The α(1)AT and TIMP-1 Gene Polymorphism in the Development of Asthma.

Asthma has been an inflammatory disorder accompanied by tissue remodeling and protease-antiprotease imbalance in lungs. The SNPs of alpha-1 antitrypsin (α(1)AT) and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes were studied for their association with asthma. Genotyping of α(1)AT and TIMP-1 genes was performed in 202 asthmatics and 204 controls. Serum levels of α(1)AT, TIMP-1 and cytokines were estimated to find if the interplay between genotypes and cellular biomarkers determines the pathogenesis of asthma. The analysis of results showed significantly low level of α(1)AT in the serum of asthmatics as compared to controls (P = 0.001), whereas cytokines were elevated in patients. No significant difference was observed in the concentration of TIMP-1 in patients and controls. Genotyping led to the identification of 3 SNPs (Val213Ala, Glu363Lys, and Glu376Asp) in α(1)AT gene. The novel SNP Glu363Lys of α(1)AT was found to be associated with asthma (P = 0.001). The analysis of TIMP-1 gene showed the occurrence of seven SNPs, including a novel intronic SNP at base G3774A. The allele frequency of G3774A and Phe124Phe was significantly higher in asthmatics as compared to controls. Thus, the SNP Glu363Lys of α(1)AT and G3774A and Phe124Phe of TIMP-1 could be important genetic markers for use in better management of the disease.

Combinatorial effect of TIMP-1 and α1AT gene polymorphisms on development of chronic obstructive pulmonary disease.

OBJECTIVE: To study the role of α(1)AT and TIMP-1 gene polymorphisms in development of COPD. DESIGN AND METHODS: Blood samples from total 408 subjects (217 COPD patients and 191 controls) were used for genotyping and estimating biolevels of α(1)AT, TIMP-1 and inflammatory cytokines. Data was analyzed to determine the role of interaction of TIMP-1 and α(1)AT genes; and interplay between various genotypes and biolevels of α(1)AT, TIMP-1 and inflammatory cytokines in development of COPD. RESULTS: Significantly low levels of α(1)AT and TIMP-1 were observed in COPD patients as compared to controls (P = 0.001), where as the inflammatory cytokines were found to be increased in patients. PIM3 allele of α(1)AT gene in COPD patients was found to be associated with low levels of α(1)AT (P = 0.001), the effect being more pronounced when PIM3 combined with rs6609533 of TIMP-1 gene (P = 0.0001). Combination of genotypes rs6609533 of TIMP-1 and PIM3 of α(1)AT containing the risk alleles was over-represented in patients (P = 0.005). CONCLUSION: The SNP rs6609533 of TIMP-1 gene interacted with PIM3 of α(1)AT to make a possible risk combination for development of COPD.

Postprandial lipaemia in patients with impaired fasting glucose, impaired glucose tolerance and diabetes mellitus.

AIMS: To compare the postprandial lipid responses in subjects with prediabetes (IFG and IGT), newly detected diabetes mellitus (NDDM) and normal glucose tolerance (NGT). METHODS: Postprandial lipid responses to a standard oral fat challenge was studied in forty-four subjects who were divided after an OGTT into NGT, pure impaired fasting glucose (PIFG), pure impaired glucose tolerance (PIGT) and NDDM. RESULTS: There was a significantly higher postprandial triglyceride (PPTg) response with a higher PPTg area under curve (p=0.004) and peak PPTg levels (p=0.003) in patients with NDDM but not with either PIFG (p>0.05) or PIGT (p>0.05) when compared with NGT. Overall, PPTg responses correlated significantly with fasting plasma glucose (p=0.001) and 2h plasma glucose (p=0.001) but not with age, sex, body mass index, waist, or insulin resistance. CONCLUSION: Subjects with newly detected diabetes mellitus displayed postprandial hypertriglyceridemia after a standard oral fat meal challenge while no such abnormality could be demonstrated in subjects with IFG or IGT. This defect is probably related to glycemic status and insulin resistance.

