Risk factors for vertical transmission of hepatitis E virus infection.

Hepatitis E virus (HEV) infection can be vertically transmitted, but the factors that transmit the disease to foetuses are still unclear. We studied a total of 144 pregnant women with HEV infection. Cord blood and newborn samples were taken for analysis. Nutritional factors were evaluated on the basis of anthropometric parameters and biochemical factors, and HEV viral load was quantified by real-time PCR. Sequencing of HEV-positive samples was performed. Approximately 14.63% (6/41) of pregnant patients with acute liver failure (ALF) died before delivery. Vertical transmission was observed in 46.09% (59/128) of HEV-IgM-positive mothers. Approximately 23.80% (10/42) of newborns in the acute viral hepatitis group and 29.41% (5/17) in the ALF group were positive for HEV-RNA. No significant difference was observed in the occurrence of vertical transmission in HEV groups. Viral load was found to be a significant predictor for vertical transmission of HEV infection adjusted with haemoglobin and folate in derivation cohort group. Incorporating these variables, a new score predicting vertical transmission of HEV was derived. Using these significant predictors, the probability for vertical transmission of HEV was well stratified in the validation group (P>.05). In conclusion, viral load was associated with vertical transmission of HEV infection. A valid prediction score model was generated that was verified in a validation cohort group.

Hepatitis B virus BCP, Precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India.

The study aims to characterize mutations of the HBV genome involving BCP, Precore/core and X regions and also defines HBV genotypes in patients of hepatocellular carcinoma (HCC). The study involved 150 HBV-related HCC cases and 136 HBV-related chronic liver disease patients without HCC as controls. HBV DNA was subjected to mutational analysis using SSCP technique, genotyping by RFLP, and direct nucleotide sequencing. HBV DNA was found in 58.7% (88/150) of the HCC cases and 74.3% (101/136) of controls. HBV mutants were observed in 44.3% of HCC cases and 43.2% of controls. HBV/D was prevalent amongst the patients and controls, followed by HBV/A. The prevalence of the TT1504 mutation in the X gene, the V1753 and T1762/A1764 mutations in the BCP region, and G1914 mutation in the core gene were significantly higher in the HCC group than in the non-HCC group. Multivariate analyses showed that the TT1504, V1753, A1762T/G1764A, and the G1914 mutations and the patient's age, sex, and HBeAg status increased the risk of HCC development significantly. Also, patients with HCC had lower levels of serum albumin, viral load, and platelet counts but higher values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, and Alpha feto-protein than those of controls (P < 0.001 for all comparisons). HBV/D was the predominant genotype associated with HCC cases seen in India. The presence of different types of HBV mutations, age, sex, HBeAg status, and viral load was found to increase significantly the risk of HCC development in India.

Significance of anti-HBc screening of blood donors and its association with occult hepatitis B virus infection: Implications for blood transfusion.

BACKGROUND & OBJECTIVES: Expansions of blood donor screening and improved laboratory detection of viral markers have remarkably reduced the risk for infection with transfusion-transmitted viruses. This study was aimed to evaluate the presence of anti-HBc and to determine the presence or absence of HBV DNA in the serum samples from HBsAg negative, anti-HBc positive blood donors in a tertiary care hospital blood bank from Delhi. METHODS: A total of 2175 HBsAg negative, first time volunteer blood donors were included in the study from blood bank, Lok Nayak Hospital, New Delhi. The blood specimens from all these subjects were evaluated for anti-HBV-core antigen (anti-HBc) serology, anti-HBV-surface antigen (anti-HBs) titres and HBeAg. The presence of HBV DNA was evaluated by testing, through polymerase chain reaction (PCR) techniques. RESULTS: Of the 2175 HBsAg negative voluntary blood donors, 413 (19.8%) were tested to be positive for anti-HBc alone. Of these, 153 (group-I) were anti-HBs negative whereas group-II comprises a total of 260 anti-HBs positive cases i.e. 89 out of 413 had anti-HBs titres of 10-99 IU/l and the remaining 171 had anti-HBs titres of 100-500 IU/l. HBV DNA was detected in 7.5 per cent anti-HBc positive samples irrespective of anti-HBs status. INTERPRETATION & CONCLUSION: Our results showed that 18.9 per cent of our donor population was anti-HBc reactive, and hence inclusion of anti-HBc testing will lead to a high discard rate. The presence of HBV DNA in fairly high percentage of anti-HBc positive samples highlighted the need for a stringent and better screening system to prevent occult HBV infection.

