Comparison of Subjective Responses to Oral and Intravenous Alcohol Administration under Similar Systemic Exposures

Objective To test whether an individual's subjective responses to alcohol are similar when the breath alcohol concentration (BrAC) trajectory resulting from oral administration is matched by intravenous administration. Background Individuals perceive the effects of alcohol differently, and the variation is commonly used in research assessing the risk for developing an alcohol use disorder. Such research is supported by both oral and intravenous alcohol administration techniques, and any differences attributable to the route employed should be understood. Methods We conducted a 2‐session, within‐subject study in 44 young adult, healthy, non‐dependent drinkers (22 females and 22 males). In the first session, subjects ingested a dose of alcohol which was individually calculated, on the basis of total body water, to yield a peak BrAC near 80 mg/dl, and the resulting BrAC trajectory was recorded. A few days later, subjects received an intravenous alcohol infusion rate profile, pre‐computed to replicate each individual's oral alcohol BrAC trajectory. In both sessions, we assessed 4 subjective responses to alcohol: SEDATION, SIMULATION, INTOXICATION, and HIGH; at baseline and frequently for 4 hours. We compared the individuals’ baseline‐corrected responses at peak BrAC and at half‐peak BrAC on both the ascending and descending limbs. We also computed and compared Pearson‐product moment correlations of responses by route of administration, the Mellanby measure of acute adaptation to alcohol, and the area under the entire response curve for each subjective response. Results No significant differences in any measure could be attributed to the route of alcohol administration. Eleven of 12 response comparisons were significantly correlated across the routes of alcohol administration, with 9 surviving correction for multiple measures, as did the Mellanby effect and area under the response curve correlations. Conclusion The route of alcohol administration has a minimal effect on subjective responses to alcohol when an individual's BrAC exposure profiles are similar

Evaluation of carcinogenic/co-carcinogenic activity of a common chewing product, pan masala, in mouse skin, stomach and esophagus

Pan masala, a dry powdered mixture of areca nut, catechu, lime, unspecified spices and flavoring agents, has gained widespread popularity as a chewing substitute in India. In this study, the carcinogenic and tumor-promoting potential of an ethanolic pan masala extract (EPME) was determined using skin of S/RVCri-ba mice and forestomach and esophagus of ICRC mice as the target tissues. Carcinogenic activity of pan masala was tested by painting the mouse skin for 40 weeks with EPME or by gavage feeding for 6 months. Following initiation with 9,10-dimethylbenz(a)anthracene (DMBA), carcinogenesis of mouse skin was promoted with different doses of EPME, while gastric- and esophageal-tumor-promoting activity was determined by administering EPME by gavage to animals initiated with diethylnitrosamine (DEN). The ability of EPME to effect progression of skin papilloma to carcinoma and cutaneous alterations after a single or multiple EPME treatment were also evaluated. EPME at 25 mg per dose promoted skin-papilloma formation between 30 and 40 weeks of treatment and enhanced the rate of conversion of papilloma to carcinoma. Induction of mild epidermal hyperplasia, dermal edema, increase in epidermal mitotic activity and the rate of epidermal and dermal DNA synthesis by EPME correlated well with its skin-tumor-promoting potential. In ICRC mice, EPME was inactive as a complete carcinogen, but effectively promoted the development of forestomach and esophageal papilloma and carcinoma in a concentration-dependent manner. The tumor incidence at 25 mg EPME per dose was comparable with that obtained in the 12-0-tetradecanoylphorbol-13 acetate(TPA)-treated group. The findings indicate that habitual pan-masala use may exert carcinogenic and co-carcinogenic influence

