concerns in PWH without indication of an AD trajectory. It is hypothesized that PWH may be at increased risk of AD due to the compounding effects of HIV and aging on the brain , chronic inflammation despite viral suppression, increased prevalence of vascular and metabolic risk factors , and potentially common pathophysiological pathways . While little work has been done in this space, several recent case reports on AD in PWH have highlighted the risk of delayed diagnosis, detailed complications determining the etiology of cognitive impairment, and underscored the clinical need for tools to differentiate HAND and aMCI . Additionally, there is some evidence from the HIV and aging literature to suggest that memory may be particularly affected in older PWH; however, most of these studies do not consider other etiologies that may be contributing to the observed findings. For example, Goodkin et al. found that there was a greater than expected effect of aging on episodic memory in PWH aged 50 and over, and Seider et al. found that verbal memory declines more rapidly with age in PWH as compared to HIV-negative comparison participants. Moreover,in a recent study using latent class analysis to examine a group of PWH aged 50 and over, we found that three classes emerged: a multi-domain impaired group, a learning and memory impaired group, and a cognitively unimpaired group . Due to the medial temporal lobe involvement in aMCI, the cognitive profile is described as “amnestic”, with encoding, storage, and rapid forgetting deficits observed as poor learning, recall, and recognition on memory tests .

Conversely, HIV particularly impacts fronto-striatal systems , and the frontostriatal involvement associated with HAND accounts for a “sub-cortical” cognitive presentation. Thus, memory deficits in HAND are characterized by relatively normal memory storage and retention but impaired encoding and retrieval resulting in poor learning and delayed recall, but intact recognition . This “subcortical” presentation in HAND has been observed even as PWH age . Therefore, recognition may be more indicative of aMCI than HAND and a useful tool for differential diagnosis . However, because recognition has historically been spared in HAND and only recently have PWH been reaching the ages at which they may develop aMCI/AD, there is little research examining recognition deficits in the context of HIV. Of note, deficits in other domains are unlikely to aid in differential diagnosis without further research. For example, while aMCI is characterized by memory deficits, other deficits, such as executive dysfunction, are also quite common in aMCI and AD . Therefore, the presence of executive functioning deficits, which are common in HAND, could be indicative of HAND, aMCI, or a mixed HAND and aMCI profile. Moreover, biomarkers may aid in differential diagnosis in the future; however, elevated amyloid beta is observed in HIV , so more research is needed in order for biomarkers to be beneficial in differential diagnosis of HAND and aMCI. Our research group at the HIV Neurobehavioral Research Program has begun to examine neuropsychological methods to identify aMCI among PWH using adapted Jak/Bondi MCI criteria. Jak/Bondi MCI criteria is an empirically based MCI criteria that has been shown to have greater associations with AD biomarkers and identify more participants who progress to dementia than traditional MCI diagnostic approaches . Our group utilized the basis of the Jak/Bondi criteria and adapted it to capitalize on the neuropsychological differences between HAND and aMCI . Thus,marijuana grow system aMCI was defined as impairment on at least two memory tests with the adaptation that at least one impaired test be a test of recognition. In a sample of 80 PWH from the National NeuroAIDS Tissue Consortium with neuropathologically characterized Aβ42 and neuropsychological testing within a year of death, 40 participants met the adapted criteria for aMCI. Twenty-nine of the participants with aMCI were also classified with HAND. The aMCI group was 3.5 times more likely to have the presence of Aβ42 plaques. Conversely, when the same sample was split into HAND and no HAND groups, the presence of Aβ42 plaques was not significantly associated with the HAND group. In sum, these findings provide preliminary data to further support that aMCI may go undetected in a large proportion of PWH with HAND, and these PWH may be misclassified or have a mixed HAND and aMCI profile. Secondly, these preliminary analyses also suggest that recognition deficits in older PWH are sensitive to AD pathology .Magnetic resonance imaging has shed light on brain changes associated with aMCI and AD and is increasingly used in clinical assessment of suspected AD . Medial temporal lobe atrophy is a core feature of aMCI/AD and has been shown to correlate with disease progression and predict progression from cognitively normal to aMCI . However, AD is also associated with more widespread cortical and sub-cortical atrophy and white matter abnormalities, particularly as the disease progresses . While neuroimaging has been used extensively to study aging and AD, mostof these neuroimaging studies exclude PWH . Consequently, it is unclear if aging/AD research is generalizable to older PWH. HIV has historically been associated with early changes to fronto-striatal circuits , although recent neuroimaging studies also report cortical atrophy . Similarly, HAND has been associated with fronto-striatal circuits, and, in more recent years, has also been associated with more cortical structures . Neuroimaging studies have examined neuroanatomical correlates of delayed recall as well as the effect of age on the brain within the context of HIV .

Studies comparing PWH with HAND and HIV-negative participants with MCI or AD have shown that hippo campal volumes were able to discern HAND and MCI/AD . Additionally, within the context of HIV, decline in memory has been associated with hippo campal atrophy . However, there are notable limitations to the current literature. For example, most studies have been couched in the context of HAND, are not aimed at examining aMCI within the context of HIV, nor do they consider other etiologies . Additionally, several neuroimaging studies examining the effect of aging in PWH have samples with mean ages in the late 30s or early 40s, which is likely before the initiation of AD pathology . Moreover, memory recognition, which could improve differentiation of HAND and aMCI, was not examined in these studies. Both HIV and aMCI are associated with chronic, low-grade inflammation . As such, inflammation may be one biological mechanism that puts PWH at greater risk of aMCI. Peripheral inflammatory markers can cross the blood-brain barrier, and there is mounting evidence to support the hypothesis that chronic inflammation exacerbates both Ab42 and p-tau pathology and plays a role in the pathogenesis of AD . There is ample evidence linking increased inflammation to brain atrophy, cognition, and cognitive decline in late life , with emerging evidence that this link is present even in midlife . Chronic inflammation is also present in PWH despite viral suppression , and is hypothesized to contribute to and exacerbate HAND . Due to this overlap, inflammation may be one factor that also puts PWH at greater risk of aMCI/AD. While the literature has highlighted the need to investigate this association, little research currently exists . Determining how inflammation impacts brain integrity and cognition in middle-aged PWH could have great implications for our overall understanding of the role of inflammation in AD and for the development of early intervention strategies to lower the risk of AD within PWH. I have begun to examine the relationship between inflammation and change in memory. These preliminary analyses included 57 PWH aged 50 and older with peripheral inflammatory markers and neuropsychological testing at baseline and at 1-year follow-up. Overall, I found that baseline concentrations of inflammatory biomarkers were not associated with baseline memory performance. However, using multi-variable linear regressions, IL-6 and TNF-a were associated with decline in delayed recall, and greater baseline concentrations of CCL2 were associated with decline in recognition . These inflammatory markers were not significantly associated with change in any other cognitive domain. Overall, these findings support the hypothesis that inflammatory markers may be related to cognitive changes associated with abnormal memory decline . As AD drug trials targeting amyloid continue to fail, there is increased focus on repositioning current drugs, such as anti-inflammatory drugs, to reduce the risk of AD .

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All patients fulfilled DSMIV criteria for drug dependence beyond nicotine dependence

Posted on November 24, 2023 by hemp2022

However, assessing dependence severity over the past 12 months could have reflected severity over the past 30 days prior to study participation, while average DPDD or CPD in the past 30 days could have also been comparable to average DPDD or CPD over the past year. Given that the sample was comprised of non-treatment seeking participants, it is plausible to hypothesize that past month alcohol and nicotine consumption closely reflect past year consumption of these substances in the current sample. Nevertheless, as patterns of alcohol or nicotine use may vary over a longer time frame, variables that capture quantity of use or frequency of use over a longer period of time would be preferred in future studies. Lastly, given that the average FTND scores of the current participants reflected low-to-moderate nicotine dependence severity, alcohol users with more severe nicotine dependence may be required to detect effects of nicotine use on brain structure. In conclusion, we examined the relationship between gray matter density and quantity of use/dependence severity for both alcohol and nicotine in 39 heavy drinking smokers using VBM. The multiple regression analysis revealed a significant negative relationship between ADS scores and gray matter density in two brains regions, such that higher ADS scores correlated with lower gray matter density in the hypothalamus and right superior frontal gyrus, after controlling for nicotine dependence severity, age, gender, and ICV. The current results may help clarify the contribution of alcohol and nicotine use to gray matter density in heavy drinking smokers,grow racks with lights which could aid in understanding the neurocognitive consequences of co-morbid substance use in heavy drinking smokers. Substance use disorders and addiction represent a global public health problem of substantial socioeconomic implications. In 2010, 147.5 million cases of alcohol and drug abuse were reported , and SUD prevalence is expected to increase over time.

Genetic factors have been implicated in SUD etiology, with genes involved in the regulation of several neurobiological systems found to be important . However, limitations intrinsic to most genetic epidemiological studies support the search for additional risk genes. Attention-deficit/hyperactivity disorder , the most common neurodevelopmental behavioral disorder, is frequently co-morbid with disruptive behaviors such as oppositional defiant disorder , conduct disorder , and SUD. The close association between ADHD and disruptive behaviors is summarized by longitudinal observations in ADHD cohorts. Children diagnosed with ADHD monitored during the transition into adolescence exhibit higher rates of alcohol, tobacco, and psychoactive drug use than control groups of children without ADHD. It has been estimated that the lifetime risk for SUD is ~50% in subjects with childhood ADHD persisting into adulthood. Reciprocally, the prevalence of ADHD is high in adolescents with SUD and the presence of an ADHD diagnosis affects SUD prognosis, with ADHD being associated with both earlier and more frequent alcohol-related relapses and lower likelihood of cannabis-dependence treatment completion. Strong evidence from family, twin, and genome-wide linkage and association studies suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD. During the last 15 years, we have collected families clustering individuals affected with ADHD and disruptive behaviors from disparate regions around the world. Although the prevalence of ADHD co-morbid with disruptive behaviors is variable across populations, we found a higher frequency of CD, ODD, and SUD in ADHD individuals than in unaffected relatives.Fine mapping of the 4q13.2 region identified variants in the adhesion G-protein-coupled receptor L3 gene that predispose to ADHD. Characterization of the association between ADHD and ADGRL3 has provided key information to better predict the severity of ADHD, the long-term outcome, the patterns of brain metabolism, and the response to stimulant medication. To the best of our knowledge, ADGRL3 linkage and association results represent some of the most robustly replicated genetic and pharmacogenetic findings in ADHD genetic research. While ADGRL3 has also shown association with disruptive behaviors in the context of ADHD, a direct link to SUD has not been systematically investigated.

In this manuscript we tested the hypothesis that ADHD risk variants harbored at the ADGRL3 locus interact with clinical, demographic, and environmental variables associated with SUD.This population isolate is unique in that it was used to identify ADHD susceptibility genes by linkage and association strategies. Detailed clinical and demographic information on this sample has been published elsewhere. The sample consists of 1176 people , mean age 28 ± 17 years, ascertained from 18 extended multigenerational and 136 nuclear Paisa families inhabiting the Medellin metropolitan area in the State of Antioquia, Colombia. Initial coded pedigrees were obtained through a fixed sampling scheme from a parent or grandparent of an index proband after having collected written informed consent from all subjects or their parent/guardian, as approved by the University of Antioquia and the NIH Ethics Committees, and in accordance with the Helsinki Declaration. Patients were recruited under NHGRI protocol 00-HG-0058 . Exclusion criteria for ADHD participants were IQ < 80, or any autistic or psychotic disorders. Parents underwent a full psychiatric structured interview regarding their offspring . All adult participants were assessed using the Composite International Diagnostic Interview , as well as the Disruptive Behavior Disorders module from the DICA-IV-P modified for retrospective use. The interview was conducted by a “blind” rater at the Neurosciences Clinic of the University of Antioquia, or during home visits. ADHD status was defined by the best estimate method. Specific information regarding clinical diagnoses and co-morbid disruptive disorders, affective disorders, anxiety, and substance use has been published elsewhere.The ADHD sample consisted of 670 adult ADHD patients, mean age 33 ± 10 years, 69% males , recruited and evaluated at the Psychiatry Department of the Hospital Universitari Vall d’Hebron according to DSM-IV TR criteria. ADHD diagnosis was based on the Spanish version of the Conners Adult ADHD Diagnostic Interview for DSM-IV. Comorbidity was assessed by Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders . ODD during childhood and adolescence was retrospectively evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version .