Long Sun-Exposures Influencing High Sub-Cutaneous Synthesis of Vitamin-D3 may be Associated with Exacerbation of Symptoms in Allergic-Asthma.

OBJECTIVES: Does excessive sun-exposure, non-use of sunscreen and/or high doses of vitamin-D3 supplements provoke exacerbation of asthma? DESIGN: Clinical examinations, retrospective records-access and questionnaire surveys were distributed to a convenience sample of allergic-asthma patient (n=183). SETTING: Patients (19-89 years) attending the outpatient respiratory clinics at Maidstone Hospital were enrolled. RESULTS: 90.3% of patients (total IgE levels ≥75 kU/L ; n=103) exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days presented with wheeze (χ2(1) = 7.46; p< 0.05) compared to only 9.7% patients of similar atopy-status, presenting with wheeze if exposed to sunlight of < 15 minutes per day for 6-7 days. 68.9% patients (with IgE levels ≥ 75 kU/L ; n=103), non-users of sunscreen (SPF 30 and above), exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days developed a wheeze, compared to fewer users of sunscreen (9.7%, n=103), exposed to the same duration of sunlight who developed asthma symptoms (p< 0.05). Vitamin-D3 supplementation in asthma-patients with clinical signs of hypovitaminosis-D (n=21), produced symptoms of morning chest-tightness (76.2%), allergic rhinitis (61.9%) and wheeze (100%), 2 weeks after initiation of treatment. CONCLUSIONS: Our results advocate direct sunlight exposure < 15 minutes per day and use of sunscreen as a novel approach to preventing atopic-asthma symptoms in allergic-asthma patients.. Activated vitamin-D3 is well-recognised to shift the immune-balance towards Th2 predominance, favouring allergic asthma. These results suggest that limiting subcutaneous synthesis of vitamin-D3 in asthma patients and re-addressing dosage of vitamin-D3 supplementation is necessary may contribute to prevent exacerbation of symptoms.

Three new novel point mutations localized within and downstream of high-mobility group-box region in SRY gene in three Indian females with Turner syndrome.

Point mutations and deletions in the SRY gene result in XY sex reversal in pure gonadal dysgenesis. To date, a majority of these affect the high-mobility group (HMG) domain of SRY, which plays a key role in its DNA binding activity. We carried out molecular genetics studies in three Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Case 1 demonstrated an insertion of T (thymine) within helix I of HMG box leading to frame shift mutation (N82X). In case 2, insertion of A (adenine) downstream of HMG box resulted in a nonsense frame shift mutation (L159fsX167). These mutations resulted in truncated and altered proteins. In case 3, G>C missense mutation is found at codon 74 within helix I of HMG box (Q74H). No other mutations were found in the SRY gene of these patients. An allele-specific oligonucleotide study further confirmed that these variants are not common polymorphisms. To our knowledge, this is the first time these mutations are described at these codons resulting in mutated SRY proteins. Lack of a second sex chromosome in a majority of cells [mosaic karyotype and mutation(s) in the SRY gene] in these patients may have triggered the short stature.

Differences between midlife female offenders and those younger than 40.

The authors studied 66 women referred for forensic evaluation and classified them into two age groups: 48 women 17-39 years old composed a young adult group and 18 women 40-54 years old composed a midlife group. The midlife group included a significantly larger number of first-time offenders with a higher frequency of medical as well as psychiatric disorders. None of the women in the midlife group was diagnosed as having antisocial personality disorder, but this was the most common diagnosis among the younger women. The authors note the implications of these findings for treatment of older female offenders, especially those in midlife.

Stress reactions of children and adolescents in war and siege conditions.

