Depressives with secondary alcoholism: psychiatric disorders in offspring

The risk of psychiatric illness among the offspring of probands with major depression and secondary alcoholism was examined. The offspring aged 6-17 (N = 107) and 18 + (N = 171) of probands with major depression (114 with depression only and 19 with secondary alcoholism) were compared with the offspring aged 6-17 (N = 87) and 18 + (N = 103) of controls (N = 82). Offspring of probands with secondary alcoholism had a threefold greater risk of alcoholism and a fivefold greater risk of antisocial personality-conduct disorder compared with offspring of probands with depression only, and a threefold greater risk of alcoholism and a 20-fold greater risk of antisocial personality-conduct disorder compared with offspring of controls. Familial aggregation of alcoholism was observed only among probands with secondary alcoholism. The presence of secondary alcoholism in depressed probands did not convey additional increase in risk of either major depression or anxiety disorders to offspring beyond that observed among offspring of probands with depression only. This suggests that depression and alcoholism are not alternate forms of expression of the same underlying illness. Assortative mating for alcoholism among parents was related to increased risk of both alcoholism and antisocial personality-conduct disorder but not of major depression among offspring. A linear effect on rates of these disorders according to the number of parents with alcoholism was observed.     

Psychiatric and familial predictors of transition times between smoking stages: results from an offspring-of-twins study

The modifying effects of psychiatric and familial risk factors on age at smoking initiation, rate of progression from first cigarette to regular smoking, and transition time from regular smoking to nicotine dependence (ND) were examined in 1269 offspring of male twins from the Vietnam Era Twin Registry. Mean age of the sample was 20.1 years. Cox proportional hazard regression analyses adjusting for paternal alcohol dependence and ND status and maternal ND were conducted. Both early age at first cigarette and rapid transition from initiation to regular smoking were associated with externalizing disorders, alcohol consumption, and cannabis use. Rapid escalation from regular smoking to ND was also predicted by externalizing disorders, but in contrast to earlier transitions, revealed a strong association with internalizing disorders and no significant relationship with use of other substances. Findings characterize a rarely examined aspect of the course of ND development and highlight critical distinctions in risk profiles across stages of tobacco involvement.     

Initial response to cigarettes predicts rate of progression to regular smoking: Findings from an offspring-of-twins design

The aim of this study was to examine the association between initial subjective effects from cigarettes and the rate of progression from first cigarette to regular smoking. Latent class analysis (LCA) was applied to subjective effects data from 573 offspring of twins ranging in age from 14 to 32 years. LCA revealed four classes: 1) High on both pleasurable and physiological responses, 2) Cough only response, 3) High on physiological, low on pleasurable responses, and 4) High on pleasurable, low on physiological responses. Classes of responses were then used to predict time from first cigarette to the onset of regular smoking in a Cox proportional hazards model. Time-varying covariates representing relevant psychiatric and psychosocial factors as well as dummy variables representing the offspring-of-twins design were included in the model. Members of classes 1 and 4 transitioned more rapidly to regular smoking than the classes characterized as low on the pleasurable response dimension. Our findings provide evidence that previously reported associations between pleasurable initial experiences and progression to regular smoking hold true as well for the rate at which that transition occurs. Furthermore, the fact that profiles of responses did not fall into global categories of exclusively pleasurable vs. exclusively negative (physiological) responses suggests the importance of considering both dimensions in combination to characterize risk for smoking-related outcomes.     

Exposure to flaxseed or its purified lignan during suckling only or continuously does not alter reproductive indices in male and female offspring.

