Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health

Targeting Mediators of Smoking Persistence with Intranasal Insulin

Rapid-acting, non-irritating nasal treatment options for smoking cessation pharmacotherapy are lacking. The halt in development is due, in part, to difficulty in delivering compounds across the blood brain barrier. Recently, in both human and animal models, insulin was shown to be capable of being transported to the cerebrospinal fluid and various brain regions via the “nose-to-brain” pathway, which bypasses the blood brain barrier, but is not free of its own unique, though different from blood brain barrier, challenges. This review will first evaluate and critique pharmacokinetic and pharmacodynamic evidence of intranasal insulin (i.e., nose-to-brain) delivery. As intranasal insulin has been shown in clinical trials to be effective in reducing nicotine cravings, in the remainder of the review, hypothesis-generating literature for additional mediators (i.e., other than the already shown nicotine craving) of smoking persistence will be reviewed. In particular, weight gain, impulsive behavior, and anhedonia have been shown to contribute to the inability to quit smoking. For each of these, after reviewing how the mediator promotes smoking, intranasal insulin literature from animal and clinical models will be critiqued in assessing whether a hypothesis may be generated that intranasal insulin may alleviate it, thereby potentially contributing to a successful smoking cessation outcome

Late Luteal Subphase Food Craving Is Enhanced in Women with Obesity and Premenstrual Dysphoric Disorder (PMDD)

Dysregulated food craving is a complex weight-related behavior. To identify novel targets for enhancing the efficacy of weight loss interventions, we examined whether food craving varies across the menstrual cycle according to the abdominal obesity type and premenstrual dysphoric disorder (PMDD) diagnosis, and, if so, whether it is related to affective symptomatology. Reproductive-age women were classified into one of the four study groups according to whether they have abdominal obesity (AO) or are abdominally lean (AL), and the presence of PMDD: (1) AO:PMDD+ (n = 13), (2) AL:PMDD+ (n = 14), (3) AO:PMDD− (n = 15), and (4) AL:PMDD− (n = 16). Self-report measures as well as urinary luteinizing hormone (LH) tests were provided by the participants across 2–3 menstrual cycles. The ratings of food cravings were similar across the menstrual cycle, except the last, late luteal subphase as the AO:PMDD+ participants had the highest food craving rating. Irritability and depression were correlated with food cravings, but not in a distinctive manner across the menstrual cycle by group. Our study found that women with abdominal obesity and PMDD display a temporal vulnerability to a food-related behavior. The possibility of shared neurobiology between the two conditions is discussed and should be examined in future studies

Visuospatial Function in Women with Premenstrual Dysphoric Disorder

Background/Objectives: Premenstrual dysphoric disorder (PMDD) is an understudied psychiatric condition affecting reproductive-age women who experience negative mood in the luteal phase of the menstrual cycle. Cognitive functions in PMDD are not well understood as patients have been tested in the luteal phase. This may confound study results due to noted emotional interferences, as well as the potential opposing effects of the sex hormones estradiol and progesterone. In the present study, we evaluated visuospatial function in the follicular phase in women with PMDD and healthy controls, and further examined the effect of estradiol as research into the hormonal mediation of visuospatial function in reproductive-age women has produced mixed results. Methods: To this end, we analyzed estradiol concentrations using the gold standard mass spectrometry. Serum samples were collected in the early follicular and mid/late follicular subphases when estradiol is low and high, respectively, while progesterone is low and steady. We assessed visuospatial function using the classic mental rotation task. Results: Women with PMDD had a higher mental rotation total score (t = 2.17; p p Conclusions: The present results provide support for new research directions into the potential biological mechanisms that underlie the pathophysiology of PMDD, represented as enhanced visuospatial ability in women with PMDD in the follicular phase. We review the theory that PMDD is a disorder of the enhanced excitation-to-inhibition ratio, with a focus on findings to date from brain imaging research

Periovulatory Subphase of the Menstrual Cycle Is Marked by a Significant Decrease in Heart Rate Variability

(1) Background: High-frequency heart rate variability (HF-HRV) is an essential ultradian rhythm that reflects the activity of the PNS to decelerate the heart. It is unknown how HF-HRV varies across the menstrual cycle (MC), and whether progesterone mediates this potential variation. (2) Methods: We enrolled 33 women in the study to attend eight clinic visits across the MC, during which we measured their resting HF-HRV and collected samples for the analysis of luteinizing hormone (LH) and progesterone. We realigned the study data according to the serum LH surge to the early follicular, mid-follicular, periovulatory, early luteal, mid-luteal and late luteal subphases. (3) Results: Pairwise comparisons between all the subphases showed significant differences between the early follicular and periovulatory subphases (β = 0.9302; p ≤ 0.001) and between the periovulatory and early luteal subphases (β = −0.6955; p ≤ 0.05). Progesterone was positively associated with HF-HRV in the early follicular subphase but not the periovulatory subphase (p ≤ 0.05). (4) Conclusions: The present study shows a significant drop in HF-HRV in the anticipation of ovulation. Further research in this area is critical given the marked cardiovascular disease mortality in women

Trajectories of Allopregnanolone and Allopregnanolone to Progesterone Ratio across the Six Subphases of Menstrual Cycle