Thirty-nine percent of ADHD patients fulfilled diagnostic criteria for SUD, 21% for disruptive behavior disorders , 21% for depression , 13% for anxiety , and 8% for phobias . The level of impairment was measured with the Clinical Global Impression included in the CAADID Part II and the Sheehan Disability Inventory. Exclusion criteria for ADHD patients were IQ < 80; pervasive developmental disorders; schizophrenia or other psychotic disorders; presence of mood, anxiety or personality disorders that might explain ADHD symptoms; birth weight ≤ 1.5 kg; and other neurological or systemic disorders that might explain ADHD symptoms. The SUD sample consisted of 494 adults recruited and evaluated at the Addiction and Dual Diagnosis Unit of the Psychiatry Department at the Hospital Universitari Vall d’Hebron with the Structured Clinical Interview for DSMIV Axis I Disorders . None were evaluated for ADHD. The control sample consisted of 483 blood donors in which DSM-IV lifetime ADHD symptomatology was excluded under the following criteria: not having been diagnosed with ADHD and answering negatively to the lifetime presence of the following DSM-IV ADHD symptoms: often has trouble keeping attention on tasks,layout commercial grow room design plans often loses things needed for tasks, often fidgets with hands or feet or squirms in seat, and often gets up from seat when remaining in seat is expected. Individuals affected with SUD were excluded from this sample. None of them had self-administered drugs intravenously. It is important to mention that the exposure criterion was not applied; therefore, this set cannot be classified as “pure” controls. All patients and controls were Spanish of Caucasian descent. This study was approved by the ethics committee of the Hospital Universitari Vall d’Hebron and informed consent was obtained from all subjects in accordance with the Helsinki Declaration.The Multimodal Treatment Study of Children with ADHD was designed to evaluate the relative efficacy of treatments for childhood ADHD, combined sub-type, in a 14-month randomized controlled trial of 579 children assigned to four treatment groups: medication management, behavior modification, their combination, and treatment as usual in community care. After the 14- month treatment-by-protocol phase, the MTA continued as a naturalistic follow-up in which self-selected use of psychoactive medication was monitored. A local normative comparison group of 289 randomly selected classmates group-matched for grade and sex was added when the ADHD participants were between 9–12 years of age. The outcomes in childhood , and adolescence and into adulthood have been reported. Substance use was assessed with a child/adolescent-reported questionnaire adapted for the MTA. The measure included items for lifetime and current use of alcohol, cigarettes, tobacco, cannabis, and other recreational drugs. Also included were items for non-prescribed use or misuse of psychoactive medications, including stimulants. The measure was modeled after similar substance use measures in longitudinal or national survey studies of alcohol and other drug use that also rely on confidential youth self-report as the best source of data. A National Institutes of Health Certificate of Confidentiality further strengthened the assurance of privacy.

Substance use was coded positive if any of the following behaviors, selected after examining distributions, were endorsed as occurring in the participant’s lifetime up to 8 years post-baseline: alcohol consumption more than five times or drunk at least once; cigarette smoking or tobacco chewing more than a few times; cannabis use more than once; or use of inhalants, hallucinogens, cocaine, or any of amphetamines/stimulants, barbiturates/sedatives, and opioids/narcotics without a prescription or misused a prescription . Each of the four types of substances, as well as daily use of tobacco and the number of substance use classes endorsed , were explored in secondary analyses. DSM-IV abuse or dependence was based on a positive parent or child report with the Diagnostic Interview Schedule for Children version 2.3/3.0 at the 6- and 8-year follow-up assessments. The DISC includes both lifetime and past year diagnoses. The Diagnostic Interview Schedule-IV was used at the 8-year follow-up for 18 + year-olds . SUD was defined as the lifetime presence of any abuse or dependence . Additional analyses explored SUD for alcohol, tobacco, and cannabis/other drugs separately. All patients in this study provided informed written consent as approved by the NIH Ethics Committee.A sample of 560 inpatients and outpatients with severe SUD from Central Kentucky psychiatric facilities was collected during a pharmacogenetics investigation. Patient interviews and medical record information DNA was extracted from whole blood or buccal swabs using standard protocols. The Paisa sample was genotyped using the service provided by Illumina . The Spanish, MTA, and Kentucky samples were genotyped for select variants using pre-designed TaqMan® SNP genotyping assays . Allelic discrimination real-time PCR reactions were performed in a 384-well plate format for each individual sample according to the manufacturer’s instructions. Briefly, 20 ng of genomic DNA were mixed with 2.5 μL of 2X TaqMan Universal PCR Master Mix and 0.25 μL of 20X SNP Genotyping Assay in a total volume of 5 μL per reaction. Assays were run in an ABI 7900HT Fast Real-Time PCR System . Allele calling was made by end-point fluorescent signal analysis using the ABI’s SDS2.3 software. In addition, we had previously collected exome genotype data from the MTA sample using the Infinium® HumanExome-12 v1.2 BeadChip kit , which covers putative functional exonic variants selected from over 12,000 individual exome and whole-genome sequences. Processed and raw intensity signals for the array data can be accessed at GEO . SNP markers harbored at the ADGRL3 gene were filtered in from this dataset and added to those genotyped using TaqMan® assays.Association studies of ADGRL3 variants with ADHD, ODD, CD, response to stimulant treatment and severity outcome have been published elsewhere for the Paisa and Spanish populations. We used ARPA to build a predictive framework to forecast the behavioral outcome of children with ADHD, suitable for translational applications. Our goal was to test the hypothesis that ADGRL3 variants predisposing to ADHD also increase the risk of co-morbid disruptive symptoms, including SUD. ARPA is a tree-based method widely used in predictive analyses because it accounts for non-linear and interaction effects, offers fast solutions to reveal hidden complex substructures and provides truly non-biased statistically significant analyses of high-dimension, seemingly unrelated data. In a visionary manuscript, D.C. Rao suggested that recursive-partitioning techniques could be useful for genetic dissection of complex traits.

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The rewarding effects of cocaine are reduced in a very specific way by CB1 receptor antagonists

Posted on November 23, 2023 by hemp2022

In addition to anecdotal evidence that cannabis increases appetite, especially for sweet food, in recreational cannabis smokers , several preclinical studies have shown that CB1 receptor agonists facilitate food reward, in particular, the hedonic response to sweet food that Berridge and Robinson call ‘liking’. For example, THC increases the intake of food and increases the consumption of sweet solutions in rats. In addition, low doses of THC increase hedonic reactions to sucrose and decrease aversive reactions to bitter quinine solutions and THC increases the palatability of sucrose in rats. Also, we recently found that the motivation to respond for food, as measured by break points in responding for food under a progressive-ratio schedule , is increased by administration of THC . Interestingly, enhancement of the motivation to respond for food by THC is dependent on actual food consumption , suggesting that both appetitive and consummatory aspects of food reward may involve the endocannabinoid system. Taken together, these findings provide a rationale for the clinical use of CB1 receptor agonists such as Marinol in anorexic cancer and HIV patients . There are contradictory reports on the effects of CBs on brain stimulation reward. Brain stimulation reward or intracranial self-stimulation is an operant procedure where animals have to press a lever to receive a small electrical current in restricted areas of the brain . Brain stimulation reward is arguably the most robust form of reinforcement and is believed to derive from the ability of electrical currents to activate, probably indirectly, the dopaminergic mesolimbic system . In support of this hypothesis, drugs that activate the dopaminergic system and increase dopamine levels in the nucleus accumbens  also facilitate brain stimulation reward , whereas drugs that block dopamine receptors reduce thresholds for self-stimulation.

Concerning, CB1 receptor agonists, Gardner and colleagues found that THC facilitates brain stimulation reward ,vertical grow rack system whereas other investigators found no effects of the syntheticagonists CP55,940 or AMG-3 and some investigators have found a reduction of brain stimulation reward with CB1 receptor agonists . These discrepancies, which are likely due to procedural differences, remain to be resolved. A caveat of all experiments with directly acting CB1 receptor agonists is that, for several reasons, these drugs do not provide a realistic picture of the physiological role of the endocannabinoids. First, anandamide is a partial agonist , whereas synthetic CB1 receptor agonists are often full agonists and have higher affinities for CB1 receptors . Second, anandamide and 2-AG have very short half-lives , whereas THC and synthetic CB1 receptor agonists have relatively long half-lives. Finally, systemic injections of these compounds result in the activation of all brain areas containing CB1 receptors, whereas physiological activation of endocannabinoid synthesis and release is likely to be region, neuron or even synapse specific . The availability of mice genetically deprived of CB1 receptors in a tissue-specific manner may help address this possibilityAssessment of the roles the endocannabinoid system plays in brain reward processes was greatly facilitated by the discovery of selective CB1 receptor antagonists/inverse agonists such as rimonabant and AM251 . CB1 receptor antagonists decrease the rewarding effects of a wide variety of abused drugs under certain conditions. For example, the rewarding effects of opioids are generally decreased in both intravenous self-administration and conditioned place preference procedures . There have also been reports that rimonabant and AM251 reduce the rewarding effects of methamphetamine , alcohol and nicotine .

CB1 receptor antagonists do not generally alter self-administration of cocaine under low fixed-ratio schedules or conditioned place preference procedures , but AM251 has been found to significantly reduce self-administration of cocaine under progressive-ratio schedules and rimonabant prevents relapse to cocaine-induced and cue-induced cocaine-seeking behaviour . This suggests that the appetitive and conditioned effects of cocaine, but not its direct reinforcing effects, depend on CB1 receptor activation. The effects of rimonabant on opioid reward may be mediated primarily in the NAcc, as blockade of CB1 receptors in this area reduces heroin self-administration . On the other hand, the modulation of ethanol reward by the CB system appears to take place both in the NAcc and in the prefrontal cortex . The brain sites where CBs act to alter the rewarding effects of nicotine and psychostimulants are not known at present. Drugs of abuse share the ability to elevate extracellular levels of dopamine in the shell of the NAcc, as measured by in vivo microdialysis, and this effect is believed to play an important role in their reinforcing effects . CB1 receptor antagonists have been shown to block the elevations of accumbal dopamine levels induced by administration of nicotine or ethanol , but not by administration of heroin , morphine or cocaine . Transient surges of dopamine in the NAcc, as measured by cyclic voltammetry, are also produced by drugs of abuse and are believed to be involved in drug seeking . Interestingly, the transient increases in dopamine produced by administration of nicotine, ethanol and cocaine in the shell of the NAcc of freely moving rats are all blocked by CB1 receptor antagonists . Consistent with a role for endocannabinoids in the rewarding effects of food and in the regulation of appetite and food intake , blocking endocannabinoid tone with CB1 receptor antagonists reduces intake of food and sweet solutions . Also, injection of rimonabant within 24 h of birth completely prevents milk intake and causes almost 100% mortality in mouse pups . The motivational effects of food measured by a progressive-ratio schedule of food reinforcement and the appetitive aspects of food reward are significantly reduced by rimonabant in rats, indicating that some aspects of food intake regulation involve reward and motivational processes.