T lymphocyte subset profile and serum alpha-1-antitrypsin in pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by the presence of non-fully reversible airflow limitation. The study was undertaken to investigate the involvement of alpha-1-antitrypsin (alpha(1)AT) and T lymphocyte subsets in the pathogenesis of COPD. Blood samples of 50 subjects, including 25 healthy volunteers and 25 patients with COPD, were analysed. Serum trypsin inhibitory capacity (STIC) was determined by enzymatic assay. CD4(+) and CD8(+) T lymphocytes were enumerated in heparinized blood using a fluorescence activated cell sorter counter. The STIC in COPD patients was found to be decreased significantly than in controls (P < 0.01). In COPD patients with lower expression levels of alpha(1)AT, a highly significant decrease in the number of CD4(+) T lymphocytes (P < 0.0009) and CD4/CD8 ratio was observed compared with control subjects (P < 0.008). The mean +/- standard error of CD8(+) lymphocytes was found to be little different (only marginally decreased) in COPD patients compared to healthy controls; however, an alteration in the individual count of CD8(+) lymphocytes cells was observed in COPD patients. Using linear regression analysis, a negative correlation was observed between STIC and CD4(+) lymphocytes and CD8(+) lymphocytes (r = -0.40, P < 0.04; r = -0.42, P < 0.03, respectively) in COPD patients. An alteration in alpha(1)AT and T lymphocyte subsets in COPD patients suggested that interplay of these factors may be responsible for the progression of COPD.

Association of the PIM3 allele of the alpha-1-antitrypsin gene with chronic obstructive pulmonary disease.

OBJECTIVE: The study investigated the association of genetic polymorphism of the alpha1AT gene with COPD. DESIGN AND METHODS: The mutations and polymorphism of alpha1AT gene were investigated by DNA sequence analysis using polymerase chain reaction. RESULTS: The frequency of the PIM3 allele in COPD patients was found to be significantly higher than the controls (P < 0.0001). Five SNPs, including a novel SNP (24_25insA), were observed near the junction of exon-intron I. The occurrence of these SNPs didn't show any association with COPD. However, the PIM3 allele of the alpha1AT gene was found to be associated with COPD. CONCLUSION: The PIM3 allele of the alpha1AT gene is found to have an association with the pathogenesis of COPD in the Indian population.

Metrondazole-induced neurotoxicity.

A 50 year old male with history of prolonged intake of metronidazole for treatment of liver abscess developed acute ataxia, disorientation, distal symmetrical sensory and proximal motor neuropathy. Patients being treated with metronidazole particularly those on high doses for prolonged period should be monitored for neurotoxicity.

Emergency treatment with ketoconazole in disseminated intravascular coagulation due to metastatic prostatic carcinoma.

We report the use of ketoconazole to control disseminated intravascular coagulation due to prostatic carcinoma. Clinical improvement in the condition of the patient was noted in 48 hours and coagulation profile became normal in 10 days.

Ocular manifestations of rheumatoid arthritis.

One hundred and seven patients of definite rheumatoid arthritis were screened for the presence of ocular manifestations of which 21 (19.63%) were observed to have ocular changes. Of these keratoconjunctivitis sicca in 19 (17.7%) patients and episcleritis in one (0.93%) were attributable to rheumatoid arthritis. Bilateral retinal haemorrhage in one patient was due to grade 3 hypertensive retinopathy. Absence of posterior subcapsular cataract in 106 (99.06%) patients who did not receive corticosteroids supports the hypothesis that steroids are the aetiologic agents and not rheumatoid arthritis.

Trigeminal and peripheral neuropathy in a patient with systemic sclerosis and silicosis.

The unusual occurrence of cranial (trigeminal) and peripheral neuropathy in a case of progressive systemic sclerosis (PSS) is described. The possible association of PSS with silicosis is also discussed.