Association of XPD Lys751Gln gene polymorphism with susceptibility and clinical outcome of colorectal cancer in Pakistani population: a case-control pharmacogenetic study.

BACKGROUND: XPD Lys751Gln polymorphism may modulate inter-individual variation in repair capacity of DNA, which may enhance a person's susceptibility to develop colorectal cancer (CRC). The analysis of XPD Lys751Gln polymorphism may provide important information for identifying high-risk individuals and for selecting the most appropriate treatment for poor prognostic CRC patients. OBJECTIVE: The overall objective was to find out the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer and the ultimate clinical outcomes. In this study a total of 300 subjects (CRC and Controls), were genotyped for XPD Lys751Gln. METHODS: Using PCR-RFLP methods, the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer was studied. In addition to overall risk assessment, genotyping results were also investigated with respect to the lifestyle risk factors, patients treated with oxaliplatin-based chemotherapy and clinicopathological characteristics. RESULTS: The overall correlation between the XPD Lys751Gln genetic variation and the CRC risk was observed to be significant with both the homozygous variant genotype Gln/Gln as well as heterozygous genotype Lys/Gln being associated with the increased risk of CRC. Additional stratified analyses revealed that XPD Lys751Gln variants remarkably increased risk of CRC in males and younger individuals (≤ 50 years), Naswar users (8.09-fold) and high intake of red meat. CONCLUSIONS: Our findings suggest that the relationship between the XPD Lys751Gln variants and lifestyle factors modulates the risk for CRC in Pakistani population.

Circulating leptin, cortisol and gender differences associated with anorexia or obesity in depression.

Objectives: To assess the role of circulating cortisol and leptin in depression associated with anorexia or obesity.Methods: Two hundred and fifty depressed patients presenting to the outpatient clinic of a psychiatric hospital and 250 non-depressed healthy volunteers were included in the study. The subjects of both groups were sub-grouped based upon their gender and BMI. Serum cortisol and leptin were determined by using respective ELISA kits.Results: The number of depressed than non-depressed subjects was three-fold higher in obese BMI groups of both genders. There were more depressed than non-depressed subjects in the underweight male BMI groups and in the overweight female BMI groups. There was a BMI-related increase in serum leptin and a decrease in serum cortisol in both genders. Depression in underweight BMI groups of both genders was associated with a decrease in serum leptin and an increase in cortisol. Higher serum leptin in obese BMI group was associated with a decrease in serum cortisol.Conclusions: Obesity is a risk factor for depression. The shift from typical to atypical depression is due to an inhibitory effect of higher circulating leptin on HPA axis activity and subsequent decrease in the lipolytic effects of cortisol.

Inhibition of hormonal and behavioral effects of stress by tryptophan in rats.

OBJECTIVES: Stress in known to alter hormonal systems. Pharmacological doses of tryptophan, the essential amino acid precursor of serotonin, increase circulating leptin and decrease ghrelin in normal healthy adults. Because systemically injected leptin inhibits stress-induced behavioral deficits and systemically injected serotonin modulates leptin release from the adipocytes, we used tryptophan as a pharmacological tool to modulate hormonal and behavioral responses in unstressed and stressed rats. METHODS: Leptin, ghrelin, serotonin, tryptophan, and behavior were studied in unstressed and stressed rats following oral administration of 0, 100, 200, and 300 mg/kg of tryptophan. RESULTS: Following oral administration of tryptophan at a dose of 300 mg/kg, circulating levels of serotonin and leptin increased and those of ghrelin decreased in unstressed animals. No effect occurred on 24-hours cumulative food intake and elevated plus maze performance. Exposure to 2 hours immobilization stress decreased 24 hours cumulative food intake and impaired performance in elevated plus maze monitored next day. Serum serotonin decreased, leptin increased, and no effect occurred on ghrelin. Stress effects on serotonin, leptin, food intake, and elevated plus maze performance did not occur in tryptophan-pretreated animals. Tryptophan-induced decreases of ghrelin also did not occur in stressed animals. CONCLUSION: The findings show an important role of serum serotonin, leptin, and ghrelin in responses to stress and suggest that the essential amino acid tryptophan can improve therapeutics in stress-induced hormonal and behavioral disorders.

Neurochemical and behavioral effects of Nigella sativa and Olea europaea oil in rats.

OBJECTIVES: In the last few decades, therapeutic uses of medicinal compounds present in food as a normal constituent has risen substantially, largely because of their fewer side effects and adequate efficacy. This study is designed to investigate a role of brain serotonin (5-HT) and dopamine (DA) in the potential nootropic, anxiolytic, and other beneficial effects of Nigella sativa (NS) and Olea europaea (OE) oil in rat models. METHODS: Animals were treated with NS and OE oil orally at doses of 0.1 ml/kg and 0.25 ml/kg for 5 weeks. Food intake and body weight change, anxiety-like effects in elevated plus maze and activity in a novel and familiar environment were monitored weekly. Effects on learning and memory after 5 weeks treatment were monitored using Morris water maze test. Neurochemical analysis was carried using HPLC-ECD method. RESULTS: NS and OE oil administration enhanced learning and memory in Morris water maze test and the effects were greater in NS than OE oil-treated animals. Low dose of OE oil increased exploration in an open field, higher dose of OE oil and both doses of NS oil produced no consistent effect on open field exploration. Effects of both oils on anxiety-like behavior, food and water intake, and activity in activity box were either not consistent or did not occur. The treatment increased homovanillic acid (HVA). 5-HT levels increased in high dose of NS oil and low dose of OE oil-treated groups. Low dose NS oil decreased 5-HT. DISCUSSION: The present study suggests that active components in NS and OE oil may prove useful in treating impaired cognition. OE oil may produce psychostimulant-like effect. Modulation of DA and serotonin neurotransmission seems important in the pharmacological effect of these oils.

Autosomal dominant syndrome of camptodactyly, clinodactyly, syndactyly, and bifid toes.

We report on a 25-year follow-up of a Pakistani kindred with a unique combination of camptodactyly and clinodactyly of 5th fingers, mesoaxial camptodactyly of toes, and ulnar deviation of 3rd fingers. The less common anomalies in the affected subjects include syndactyly involving all digits, and bifid toes. This condition is grossly bilateral, symmetrical, and affects upper and lower limbs of the 26 affected subjects in the kindred. The comparable number of affected male and female subjects (chi(2) = 0.154, P < 0.1), disease allele transmission by mother and father, and the malformation segregation in four consecutive generations are strongly suggestive of autosomal dominant inheritance. Differential diagnosis considered syndactyly types II, III, and V. Only type II syndactyly manifests noticeable phenotypic overlap with the clinical presentation in this family; however, the typical type II syndactyly changes are absent. To the best of our knowledge, this autosomal dominant limb phenotype has not been reported previously.