In addition, AM251 decreases hedonic reactions to sucrose and increases aversive reactions to quinine . Consistent with these preclinical findings, rimonabant has been found to be effective in the clinical treatment of obesity , although the clinical efficacy of this agent appears to be primarily due to its ability to alter peripheral lipid metabolism, rather than to reduce food intake . As in the case of CB1 receptor agonists, the effects of CB1 receptor antagonists on brain stimulation reward are somewhat controversial. Rimonabant has been shown to increase the threshold for brain stimulation reward in some studies or to produce no change in brain stimulation reward thresholds in other studies .Mice genetically engineered to lack CB1 receptors do not show dramatic changes in body weight, food consumption or fertility , suggesting that CB1 receptors modulate rather than mediate basic reward functions or that other systems can compensate for their absence. By using CB1-null mice, the role of CB1 receptors in the rewarding effects of drugs of abuse has been confirmed. For example, in these mutant mice morphine is not self administered , does not induce conditioned place preferences and does not elevate dopamine levels in the NAcc . Also, the rewarding effects of alcohol are reduced in CB1-null mice, as demonstrated by data showing that CB1-null mice do not develop conditioned place preference with this drug and that they do not prefer it over water in a two-bottle free-choice paradigm . However, another study reported that CB1-null mice show slight and short-lasting decreases in preference for ethanol. Development of conditioned place preferences with cocaine is unaltered in CB1-null mice . On the other hand, development of cocaine self-administration behaviour under fixed-ratio schedules of reinforcement in CB1-null mice was reported to be unaltered when mice were restrained , but was reduced in freely moving mice . In addition, cocaine self-administration was significantly reduced under a progressive-ratio schedule of self-administration in CB1-null mice . These contrasting results highlight the fact that, when working with genetically modified mice such as CB1-null mice, not only methodological differences but also differences in the genetic background may result in very different and sometimes contrasting behavioural outputs . It is interesting to note that CB1-null mice show normal elevations in dopamine levels in the NAcc following administration of cocaine ,grow vertical but no elevations following administration of morphine or ethanol , compared with wild-type controls. Finally, CB1-null mice do not develop conditioned place preferences to nicotine , but they self-administer the drug like wild-type controls . It remains to be seen whether increasing the effort needed to obtain nicotine, as with cocaine , could reveal a role of CB1 receptors in some aspects of nicotine reinforcement as suggested by the results with CB1 receptor antagonists . CB1-null mice have also provided evidence for the involvement of the endocannabinoid system in food reward. For example, CB1-null mice eat less than their wild-type control litter mates after food restriction . Moreover, CB1-null mice respond less for sucrose in a two-lever paradigm, have lower break points under progressive-ratio schedules of sucrose delivery and show less preference for sucrose over water in a two-bottle free-choice procedure .

Genetic ablation of CB1 receptors results in small reduction in body weight, reduction in adiposity and resistance to diet-induced obesity . However, as in the case of CB1 receptor antagonists, these effects appeared to be related more to increased metabolic energy consumption than to differences in rewarding effects of food or hypophagia . Interestingly, in the study by Fride et al. , administration of rimonabant in mice pups lacking CB1 receptors still induced a decrease in milk intake and survival rate, suggesting that some of the effects of CBs on food intake may be mediated by still uncharacterized CB receptors. To date, no study has investigated the effects of CB1 receptor deletion on brain stimulation reward. On the other hand, it should be noted that CB1-null mice show increased anhedonia after chronic mild stress , a measure of reduced activity of the reward system and a model of depression , further supporting a role for the endocannabinoid system in brain reward functions.Although measurements of the effects of systemic or intracranial injections of anandamide provide useful information on the functions of the endocannabinoid system, to provide support for a role of neurally released anandamide in brain reward processes it is also important to measure anandamide released in the brain by different abused drugs, by food and by electrical brain stimulation. Release of neurotransmitters such as dopamine or glutamate can be readily measured by micro-dialysis techniques, but only a few studies have employed microdialysis techniques to measure extracellular brain levels of endocannabinoids . Thus, most information on the modification of endocannabinoid levels comes from measurements of tissue levels in different brain areas. Measuring tissue level of anandamide has the limitation that only one time point can be established at a time, limiting information on the pattern of endocannabinoid release. Using tissue levels, it has been demonstrated that chronic administration of several drugs of abuse leads to region specific increases in anandamide levels. For example, when administered chronically, THC decreases levels of anandamide in the striatum , ethanol decreases levels of anandamide in the midbrain but not in the striatum , nicotine decreases levels of anandamide in the striatum but not in the midbrain , and cocaine and morphine do not alter anandamide levels, either in the striatum or midbrain . However, it is difficult to determine from these studies whether measured levels of endocannabinoids reflected the consequences of chronically administered drug or withdrawal. Vigano et al. compared the effects of chronic versus acute administration of morphine on endocannabinoid levels in the brain. They found that acute administration of morphine increased anandamide levels in the striatum, whereas chronic treatment with the drug failed to do so. In addition, they found that chronic treatment with morphine did not alter the ability of a challenge dose of morphine to increase anandamide levels in the striatum; that is, repeated administration of morphine did not induce sensitization or tolerance to this effect . Thus, chronic administration of drug followed by withdrawal, chronic administration of drug followed by an acute drug challenge and acute administration of drug can lead to very different changes in brain anandamide levels. Such profiles of release may indicate that anandamide is released in response to relevant changes in homoeostasis but not when an adaptive response has already occurred.

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Findings remained unchanged after controlling for verbal intellectual functioning

Posted on November 22, 2023 by hemp2022

The rapid event-related design of the BART fMRI task created some special challenges for analysis. Because the task moved very quickly through the Think, Pump, Wait, Inflate, Pop or Win, and Rest conditions , it is possible that there was overlap of the hemodynamic response across task conditions. However, the deconvolution process is generally effective at disentangling the individual hemodynamic response functions so that the BOLD response pattern specific to each task condition can be appropriately measured. Rapid event-related designs are also limited by a lower signal-to-noise ratio, compared to blocked designs or slower event-related designs. This ultimately leads to a loss of statistical power. Also, some of the task conditions may not have been perceived as separate, distinct events to participants, and thus BOLD response may not be qualitatively different between these conditions. For example, the “Wait” control condition occurred immediately after subjects inputted their number of pumps. Although the active “Inflate” condition was designed to measure the anticipation stage of decision making, the “Wait” condition may have captured some anticipatory response as well. The visual display of a balloon inflating likely added an element of anticipation above and beyond the “Wait” phase ; however, both “Rest” and “Wait” conditions were used as control conditions for the “Inflate” conditions, in order to address this issue. It is somewhat surprising that heavy drinkers and controls showed very few differences on BART task performance variables. This contrasts with previous studies using BART paradigms which have found group differences between adolescent smokers and non-smokers and adolescents with “serious substance use and conduct problems” and controls . However other studies have not shown differences between adolescent substance users and non-users . One reason for the lack of performance differences may be that the version of the BART used in this study differs from the original design of the task where participants are asked to sequentially input discrete pumps, one by one, to pump up the balloons . It may be that inputting each pump separately allows for anticipation to build to higher levels,indoor cannabis grow system leading to an increased response to reward or loss which may further risk-taking performance on the task.

Some studies have also analyzed the first and second half of the BART separately, to examine group differences in risky decision-making as the task progresses. A preliminary study of the BART in the current sample used this method and found that heavy drinking adolescents had a greater number of pumps on the second half of the task compared to controls, though after 5 weeks of abstinence, the groups were equivalent . In addition, at baseline, number of pumps on the second half of the task was positively correlated with number of recent alcohol binges and number of drinks per day. Although the lack of group differences in BART task performance within the current study allows for easier interpretation of the fMRI data, it is also important to consider the real-world generalizability of any laboratory measure of an abstract concept like risky decision-making. Another limitation to this study and all fMRI studies is that other variables may have affected the magnitude of the BOLD response other than the construct of interest . For example, heavy drinkers and controls differed in their use of cannabis and nicotine. However, findings remained unchanged after controlling for cannabis use. While tobacco use was not controlled for in this study, the level of use in the heavy drinking group was relatively low, and no participants met criteria for tobacco dependence. Therefore it is unlikely that tobacco use could have accounted for variability in BOLD response. Heavy drinkers and controls also differed in terms of verbal intellectual functioning and level of externalizing problems. However, level of externalizing problems was not controlled for, primarily because the difference observed on this variable was thought to represent a naturally occurring difference between adolescents who use substances and those who do not. Cerebral blood flow was not measured in this study and is known to have some effect on BOLD response. As resting state perfusion can affect the magnitude of the BOLD response , it is possible that differences in cerebral blood flow could explain BOLD response differences between heavy drinkers and controls.

A recent study by Jacobus and colleagues found that for heavy adolescent marijuana users, cerebral blood flow was reduced in four cortical regions and increased in one region at baseline ; however, after four weeks of abstinence, no between-group differences in cerebral blood flow were found. In extrapolating these findings to adolescent heavy alcohol users, it seems possible that cerebral blood flow could have an impact on the baseline between-group differences in BOLD response in this study, but may be less likely to impact BOLD response differences at the +2weeks and +4weeks time points. The issue of test-retest reliability of the BOLD response should be considered. There has been some controversy about this topic in the literature, as some studies have found high test-retest BOLD signal reliability , and others have reported considerable within-subject variation in BOLD signal change across scan sessions . Changes in BOLD signal response across different scan sessions for the same subject can occur for several reasons, such as fluctuating mood/anxiety/alertness states , levels of effort , motion, scanner drift , physiological changes , and developmental maturation. Many of these variables were measured and controlled for in this study. Specifically, acute anxiety and alertness were found to be equivalent between groups and are therefore unlikely to affect results. In addition, subpar effort was controlled for by removing subjects with five or more “Too Slow” outcomes within a given scan session, as it was assumed that subjects with a high degree of “Too Slow” responses were not adequately engaged in the task. Excess motion was controlled for by removing participants with more than 20% repetitions containing excessive head motion. Field maps applied to the fMRI acquisitions also helped to control the BOLD signal stability across scans, as this process minimizes warping and signal dropout, as well as reduces mislocalization errors, especially in frontal regions. Physiological changes and scanner drift were more difficult to control for and thus there is a small probability that these variables could have affected the reliability of the BOLD signal across repeated assessments in this study. Finally, the probability of Type I error in this study is likely higher than desired due to the large number of tests that were run within each hypothesis.