Long-term carcinogenicity of pan masala in Swiss mice

Carcinogenicity of pan masala, a dry powdered chewing mixture of areca nut, catechu, lime, spices and flavoring agents was evaluated by means of the long-term animal bio-assay 6- to 7-week old male and female S/RVCri mice were divided randomly into intermediate and lifetime exposure groups and fed normal diet without pan masala - (zero dose) or diet containing 2.5% and 5% pan masala. Animals in the intermediate-exposure group (n = 10/gender/dose group) were killed after 6, 12 or 18 months of treatment, while those in the lifetime-exposure group (n = 54/gender/dose group) were killed when moribund or at the termination of the experiment at 24 months. Several tissues were processed for histopathological examination. The body weight and survival rate of mice fed pan masala were lower than that of the controls. Histopathological observations of tissues from control animals did not reveal any neoplastic alterations. However, lifetime feeding of pan masala induced adenoma of the liver, stomach, prostate and sebaceous glands, also forestomach papilloma, liver hamartoma, hepatoma and hemangioma, carcinoma of the forestomach, adenocarcinoma of the lung and liver, and testicular lymphoma. Neoplastic lesions appeared mainly in the liver (n = 13), stomach (n = 3) and lung (n = 8). Lung adenocarcinoma, the most frequent malignant tumor type, was observed in 2/120 mice in the intermediate-exposure group and in 8/216 animals in the lifetime-exposure group. Statistical analysis of tumor-induction data revealed a significant dose-related increase in lung adenocarcinomas but not in liver and stomach neoplasms indicating that lung is the major target tissue for the carcinogenic action of pan masala

Salivary cortisol response to infant distress in pregnant women with depressive symptoms.

The Hypothalamic-Pituitary-Adrenal (HPA) axis has been proposed as a potential underlying biological mechanism linking prenatal depression with adverse offspring outcomes. However, it is unknown whether the reactivity of this system to stress is altered in pregnant women experiencing depression. The objective of this study was to investigate whether salivary cortisol response to a distressed infant film is enhanced in pregnant women with symptoms of depression compared with non-depressed controls. Salivary cortisol and subjective mood responses to the film were measured in 53 primiparous women, between 11 and 18 weeks gestation. Both groups showed similar increases in state anxiety in response to the film, but there was a significantly increased cortisol response in women experiencing symptoms of depression. Depression during pregnancy is associated with increased reactivity of the HPA axis. This is consistent with altered HPA axis functioning being a key mechanism by which prenatal mood disturbance can impact upon fetal development

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders

The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA;N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD

The Influence of Airway Closure Technique for Right Pneumonectomy on Wall Tension During Positive Pressure Ventilation: An Experimental Study

Bronchopleural fistula (BPF) remains a significant source of morbidity and mortality after right pneumonectomy (RPN). Postoperative mechanical ventilation represents a primary risk factor for BPF. We undertook an experiment to determine the influence of airway diameter on suture line tension during mechanical ventilation after RPN. RPN was performed in 6 fresh human adult cadavers. After initial standard bronchial stump closure (BSC), the airway suture lines were subjected to 5 cm H2O incremental increases in airway pressures beginning at 5–40 cm H2O. To minimize airway diameter, a carinal resection was then performed with trachea to left main bronchial anastomosis and the airway suture lines subjected to similar incremental airway pressures. Wall tension (N/m) at the suture lines was measured using piezoresistive sensors at each pressure point. As delivered airway pressure increased, there was a concomitant increase in wall tension after BSC and carinal resection. At every point of incremental positive pressure, wall tension was however significantly lower after carinal resection when compared to BSC (P < 0.05). Additionally the differences in airway tension became even more significant with higher delivered airway pressure (P < 0.001). Airway diverticulum after BSC leads to significantly increased tension on the bronchial closure with positive airway pressure as compared to a closure which minimize airway diameter after RPN. This supports the role of Laplacian Law where small increases in airway diameter result in significant increases on closure site tension. Techniques which reduce airway diameter at the airway closure will more reliably reduce the incidence of BPF following RPN

Parental attachment and depressive symptoms in pregnancies complicated by twin-twin transfusion syndrome: a cohort study

