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Translational Psychiatry Jan 2022Compulsivity is a poorly understood transdiagnostic construct thought to underlie multiple disorders, including obsessive-compulsive disorder, addictions, and binge...
Compulsivity is a poorly understood transdiagnostic construct thought to underlie multiple disorders, including obsessive-compulsive disorder, addictions, and binge eating. Our current understanding of the causes of compulsive behavior remains primarily based on investigations into specific diagnostic categories or findings relying on one or two laboratory measures to explain complex phenotypic variance. This proof-of-concept study drew on a heterogeneous sample of community-based individuals (N = 45; 18-45 years; 25 female) exhibiting compulsive behavioral patterns in alcohol use, eating, cleaning, checking, or symmetry. Data-driven statistical modeling of multidimensional markers was utilized to identify homogeneous subtypes that were independent of traditional clinical phenomenology. Markers were based on well-defined measures of affective processing and included psychological assessment of compulsivity, behavioral avoidance, and stress, neurocognitive assessment of reward vs. punishment learning, and biological assessment of the cortisol awakening response. The neurobiological validity of the subtypes was assessed using functional magnetic resonance imaging. Statistical modeling identified three stable, distinct subtypes of compulsivity and affective processing, which we labeled "Compulsive Non-Avoidant", "Compulsive Reactive" and "Compulsive Stressed". They differed meaningfully on validation measures of mood, intolerance of uncertainty, and urgency. Most importantly, subtypes captured neurobiological variance on amygdala-based resting-state functional connectivity, suggesting they were valid representations of underlying neurobiology and highlighting the relevance of emotion-related brain networks in compulsive behavior. Although independent larger samples are needed to confirm the stability of subtypes, these data offer an integrated understanding of how different systems may interact in compulsive behavior and provide new considerations for guiding tailored intervention decisions.
Topics: Cognition; Compulsive Behavior; Female; Humans; Neurobiology; Obsessive-Compulsive Disorder; Phenotype
PubMed: 35013101
DOI: 10.1038/s41398-021-01773-1 -
International Journal of Molecular... Dec 2021Oxidative and nitrosative stress plays a pivotal role in the incidence of metabolic disorders. Studies from this lab and others in iNOS mice have demonstrated occurrence...
Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin.
Oxidative and nitrosative stress plays a pivotal role in the incidence of metabolic disorders. Studies from this lab and others in iNOS mice have demonstrated occurrence of insulin resistance (IR), hyperglycemia and dyslipidemia highlighting the importance of optimal redox balance. The present study evaluates role of nitrite, L-arginine, antidiabetics (metformin, pioglitazone) and antibiotics (ampicillin-neomycin combination, metronidazole) on metabolic perturbations observed in iNOS mice. The animals were monitored for glucose tolerance (IPGTT), IR (insulin, HOMA-IR, QUICKI), circulating lipids and serum metabolomics (LC-MS). Hyperglycemia, hyperinsulinemia and IR were rescued by nitrite, antidiabetics, and antibiotics treatments in iNOS mice. Glucose intolerance was improved with nitrite, metformin and pioglitazone treatment, while ampicillin-neomycin combination normalised the glucose utilization in iNOS mice. Increased serum phosphatidylethanolamine lipids in iNOS mice were reversed by metformin, pioglitazone and ampicillin-neomycin; dyslipidemia was however marginally improved by nitrite treatment. The metabolic improvements were associated with changes in selected serum metabolites-purines, ceramide, 10-hydroxydecanoate, glucosaminate, diosmetin, sebacic acid, 3-nitrotyrosine and cysteamine. Bacterial metabolites-hippurate, indole-3-ethanol; IR marker-aminoadipate and oxidative stress marker-ophthalmate were reduced by pioglitazone and ampicillin-neomycin, but not by nitrite and metformin treatment. Results obtained in the present study suggest a crucial role of gut microbiota in the metabolic perturbations observed in iNOS mice.