Although Hypotheses 1 and 2 included corrections for multiple comparisons within each ROI , there was no comparable correction for the number of comparisons examined across ROIs . Hypothesis 3 also did not employ any multiple comparison corrections, and these analyses should be considered exploratory. Taken together, the results of this study suggest that heavy drinkers display abnormalities in neural functioning during risky decision-making compared to their non-drinking peers, particularly in the right insula during anticipation and the ventromedial prefrontal cortex during evaluation of negative outcomes. Abnormalities in these regions appear to resolve after two to three weeks of abstinence. In addition, heavy drinkers showed some changes in BOLD response across repeated assessments , which provide further support for a neural recovery hypothesis. However, after five weeks of abstinence, heavy drinkers and controls show some differences in neural functioning that persist across time. This suggests that other regions of the brain may take longer to fully recover, or, that there are pre-existing differences in these regions,indoor weed growing accessories which could represent vulnerabilities for future substance use. In addition, this study suggests that differences in neural functioning in reward-related regions can effectively predict real-world report of risk-taking behavior. These findings are important as they suggest that neural functioning may be used as a potential biomarker for risk-taking vulnerability in the future. Future directions for this study should first include replication within a larger sample, to increase confidence in the findings. Second, an examination of the effect of length of abstinence from alcohol prior to study entry on BOLD response in the heavy drinking group will be necessary to determine whether variability in length of abstinence may have contributed to the between-group differences observed in this study. It would also be informative to analyze the first and second half of the BART task separately, as Hansen and colleagues did with the non-fMRI BART task. In addition, an examination of gender differences could be important, given results from previous studies suggesting that females may be especially susceptible to the effects of heavy alcohol use. Measures of hangover severity and withdrawal effects could also be investigated as possible moderating factors of group differences in BOLD response to risky decision-making, as these have been implicated as significantly related to performance on cognitive tasks in heavy alcohol users. The ultimate goal of this study and others like it should be to disseminate findings to youth and families, and to provide psycho education through the creation of prevention materials and public service campaigns. By understanding how the brain responds to risky decision-making after recent alcohol use, and how the brain’s circuitry may “repair” itself with sustained abstinence, adolescents could become motivated to remain abstinent from alcohol, which ultimately, would reduce the rates of accidents and deaths in this age group as a result of risky behavior. This work is being prepared for submission for publication as “fMRI Correlates of Risky Decision-Making in Adolescent Alcohol Users: The Role of Abstinence.” The dissertation author will be the primary author of this material along with co-authors Alan Simmons, Ph.D., Carmen Pulido, Ph.D., Susan Tapert, Ph.D., and Sandra Brown, Ph.D.

Two endogenous agonists of cannabinoid receptors have been well characterized and are now widely used in research: anandamide , and 2-arachidonoylglycerol . Both molecules derive chemically from the polyunsaturated fatty acid, arachidonic acid, which is used in nature as the starting material for other important signaling compounds, such as the eicosanoids. Additional endocannabinoid-related compounds present in the body include virodhamine, which may act as an endogenous antagonist of CB1 receptors, and arachidonoylserine, which may engage an as-yet-uncharacterized cannabinoid-like receptor expressed in the vasculature. As is well-known, the Cannabis plant contains more than 60 cannabinoids, which include -D9 -tetrahydrocannabinol , cannabigerol, cannabidiol, cannabinol, cannabichromene and cannabicyclol. Attention has been mostly focused on D9 -THC, because of its multiple biological properties. Nevertheless, less studied compounds such as cannabidiol may also be important, although we do not yet know at which receptors they may act to achieve their effects. D9 -THC is the only natural cannabinoid presently used in the clinic. In addition to these plant-derived cannabinoids, an extensive set of synthetic cannabinergic agonists has been developed over the last 30 years. Products of these efforts include CP-55940 , created by opening one of the rings of the tricyclic D9 -THC structure and introducing other small changes in its structure; HU-210 , a very potent cannabinoid agonist resembling some D9 -THC metabolites; and WIN55212-2 , which belongs to an altogether different class of chemicals, the aminoalkylindoles. Additionally, the metabolically stable synthetic analog of anandamideR-methanandamide is routinely used as a pharmacological probe to circumvent the short half life of the natural substance. Two important new additions to this armamentarium under discussion at the workshop include a peripherally acting cannabinoid agonist in preclinical development by Novartis for the treatment of neuropathic and inflammatory pain , andBAY-387271 , a centrally acting cannabinoid agonist in Phase II clinical studies for the treatment of stroke. The interest of the pharmaceutical industry in the application of cannabinoid agonists to the treatment of pain conditions is not recent. Indeed, most of the compounds now in experimental use derive from such an interest. Historically however cannabinoid agonist development has not proved clinically fruitful, largely because of the profound psychotropic side effects of centrally active cannabinoid agonists, hence the attention given to peripherally acting cannabinoids, which exhibit significant analgesic efficacy and low central activity in animal models. Neuroprotection is a relatively new area for cannabinoid agonists, but one that appears to be already well advanced. Preclinical studies have made a convincing case for the efficacy of cannabinoid agents not only in experimental brain ischemia, but also in models of Parkinson’s disease and other forms of degenerative brain disorders.

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Other factors such as gender and family history of AUDs may moderate this relationship

Posted on November 21, 2023 by hemp2022

Cognitive theories attempting to explain adolescent risk-taking as the result of underdeveloped decision-making skills have found little, if any support, as studies demonstrate that adolescents show an adequate understanding of the steps involved in the decision-making process, such as weighing pros and cons. In fact, children as young as 4 years old have some understanding of consequence probabilities and adolescents and adults show equal levels of awareness of the consequences associated with risky behaviors . In some cases, adolescents may even overestimate their personal vulnerability to risk consequences compared to adults . Further, interventions designed to provide adolescents with information about the risks of substance use, drinking and driving, and unprotected sex have proved largely unsuccessful and have done little to change adolescents’ actual behavior . Simplified theories of “immature cognitive abilities” in adolescence are also inconsistent with a developmental perspective, as the increase in cognitive sophistication from childhood to adolescence would imply a decrease in risk-taking behaviors with age, rather than an increase . Steinberg proposes an alternative view of adolescent risk-taking behavior that is rooted in developmental neuroscience. Specifically, heightened risk-taking in adolescence is described as the product of a “competition” between a socioemotional network that is sensitive to social and emotional stimuli , and a cognitive control network that is responsible for regulating executive functions such as planning, organization, response inhibition, and self-regulation. The socioemotional network relies on limbic and paralimbic structures such as the amygdala, ventral striatum, orbitofrontal cortex,cannabis plant growing ventromedial prefrontal cortex, and superior temporal sulcus, while the cognitivecontrol network consists of lateral prefrontal and parietal cortices as well as the anterior cingulate . During adolescence, the brain undergoes significant structural, functional, neurochemical, and hormonal changes that directly impact the development of the socioemotional and cognitive control networks, among other regions.

Specifically, synaptic pruning and myelination processes result in reduced gray matter volume and increased white matter volume by late adolescence/early adulthood . Increases in white matter during adolescence are associated with greater structural connectivity and faster, more efficient neural communication between brain regions . Evidence from neuroimaging studies note that dramatic changes occur in the brain’s dopaminergic system at puberty, primarily in prefrontal and striatal regions . Specifically, dopamine activity shows substantial decreases in the nucleus accumbens, an important region of the ventral striatum well known for its role in reward processing. Dopamine has been implicated as a primary mechanism of affective and motivational regulation and is linked to the socioemotional network ; thus, the sudden decrease in this neurochemical creates a “dopamine void” which may compel adolescents to seek out novel and risky behaviors to compensate . Changes in brain regions associated with the cognitive control network also take place in adolescence, including gray matter decreases and white matter increases in the prefrontal cortex, and an overall increase in synaptic connections among cortical and subcortical regions of the brain . In contrast to the acute changes that occur to socioemotional regions with puberty, changes in the cognitive control network are gradual and typically continue into the mid-twenties. As a result of timing differences in the developmental brain changes that occur during adolescence, there appears to be a “timing gap” between the maturation of the socioemotional network and the maturation of the cognitive control network. Greater motivational drives for novel and rewarding experiences combined with an immature cognitive control network may predispose adolescents to risky behavior, including substance use. This becomes especially relevant under conditions of high emotional arousal , where the socioemotional network is likely to become highly activated and the cognitive control network must “work harder” to override it . While neurochemical modifications and other developmental brain changes may contribute to adolescents’ increased propensity for risk-taking , it is paradoxical, as the brain may be especially vulnerable to the insult of alcohol during this critical time . A handful of studies have shown a deleterious effect of heavy alcohol use on adolescents’ neuropsychological performance in varied domains, including visuospatial abilities , verbal and non-verbal retention , attention and information processing , and language and academic achievement .

Female adolescent alcohol users have also shown deficits on tasks of executive functioning, specifically those involving in planning, abstract reasoning, and problem-solving . Post-drinking effects, such as hangover severity and withdrawal symptoms have been demonstrated to be important predictors of alcohol-related neurocognitive impairment, as greater self reported withdrawal symptoms have been linked with poorer visuospatial functioning and poorer verbal and non-verbal retention . Longitudinal studies have examined whether observed neurocognitive deficits in this population represent premorbid risk factors for use or consequences of heavy alcohol use. In one study, after controlling for recent alcohol use, age, education, practice effects, and baseline neuropsychological functioning, substance use over an 8-year follow-up period significantly predicted neuropsychological functioning at Year 8. Specifically, adolescents who reported continued heavy drinking and greater alcohol hangover or withdrawal symptoms showed impairment on tasks of attention and visuospatial functioning compared to non-using adolescents . These findings were replicated in a prospective study that characterized at-risk adolescents prior to initiating alcohol use. For females, initiation of alcohol use over the follow-up period was associated with worsening visuospatial functioning, while greater hangover symptoms over the follow-up period predicted poorer sustained attention in males . Taken together, these studies suggest that heavy drinking during adolescence is associated with deficits in cognitive performance, which likely result from, rather than predate, alcohol use.Specifically, evidence suggests that females may be more vulnerable to the negative impact of heavy alcohol use in adolescence , and a positive family history of AUDs has been associated with worse neurocognitive performance in adolescent heavy alcohol users, particularly in language and attention domains . Structural magnetic resonance imaging studies provide evidence for anatomical brain abnormalities in adolescents with histories of heavy lifetime alcohol use, compared to their non-using peers.

The hippocampus appears to be one area of potential vulnerability, as decreased bilateral hippo campal volumes have been observed in adolescents meeting criteria for AUDs, with smaller hippo campi related to earlier onset and longer duration of the disorder . Nagel, Schweinsburg, Phan, and Tapert found similar results, with smaller left hippo campal volumes observed in heavy alcohol-using adolescents compared to controls, even after excluding teens with co-occurring Axis I disorders. Hippo campal volume did not correlate with degree of alcohol use in this study, suggesting that between-group differences may be reflective of premorbid factors, and not solely the result of heavy alcohol use. Another area of the brain that may be especially vulnerable to the effects of heavy alcohol use in adolescence is the prefrontal cortex. As a key component of both the cognitive control and socioemotional networks, this region is important to the study of risk-taking. In a sample of adolescents with co-occurring psychiatric and AUDs, DeBellis and colleagues found significantly smaller prefrontal cortex volumes in alcohol users compared to controls. These findings were replicated by Medina and colleagues in a sample of alcohol dependent adolescents without psychiatric disorders; however,vertical grow rack system a significant group by gender interaction was observed. Specifically, alcohol dependent females showed smaller prefrontal cortex and white matter volumes than female controls, and alcohol dependent males showed larger prefrontal and white matter volumes than male controls. In a cortical thickness study of adolescent binge drinkers, Squeglia, Sorg, and colleagues found alcohol use by gender interactions in four left frontal brain regions, where female binge drinkers had thicker cortices than female controls and male binge drinkers had thinner cortices than male controls. Thicker frontal cortices corresponded with poorer visuospatial, inhibition, and attention abilities for females and worse attention abilities for males, providing further evidence that females may be especially vulnerable to brain changes brought on by heavy alcohol use in adolescence. Diffusion tensor imaging studies have yielded corroborating evidence of altered brain development in adolescent heavy alcohol users. In one study, adolescents with histories of binge drinking showed decreased white matter integrity in 18 major fiber tract pathways, specifically in the frontal, cerebellar, temporal, and parietal regions . Another study found reduced white matter integrity in the corpus callosum of youth with AUDs, particularly in the posterior aspect . In addition, reduced white matter integrity in this region was related to longer durations of heavy drinking, larger quantities of recent alcohol consumption, and greater alcohol withdrawal symptoms .