Based on the reported health benefits of flaxseed, many Canadians are choosing to consume flaxseed or flaxseed-containing foods. However, the safety of exposure to flaxseed during early life such as the suckling period has not been studied, despite the fact that components in flaxseed with potential hormone-like effects can be transferred to nursing offspring via mother's milk. Previous investigations demonstrated that maternal feeding of a 10% flaxseed diet during pregnancy and lactation resulted in estrogenic effects on reproductive indices among male and female offspring. These effects were attributed to the potential estrogenic activity of enterodiol and enterolactone, the two major mammalian lignans that are converted from secoisolariciresinol diglycoside (SDG) in flaxseed by colonic bacteria; however, the effect of exposure to purified SDG at the level of a 10% flaxseed diet was not studied. The objective of this study was to determine whether maternal feeding of flaxseed during lactation altered reproductive indices in male and female offspring. Rat dams were fed basal diet (BD) or BD containing either 100% flaxseed (10F) or the equivalent quantity of SDG present in the 10% (10S) flaxseed diet from the start of lactation until pups were 21 d old. At the end of lactation (postnatal day IPND] 21), suckling pups either continued on the mother's diet or were switched to BD until adolescence (PND 50) or young adulthood (PND 132) to determine if continuous exposure to flaxseed or SDG altered reproductive indices. The reproductive indices that were measured included anogenital distance from birth through PND 21, age and body weight at puberty onset (females only), estrous cycle length, reproductive organ weights at PND 50 and 132, and histological analysis of reproductive organs (uterus, ovaries, prostate) at PND 132. There were no significant effects of exposing male or female offspring to flaxseed or SDG during suckling only or during suckling through the postsuckling period on any of the reproductive indices measured. These findings are in contrast to the estrogenic effects observed in male and female offspring exposed to flaxseed during fetal life through suckling and suggest that fetal life is a more hormone-sensitive period of development. Although maternal feeding of flaxseed during lactation appears to be safe with respect to reproductive indices among offspring, future investigation is required to elucidate whether there are any long-term implications with respect to fertility.     

Response to alcohol in females with a paternal history of alcoholism

Rationale Several studies have demonstrated that males with a family history of alcoholism (FHP) show less of a response to alcohol (e.g. lower ratings of intoxication) than males without a family history of alcoholism (FHN). The purpose of this pilot study was to determine if FHP females also showed a reduced sensitivity to alcohol compared to FHN females. Objectives To determine if FHP females (n=16) were less sensitive to the subjective effects and performance-impairing effects of alcohol compared to FHN females (n=16). Methods The effects of placebo and alcohol (0.25, 0.50, 0.75 g/kg, based on total body water) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect and subjective ratings of drug effect. Results There were no differences in breath alcohol levels between FHN and FHP women. FHP women were less impaired by alcohol than FHN women, as shown by DSST scores and observer-ratings. However, FHP women were more impaired on the Digit Recall task after alcohol than FHN women and they tended to have higher ratings of "Good Drug Effect," "Drug Liking" and "Willingness to Take Again." Of note, FHP women reported more dysphoric mood than FHN women in the absence of alcohol administration. Conclusions The results of the present study suggest that FHP women may have a reduced response to alcohol on some measures, but FHP women report greater positive effects on other measures. Overall, the differences between FHP and FHN women are subtle compared to the previous studies demonstrating a reduced response to alcohol in FHP men.     

The role of PDE5-inhibitors in cardiopulmonary disorders: from basic evidence to clinical development

Phosphodiesterases (PDE) are a class of proteins whose most relevant biological activity concerns the modulation of intracellular levels of cyclic nucleotides, e.g., cGMP and cAMP. PDE isoenzyme 5 (PDE5) is specifically involved in cGMP inactivation in the smooth muscle cell. Chemical inhibition of PDE5 by sildenafil, tadalafil or vardenafil recently became a valid therapeutic option aimed at overexpressing the molecular pathway originated from nitric oxide and expressed via increased cell cGMP availability. Based on the optimal tolerability and proven efficacy in various human disorders, EMEA and FDA have approved PDE5 inhibition as an efficient therapy in some cardiovascular, pulmonary and vascular diseases. More specifically, PDE5 inhibition appears successful for the treatment of idiopathic arterial pulmonary hypertension. Furthermore, PDE5 inhibition resulted in important protective effects in the myocardium, i.e., antyhypertrophic and antiapoptic, as well as vascular functions, i.e., increased tolerance to ischemia/reperfusion injury and improved endothelial function, thereby implying a potential usefulness in the treatment of patients with heart failure and coronary artery disease. Evidence currently available for considering PDE5-inhibition an additional opportunity in the treatment of common cardiopulmonary disorders is here provided.     

