Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice.

Serotonin (5-hydroxytryptamine, 5-HT) and brain-derived neurotrophic factor (BDNF) are two signaling molecules that have important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B), levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of type-2 transglutaminase (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the post-mortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2-overexpressed mice. Taken together, these post-mortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression.

Biochemical and reproductive effects of gestational/lactational exposure to lead and cadmium with respect to testicular steroidogenesis, antioxidant system, endogenous sex steroid and cauda-epididymal functions.

This study investigated the effects of gestational and lactational exposure to lead and cadmium on testicular steroidogenesis, antioxidant system and male accessory gland functions in F1 generation rats to understand the biochemical mechanisms involved in endocrine disruptions. Pregnant rats were subcutaneously administered with 0.05 mg kg(-1) body wt\ day(-1) of sodium acetate (control), lead acetate, cadmium acetate and (lead acetate + cadmium acetate) throughout the gestational-lactational period, and all animals from each of the experimental groups were sacrificed by decapitation on post-natal day 56 for performing various biochemical assays. We observed significant reduction in the activities of testicular key steroidogenic enzymes and serum testosterone concentration along with significant depletion in cholesterol, ascorbic acid and reduced glutathione contents in all the metal-treated groups. Reductions in the activities of catalase and superoxide dismutase with concomitant increase in the levels of thiobarbituric acid reactive substance were observed in experimental groups. Both sperm contents and sperm motility patterns were significantly altered in all the metal-treated groups, suggesting the direct/indirect spermotoxic effects of lead and cadmium. The inhibitory effects of lead, cadmium and combined exposure on testicular steroidogenesis machinery, along with the male accessory gland functions, are indicative of multiple targets of lead and cadmium to disrupt male reproductive functions.

Effect of lead and cadmium co-exposure on testicular steroid metabolism and antioxidant system of adult male rats.

The mechanism of testicular toxicity of lead (Pb) and cadmium (Cd) is poorly understood. Previous studies focused on single metal-related changes in testicular toxicity. This study points towards the possible involvement of Pb- and Cd-induced oxidative stress in the suppression of steroidogenesis. The oxidative status of testis of adult male rats exposed to Pb acetate and cadmium acetate either alone or in combination at a dose of 0.025 mg kg(-1) body weight of metal intraperitoneally for 15 days was studied. Pb and Cd caused an increase in reactive oxygen species (ROS) by elevating testicular malondialdehydes (MDA) and decrease in activities of testicular antioxidant enzymes superoxide dismutase (SOD), catalase, glucose 6 phosphate dehydrogenase (G6PDH) and glutathione-S-transferase (GST) in mitochondrial and/or post-mitochondrial fraction. Activities of steroidogenic enzymes 3ß and 17ß-hydroxysteroid dehydrogenase also decreased significantly leading to altered testosterone production. Metal-exposed groups showed significantly decreased testicular and epididymal sperm count. Epididymal sperm motility and viability was also decreased on Pb and Cd exposure. Cd exposure showed more toxic effect than lead exposure, while combined exposure demonstrated least toxicity. In vitro experiments showed that vitamin C restores steroidogenic enzyme activities, suggesting that Pb- and Cd-induced ROS inhibits the testicular steroidogenesis.

Age differences in genetic knowledge, health literacy and causal beliefs for health conditions.

OBJECTIVES: This study examined the levels of genetic knowledge, health literacy and beliefs about causation of health conditions among individuals in different age groups. METHODS: Individuals (n = 971) recruited through 8 community health centers in Suffolk County, New York, completed a one-time survey. RESULTS: Levels of genetic knowledge were lower among individuals in older age groups (26-35, p = 0.011; 36-49, p = 0.002; 50 years and older, p<0.001) compared to those in the youngest age group (18-25). Participants in the oldest age group also had lower health literacy than those in the youngest group (p <0.001). Those in the oldest group were more likely to endorse genetic (OR = 1.87, p = 0.008) and less likely to endorse behavioral factors like diet, exercise and smoking (OR = 0.55, p = 0.010) as causes of a person's body weight than those in the youngest group. Higher levels of genetic knowledge were associated with higher likelihood of behavioral attribution for body weight (OR = 1.25, p <0.001). CONCLUSIONS: Providing additional information that compensates for their lower genetic knowledge may help individuals in older age groups benefit from rapidly emerging genetic health information more fully. Increasing the levels of genetic knowledge about common complex diseases may help motivate individuals to engage in health promoting behaviors to maintain healthy weight through increases in behavioral causal attributions.

Detecting cardiac involvement in sarcoidosis: a call for prospective studies of newer imaging techniques.