There is evidence that poorer white matter integrity may be both a consequence of adolescent alcohol use and a predisposing risk factor for use. Specifically, in a study of 11- to 15-year-old alcohol naïve youth, Herting, Schwartz, Mitchell, & Nagel, found that youth with a positive family history of AUDs had poorer white matter integrity in several brain regions, along with slower reaction time on a task of delay discounting, when compared to youth without a family history of AUDs. In addition, Jacobus, Thayer, Trim, Bava, and Tapert found that poorer white matter integrity measured in 16- to 19-year old adolescents was related to more self-reported substance use and delinquency/aggression at an 18-month follow-up. In fMRI studies, altered neural processing has been observed in heavy drinking adolescents during cognitive tasks of spatial working memory , verbal encoding, and visual working memory . Tapert and colleagues found that adolescents with a history of heavy drinking over the past 1-2 years showed increased blood oxygen level-dependent response in bilateral parietal regions during a SWM task, but decreased BOLD activation in the occipital and cerebellar regions compared to lighter drinkers. In addition, BOLD activation abnormalities were associated with more withdrawal, hangover symptoms, and greater lifetime alcohol consumption. Similarly, in a study of verbal encoding, Schweinsburg, McQueeny, Nagel, Eyler, and Tapert showed that adolescent binge drinkers had more BOLD response in the right superior frontal and bilateral posterior parietal regions but less BOLD response in the occipital cortex, compared to non-drinkers. Control adolescents also showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. A 2011 follow-up to this investigation found increased dorsal frontal and parietal BOLD response among 16- to 18-year-old binge drinkers, and decreased inferior frontal response during verbal encoding . Squeglia, Pulido, and colleagues found comparable results during a VWM task, in that heavy drinking adolescents showed more BOLD response compared to matched controls in right inferior parietal, right middle and superior frontal, and left medial frontal regions, but less BOLD response in left middle occipital regions. Notably, this investigation included a longitudinal component with a separate sample of adolescents in which the brain areas showing group differences in BOLD response to the VWM task were identified as ROIs. Adolescents were scanned at baseline before they ever used alcohol or drugs and then scanned again at a 3-year follow-up time point. Adolescents from this sample who transitioned into heavy drinking during the follow-up period showed less BOLD response to the VWM task compared to continuous non-drinkers in frontal and parietal regions at baseline; in addition, BOLD response in these regions increased significantly over the follow-up period for the heavy drinkers, while controls’ BOLD response did not change significantly over time. Finally, less BOLD activation at baseline predicted subsequent substance use, above and beyond age, family history of AUDs, and baseline externalizing behaviors. Taken together, results from these studies suggest that the adolescent brain is indeed sensitive to the insult of excessive alcohol use, and structural alterations and neural reorganization may result from continued heavy drinking. In turn, this altered brain development may trigger cognitive, emotional, and behavioral changes, leading to further alcohol use and other risk-taking behaviors. As the majority of fMRI studies of adolescent alcohol users to date are cross sectional in nature, it is difficult to determine whether the observed neural abnormalities predate the onset of alcohol use, or are consequences of alcohol use. However, results of the Squeglia, Pulido et al. study suggest that a combination of both explanations may be most accurate. Specifically, neural functioning differences may be evident prior to the initiation of drinking, but early alcohol use may also change the trajectory of normative brain development observed in adolescence, leading to less efficient neural processing over time.

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Similar findings were also reported in genetic mouse models of diabetic nephropathy

Posted on November 20, 2023 by hemp2022

Although not observed under controlled conditions, MDMA use beyond research settings has been associated with SS in case reports and toxicology studies . The vast majority of SS clinical case reports in published literature include a combination of two or more serotonergic agents including various classes of antidepressants, and other medications with serotonergic activity such as opioids , antibiotics , antihistamines , and atypical antipsychotics . Given the high percentage of the PTSD population for whom serotonin modulating therapeutics are prescribed and the high prevalence of other PTSD comorbid conditions, including substance use , depression , anxiety , sleep , and pain disorders treated by serotonergic drugs, further exploration of MDMA related Adverse Events reports from the drug safety surveillance database in the FDA Adverse Event Reporting System is warranted. In this study, we evaluated individual cases listing MDMA use associated with SS and reported to FAERS through MedWatch . We evaluated reports for the presence of MDMA as the sole reported compound, and for the presence of any additional substances or medications, particularly those that might increase the risk of SS due to their inherent serotonergic activity.The kidneys play a central role in normal body homeostasis through a variety of functions, including removal of byproducts of metabolism, clearance of toxins, regulation of body volume status, electrolytes and systemic hemodynamics, and production of hormones such as erythropoietin and active vitamin D. Hence, it is not surprising that kidney damage is associated with significant morbidity and mortality. The latter is true whether the decline in renal function is part of an acute process such as acute kidney injury due to tubular necrosis,growing cannabis indoors or a more chronic process such as chronic kidney disease caused by hypertension or diabetes. Furthermore, the mechanisms responsible for renal injury are complex and can be varied.

While these mechanisms are regularly categorized based on the type of injury and anatomic part of the nephron affected , there is significant overlap between these categories. For instance, there is evidence indicating that AKI can result in CKD. In addition, there is frequent overlap between the different anatomic sites of injury given that damage to one part of the nephron over a period of time can result in injury to other sites. For example, while diabetic kidney disease often manifests with glomerular injury and proteinuria, over an extended period of time it also results in tubulointerstitial damage and fibrosis leading to progressive CKD and end-stage kidney disease. Therefore, understanding the underlying pathways whose alterations can result in various forms of renal damage and injury can play an important role in devising effective therapies to prevent and treat kidney disease. In this regard, there is accumulating evidence that indicates that the endocannabinoid system plays a major role in normal renal physiology. In addition, there are data demonstrating that alterations of this pathway can lead to the pathogenesis of both acute and chronic kidney disease. Therefore, evaluation of the EC system can be a promising area of discovery, which may result in the generation of potentially novel therapies aimed at treating various forms of kidney disease. The EC system comprises endogenous fatty acidderived ligands, their receptors, and the enzymes required for their biosynthesis and degradation.The most wellcharacterized ECs are N-arachidonoyl ethanolamide, also known as anandamide , and 2-arachidonoylsn-glycerol .These lipid-derived molecules are generated on-demand by the metabolism of membrane phospholipids in response to various stimuli, including elevated intracellular calcium or metabotropic receptor activation.After production, they bind to the local cannabinoid receptors in an autocrine or paracrine manner, although measurable concentrations of these ligands can also be found in the blood, cerebrospinal fluid, and lymph.While the potential endocrine actions of these ECs remain an area of active research, it is well established that they act locally by binding with two widely studied cannabinoid receptors, cannabinoid subtype-1 and subtype-2 .

AEA and 2-AG can subsequently be taken up by cells through a high-affinity uptake mechanism and rapidly degraded through the action of the enzymes, fatty acid amide hydrolase , and monoacylglycerol lipase , respectively.While the role of the EC system has been initially a focus of extensive research in the central nervous system, over the course of the past two decades, a significant number of studies have confirmed its presence and importance in the peripheral organs, including the kidneys. In this regard, substantial concentrations of ECs, the machinery required for their biosynthesis and degradation, as well as CB receptors have been detected in kidney tissue.The effects produced by the actions of this system in the normal and pathological conditions of the kidney, however, have not been fully delineated given the many complexities involved in the production and breakdown of EC ligands.In addition, the differential distribution and actions of the CB1 and CB2 receptors in various structures and cell subtypes in the kidney can ultimately result in varied signaling outcomes whose overall impact will be difficult to predict. Accordingly, identifying the physiologic and pathophysiologic roles of the EC system in the field of nephrology remains an active area of exploration.It has been shown that CB1 and CB2 belong to a class of seven transmembrane domain G-protein-coupled receptors that are functionally dependent on the activation of heterotrimeric Gi /G0 proteins.Although the activation of both receptors results in the inhibition of adenylyl cyclase enzyme and increased activity of mitogen-activated protein kinase , CB1 activation has also been shown to stimulate nitric oxide synthase and directly control the activation of ion channels. The latter include the inwardly rectifying and A-type outward potassium channels, D-type outward potassium channels, and Ntype and P/Q-type calcium channels.Despite the common G-protein subunit shared between CB1 and CB2 receptors, their activation can produce opposing biological effects in normal and diseased states, in part due to the abundance and localization of these cannabinoid receptors and their EC ligands. While the CB1 receptor was initially thought to be localized to the central and peripheral nervous system,it has been shown to be present in peripheral organs such as the kidneys.For instance, the presence of functional CB1 receptor has been demonstrated in proximal convoluted tubules, distal tubules, and intercalated cells of the collecting duct in the human kidney.

Furthermore, CB1 receptor expression has also been found in other parts of the nephron in rodents, such as the afferent and efferent arterioles,thick ascending limbs of the loop of Henle,and glomeruli,as well as in various kidney cell sub-types such as glomerular podocytes, tubular epithelial cells,and cultured mesangial cells Similarly, the expression of CB2 receptors, although previously thought to be predominantly in immune cells,has also been demonstrated in renal tissue.For example, CB2 receptor expression has been localized to podocytes,proximal tubule cells, and mesangial cells in human and rat renal cortex samples. In addition to differential expression of CB receptors in different tissues and cells, the complex regulation of the biosynthesis and degradation of the kidney’s high basal levels of ECs through downstream enzymes contributes to the varied signaling effects of these ligands.While the renal cortex displayed similar levels of AEA and 2-AG, AEA was demonstrated to be enriched in the kidney medulla compared with the cortex,growing indoor cannabis while the levels of 2-AG in the medulla were similar to those of both ECs in the cortex.Moreover, AEA is present in cultured renal endothelial and mesangial cells at low levels and can be synthesized from arachidonic acid and ethanolamine and catabolized by AEA amidase in these kidney cell sub-types.The expression of FAAH was shown to be augmented in the renal cortex in comparison to its low expression levels in the medulla.Considering the diverse localization of the ECs and their receptors, as well as the complexities involved in their synthesis and catabolism, this system can play various roles in kidney function. Under normal conditions, the EC system is capable of regulating renal homeostasis as demonstrated by its control over renal hemodynamics, tubular sodium reabsorption, and urinary protein excretion. These effects are largely imparted through the activation of the CB1 receptor. In the following sections, we describe some effects of EC system activation on renal physiologic function .Under normal physiologic conditions, the EC system plays a critical role in the regulation of renal hemodynamics. For instance, it was shown that intravenous administration of AEA decreased glomerular filtration rate and increased renal blood flow in rodents, independent of changes in blood pressure.In vitro studies showed that AEA can vasodilate juxtamedullary afferent or efferent arterioles through a CB1-dependent process, normally inhibited by nitric oxide synthase,to regulate glomerular filteration rate . The actions of the AEA signaling system are likely conducted through endothelial and mesangial cells, which are capable of producing and metabolizing AEA,as well as through the hyperpolarization of smooth muscle cells via the activation of potassium channels.It should be noted that there are also non-CB1 receptor–dependent mechanismsby which ECs can mediate a vasodilatory effect and thereby regulate renal hemodynamics.Future studies need to further elucidate the role of the latter mechanisms in normal renal physiologic homeostasis.It is well known that diabetes has major renal complications, including progressive kidney disease and pathology, a condition known as diabetic nephropathy.