Vitamin D deficiency in alcohol-use disorders and its relationship to comorbid major depression: A cross-sectional study of inpatients in Nepal

Background

Mounting evidence suggests that deficiency of vitamin D may be associated with major health problems, including alcohol-use disorders (AUD) and major depression (MD). This study aimed to identify the vitamin D status of Nepalese inpatients with an AUD. We explored socio-demographic and alcohol-use related correlates and the relationship between vitamin D deficiency and comorbid MD.

Methods

A cross-sectional study was conducted on AUD inpatients (N = 174) at eight alcohol/drug treatment centres around Kathmandu. Structured questionnaires were administered to assess the socio-demographic and alcohol-use parameters and to establish DSM-IV diagnoses of AUD and MD. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25(OH)D) concentration of <50 nmol/L.

Results

The prevalence of vitamin D deficiency was 64%. Higher age, having a stable job or business, shorter time since last alcohol intake and winter serum samples were related to having lower 25(OH)D levels. Several features of AUD severity were associated with low vitamin D levels: guilt about drinking, using alcohol as eye-opener, and history of relapse after alcohol treatment (p ≤ 0.03). Patients with a comorbid major depression, in particular secondarily depressed cases, were less likely to have vitamin D deficiency (X² = 6.8; p = 0.01).

Conclusions

This study confirms high rates of vitamin D deficiency in alcohol treatment sample and shows a positive association between vitamin D deficiency and severity of alcohol-use disorders. Competing risk and other confounders may help explain the vitamin D status among patients with alcohol-use disorders and comorbid major depression.     

Post‐partum testosterone administration does not reverse the effects of perinatal exposure to cadmium on rat offspring development

This study investigated the effects of perinatal cadmium exposure on physical and reflexologic development of pup rats. It was examined if the immediate postpartum testosterone administration was able to reverse the toxic effects of the metal. Forty Wistar pregnant rats were divided into three groups: control and 10 and 20 mg kg^?1 per day of cadmium chloride. These dams were treated from gestational days 18 to 21, and until the 7th lactation day. Immediately after birth, half of the offspring from the experimental and control groups received 50 µL of testosterone 0.2% i.p. The maternal body weight gain, food and water consumption were measured during the treatment period. In pups, the body weight, body length, physical landmarks, reflex development and the general activity were assessed. Results showed that: only 20 mg kg^?1 cadmium induced maternal toxicity; pup body weight and body weight gain were reduced in all experimental groups; only the cadmium‐exposed offspring not treated with testosterone treatment showed a reduction in body length and body length gain; cadmium highest dose reduced the anogenital index in pups and delayed physical and reflexes development; and cadmium effects on the offspring, except in body length gain, were not reversed by testosterone. The results indicate that perinatal maternal exposure to cadmium promoted changes in the development of male rat offspring, reprogramming the pup's development. Testosterone administration was not able to reverse the cadmium effects, even on those parameters more directly related to the androgenic system as the testis descent and anogenital distance delays. Copyright © 2009 John Wiley & Sons, Ltd.     

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.     

Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: neurobehavioral effects in offspring from a one-generation reproduction study

Within the framework of an EU project on risk assessment of brominated flame retardants, TBBPA was studied for neurobehavioral effects in rats. To permit benchmark dose analysis, eight dose levels were chosen ranging from 0 to 3000mg/kg body weight. Exposure of parental rats started 10 and 2 weeks before mating in males and females, respectively, and was continued throughout mating, gestation and lactation. After weaning, exposure was continued in the offspring throughout life. Previous studies had indicated TBBPA-induced effects on thyroid hormones. Because of the known implication of thyroid hormones in neurodevelopment, the present experiments tested if TBBPA exposure affects thyroid-dependent neurobehavioral functions in offspring, such as auditory responses and conditioned fear. Sweet preference was included because of sex-specific effects in littermates. No statistically significant effects were found on context or cue conditioned fear or sweet preference. Auditory responses were examined with brainstem auditory evoked potentials (BAEPs) at approximately 50-110 days of age. BAEP thresholds and wave IV latency were increased in exposed female rats in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II-IV showed exposure-related increases at low frequencies. The outcome pattern suggests a predominant cochlear effect of TBBPA in females while in males neural effects are more apparent. According to benchmark analysis, the critical effect doses (CED) for prolongations of wave IV latency at 0.5kHz were in the range of 35-70mg/kg body weight with lower bounds (BMDL) of approximately 8mg/kg in males and females. The BMDL values for elevation of hearing thresholds in females were in the range of 1-40mg/kg body weight, depending on frequency. The benchmark doses for effects on the BAEP were similar to values for decreases in circulating thyroid hormones. The comparison of the exposure level at which the most sensitive effect was found with current human exposure levels yielded a margin of exposure of about 5, according to a recent risk assessment. Further investigations are needed to examine exposure pathways, fate in the body and effects of TBBPA.     

