Current therapeutic strategy in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disorder that places a substantial burden on patients, their families, and society. Alzheimer's disease (AD) is the sixth leading cause of all deaths in the United States, and the fifth leading cause of death in Americans aged 65 and older. During the past years, several agents have been approved that enhance cognition and global function of AD patients, and recent advances in understanding AD pathogenesis has led to the development of numerous compounds that might modify the disease process. A wide array of antiamyloid and neuroprotective therapeutic approaches are under investigation on the basis of the hypothesis that amyloid beta (Aß) protein plays a pivotal role in disease onset and progression and that secondary consequences of Aß generation and deposition, including tau hyperphosphorylation and neurofibrillary tangle formation, oxidation, inflammation, and excitotoxicity, contribute to the disease process. Interventions in these processes with agents that reduce amyloid production, limit aggregation, or increase removal or vaccination and immunization might block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation might be beneficial disease-modifying strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell-related approaches are also under investigation.  

Breath carbon monoxide concentration in cigarette and bidi smokers in India.

OBJECTIVE: To measure and compare the breath carbon monoxide (CO) levels in cigarette and bidi smokers in India. METHODS: Breath CO was measured in 389 smokers (241 cigarette smokers,148 bidi smokers) using portable breath CO analyser (Bedfont-England, Smokelyzer). Tobacco contents and length of single stick of different brands of cigarette and bidi were also measured. RESULTS: Their mean age was 38.7 +/- 13.4 years. The average duration of smoking was 18.2 +/- 13.0 years. Average breath CO levels were 15.6 +/- 7.0 ppm in smokers and 4.07 +/- 1.16 ppm in non-smokers. Average breath CO level was significantly higher in bidi smokers (18.9 +/- 7.7 ppm) compared to cigarette smokers (13.6 +/- 5.8 ppm) when total consumption of cigarette/bidi was more than five pack-years (p = 0.002). Average tobacco weight of bidi (216.8 mg) was significantly less than cigarette (696 mg). CONCLUSIONS: Bidi is equally or more harmful than cigarette smoking. One bidi may be considered to one cigarette for calculating "pack-years" of smoking.

Genotypic analysis of XRCC4 and susceptibility to cervical cancer.

Background: XRCC4 encodes a DNA repair protein which maintains genome stability by repairing double-strand breaks by the error-prone method. Defects in the protein-encoding gene lead to impairment of DNA repair process and accumulation of DNA damage, a hallmark of cancer development. We hypothesised that variants in XRCC4 are linked to cervical cancer.Material and methods: Genotyping of XRCC4 variants viz. intron3 DIP (rs28360071), intron7 DIP (rs28360017), G-1394T(rs6869366) and G-652T (rs2075685) was carried out in 246 women with cervical cancer cases and 246 control women.Results: There were several links to cervical cancer: intron3 DIP (rs28360071) II genotype (p = 0.002) and I allele (odds ratio is 0.54-0.89) (p = 0.004), intron7 DIP (rs28360017) II genotype (p = 0.003) and I allele (odds ratio 0.68 [0.53-0.88]) (p = 0.004), and G-652T (rs2075685) genotype (p = 0.044) and the T allele (odds ratio 1.35 [1.03-1.77]) (p = 0.032). In combining data into haploviews, the DDGG allele combination had an odds ratio of 0.12 (0.04-0.39) (p= 0.029) and the IIGT combination an odds ratio of 3.08 (1.25-7.55) (p = 0.01) for cervical cancer.Conclusion: Our results suggested that homozygous 'I' and 'T' genotypes in certain XRCC4 sequences may be associated with the development of cervical cancer and so may be a useful biomarker to predict cervical cancer susceptibility.

Cytokine gene variants and treatment outcome of cisplatin-based concomitant chemoradiotherapy in cervical cancer.

Background: Cervical cancer is the second most common cancer among women after breast cancer. Its standard treatment is cisplatin-based concomitant chemoradiotherapy. Chronic inflammation in uterine cervix triggers both pro- and anti-inflammatory pathways. The unpredictability in toxicity and efficacy of treatment is a major challenge. We hypothesized a link between IL-1, IL-6 and TNF gene variants and treatment response.Material & Methods: We genotyped 246 cervical cancer cases and 246 controls by PCR, PCR-RFLP and ARMS-PCR. Treatment and response were evaluated by RECIST criteria. Chemotherapy and radiation doses were same for all patients, whilst 48 were followed-up for 36 months after treatment.Results: SNPs in IL-1RN, IL-1ß, IL-6 and TNFα were linked with cervical cancer. Cases with certain allele combinations in IL-1RN, IL-1ß, IL-6(-597A/G) and TNF-α showed odds ratios (95% CI) of up to 17.54 (2.7-24.08) for the presence of cervical cancer. Variant IL-1ß (-511T/C) was linked to vital status but none were linked to overall survival.Conclusion: Certain cytokine gene variants may help detect susceptibility to cervical cancer and predict response to chemoradiotherapy.

Interaction of antioxidant gene variants and susceptibility to type 2 diabetes mellitus.

Background: Diabetes is the seventh most common disease leading to death with a global estimate of 425 million diabetics, expected to be 629 million in 2045. The role of reactive metabolites and antioxidants, such as glutathione, glutathione peroxidase, superoxide dismutase and catalase in type 2 diabetes mellitus (T2DM) provides an opportunity for identifying gene variants and risk genotypes. We hypothesised that certain antioxidant gene-gene interactions are linked with T2DM and can model disease risk prediction.Materials and methods: Genotyping of single nucleotide polymorphisms (SNPs) in antioxidant genes for glutathione (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) was performed in 558 T2DMs and 410 age and sex matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), routine lab indices by standard techniques.Results: The null/null allele combination of GSTM1del and GSTT1del increased disease risk up to 1.7-fold. The combination of SNPs in GSTM1del, GSTT1del, GSTP1 + 313A/G and in CAT-21A/T, SOD2 + 47C/T, GPx1 + 599C/T increased the risk of diabetes 13.5 and 2.1-fold, respectively. Interaction of SNPs GSTM1del, GSTT1del, GSTP1 + 313A/G (105Ile/Val), CAT-21A/T, SOD2 + 47C/T, GPx1 + 599C/T were significantly linked with disease risk >5 × 103 fold.Conclusion: As the number of gene combinations increase, there is a rise in the odds ratio of disease risk, suggesting that gene-gene interaction plays an important role in T2DM susceptibility. Individuals who possess the GSTM1del, GSTT1del, GSTP1 105I/V(+313A/G), CAT-21A/T, SOD2 + 47C/T and GPx1 + 599C/T are at very high risk of developing T2DM.