Diabetic nephropathy is characterized by glomerular hypertrophy and hyper filtration, which can result in albuminuria, renal fibrosis, GFR decline, and end-stage renal disease.Several studies have examined the role of the EC system in diabetes-related podocyte, mesangial and tubular cell injury, as well as the function of CB receptor activation on the adverse outcomes of diabetic nephropathy . The evaluation of mouse models of diabetic kidney disease and renal tissue from humans with advanced diabetic nephropathy have shown elevated levels of CB1 receptor expression in the kidney, and in particular in glomerular podocytes and mesangial cells.In addition, in vitro studies have shown CB1 receptor upregulation with exposure to increased glucose and albumin concentrations in mesangial cells andproximal tubule cells, respectively.Furthermore, the CB1 receptor has been found to be over expressed in glomerular podocytes in experimental mice with diabetic nephropathy.The potential consequences of the latter changes were shown in another study that found that hyperlipidemia, as induced by diabetic nephropathy, can be associated with palmitic acid–induced apoptosis in proximal tubular cells. These actions are mediated through upregulated CB1 receptor expression.Given the evidence indicating a deleterious role for the CB1 receptor in diabetic nephropathy, several studies have investigated the utility of CB1 antagonist/inverse agonists as a potential therapeutic option for diabetic kidney disease.In a streptozotocin -induced mouse model of diabetic nephropathy, albuminuria was reduced as a result of CB1 receptor blockade through a selective CB1 receptor antagonist.It was found that a marked reduction in proteinuria occurred through the preservation of glomerular podocytes and restoration of the expression of podocyte proteins nephrin, podocin, and zonula occludens-1. In addition, CB1 antagonism was also found to be associated with decreased glomerular and proximal tubular apoptosis, ultimately leading to improvements in renal function.In Zucker diabetic fatty rats, which develop type 2 diabetes due to obesity caused by a dysfunctional leptin receptor, chronic administration of a CB1 receptor inverse agonist restored GFR, reduced proteinuria, and improved the markers of podocyte health through modulation of the renin–angiotensin system and inhibition of apoptosis.While diabetic kidney disease is associated with increased expression of the CB1 receptor in various parts of the nephron, there is also evidence that CB2 receptor expression is significantly reduced. For example, STZ induced diabetic nephropathy in mice is associated with the down regulation of glomerular podocyte CB2 receptor expression.Similarly, there is decreased expression of the CB2 receptor in proximal tubule cells following exposure to elevated concentrations of albumin and glucose.Furthermore, CB2 receptor activation has been shown to ameliorate albuminuria, restore podocyte protein expression, reduce monocyte infiltration, and decrease the expression of renal profibrotic markers in rats with obesity-related nephropathy. CB2 agonism in obese diabetic nephropathy BTBR ob/ob mouse strain also reduced albuminuria, ameliorated dysfunctional nephrin expression in podocytes, and reduced mesangial matrix expansion, fibronectin accumulation, and sclerotic damage.These studies demonstrate that antagonism of CB1 receptors and activation of CB2 receptors using selective pharmacological ligands is associated with the restoration of renal structure and function, specifically albuminuria and the expression of inflammatory markers, in genetic and experimental models of diabetic nephropathy.Obesity is associated with and acts as a risk factor for the development of diabetic nephropathy,with obese individuals possessing a higher risk of progressing to end-stage renal disease.

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Studies of typically developing adolescents show increases in FA and decreases in MD

Posted on November 17, 2023 by hemp2022

Conversely, both CPD and ND were negatively genetically associated with hundreds of other diseases in BioVU , including those known to be associated with smoking, such as chronic airway obstruction, lung cancer, and metabolic diseases . Most of the associations between CPD or ND and psychiatric disorders were attenuated, and no longer significant, when we adjusted for TUD or AUD . We repeated our analyses using a quantitative measure of ND and obtained very similar findings . All pairs of PRSs showed significant correlations, except for AUDIT-C PRS and ND PRS . All r coefficients were positive, the strongest association being between CPD and FTND , except for AUDIT-C’s associations with and CPD and with FTND, which showed a negative association . The current study examines smoking and alcohol consumption phenotypes as genetic surrogates for nicotine dependence and alcohol misuse, respectively, using PRSs constructed from well-powered GWAS in the UKB and other population-based non-UKB cohorts. In applying the PRSs to a large pheWAS, we found that smoking consumption was a good proxy for dependence, but alcohol consumption was not a good proxy for alcohol misuse . Ascertainment bias may explain some of the inverse genetic correlations between alcohol consumption and, for example, obesity and type 2 diabetes . UKB and other similar collections based on voluntary participation, are only available to individuals who are relatively healthy and who have both the means and opportunity to participate, resulting in an over representation of data from individuals with higher education levels and socioeconomic status and alcohol consumption than the general population but, crucially, lower levels of metabolic disorders and problem drinking. Importantly, both alcohol consumption and alcohol misuse were measured in UKB. Thus,mobile vertical grow racks the difference between alcohol consumption and misuse could indicate that the genetic overlap between alcohol consumption and AUD is dependent on the specific patterns of drinking .

For example, Polimanti et al identified a positive genetic correlation between alcohol dependence and alcohol drinking quantity , but not frequency. Similarly, Marees et al showed that high alcohol consumption frequency was associated with high socioeconomic status and low risk of substance use disorders and other psychiatric disorders, whereas the opposite applied for high alcohol consumption quantity. Furthermore, these genetic correlations may be dissimilar to those observed when analyzing alcohol consumption in alcohol dependent individuals; such studies have yet to be performed. Notably, even though studying alcohol consumption has shown some utility, it is apparent that this phenotype measured in volunteer collections is not an optimal proxy for AUD. Similar observations have recently been described for cannabis use versus disorder with regards to proxy measures of psychosocial and anthropometric indices . Initial stages of recreational use may be etiologically distinct from later stages of pathological use for commonly used substances such as alcohol and cannabis, with only the latter stages of dependence and abuse indexing vulnerability to psychiatric impairment. Whereas use of nicotine may be a more addictive, alcohol, particularly measured in population-based cohorts such as the UKB, may represent a social habit. In contrast with alcohol, the genetic correlation between smoking consumption and ND was almost identical, and both scores showed similar patterns of genetic association with psychiatric and smoking-related comorbid diseases. We speculate that consumption phenotypes represent distinct indices of use depending on the drug: cigarette smoking may be a more accurate phenotype than drinks consumed , in addition to being a better index outcome of problematic use, such that quantity of cigarettes smoked may reflect ND. Indeed, CPD is a major component of standard measures that are used to define ND, most notably the Fagerström Test for ND. Although studying the genetics of ND alongside other smoking traits is key to gaining a better understanding of the neurobiological processes that influence the trajectory of smoking behaviors and their treatment implications, our findings suggest that smoking consumption phenotypes measured in volunteer cohorts can capture relevant sources of genetic information applicable to later stages of dependence and abuse.

Our analyses are not without limitations. We lack information regarding the potencies of cigarette and alcohol products used by individuals in the discovery and target samples. High-potency substance use is associated with increased severity of dependence, especially at younger ages. Relatedly, our results may be restricted to PRSs calculated in populations with low levels of alcohol-related problems, like UKB. Furthermore, although we used a proxy measure of alcohol misuse , instead of a clinical diagnosis of AD, the pheWAS findings using problematic alcohol use in BioVU suggest that the results of AUDIT-P PRS are similar to AD PRS . In addition, results from our sensitivity analyses revealed that the associations were slightly attenuated after diagnosis of AUD or TUD were included as covariates. It is plausible that many of the relationships between alcohol misuse and ND and psychopathology, detected in BioVU, may be consequences of an AUD or TUD diagnosis rather than due to shared genetic risk. Alternatively, these associations could reflect pleiotropy or be a causal peripheral effect of alcohol/nicotine persistent/pathological use. The reduction in the number of statistically significant associations after adjustment for AUD or TUD may imply shared genetic liability between these disorders and comorbid psychopathology, or that, simply, our correction for AUD or TUD was too stringent considering that most of the effect sizes were essentially unchanged and that we expected some degree of collinearity between AUD/TUD diagnosis and the PRSs that we calculated. Future studies should aim at exploring causal mechanisms. Lastly, our estimates of genetic overlap may be sensitive to environmental factors, for example when comparing results from UKB to younger cohorts. In summary, we performed a pheWAS of consumption and dependence/misuse polygenic scores. We conclude that smoking consumption measured in healthy volunteer cohorts is a powerful proxy for genetic studies of ND . For alcohol consumption, by using multivariate approaches that give statistically-derived weights to alcohol phenotypes or by including further restrictions to the study cohort , we may be able to mitigate some of the inverse associations between alcohol consumption and poor health and, in doing so, we may realize the full potential of alcohol consumption phenotypes as proxies for AUD.

Moreover, and as a collateral finding, we identified very robust associations between well-characterized measures of alcohol and nicotine consumption, misuse, and clinical diagnoses from a real world medical-center setting . These series of analyses demonstrate the value of using broad electronic health record measures for genetic studies of substance use disorders. Adolescence is a time of subtle, yet dynamic brain changes that occur in the context of major physiological, psychological,vertical cannabis grow systems and social transitions. This juncture marks a gradual shift from guided to independent functioning that is analogized in the protracted development of brain structure. Growth of the prefrontal cortex, limbic system structures, and white matter association fibers during this period are linked with more sophisticated cognitive functions and emotional processing, useful for navigating an increasingly complex psychosocial environment. Despite these developmental advances, increased tendencies toward risk-taking and heightened vulnerability to psychopathology are well known within the adolescent milieu. Owing in large part to progress and innovation in neuroimaging techniques, appreciable levels of new information on adolescent neurodevelopment are breaking ground. The potential of these methods to identify biomarkers for substance problems and targets for addiction treatment in youth are of significant value when considering the rise in adolescent alcohol and drug use and decline in perceived risk of substance exposure . What are the unique characteristics of the adolescent brain? What neural and behavioral profiles render youth at heightened risk for substance use problems, and are neurocognitive consequences to early substance use observable? Recent efforts have explored these questions and brought us to a fuller understanding of adolescent health and interventional needs. This paper will review neurodevelopmental processes during adolescence, discuss the influence of substance use on neuromaturation as well as probable mechanisms by which these substances influence neural development, and briefly summarize factors that may enhance risk-taking tendencies. Finally, we will conclude with suggestions for future research directions.The developmental trajectory of grey matter follows an inverted parabolic curve, with cortical volume peaking, on average, around ages 12–14, followed by a decline in volume and thickness over adolescence . Widespread supratentorial diminutions are evident, but show temporal variance across regions . Declines begin in the striatum and sensorimotor cortices , progress rostrally to the frontal poles, then end with the dorsolateral prefrontal cortex , which is also late to myelinate . Longitudinal charting of brain volumetry from 13–22 years of age reveals specific declines in medial parietal cortex, posterior temporal and middle frontal gyri, and the cerebellum in the right hemisphere, coinciding with previous studies showing these regions to develop late into adolescence . Examination of developmental changes in cortical thickness from 8–30 years of age indicates a similar pattern of nonlinear declines, with marked thinning during adolescence. Attenuations are most notable in the parietal lobe, and followed in effect size by medial and superior frontal regions, the cingulum, and occipital lobe .