Sensitised locomotion does not predict conditioned locomotion in cocaine-treated mice: further evidence against the excitatory conditioning model of context-dependent sensitisation.

The excitatory conditioning model of contextual sensitisation proposes that the progressive emergence of the locomotion-activating effect of cocaine (or any other stimulant drug) characterising that phenomenon is due to a growing conditioned response (the test context cues) that mimics the unchanging unconditioned response (the drug effect). The present study aimed at verifying whether the relationship between the amplitude of sensitisation and the size of the conditioned response was positive, a direct implication of that view. Sensitisation to the locomotion-activating effect of cocaine (10 mg/kg, s.c.) was firstly generated over 10 daily sessions in 25 mice (strain C57Bl/6J), another lot of 25 mice receiving the same dose of cocaine outside of the testing context. Conditioned locomotion was assessed 24 h later. No significant linear correlations were found between the magnitude of the conditioned response and the magnitude of the sensitised response (delta scores), the rate of sensitisation (individual regression coefficients) or the magnitude of the initial unconditioned response to cocaine (scores in the first session of sensitisation treatment). Accordingly, there was no significant correlation between the magnitude of the initial unconditioned response and the magnitude of the sensitised response or that of the initial unconditioned response. Therefore, the conditioned response is neither necessary nor sufficient for the development of context-dependent sensitisation of the locomotion-activating effect of cocaine, a conclusion that refutes the excitatory conditioning model of that chronic effect.     

Dehumanization of psychiatric patients: Experimental and clinical implications in severe alcohol-use disorders

Dehumanization, defined as the denial of one's membership to humanity, is a process repeatedly reported in extreme contexts (e.g., genocides) but also in everyday life interactions. Some antecedents of dehumanizing experiences (e.g., social exclusion, negative stereotypes) have been reported among patients presenting psychiatric disorders, but dehumanization's experience remains completely unexplored in addictive disorders. We propose a theoretical model and research agenda to overcome this limitation and to improve our understanding of dehumanization's experience in psychiatry, with a special focus on alcohol-related disorders. We also propose much-needed clinical avenues to reduce dehumanization in clinical contexts, centrally by (1) improving dehumanization awareness among medical workers; (2) reducing the need for healthcare workers to use dehumanization to alleviate professional exhaustion; and (3) optimizing medical training to increase empathy toward patients. Finally, some additional improvements are proposed to promote patient's choices, comfort, dignity, and ultimately humanity in hospitals.     

Sexual differentiation and reproductive development of female rat offspring after paternal exposure to the anti-tumor pharmaceutical cisplatin

Cisplatin (CP) is used to treat a number of cancers, including testicular cancer. Studies indicate that CP-treatment can impair spermatogenesis in humans and rodents by germ cell DNA binding, through different modes of action. CP-paternal exposure resulted in adverse effects in F1 male offspring. In this study, F1 female offspring was assessed for reproductive development after CP-paternal exposure. Peri-pubertal male rats, treated with 1 mg/Kg/day of CP or vehicle for 3 weeks, were mated with unexposed females. F1 female offspring of CP-treated fathers showed a decrease in fetal ovary germ cells, in estrous cycle length and FSH levels, and an increase in the percentage of antral follicles in adults. Based on our previous results and the findings of the present work we concluded that CP-paternal exposure leads to adverse effects on rat male and female reproductive development, raising concern, in humans, for children born to men exposed to CP.     