BACKGROUND: Twin-twin transfusion syndrome (TTTS) is a highly morbid condition in which treatment exists, but the pregnancy remains high-risk until delivery. It may have serious sequelae, including fetal death, and in the longer term, neurodevelopmental problems. The aim of this study is to assess antenatal and postnatal parental attachment and depressive symptoms in those with pregnancies affected by TTTS. METHODS: Couples attending for fetoscopic laser ablation treatment of TTTS were asked to complete Condon's Maternal/Paternal Antenatal/Postnatal Attachment Scale as appropriate, and the Edinburgh Depression Scale the day before ablation, 4 weeks post-ablation, and 6-10 weeks postnatally. RESULTS: 25/27 couples completed the pre-ablation questionnaire (median gestational age 19 + 3 weeks [interquartile range 18 + 2-20 + 6]). 8/18 eligible couples returned the post-ablation questionnaire. 5/17 eligible couples returned the postnatal questionnaire. There was no significant difference in parento-fetal attachment when mothers were compared to fathers at each time point, however parento-fetal attachment did increase over time in mothers (p = 0.004), but not fathers. Mothers reported more depressive symptoms antenatally compared to fathers (p < 0.02), but there was no difference postnatally. 50% women reported Edinburgh Depression Scale scores above the cut-off (≥15) 4 weeks post-ablation. Over time maternal depressive symptoms decreased (p = 0.006), however paternal depressive symptoms remained the same. CONCLUSIONS: This is the first attachment and depression study in a UK cohort of parents with pregnancies affected by TTTS. Although this was a small cohort and the questionnaires used had not been validated in these circumstances, the results suggest that centres caring for these couples should be aware of the risk of maternal and paternal antenatal depression, and screen and refer for additional psychological support. Further work is needed in larger cohorts. TRIAL REGISTRATION: ISRCTN 13114861 (retrospectively registered)

Functional abdominal complaints in pre-school children: parental reports of health-related quality of life

Purpose The aim of this study is to assess the influence of functional abdominal complaints (FAC) on health-related quality of life in a group of Dutch pre-school children. Methods Parents of children aged up to 6.0 visiting the outpatient pediatric department, Erasmus MC-Sophia, Rotterdam, The Netherlands in the period January 2005-December 2006 for functional abdominal complaints during at least 3 months were asked to complete the Infant/Toddler Quality of life Questionnaire (ITQOL), and questions of the abdominal pain index for use by parents to report pain symptoms in pre-school children. ITQOL scale scores of children with FAC were compared against with Dutch reference values. The abdominal pain index was tested for internal consistency and test-retest reliability. Correlations between ITQOL scale scores and abdominal pain index were assessed by Spearman's rank test. Results Results are based on 81 questionnaires completed by parents of children with FAC (response rate 61%). Children had a median age of 46 months (interquartile range 27-59), 48% girls. A significant impact was observed on most aspects of quality of life, particularly for physical functioning, general development, bodily pain, temperament and moods, general health perceptions and parental emotional impact. Parents of children with functional constipation tended to report lower scores than those of children with other FAC. The abdominal pain index appeared to be valid and was significantly correlated with ITQOL scales bodily pain and general health perceptions. Conclusions A substantial lower health-related quality of life is reported in pre-school children with functional abdominal complaints, with effects on physical, emotional and parental domains. The 5-question severity index of abdominal pain appeared a valid tool and may be helpful to quickly assess the severity of abdominal pain in clinical practice

Шкала оценки сопутствующих заболеваний у ареактивных пациентов (CoCoS): лингвокультурная адаптация русскоязычной версии (сообщение)