The mechanisms underlying cortical volume and thickness decline are suggested to involve selective synaptic pruning of superfluous neuronal connections, reduction in glial cells, decrease in neuropil and intra-cortical myelination . Regional variations in grey matter maturation may coincide with different patterns of cortical development, with allocortex, including the piriform area, showing primarily linear growth patterns, compared to transition cortex demonstrating a combination of linear and quadratic trajectories, and isocortex demonstrating cubic growth curves . Though the functional implications of these developmental trajectories are unclear, isocortical regions undergo more protracted development and support complex behavioral functions. Their growth curves may reflect critical periods for development of cognitive skills as well as windows of vulnerability for neurotoxic exposure or other developmental perturbations.In contrast to grey matter reductions, white matter across the adolescent years shows growth and enhancement of pathways . This is reflected in white matter volume increase, particularly in fronto-parietal regions . Diffusion tensor imaging , a neuroimaging technique that has gained widespread use over the past decade, relies on the intrinsic diffusion properties of water molecules and has afforded a view into the more subtle micro-structural changes that occur in white matter architecture. Two common scalar variables derived from DTI are fractional anisotropy , which describes the directional variance of diffusional motion, and mean diffusivity , an indicator of the overall magnitude of diffusional motion. These measures index relationships between signal intensity changes and underlying tissue structure, and provide descriptions of white matter quality and architecture . High FA reflects greater fiber organization and coherence, myelination and/or other structural components of the axon, and low MD values suggest greater white matter density .These trends continue through early adulthood in a nearly linear manner , though recent data suggest an exponential pattern of anisotropic increase that may plateau during the late-teens to early twenties . Areas with the most prominent FA change during adolescence are the superior longitudinal fasciculus, superior corona radiata, thalamic radiations, and posterior limb of the internal capsule . Other projection and association pathways including the corticospinal tract, arcuate fasciculus, cingulum, corpus callosum, superior and mid-temporal white matter, and inferior parietal white matter show anisotropic increases as well . Changes in subcortical and deep grey matter fibers are more pronounced, with less change in compact white matter tracts comprising highly parallel fibers such as the internal capsule and corpus callosum . Fiber tracts constituting the fronto-temporal pathways appear to mature relatively later , though comparison of growth rates among tracts comes largely from cross-sectional data that present developmental trends. The neurobiological mechanisms contributing to FA increases and MD decreases during adolescence are not entirely understood, but examination of underlying diffusion dynamics point to some probable processes. For example, decreases in radial diffusivity , diffusion that occurs perpendicular to white matter pathways, suggests increased myelination, axonal density, and fiber compactness , but have not been uniformly observed to occur during adolescence. Similarly, changes in axial diffusivity , diffusion parallel to the fibers’ principle axis, show discrepant trends, with some studies documenting decreases , and others increases in this index .

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There are encouraging examples of sound policy at both the federal and state levels

Posted on November 16, 2023 by hemp2022

As SUDs, particularly involving opioids, increasingly affects pregnant women and their families, it is important to better understand how state policy environments with respect to substance use in pregnancy have evolved and the nature of policies being enacted by states. Professional societies and federal agencies universally endorse supportive policies and oppose punitive policies. Statements from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the Centers for Disease Control and Prevention, the Substance Abuse and Mental Health Services Administration, the American Nurses Association, and several others all warn that policies penalizing pregnant women and imposing negative consequences for disclosing substance use to health care providers increase the fear of legal penalties and discourage women from seeking prenatal care and addiction treatment during pregnancy. Guidance documents and professional society committee opinions further suggest that punitive policies may lead to disengagement from care and poor pregnancy outcomes, although few studies have examined this issue. Expert consensus is grounded in the view of substance misuse in pregnancy as a medical condition requiring integrated care for both the pregnancy and the SUD and the recognition that supportive policies reduce barriers to care. For example, punitive policies enacted, in part, to reduce neonatal opioid withdrawal syndrome , have the opposite effect. Infants born in states that implemented policies that punish pregnant women for substance use had higher rates of NOWS than those born in states without such policies.The change in state policy environments with respect to substance use in pregnancy from 2000 to 2015 are detailed in the maps in Figure 1. Six types of relevant policies were examined: those that define substance use in pregnancy as child abuse or neglect, criminalize it, or consider it grounds for civil commitment,vertical growing system mandate testing of infants with suspected prenatal substance exposure or pregnant women with suspected substance use; require reporting of suspected prenatal substance use to officials at local health and human services departments; create or fund targeted programs for pregnant and postpartum women with SUDs; prioritize pregnant women’s access to SUD treatment programs; and prohibit discrimination against pregnant women in publicly funded SUD treatment programs.

Consistent with prior work and others’ approach, policies imposing legal consequences for substance use or requiring health professionals to test for or report suspected substance use to authorities were considered punitive. Policies reducing barriers for pregnant women with SUD or those that expand treatment were considered supportive. If a state enacted a policy with both punitive and supportive components, it was considered to have a mixed policy environment. Enactment dates were obtained from the Guttmacher Institute18 and supplemented with information from the National Conference of State Legislatures, ProPublica, and published studies retrieved through a targeted literature review.In addition, state statutes were reviewed to capture language illustrative of policy categories. Box 1 shows an example punitive policy enacted in North Dakota in 2003 and Box 2 contains a supportive policy enacted in Kentucky in 2015. Figure 1 shows substantial state policy activity in this area, with more states adopting punitive policies than supportive policies. This increase, from 18 states with at least one punitive policy in 2000 to 33 states in 2015, was primarily driven by states adopting policies considering substance use in pregnancy to be child abuse, grounds for civil commitment, or a criminal act, as well as policies requiring healthcare professionals to report suspected prenatal drug use. By 2015, states with only punitive policies increased from six to eight, while states with only supportive policies declined from 17 to 8. States with both types of policies doubled from 12 in 2000 to 25 by 2015, and only 10 states had no policies specific to substance use in pregnancy in 2015, down from 16 in 2000. While encouraging that 28 states had supportive policies in 2000, only 4 additional states adopted supportive policies in the subsequent 15 years. The maps in Figure 1 are consistent with a pattern described in 199824 of more states enacting punitive policies than policies expanding treatment for women with SUD and echo the punitive approaches taken towards women with crack cocaine use in the 1980s and 1990s.These policies disproportionately affected Black women and women living in poverty,and continue to do so today.While the government’s current approach to substance use in the general population is “remarkably less punitive” than its approach a few decades ago, it has recently been observed that “…pregnancy may represent an exception to the overall national willingness to treat the opioid epidemic as an issue of public health and not of law enforcement.”In addition, as one journalist put it, “There’s a growing consensus in the U.S. that drug addiction is a public health issue, and sufferers need treatment, not prison time. But good luck if you are pregnant.”Despite overwhelming consensus on the principle of a non-punitive approach towards substance use in pregnancy , the increase in punitive policies over the past two decades suggests that the gap between principles and practice is widening. What is needed is a holistic, public health-and prevention-oriented approach to substance use in pregnancy, consistent with the statements in Table 1.

Imagine for a moment that pregnant women with diabetes, or epilepsy, or major depressive disorder, all of which are chronic medical conditions that confer some level of risk to the fetus, faced criminal charges and imprisonment if convicted of harming their infants. These examples illustrate just how differently many in the public and medical community view addiction. Addiction is a chronic medical condition, but pregnancy is a temporary period in the life course of a woman dealing with the recurring and remitting illness of addiction. Yet, too often, policies, health systems, and health services are designed to engage individuals in treatment only during pregnancy which is insufficient. Instead, women with SUD should be engaged throughout their life course.Women with SUD need comprehensive, coordinated, evidence-based, trauma-informed, family-centered care not only during the 40 or so weeks of pregnancy but in the preconception, postpartum, and inter-conception periods—as well as throughout the life course for those not able to or not choosing to have children. This care should be delivered in a compassionate and non-punitive environment, and clinicians, policymakers, and public health officials all have a role to play in achieving this goal. For example, recent federal legislation takes a much-needed public health approach to this issue, building on prior efforts to address gaps in the continuum of care for women who are pregnant and postpartum and strengthening Plans of Safe Care for infants with prenatal substance exposure. There has been a slow but noticeable shift in federal policy language towards less stigmatizing terminology and “people-first” language, such as an “individual in recovery” as opposed to a “drug addict,” and replacing “NAS baby” with “infant experiencing withdrawal.” Certain states are taking a dyadic approach to the challenge of mothers and infants affected by opioids. Medicaid policy levers have also shown promise. In Virginia, the Addiction and Recovery Treatment Services program,launched in 2017 to increase access to services for Medicaid members with SUDs, increased residential treatment capacity and removed the 16-bed reimbursement limit, which was a barrier to children and mothers remaining together during the mother’s treatment. ARTS successfully increased the percentage of pregnant women with SUDs receiving treatment from 2% to 18% a year after implementation. Further research is needed to examine factors that may influence state-level variation in both the implementation and impact of different policy responses to substance use among pregnant women,vertical growing towers but these are promising models. It is also encouraging that both federal and state policymakers are testing innovative ways to expand SUD treatment for women who are pregnant and parenting, including through telehealth and through telementoring and remote capacity building, based on the Project ECHO model.Importantly, public health and health systems are collaborating to address the often-overlooked “fourth trimester,” the vulnerable early postpartum period in which a lot of the support and services a pregnant woman was eligible for rapidly fall away.

Finally, the recommendation by multiple professional societies to extend postpartum Medicaid coverage to one year postpartum is garnering much-needed attention from policymakers.In conclusion, effectively addressing SUD, including opioid misuse, among pregnant women is a pressing public health issue, given both the dramatic increase in NOWS2 as well as the deleterious effects of untreated maternal opioid use disorder on both mothers and young children.Policymakers are aware of this issue, given the rapid pace of enacting policies addressing substance use in pregnant women. However, the greater increase in punitive compared to supportive policies is a concern. Better understanding how policies related to prenatal substance use affect maternal and child outcomes is essential as decision makers seek to best support pregnant women with SUDs. Women who use substances during pregnancy are at increased risk for poor perinatal outcomes, including preterm labor, low birth weight, congenital abnormalities, and stillbirths, and there can be additional long lasting physical, mental, behavioral and neurodevelopmental consequences for their children . Recognizing prenatal substance use as a primary cause of preventable birth defects, US guidelines consider substance use screening and referral to be essential for prenatal care . Alcohol and nicotine are among the most commonly used substances by women before and during pregnancy. Prenatal alcohol use is associated with structural impairments, increased risk for adverse birth outcomes , fetal alcohol spectrum disorder and fetal alcohol syndrome, and neurodevelopmental problems in childhood . Prenatal nicotine use is associated with pregnancy complications , poor infant outcomes , sudden infant death syndrome, birth defects, and long-term health issues in childhood . National data indicate that alcohol use is increasing over time, and nicotine use is decreasing over time, among US women of reproductive age . However, corresponding with growing awareness of the potential harms of alcohol and nicotine use during pregnancy, initial data suggest that prenatal alcohol and nicotine use are decreasing over time . For example, data from the National Survey of Drug Use and Health indicate that among US adult pregnant women, any past-month use of alcohol during pregnancy decreased non-significantly from 9.6% in 2002 to 8.4% in 2016, and any past month cigarette smoking decreased significantly from 17.5% in 2002 to 10.3% in 2016 .Past-month alcohol and nicotine use is most common during the first trimester of pregnancy , during which time women may not realize that they are pregnant. Although healthcare systems are well poised to screen women of reproductive age for substance use, it is challenging to predict which women are at risk for using nicotine and alcohol when they become pregnant, and health care systems have limited resources and require better data to prioritize whom to target with education about prenatal substance use prior to conception. Initial data from nationally representative studies indicate that lower socioeconomic status, lower education, White race, and serious psychological distress are associated with higher risk of nicotine use during pregnancy , while younger age, other substance use, depression, higher socioeconomic status, higher education, and being unmarried are associated with greater risk of alcohol use during pregnancy . Less is known about risk factors that are associated with continued use versus quitting alcohol or nicotine among those who use these substances prior to pregnancy. Given the health risks associated with alcohol and nicotine use during pregnancy, and the changing prevalence and patterns of use of these substances among women of reproductive age in the US , research is needed to better understand trends in prenatal use of alcohol and nicotine and to identify factors associated with quitting versus continuing to use these substances during pregnancy. The primary objective of this study was to examine trends in daily, weekly, and monthly or less self reported use of alcohol and nicotine in the year before pregnancy and during pregnancy from 2009 to 2017, among a diverse population of pregnant women within a large healthcare system with screening for substance use as part of standard prenatal care. We also examined whether frequency of alcohol and nicotine use in the year before pregnancy were associated with continued use of these substances during pregnancy.Kaiser Permanente Northern California is an integrated multi-specialty healthcare delivery system that provides care to more than 4 million diverse members who are representative of the Northern California region .