Diagnosis of cardiac involvement in sarcoidosis is challenging and usually relies on a combination of clinical findings and imaging abnormalities. The case of a 53-yr-old female is described who presented with ventricular tachycardia and suspected angiosarcoma involving the right atrium and superior vena cava. A combination of magnetic resonance imaging and (18)F-2-fluoro-2-deoxyglucose-positron emission tomography were essential to the diagnosis of cardiac sarcoidosis. Reversibility of the disease was predicted more clearly by (18)F-2-fluoro-2-deoxyglucose-positron emission tomography than by magnetic resonance imaging, and clinical activity was predicted by persistent hypermetabolism on serial (18)F-2-fluoro-2-deoxyglucose-positron emission tomography.

Male exposure mediated adverse reproductive outcomes in carbon disulphide exposed rayon workers.

The authors examined 100 carbon disulphide (CS2) exposed male workers who had been employed ten years prior to study were selected for the study. They were virtually obliged to participate in the study by the Medical Labor Inspector and all of them participated voluntary. The aim was to assess the effects of occupational exposure to carbon disulphide concentrations below the threshold limit value (31 mg/m3) on the reproductive functions with special emphasis on miscarriages. Specially, workers history records were build up on number of children, miscarriages and general weakness, mental fatigue etc. It was found that the incidences of number of miscarriages against number of living children correlated well with environmental concentration of CS2. Where the average CS2 levels were 1.695 ppm, the incidences of miscarriages was 5.71% (group 1). Where as in group 2 environmental concentrations were 12.28 ppm and the incidences of miscarriages were 18.91%. It was also found that in the spinning department the exposure exceeds many times the Threshold Limit Values (TL V).

India-US case-control study of age-related cataracts. India-US Case-Control Study Group.

In a hospital-based case-control study of 1441 patients with age-related cataracts and 549 controls, we studied associations between types of cataract--nuclear, cortical, posterior subcapsular, and mixed--and a number of physiologic, behavioral, environmental, and biochemical variables. Using polychotomous logistic regression analysis, we found an increased risk of cataract with lower educational achievement (all types of cataract), decreased cloud cover at place of residence (all types), use of aspirin less than once a month (posterior subcapsular and mixed), diets low in selected nutrients (posterior subcapsular, nuclear, and mixed), higher blood pressure (nuclear and mixed), lower body mass index (nuclear and mixed), use of cheaper cooking fuels (cortical, nuclear, and mixed), and lower levels of an antioxidant index based on red blood cell levels of glutathione peroxidase and glucose-6-phosphate dehydrogenase and plasma levels of ascorbic acid and vitamin E (posterior subcapsular and mixed). All risks cited were significantly different from those for the other cataract types, a finding that emphasizes the need to investigate the epidemiology of specific types of cataract.

Copper and zinc level in biological samples from healthy subjects of vegetarian food habit in reference to community environment.

Many epidemiologists have found a correlation between copper and zinc in the community environment and diseases, such as myocardial and vascular pathologies, and diabetes. The purpose of this study was to investigate the total daily intake of these two metals in cooked food, drinking water and air and their respective levels in blood and urine. A chronobiological methodology has been adopted to establish the reference values of these two metals in biological samples. It has been observed that the daily intake of copper is within the recommended value, whereas its urinary excretion is high. The daily intake of zinc is below the recommended value and its urinary excretion is also high. Both the metals showed a temporal oscillation pattern in blood and urine. A possible chronic zinc deficiency has been anticipated in this particular ethnic group of vegetarian food habit.

Accumulation and interrelationship of cadmium and zinc in human kidney cortex.

Cadmium and zinc have been analyzed in 102 normal human kidney cortex tissues collected from Indian hospitals. Cadmium and zinc were found to accumulate as age increased to 60 years, and had a log-normal distribution. Concentrations of cadmium and zinc in kidney cortex and cadmium/zinc ratios were comparable to those in other studies. The relationship between cadmium and zinc in kidney cortex gave a slope constant of 0.96 (YZn = 0.96XCd + 21.4).

The importance of reverse triiodothyronine in hypothyroid children on replacement treatment.

Reverse triiodothyronine (rT3), triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) values were measured by radioimmunoassay in 40 children with congenital hypothyroidism who were being given levothyroxine (0.05-0.35 mg/day) and in 14 normal controls. In 15 of the children with hypothyroidism the treatment, judged by serum T4 and TSH values and thyrotrophin releasing hormone (TRH) test, seemed to be adequate and their mean rT3 value and rT3:T4 ratio were comparable with the controls. The remaining 25 children had a raised serum T4 and a low TSH value. Only 4 (16%) of these children had an abnormally high T3 concentration but the rT3 value was raised in 23 (92%) and their mean rT3 value and rT3:T4 ratio were significantly higher than in the control children. Less than 20% of this 'overtreated' group, however, had clinical hyperthyroidism. We suggest that in patients on T4 replacement treatment the peripheral thyroid homeostatic mechanisms produce larger amounts of rT3, thereby preventing high T3 values where serum T4 values are raised. This may explain why the 'overtreated' children showed no clinical evidence of hyperthyroidism. These findings emphasise the protective and selective role of peripheral monodeiodination.