Exposure of pregnant mice to an air pollutant aerosol increases asthma susceptibility in offspring

Air pollution contributes to both exacerbation and development of bronchial asthma. Studies showed that coexposure to air pollution directly promotes sensitization to inhaled allergen in neonatal mice. The aim of this study was to investigate whether prenatal exposure to air pollution could also increase susceptibility to development of asthma in early life. Pregnant female BALB/c mice were exposed to aerosolized leachate of residual oil fly ash (ROFA, 50 mg/ml, 30 min) at 5, 3, and 1 d before delivery. Offspring were treated once at 3 d of age with ovalbumin (OVA, 5 mug) and alum (ip), an intentionally suboptimal dose for sensitization, exposed to aerosolized OVA (1%, 10 min) at 12-14 d or 32-35 d of age, and evaluated 2 d after the final exposure. The offspring of ROFA-exposed mothers (ROFA group) revealed increasing airway hyperresponsiveness (higher enhanced pause [Penh] to methacholine challenge) and elevated substantial numbers of eosinophils in the bronchoalveolar lavage flued (BALF). Histopathology revealed prominent inflammation in the lungs of ROFA group and showed increased allergen-specific IgE and IgG1 levels. Their cultured splenocytes showed an enhanced interleukin (IL)-4/interferon (IFN)-gamma cytokine, indicating Th2 skewed immunity. Data indicate that exposure of pregnant female mice to an air pollutant aerosol increased asthma susceptibility in their offspring.     

Absence of paternal sociopathy in the etiology of severe alcoholism: is there a type III alcoholism?

Twenty-nine pairs of alcoholic siblings who were part of a large scale family study were assessed for presence of clinical characteristics that might distinguish these individuals and their families from those typically ascertained through random selection. It was expected that ascertainment of families through two alcoholic brothers would increase the likelihood of finding families showing evidence of greater clinical severity. Ascertainment through a pair of alcoholic siblings reduces the likelihood of sporadic cases and increases the likelihood that the transmission of the subtype of alcoholism seen is a result of a major genetic effect. Presence of a third major type of alcoholism with features distinct from Cloninger's Type II alcoholism was revealed. Further, it would appear that the form seen in this series of families is more severe and does not require the presence of a sociopathic father, as does the Type II alcoholic.     

Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.     

Neurochemical, but not behavioral, deviations in the offspring of rats following prenatal or paternal inhalation exposure to ethanol

In addition to its widespread social use, ethanol is used extensively as an industrial solvent. Inhalation exposures to ethanol which produce narcosis in maternal rats are not teratogenic. The present study sought to extend the previous research by including offspring from paternal exposures, and testing for behavioral disorders in the offspring following maternal or paternal exposures. Groups of 18 male (approximately 450 g) and 15 female (200-300 g) Sprague-Dawley rats were exposed 7 hours/day for six weeks or throughout gestation to 16000, 10000, or 0 ppm ethanol by inhalation and then mated with untreated rats. Litters were culled to 4 males and 4 females, and were fostered within 16 hours after birth to untreated dams which had delivered their litters within 48 hours previously. Offspring from paternally or maternally exposed animals performed as well as controls on days 10-90 in tests of neuromotor coordination (ascent on a wire mesh screen, rotorod), activity levels (open field, modified-automated open field, and running wheel), and learning ability (avoidance conditioning and operant conditioning). In addition, brains of 10 21-day-old pups were analyzed for neurochemical differences from controls in concentrations of protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, 5-hydroxytryptamine, substance P, Met-enkephalin, and beta-endorphin. Levels of acetylcholine, dopamine, substance P, and beta-endorphin were essentially unchanged in the offspring of rats exposed to ethanol. Complex, but significant changes in levels of norepinephrine occurred only in paternally exposed offspring. 5-Hydroxytryptamine levels were reduced in the cerebrum, and Met-enkephalin levels were increased in all brain regions of offspring from both maternally and paternally exposed rats.