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It was difficult to determine which bands belonged to the rope and which to the contaminant

Posted on November 15, 2023 by hemp2022

Our results do not contradict those of Wang et al. and Dick et al. ; the results are mutually consistent. Instead, they reveal a novel age-specific risk factor undetectable by solely examining the condition of alcohol dependence rather than its age of onset. In view of the age differences between the sample studied in this paper, and the sample used in the studies of Wang et al. and Dick et al. it is not possible that they should contradict one another. In the Wang et al. study, about 5% of the alcohol dependent subjects had ages of onset of less than 16 years of age. This is too small a fraction to have an effect on the results. As we noted in our discussion of the trend tests, in our study the genotypic distributions of the alcohol dependent subjects change with age of onset. While we do not observe a significant SNP effect in the oldest age range with DTSA, the fraction of subjects with the minor allele in those who become alcohol dependent is greater than the fraction of subjects with the minor allele in those who do not become alcohol dependent . This trend acts to produce a similar genotypic distributions for alcohol dependent and non alcohol dependent subjects when considered regardless of age of onset. In terms of the methodology, DTSA requires that there be differences in genotypic distributions between alcohol dependent and non alcohol dependent subjects to give a statistically significant results for a SNP; this is not true for the family based method used by Wang et al. . Our interpretation is that family based studies are more powerful than the type of association study employed here; the absence of a distributional difference does not mean that there is no genetic effect. It is important to note that the objectives of the twin studies considered here and of this study are quite different. The twin studies investigate the presence of a “disease” condition, although exactly which condition varies considerably among studies. The objective of this study,vertical farming suppliers as a survival analysis, is to analyze the factors contributing to an event, the onset of a condition. Once the condition has come to pass, it is not of further interest in survival analysis.

The genetic effects which produce the condition are only significant at the onset of the condition, and their effects persist only if the subsequent onset of the condition in other subjects is attributable to them. In the twin studies post-onset presence of the condition is part of the outcome analyzed. That is, in the longitudinal studies using multistage models, the affected subjects are retained throughout the study subsequent to their becoming affected, while in the survival analysis method used in this study, the affected subjects are removed from consideration in the study once they have become affected, and no longer influence the results. Therefore, although the use of a longitudinal multi-stage model in van Beek et al. and Baker et al. enables genetic influences to have age-specific characteristics, these effects are modeled as persisting through time as a result of an effect at a single age range. If early onset alcohol use is associated with the more genetically determined form of alcoholism then it would be expected that genetic factors leading to early drinking and dependence would be manifest. Our results are consistent with this hypothesis. The pattern of genetic results obtained here, albeit from a single gene, is weighted towards the strongest effects manifesting themselves in the youngest age range. However, most twin studies find low genetic influences at younger ages and increases in genetic influences with age , although not all twin studies have this conclusion . These results can be understood after examination of the populations from which the twin samples are drawn and the outcomes which are modeled. The samples in the twin studies are drawn from the general population, not from the densely affected families which form the bulk of the sample used here. Thus genetic effects will be more difficult to find in the twin studies, particularly for the rarer, more genetically affected conditions. In a number of studies outcome definitions are broad, and are not subject to as strong genetic effect as more restricted outcomes such as alcohol dependence or externalizing disorders. The most dramatic example of this is the difference between the cross-sectional results from the Minnesota twin studies in which the outcomes are narrowly defined and the cross-sectional results from a Dutch twin study with the very broad outcome of having one or more alcohol abuse symptoms. The Minnesota twin studies have A > 0.6 for ages 11 and 17, while the Dutch twin study has A < 0.3 for ages 15–17 and 18–20, where A is the additive genetic effect.

Mid-adolescence is a vulnerable developmental period for cigarette smoking uptake, the onset of mental health conditions, and the emergence of comorbid tobacco use and mental health problems . The over-representation of smoking among adolescents with mental health problems generalizes across various conditions , remains robust after controlling for confounders, and is mediated by theoretically-relevant factors suggesting a causal relation . The rapid emergence and appeal of novel tobacco and nicotine products such as electronic cigarettes raises the question as to whether the same adolescent subgroup with mental health problems is at risk for using these products . This is important to address because this population may be particularly vulnerable to nicotine addiction, given that neural plasticity during adolescence and neuropathology in psychiatric conditions can enhance the brain’s sensitivity to nicotine . E-cigarettes—electronic devices that deliver inhaled nicotine emulate the sensorimotor properties of conventional cigarettes—are gaining popularity among adolescents. According to 2014 estimates, past 30 day use of e-cigarettes is more common than conventional cigarettes among U.S. 8th- and 10th- graders, and many adolescent e-cigarette users have never tried conventional cigarettes . E-cigarettes may be an attractive alternative to conventional cigarettes among youth because of beliefs that they are less harmful, addictive, malodorous, and costly than conventional cigarettes . Furthermore, e-cigarettes come in flavors appealing to youth and may be easier to obtain than conventional cigarettes because of inconsistent enforcement of restrictions against sales to minors . Such factors may facilitate e-cigarette initiation in adolescents who would not otherwise smoke conventional cigarettes and may perhaps have fewer risk factors for smoking —including mental health problems. Dual use of conventional and e-cigarettes is also common in adolescents , raising the possibility that some adolescents may use e-cigarettes to substitute for conventional cigarettes in situations where smoking is restricted. Indeed, school bathrooms and staircases are among the most common places adolescents report using e-cigarettes .

Given that adolescents with mental health symptoms are more prone to nicotine dependence , these populations could be more likely to initiate use of e-cigarettes to bridge situations when they are not able to smoke, which ultimately could perpetuate the over-representation of smoking among individuals with mental health problems. While research has yet to characterize the psychiatric comorbidity with patterns of conventional and e-cigarette use in adolescents, a recent study of Hawaiian adolescents found that alcohol/marijuana use and other psychosocial risk factors were highest in dual users, moderate in e-cigarette only users, and lowest in non-users . Most pairwise comparisons involving conventional cigarette only users were not significant in that study, perhaps limited by reduced statistical power due to the smaller size of this group . Given these findings, stratification of psychiatric comorbidity across dual use, single-product use, and non-use in adolescents is plausible. The current study characterized the mental health of adolescents who reported ever using ecigarettes, conventional cigarettes, both, or neither. To provide a wide-ranging picture of psychiatric comorbidity,vertical farming systems cost traditional syndrome-based indices of various depressive, manic, anxiety, and substance use disorders were administered. Consistent with NIMH’s Research Domain Criteria Initiative , we also assessed several transdiagnostic phenotypes implicated in multiple internalizing and externalizing psychopathologies and conventional cigarette use . Up to this point, data on the psychiatric comorbidity associated with ecigarette and dual use is virtually absent, leaving unclear as to how the mental health of these two groups compare to conventional cigarette users and non-users. Given that conventional cigarettes and e-cigarettes have both similarities and differences, whether the patterns of psychiatric comorbidity are similar or different between e-cigarette only users and conventional cigarette users is unclear. As the first study to comprehensively characterize psychiatric comorbidity in adolescent e-cigarette and dual use, this study may yield data that is important to tobacco policy by identifying adolescent populations that are psychiatrically vulnerable and potentially at risk for use of traditional and emerging tobacco products. Such data could highlight the need to protect psychiatrically vulnerable adolescents from tobacco product use take via targeted tobacco product regulation and behavioral health prevention programming for this populations.This report is based on a cross-sectional survey of substance use and mental health among 9 th grade students enrolled in ten public high schools surrounding Los Angeles, CA, USA.

The schools were recruited based on their adequate representation of diverse demographic characteristics. The percentage of students eligible for free lunch within each school on average across the ten schools was 31.1% . Students not in special education or English as a Second Language programs were eligible . Of the students who assented to participate , 3,383 provided active parental consent and enrolled in the study. In-classroom paper-and-pencil surveys were administered across two 60-minute data collections during the fall of 2013, conducted less than two weeks apart. Some students did not complete all questionnaires within the time allotted or were absent for data collections , leaving a final sample of 3310. The University of Southern California Institutional Review Board approved the protocol. Based on patterns of lifetime use, the sample was divided into: use of neither electronic nor conventional cigarettes ; use of conventional cigarettes only ; use of electronic cigarettes only ; use of electronic and conventional cigarettes . Primary analyses used generalized linear mixed models that accounted for clustering of data within school, in which the 4-level cigarette use group variable was a categorical regressor variable and a mental health indicator was the outcome variable, with separate models for each outcome. GLMM specified binary and continuous distributions for the lifetime substance use status and mental health quantitative outcomes, respectively. Because of skewed distributions on the three substance use problems measures, Poisson distributions were specified for these outcomes. For outcomes with omnibus groups differences, we conducted follow up pairwise contrasts using an adjusted p-value, correcting for study-wise false discovery rate of 0.05. GLMMs were adjusted for gender, age, ethnicity, and highest parental education; missing data on covariates were accounted for by dummy coding a ‘missingness’ variable to allow inclusion in analyses. Results are reported as standardized effect size estimates .As illustrated in Table 2, there were omnibus differences across the four groups for all outcomes. Pairwise contrasts indicated that adolescents who used conventional cigarettes only reported worse mental health than non-users and e-cigarette only users on multiple internalizing emotional syndromes and transdiagnostic phenotypes . On these internalizingemotional outcomes, the conventional cigarettes only and dual use groups did not significantly differ. For some internalizing outcomes , e-cigarette only users had higher elevations than non-users, but lower problem levels than conventional only or dual users. Relative to non-users, use of either product was related to the externalizing phenotypes of poorer inhibitory control and impulsivity. An ordered effect of dual use vs. e-cigarette use only vs. non-use was found for elevations in mania, positive urgency, and anhedonia. An ordered effect of dual use vs. either single product use vs. non-use was also found for lifetime use status and level of abuse/problems for all substances. Given the differences in patterns across internalizing and externalizing and positive-emotion seeking behaviors, syndromes, and traits, we plotted standardized T-scores of the outcomes by conventional/e-cigarette use status separately in the two domains. These figures respectively illustrate general trends of: differentiation of conventional and dual cigarette use from never and e-cigarette use on most internalizing outcomes , and tri-level ordered differentiation of never vs. single product vs. dual use on externalizing outcomes . Analyses of the substance problem outcomes utilizing the overall sample cannot distinguish between substance ever-users who report zero drug/alcohol-related problems and substance never-users.

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