OBJECTIVE: This was a study of posttraumatic stress symptoms in children and adolescents during siege conditions in Sarajevo. METHOD: Seven hundred ninety-one students aged 7-15 years were surveyed to assess symptoms of posttraumatic stress and level of deprivation. RESULTS: Girls reported more stress than boys. Loss of family members and deprivation of basic needs were associated with more symptoms. CONCLUSIONS: Personal experiences of siege are related to increased stress.

Sister chromatid exchange frequency in breast cancer cases.

Sister chromatid exchange (SCE) were studied in 22 patients with breast cancer (i.e., four stage II; 12 stage III, six stage IV) and 10 normal healthy females as age-matched controls. The data obtained in these cases followed a Poisson distribution. An apparent increase in the average rate of SCE/cell was observed with the advancing stage of breast cancer.

Status of chromosome breaks and gaps in breast cancer. a follow-up study.

Genetic susceptibility and environmental factors are believed to be responsible for chromosomal instabilities and higher incidence of breast cancer. We conducted a follow-up study to find the levels of chromosome breaks and gaps in 20 premenopausal women with breast cancer before surgery, 1 month after surgery, and 3 years after surgery with respect to 20 age- and gender-matched controls. The mean level of chromosome breaks and gaps was found to be significantly higher (P<0.001) in breast cancer patients (before surgery) as compared with the controls. The chromosome breaks and gaps after 1 month of surgery were observed significantly decreased (P<0.005) when compared with that of patients before the surgery. Further significant increase in chromosome breaks and gaps was found after 3 years of surgery as compared with both the patients after 1 month of surgery (P<0.05) and controls (P<0.005). The significant increase in chromosome breaks and gaps in breast cancer patients (before surgery) may be due to the effects of genetic susceptibility to environmental carcinogens and endogenous factors. However, the decrease in this level after 1 month of surgery may be due to the removal of cancerous tissues, which in turn removes the effect of mutagens and clastogenic factors. Further increase in chromosome breaks and gaps after 3 years of surgery may be due to the long-term effects of therapeutic agents and genetic susceptibility to environmental carcinogens in the patients. The study furthermore suggests that the high level of chromosome breaks and gaps after 3 years of surgery may be a risk factor for the development of secondary tumor in patients.

Sister chromatid exchange (SCE) studies in breast cancer patients: a follow-up study.

Sister chromatid exchanges (SCEs) were studied in 20 patients with breast cancer (stage II) before surgery, one month after surgery, and after three years as a follow-up study. Data from 50 age-matched, normal healthy females, preferably from the affected families, served as controls. In each patient, 50 well-spread metaphases were scored for SCEs. The mean values of SCEs per metaphase were 5.80, 4.69, and 5.98 in breast cancer patients before surgery, one month after surgery, and after a gap of three years as a follow-up, respectively. The one-way analysis of variance was applied and it was found that there was a highly significant difference in the frequency of sister chromatid exchanges in these patients before surgery, one month after surgical removal of cancerous tissue, and after three years as a follow-up study. The elevated level of SCEs three years after surgical removal of cancerous tissue predict the chances of development of another type of cancer.

Role of lipids, lipoproteins and vitamins in women with breast cancer.