Topics: Ampicillin; Animals; Drug Therapy, Combination; Dyslipidemias; Glucose; Homeostasis; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metabolome; Metabolomics; Metformin; Mice, Inbred C57BL; Mice, Knockout; Neomycin; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Pioglitazone; Mice
PubMed: 35008623
DOI: 10.3390/ijms23010195 -
Journal of Neurology May 2022A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or...
A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.
Topics: Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Recurrence
PubMed: 34999925
DOI: 10.1007/s00415-021-10956-1 -
Stress and Health : Journal of the... Oct 2022The COVID-19 pandemic imposed profound effects on health and daily life, with widespread stress exposure and increases in psychiatric symptoms. Despite these challenges,...
The COVID-19 pandemic imposed profound effects on health and daily life, with widespread stress exposure and increases in psychiatric symptoms. Despite these challenges, pandemic research provides unique insights into individual differences in emotion and cognition that predict responses to stress, with general implications for understanding stress vulnerability. We examined predictors of responses to COVID-19-related stress in an online sample of 450 emerging adults recruited in May 2020 to complete questionnaires assessing baseline stress and psychiatric symptoms, rumination, cognitive reappraisal use and intolerance of uncertainty. Stress and symptoms were re-assessed 3 months later (N = 200). Greater pandemic-related stressful events were associated with increases in symptoms of depression, anxiety and alcohol use severity. Additionally, individual differences in emotional and cognitive styles emerged as longitudinal predictors of stress responses. Specifically, greater rumination predicted increased depression. Reduced cognitive reappraisal use interacted with stress to predict increases in alcohol use. An unexpected pattern emerged for intolerance of uncertainty, such that stress was associated with increases in depression for those high in intolerance of uncertainty but increases in alcohol use at relatively low levels of intolerance of uncertainty. These results highlight unique vulnerabilities that predict specific outcomes following stress exposure and offer potential prevention targets.
Topics: Adult; Anxiety; Anxiety Disorders; COVID-19; Depression; Humans; Pandemics
PubMed: 34979053
DOI: 10.1002/smi.3125 -
The Lancet. Haematology Jan 2022Patients with essential thrombocythaemia or polycythaemia vera have several symptoms that can worsen their quality of life. We aimed to assess how symptom burden changes... (Randomized Controlled Trial)
Randomized Controlled Trial
Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials.
BACKGROUND
Patients with essential thrombocythaemia or polycythaemia vera have several symptoms that can worsen their quality of life. We aimed to assess how symptom burden changes over time with cytoreductive therapy.
METHODS
We performed a post-hoc analysis of data from MPN-RC 111-a single-arm, open-label, phase 2, multicentre trial at 17 hospitals and cancer centres in Italy and the USA, evaluating the clinical-haematological response to pegylated interferon alfa-2a in patients who were resistant or intolerant to hydroxyurea (NCT01259817)-and MPN-RC 112-a randomised, open-label, phase 3, multicentre trial at 25 hospitals and cancer centres in France, Germany, Israel, Italy, the UK, and the USA, comparing the clinical-haematological response to pegylated interferon alfa-2a versus hydroxyurea in therapy-naive patients with either high-risk essential thrombocythaemia or polycythaemia vera (NCT01258856). Patients completed the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire through 12 months after initiation of treatment as secondary endpoints. In this post-hoc analysis, we examined the association of symptom burden with the clinical-haematological response at 12 months and the effect of baseline symptom burden (ie, high burden [total symptom score ≥20] vs low burden [total symptom score <20]) on subsequent changes in symptoms, estimated via mixed models. A clinically significant improvement in symptom burden was defined as 50% or greater improvement in the MPN-SAF total symptom score from baseline to 12 months in patients with a total symptom score greater than zero at baseline.