Background: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio to progesterone, varies across all six subphases of the menstrual cycle. Two enzymes—5α-dihydroprogesterone and 5α-reductase—convert progesterone to allopregnanolone, and, based on immunohistochemical studies in rodents, the activity of 5α-reductase is considered the rate-limiting step in the formation of allopregnanolone. It is not clear, however, whether the same phenomenon is observed across to the menstrual cycle, and, if so, at what point this takes place. Methods: Thirty-seven women completed the study during which they attended eight clinic visits across one menstrual cycle. We analyzed their allopregnanolone and progesterone serum concentrations using ultraperformance liquid chromatography–tandem mass spectrometry, and we implemented a validated method to realign the data from the original eight clinic study visits, following which we imputed the missing data. Hence, we characterized allopregnanolone concentrations, and the ratio of allopregnanolone:progesterone at six menstrual cycle subphases: (1) early follicular, (2) mid-follicular, (3) periovulatory, (4) early luteal, (5) mid-luteal, and (6) late luteal. Results: There were significant differences in allopregnanolone levels between (1) early follicular and early luteal, (2) early follicular and mid-luteal, (3) mid-follicular and mid-luteal, (4) periovulatory and mid-luteal, and (5) mid-luteal and late luteal. We detected a sharp drop in allopregnanolone:progesterone ratio in the early luteal subphase. Within the luteal subphase, the ratio was the lowest in the mid-luteal subphase. Conclusions: Allopregnanolone concentrations are the most distinct, relative to the other subphases, in the mid-luteal subphase. The shape of the allopregnanolone trajectory across the cycle is similar to that of progesterone; however, the proportion of the two neuroactive steroid hormones is drastically different due to enzymatic saturation, which takes place at the start of the early luteal subphase, but continuing through, and peaking, in the mid-luteal subphase. Hence, the estimated activity of 5α-reductase decreases, but does not cease, at any point across the menstrual cycle

Stress-induced changes in mood and cortisol release predict mood effects of amphetamine

Cilj ovog rada je ukazati na važnost kvalitetne komunikacije s osobama s teškoćama u razvoju i invaliditetom te prikazati načine na koje treba komunicirati s njima. Također, potrebno je ukazati i koliko su važne komunikacijske vještine za uspješno komuniciranje s osobama koje imaju određene teškoće u razvoju. Stoga, ovaj rad ne sastoji se samo od teoretskog dijela, nego i istraživačkog dijela. Istraživanje će se provesti u određenoj udruzi za djecu i osobe s teškoćama u razvoju i invaliditetom s djecom i osobama koja tamo borave, roditeljima djece te odgojiteljima koji se bave i druže s djecom i osobama kada borave u udruzi. Metode istraživanja koje će se koristiti u ovome radu su metode prikupljanja podataka, odnosno intervju i anketa kojim će se saznati nešto više o osobama s teškoćama u razvoju i načinu njihova komuniciranja. Struktura rada će obuhvaćati: Uvod, Teorijski dio, Metode istraživanja (uzorak ispitanika, mjerne instrumente), Rezultate i interpretaciju rezultata, Zaključak, Smjernice za daljnja istraživanja, Popis literature te Priloge (Suglasnosti i Mjerne instrumente)

Reduced Dehydroepiandrosterone-Sulfate Levels in the Mid-Luteal Subphase of the Menstrual Cycle: Implications to Women’s Health Research

The regulation of DHEA-sulfate by steroid sulfotransferase (SULT) and steryl-sulfatase (STS) enzymes is a vital process for the downstream formation of many steroid hormones. DHEA-sulfate is the most abundant steroid hormone in the human body; thus, DHEA-sulfate and its hydrolyzed form, DHEA, continue to be evaluated in numerous studies, given their importance to human health. Yet, a basic question of relevance to the reproductive-age female population—whether the two steroid hormones vary across the menstrual cycle—has not been addressed. We applied a validated, multi-step protocol, involving realignment and imputation of study data to early follicular, mid-late follicular, periovulatory, and early, mid-, and late luteal subphases of the menstrual cycle, and analyzed DHEA-sulfate and DHEA serum concentrations using ultraperformance liquid chromatography tandem mass spectrometry. DHEA-sulfate levels started to decrease in the early luteal, significantly dropped in the mid-luteal, and returned to basal levels by the late luteal subphase. DHEA, however, did not vary across the menstrual cycle. The present study deep-mapped trajectories of DHEA and DHEA-sulfate across the entire menstrual cycle, demonstrating a significant decrease in DHEA-sulfate in the mid-luteal subphase. These findings are relevant to the active area of research examining associations between DHEA-sulfate levels and various disease states

Contribution of Common <em>PCSK1</em> Genetic Variants to Obesity in 8,359 Subjects from Multi-Ethnic American Population

<div><p>Common <i>PCSK1</i> variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common <i>PCSK1</i> variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (<i>P</i> = 0.006) and obesity (<i>P</i> = 0.018) but also increased the obesity incidence during the 20 years of follow-up (HR = 1.53 [1.07–2.19], <i>P</i> = 0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (<i>P</i> = 0.028) and obesity (<i>P</i> = 0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR = 1.23 [1.05–1.45], <i>P</i> = 9.5×10⁻³). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (<i>P</i> = 4.2×10⁻³) and obesity (<i>P</i> = 3.4×10⁻³) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (<i>P</i> = 0.756 and <i>P</i> = 0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full <i>PCSK1</i> locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common <i>PCSK1</i> variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings.</p> </div