OBJECTIVES: Improper balance between the production of reactive oxygen metabolites (ROMs), and antioxidative defense system have been defined as oxidative stress in various pathologic conditions. Lipids, lipoproteins and antioxidative vitamins have been associated with the risk of breast cancer. The present case-control study was conducted to investigate the status of antioxidative vitamins (A, C and E), lipids (total cholesterol; TC and triglycerides; TG), lipoproteins (high-density lipoprotein cholesterol; HDL-C and low-density lipoprotein cholesterol; LDL-C) and retinol-binding protein (RBP) in breast cancer patients. The aim of the study was to find out oxidative stress in breast cancer. DESIGN AND METHODS: Plasma lipids, lipoproteins and vitamins were estimated in 54 untreated breast cancer patients of different clinical stages and in 42 age- and sex-matched controls. RESULTS: Plasma TC (p < 0.05), and LDL-C and TG (p < 0.01) were found to be significantly elevated among breast cancer patients as compared to the controls. On the other hand, plasma HDL-C concentration (p < 0.001) and vitamin C and E (p < 0.01) were observed significantly decreased in breast cancer patients than in the controls. The maximum changes in plasma TC, and vitamin C and E concentrations were observed in breast cancer patients with stage IV when compared with controls. CONCLUSION: The study suggests that higher levels of TC and TG may play important role in carcinogenesis. Furthermore, the elevated plasma LDL-C concentration, which is more susceptible to oxidation, may result in higher lipid peroxidation in breast cancer patients. However, decreased concentrations of HDL-C and vitamin C and E are not likely to be sufficient enough to counter higher ROMs production reported earlier in breast cancer patients that may cause oxidative stress leading to cellular and molecular damage thereby resulting in cell proliferation and malignant conversions.

Sister-chromatid exchange (SCE) rate in normal and abnormal sexual development in males and females.

Thirty-three patients with abnormal sexual development (9 male hypogonads, 20 females with primary amenorrhea and 4 cases of ambiguous genitalia), 10 normal males and 8 normal females (below the age of 30 years) were evaluated for SCE/cell and for SCE distribution according to chromosome groups (A to G). Smokers and alcoholics and subjects under medication were excluded from the study. The average rates of SCE/cell in male hypogonads, primary amenorrhea and ambiguous genitalia were 4.23 +/- 1.51, 4.02 +/- 0.90 and 4.33 +/- 1.34, respectively, whereas in normal males and females the average rates were 4.27 +/- 0.69 and 4.49 +/- 0.87, respectively. The SCE data followed a Poisson distribution. Chi-square testing showed a statistically significant difference only in B-group chromosomes when male hypogonads were compared with normal males (p less than 0.02) and females with primary amenorrhea were compared with normal females (p less than 0.02), suggesting the importance of the study of SCE frequency distribution at chromosome group level to bring out the differences otherwise concealed in average rates.

Effect of nitric oxide and malondialdehyde on sister-chromatid exchanges in breast cancer.

Nitric oxide (NO) and malondialdehyde (MDA) play a significant role in DNA damage, sister-chromatid exchanges (SCEs) and carcinogenesis. Here, we determine plasma NO and MDA to evaluate their role in carcinogenesis and their effect on the frequency of SCEs in 45 female breast cancer patients and in 35 age- and sex-matched controls. Plasma NO (P<0.01) and MDA (P<0.001) was significantly higher in the breast cancer group, and a direct correlation were found between plasma NO and MDA concentration and tumour grade. Patients with stage II disease showed the highest levels of both NO and MDA, compared with controls. Simultaneously, SCE frequency per lymphocyte in the breast cancer group was found to be significantly (P<0.001) higher; the greatest increase being found in patients with stage IV disease. Positive correlation was found between SCEs and both NO and MDA in the breast cancer group; however, both NO and MDA production decreased with increasing severity of the disease. Lower NO production in stage IV disease may be due to lower expression of nitric oxide synthase (NOS), further facilitating the production of superoxide anions (O2*-). The reaction between NO and O2*- results in peroxynitrite (OONO-) formation, which works efficiently at the molecular level and may induce higher SCE frequency. This work suggests that further cytogenetic and molecular study is required to provide definite answers for the therapeutic use of NO in breast cancer.

Frequency of acrocentric association in abnormal sexual development in males and females.

A significant difference (P less than 0.05) was observed in a chi 2 comparison of DD, GG and DG-DI associations between male hypogonads and females with primary amenorrhea. This difference increased still further (P less than 0.01) when only DD and GG associations were compared between males and females with abnormal sexual development (ASD). Similarly, when normal males and females were compared for DI, TRI, TETRA, DD vs GG and DG vs GG acrocentric chromosome associations, a significant difference (P less than 0.05) was again observed. The sex difference was also apparent in TRI and TETRA acrocentric associations both in abnormal and normal sexual development males and females. These results suggested that probably sex difference (may be hormonal) influences the number and/or type of acrocentric chromosomes involved in association between males and females with ASD and also between normal males and females.