FINDINGS
135 patients were enrolled in MPN-RC 111 between Feb 15, 2012, and Dec 23, 2015, and 168 were enrolled in MPN-RC 112 between Sept 24, 2011, and June 30, 2016. For this analysis, we included data from 114 patients from MPN-RC 111 (64 [56%] with essential thrombocythaemia and 50 [44%] with polycythaemia vera; 56 [49%] were female, and 100 [91%] of 110 were white) and 166 patients from MPN-RC 112 (79 [48%] with essential thrombocythaemia and 87 [52%] with polycythaemia vera; 68 [41%] were female, and 145 [93%] of 156 were white). At 12 months, a clinically significant improvement in symptom burden was reported by 12 (32%) of 38 complete responders and seven (20%) of 35 partial responders treated with pegylated interferon alfa-2a in MPN-RC 111; five (19%) of 27 complete responders and six (18%) of 34 partial responders treated with pegylated interferon alfa-2a in MPN-112; and eight (27%) of 30 complete responders and six (22%) of 27 partial responders treated with hydroxyurea in MPN-112. More complete and partial responders reported a clinically significant improvement than did non-responders (44 [22%] of 191 complete and partial responders vs four [5%] of 76 non-responders; Fisher's exact p=0·0003). Symptom burden improved between 3 and 12 months in patients with high baseline symptom burden, both those treated with pegylated interferon alfa-2a (mean total symptom score change -10·2, 95% CI -13·2 to -7·2) and those treated with hydroxyurea (-6·8, -11·2 to -2·4). However, symptom burden worsened between 3 and 12 months in patients with low baseline symptom burden (patients treated with pegylated interferon alfa-2a: mean total symptom score change 3·2, 95% CI 0·9 to 5·4; patients treated with hydroxyurea: 3·4, 0·6 to 6·2).
INTERPRETATION
Results can inform treatment decisions, including treatment timing and goals in managing essential thrombocythaemia and polycythaemia vera, because measuring symptom burden from the patient perspective is crucial to understanding treatment efficacy and tolerability.
FUNDING
US National Cancer Institute of the National Institutes of Health, and Roche Genentech.
Topics: Female; Humans; Hydroxyurea; Interferon-alpha; Male; Polycythemia Vera; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Thrombocythemia, Essential
PubMed: 34971581
DOI: 10.1016/S2352-3026(21)00343-4 -
Molecular Metabolism Jan 2022The goal of this study was to determine the glucometabolic effects of acute activation of G signaling in skeletal muscle (SKM) in vivo and its contribution to...
OBJECTIVE
The goal of this study was to determine the glucometabolic effects of acute activation of G signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis.
METHODS
To address this question, we studied mice that express a G-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two G-coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β-adrenergic receptor and CRF receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively).
RESULTS
Acute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β-adrenergic and, potentially, CRF receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM G signaling.
CONCLUSIONS
Selective activation of G signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous G-coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release.
Topics: Animals; Clenbuterol; Diabetes Mellitus, Type 2; Female; GTP-Binding Protein alpha Subunits, Gs; Glucose; Glucose Intolerance; Homeostasis; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Obesity; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 34883278
DOI: 10.1016/j.molmet.2021.101415 -
Oxidative Medicine and Cellular... 2021Maternal exposure to cadmium causes obesity and metabolic changes in the offspring, including nonalcoholic fatty liver disease-like pathology. However, whether maternal...
Maternal exposure to cadmium causes obesity and metabolic changes in the offspring, including nonalcoholic fatty liver disease-like pathology. However, whether maternal cadmium exposure accelerates liver cancer in the offspring is unknown. This study investigated the impact of early-life exposure to cadmium on the incidence and potential mechanisms of hepatocellular carcinoma (HCC) in offspring subjected to postweaning HCC induction. HCC in C57BL/6J mice was induced by diethylnitrosamine (DEN) injection at weaning, followed by a long-term high-fat choline-deficient (HFCD) diet. Before weaning, liver cadmium levels were significantly higher in mice with early-life cadmium exposure than in those without cadmium exposure. However, by 26 and 29 weeks of age, hepatic cadmium fell to control levels, while a significant decrease was observed in copper and iron in the liver. Both male and female cadmium-exposed mice showed increased body weight compared to non-cadmium-treated mice. For females, early-life cadmium exposure also worsened insulin intolerance but did not significantly promote DEN/HFCD diet-induced liver tumors. In contrast, in male mice, early-life cadmium exposure enhanced liver cancer induction by DEN/HFCD with high incidence and larger liver tumors. The liver peritumor tissue of early-life cadmium-exposed mice exhibited greater inflammation and disruption of fatty acid metabolism, accompanied by higher malondialdehyde and lower esterified triglyceride levels compared to mice without cadmium exposure. These findings suggest that early-life exposure to low-dose cadmium accelerates liver cancer development induced by a DEN/HFCD in male mice, probably due to chronic lipotoxicity and inflammation caused by increased uptake but decreased consumption of fatty acids.