   Identification of complications and control of comorbidities are essential in monitoring the patients with chronic disorders of consciousness and predicting their outcomes. The researchers of the Department of Biotechnological and Applied Clinical Sciences of the University of L'Aquila (Italy) developed the Comorbidities Coma Scale (CoCoS) for a comprehensive assessment of such patients. Lack of an officially validated version of the scale hampers its use in Russia, while using versions which have not been completely validated prevents clinicians from obtaining reliable results when examining patients with chronic disorders of consciousness.   Aim. To develop the official Russian language version of the Comorbidities Coma Scale, considering various linguistic and cultural parameters, as a part of the 1st stage of the validation study.   Material and methods. The first stage of validation was completed: direct and reverse translation of the scale was performed by two independent medical translators. The translated version was assessed by an expert board including an expert translator, neurologists, and critical care specialists. Pilot test and two meetings of the expert board, before and after testing, were arranged to assess the results and approve the final Russian version of the scale.   Results. During the first meeting of the expert board, corrections were made in the Russian language version of the scale in terms of language and cultural adaptation. Pilot testing was carried out based on the inclusion and exclusion criteria. The researchers had no difficulties in understanding and interpreting the instructions for the scale. The second meeting of the expert board was held thereupon, and the final version of the Russian language version of the scale was adopted, which is available on the website of the Center for Validation of Health Status Questionnaires and Scales of the Research Center of Neurology.   Conclusion. The first stage of validation, i. e., linguistic and cultural adaptation, was carried out at the Research Center of Neurology (Moscow, Russia). For the first time, the Russian version of the scale for assessing comorbidities in patients with chronic disorders of consciousness was presented and approved for the practical use. The future publications will address the psychometric results of the scale such as sensitivity, validity, reliability.   Выявление осложнений и контроль над течением сопутствующих заболеваний является важнейшим этапом в отслеживании динамики и прогнозе исходов у пациентов с хроническими нарушениями сознания. Для проведения оценки состояния у данной категории пациентов сотрудниками департамента биотехнологических и прикладных клинических наук университета L'Aquila (Италия) была разработана шкала — Comorbidities Coma Scale (CoCoS). Отсутствие официально валидированной версии данной шкалы затрудняет ее применение в России, а использование версий, не прошедших все необходимые этапы валидации, препятствует получению достоверных результатов при обследовании пациентов с хроническими нарушениями сознания.   Цель. Разработка официальной русскоязычной версии Шкалы оценки сопутствующих заболеваний у ареактивных пациентов с учетом языковых и культурных особенностей ее пользователей в рамках проведения 1-го этапа валидационного исследования.   Материал и методы. Письменное разрешение на адаптацию шкалы CoCoS было получено сотрудниками группы валидации международных шкал и опросников Научного центра неврологии (ФГБНУ НЦН, г. Москва, Россия) у разработчика оригинальной версии Francesca Pistoia. Провели первый этап валидации: выполнен прямой и обратный перевод шкалы двумя независимыми медицинскими переводчиками. Произведена оценка разработанной версии экспертной комиссией с участием переводчика-эксперта, неврологов и анестезиологов-реаниматологов. Провели пилотное тестирование на 15 пациентах с диагнозом хронического нарушения сознания и два заседания экспертной комиссии до и после тестирования для оценки результатов и утверждения окончательной русскоязычной версии шкалы.   Результаты. В ходе первого заседания экспертной комиссии внесли поправки в русскоязычную версию шкалы в рамках языковой и культурной адаптации: были изменены единицы измерения лабораторных показателей с мг/дл на ммоль/л в 7-м и 14-м пунктах (оценка гликемии и концентрации креатинина, соответственно). Изменен термин «надаортальные сосуды» на «брахиоцефальные артерии» в 10-м пункте, сопоставлены предложенные варианты повреждения мягких тканей со стадиями развития пролежней согласно NPUAP — EPUAP [18] в 21-м пункте, добавлен параметр индекс массы тела (ИМТ) для оценки выраженности недостаточности питания. В ходе пилотного тестирования с учетом критериев включения и исключения сложностей при понимании и интерпретации инструкций шкалы у исследователей не возникло. По итогам состоялось второе заседание экспертной комиссии, на котором приняли окончательный вариант русскоязычной версии шкалы. Он доступен для ознакомления на сайте группы валидациимеждународных шкал и опросников ФГБНУ НЦН https://www.neurology.ru/reabilitaciya/centr-validacii-mezhdunarodnyh-shkal-i-oprosnikov, а также по QR-коду.   Заключение. На базе ФГБНУ НЦН выполнили первый этап валидации — лингвокультурную адаптацию. Впервые представили и рекомендовали к использованию русскоязычную версию Шкалы оценки сопутствующих заболеваний у ареактивных пациентов. В последующих публикациях будут представлены результаты оценки психометрических свойств (чувствительность, валидность, надежность) русскоязычной версии данной шкалы