Chromatid association in acrocentric chromosomes of abnormal sexual development (ASD) cases.

Concordant/discordant associations at chromatid level were compared and found significant (P less than 0.05) in females with primary amenorrhea. This probably suggested that the acrocentric association pattern in this group of ASD and infertility did not follow a random segregation in subsequent cell divisions and that the concordant acrocentric chromosomes have regularly established physical connections with one another, held together for several cell cycles. It could only be speculated that the association of acrocentric chromosome anomalies in some females with abnormal sex chromosomes are due to this reason. In the event that chromosome association has a bearing on chromosome aberrations, the non-random pattern of acrocentric association probably would increase the choice for translocation and non disjunction in the somatic cells in females with primary amenorrhea during ontogenesis.

Antituberculosis drug-induced hepatitis: risk factors, prevention and management.

Apart from infectious or viral hepatitis, other most common non-infectious causes of hepatitis are alcohol, cholestatic, drugs and toxic materials. The most common mode that leads to liver injuries is antituberculosis drug-induced hepatitis. The severity of drug-induced liver injury varies from minor nonspecific changes in hepatic structure to fulminant hepatic failure, cirrhosis and liver cancer. Patients receiving antitubercular drug frequently develop acute or chronic hepatitis. The time required for the metabolites to reach hepatotoxic levels is much earlier with isoniazid plus rifampicin treatment than isoniazid alone and this has been shown to be synergistic rather than additive. Antituberculosis drug (ATT)-inducible cytochrome P-4502E1 (CYP2E1) is constitutively expressed in the liver. Recent studies show that polymorphism of the N-acetyltransferase 2 (NAT2) genes and glutathione-S-transferase (GST) are the major susceptibility risk factors for ATT-induced hepatitis. The hepatic NAT and GST are involved in the metabolism of several carcinogenic arylamines and drugs. The NAT2 enzyme has a genetic polymorphism in human. N-acetyltransferase 2 genes (NAT2) have been identified to be responsible for genetic polymorphism of slow and rapid acetylation in humans. Slow acetylators of NAT2 prove to develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Deficiency of GST activity, because of homozygous null mutations at GSTM1 and GSTT1 loci, may modulate susceptibility to drug and xenobiotic-induced hepatotoxicity. Polymorphisms at GSTM1, GSTT1 and NAT2 loci had been linked to various forms of liver injury, including hepatocellular carcinoma.

Genetic polymorphism of glutathione S transferases M1 and T1 in Indian patients with hepatocellular carcinoma.

OBJECTIVE: Our aim was to evaluate whether the association of GSTM1/T1 gene polymorphisms modifies the risk of Hepatocellular carcinoma (HCC) and what is its correlation with other predisposing risk factors like alcohol intake, cigarette smoking and hepatitis B and C infections. STUDY DESIGN/SETTING: It was a case-control study, included 254 HCC cases compared with 525 hospital-based age and sex matched cases of chronic liver disease without HCC as controls from Indian population. The GSTM1 and GSTT1 genotypes were detected using conventional multiplex PCR method. RESULTS: In this case-control study, we observed a positive correlation between age, HBV and HCV infection, smoking habit of > 20 packs/year, alcohol consumption of > 100 g/day and risk of liver cancer. We found significantly increased risk associated with GSTM1 null genotype (OR = 3.49; 95% CI = 2.52-4.84) as well as GSTT1 null genotype (OR = 3.12; 95% CI = 2.19-4.45), respectively. However, an increased risk of HCC was observed among heavy drinkers with GSTM1 (OR = 2.01; 95% CI = 1.11-3.66). Further, cigarette smoking showed a non-significant association with GSTT1 (OR = 1.49; CI = 0.69-3.25). CONCLUSION: Our results suggest that the variants in low penetrance gene such as GSTM1 and GSTT1 are associated with an increased liver cancer risk. Further, an influence of GSTM1/T1 null genotypes may contribute in the etiology of HCC in patients with higher cigarette and alcohol consumption.