Topics: Animals; Animals, Newborn; Cadmium; Choline; Diet, High-Fat; Diethylnitrosamine; Disease Models, Animal; Fatty Acids; Female; Liver; Liver Neoplasms; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Triglycerides
PubMed: 34876963
DOI: 10.1155/2021/1427787 -
Molecules (Basel, Switzerland) Oct 2021Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role... (Review)
Review
Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN's bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator.
Topics: Alcohol Drinking; Alcoholism; Aldehyde Dehydrogenase; Animals; Humans; Nitroglycerin; Vasodilator Agents
PubMed: 34770988
DOI: 10.3390/molecules26216581 -
Medicine and Pharmacy Reports Nov 2021Pancreatitis is an inflammatory disease associated with disorders of nutrient assimilation and, as a result, with significant changes in the nutritional status. All...
Pancreatitis is an inflammatory disease associated with disorders of nutrient assimilation and, as a result, with significant changes in the nutritional status. All patients with acute pancreatitis should be considered at nutritional risk and should be screened using validated screening methods. The optimal nutritional treatment for acute pancreatitis has been debated for decades. The traditional approach was "nothing in the mouth", only parenteral nutrition until the acute symptoms disappear and the level of serum pancreatic enzymes decreases. However, this tactic can contribute to various complications, starting with malnutrition and ending with sepsis due to damage of the intestinal mucosa. Clinical trials and meta-analyses have shown that patients with acute pancreatitis can tolerate oral nutrition and that oral / enteral nutrition is associated with a shorter hospital stay and a lower rate of complications compared to solely parenteral. Therefore, early oral nutrition with a low-fat "soft food" is recommended. In case of oral feeding intolerance, enteral nutrition is preferable, but not parenteral supply. A combination of enteral and parenteral nutrition may be recommended in patients who do not tolerate a sufficient amount of enteral nutrition. Malnutrition in chronic pancreatitis cannot be detected using BMI alone, and a detailed nutritional assessment is required, including assessment of symptoms and organic functions, anthropometry, and biochemical tests. Nutritional therapy in chronic pancreatitis should be multifactorial and based on abstinence from alcohol and nicotine, and diet modification. International guidelines no longer recommend severe dietary fat restriction; on the contrary, a physiological diet is recommended, but with adequate replacement of pancreatic enzymes. In case of intolerance to physiological nutrition, a low-fat diet with oral nutritional supplements is recommended to replenish energy and nutrients. This is a review of recent studies and guidelines on nutrition in pancreatitis for physicians and medical trainees.
PubMed: 38912407
DOI: 10.15386/mpr-2515 -
Journal of Clinical Medicine Oct 2021Auto-brewery syndrome (ABS) is a rare, unstudied, unknown, and underreported phenomenon in modern medicine. Patients with this syndrome become inebriated and may suffer... (Review)
Review
Auto-brewery syndrome (ABS) is a rare, unstudied, unknown, and underreported phenomenon in modern medicine. Patients with this syndrome become inebriated and may suffer the medical and social implications of alcoholism, including arrest for inebriated driving. The pathophysiology of ABS is reportedly due to a fungal type dysbiosis of the gut that ferments some carbohydrates into ethanol and may mimic a food allergy or intolerance. This syndrome should be considered in patients with chronic obstruction or hypomotility presenting with elevated breath and blood alcohol concentrations, especially after a high carbohydrate intake. A glucose challenge test should be performed as the confirmatory test. Treatment typically includes antifungal drugs combined with changes in lifestyle and nutrition. Additional studies are particularly needed on the human microbiome to shed light on how imbalances of commensal bacteria in the gut allow yeast to colonize on a pathological level.
PubMed: 34682761
DOI: 10.3390/jcm10204637