A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Blood levels of polycyclic aromatic hydrocarbons in children and their association with oxidative stress indices: an Indian perspective.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), some ubiquitous environmental contaminants are capable to cause oxidative stress, during its metabolism. It is believed that many diseases that have a common origin in oxidative stress begin in childhood. Considering oxidative stress evolved during PAHs metabolism as one main mechanism responsible for health hazards related to PAHs exposure in children, we biomonitored blood PAHs levels in connection with redox status among children of Lucknow (India). METHODS: The study consisted of children (n = 50) who visited to the Pediatrics Department (KGMU) Lucknow for usual health check-up camp over the study period (August 2005-July 2006). Blood samples were drawn and levels of acenaphthylene, anthracene, phenanthrene, fluoranthene, naphthalene, pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene and benzo(a)pyrene were determined by HPLC-FD/UV. Malondialdehyde (MDA), glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activity were also determined to evaluate redox status. RESULTS: Significantly elevated carcinogenic blood PAHs levels (125.55 +/- 26.99ppb, p < 0.05) were found in rural children compared to children from urban region (23.96 +/- 13.46). Results revealed that remoteness between residence and highway/traffic, significantly influences the blood levels of carcinogenic PAHs. There were significant correlations between total PAHs and MDA (r = 0.82, p < 0.001), carcinogenic PAHs and SOD activity (r = 0.35, p < 0.01), Total PAHs and blood GSH level (r = - 0.49, p < 0.01) and carcinogenic PAHs and CAT activity (r = 0.42, p < 0.01). Blood MDA level was also found correlated with increasing body mass index (BMI) (r = 0.29, p < 0.05). CONCLUSION: Our results showed blood PAHs levels in children significantly correlated with oxidative stress and altered antioxidant status. It supports our hypothesis that the children exposed to high PAHs level will suffer more to oxidative stress that may lead to possible health risks. Additional studies with large sample size are considered necessary to strengthen the database and also to explore the PAHs associated health risks in children.

Association of Prolonged QTc Dispersion with Diastolic Dysfunction of the Left Ventricle in Patients with Non ST Segment Elevation Myocardial Infarction.

Diastolic function usually declines before systolic function, and this precedes clinical signs in patients with acute coronary syndrome. Therefore, diagnosis of diastolic dysfunction is very important for early diagnosis, follow-up, treatment, and prognostic evaluation in heart failure with preserved ejection fraction (HFpEF) patients. The main objective of the study was to find out association between prolonged QTc dispersion and left ventricular diastolic dysfunction in Non ST Segment Elevation Myocardial Infarction (NSTEMI) patients in HFpEF. This cross sectional analytical study was conducted in the Department of Cardiology and 60 patients were included as study population from August 2015 to July 2016. Then the study population was divided into two groups, each group consisted of 30 patients. NSTEMI patients with prolonged QTc dispersion treated as Group I and NSTEMI patients with normal QTc dispersion treated as Group II. The study shows 20.0% vs. 26.6% patients had detected as Grade I in Group I and Group II respectively with statistically insignificant association (p=0.16). On the contrary, 30.0% vs. 13.4% patients had detected as Grade II in Group I and Group II respectively with statistically significant association (p=0.001). Again, 40.0% vs. 10.0% patients had detected as Grade III in Group I and Group II respectively with statistically significant association (p=0.001). QTc dispersion was found sequentially significant increased (p=0.007) among 3 grades of LVDD (63.6±4.9 vs. 79.4±8.6 vs. 98.2±28.8). QTc dispersion in surface ECG which is a cheap, non-invasive, easily available tool can help us predicting left ventricular diastolic dysfunction in patients with NSTEMI.

Low level lead exposure and oxidative stress: current opinions.

Lead continues to pose a serious threat to the health of many children as well as adults. Concern about lead exposure as a significant public health problem has increased as evidence has mounted regarding adverse health effects at successively lower levels. This issue is complicated by the fact that there is no demonstrated biological function of lead in human. Lead potentially induces oxidative stress and evidence is accumulating to support the role of oxidative stress in the pathophysiology of lead toxicity. Lead is capable of inducing oxidative damage to brain, heart, kidneys, and reproductive organs. The mechanisms for lead-induced oxidative stress include the effects of lead on membranes, DNA, and antioxidant defense systems of cells. Recent epidemiological and toxicological studies have reported that lead exposure causes several diseases including hypertension, kidney disease, neurodegenerative disease and cognitive impairment. Although all these diseases include components of oxidative stress, the relevance of oxidative stress to lead-related diseases with low lead exposure has been criticized because most of the mechanistic studies have been conducted at moderate to higher dose levels. The association between low level lead exposure and oxidative stress has not been explored systematically. The present review focuses on mechanisms for lead-induced oxidative stress and relevance of oxidative stress to lead-related human disease with low lead exposure.

Interaction of lead with some essential trace metals in the blood of anemic children from Lucknow, India.

BACKGROUND: The effects of lead on the hematological system results in the inhibition of heme synthesis and in anemia. Lead may affect the absorption and metabolism of essential trace metals also. There is little information especially from the northern region of India regarding the relationship between blood lead levels>or=10 microg/dl and anemia in children. We performed a cross-sectional study to evaluate the association of blood lead levels>or=10 microg/dl with anemia, and its effect on hematological system and some essential trace metals in children. METHODS: A total of 75 children aged 1-7 years, 50 anemic (Hb8 g%), drawn from Lucknow, India and nearby areas were recruited to determine blood levels of lead, iron, zinc, copper, and calcium along with hematological parameters [delta-aminolevulinic acid dehydratase (delta-ALAD) hemoglobin (Hb), hematocrit, and ascorbic acid]. RESULTS: Based on Centre for Disease Control and Prevention's intervention level of blood lead, children were categorized into those with blood lead<10 microg/dl (6.89+/-2.44) (n=19) (GI) and those with blood lead<10 microg/dl (21.86+/-7.58) (n=56) (GII). After adjustment for child's age, sex, and area of residence, children with blood lead levels>or=10 microg/dl were 2.87 (95% CI: 1.60-2.87) times as likely to have anemia as children with blood lead levels<10 microg/dl. The differences of the adjusted mean values of Hb, delta-ALAD, and hematocrit were significantly lower in children from the GII group when compared to children from the GI group (p<0.01, p<0.01, and p<0.05, respectively). Among essential trace metals, adjusted mean levels of blood iron, zinc, and calcium were significantly lower in GII as compared to GI (P<0.05 each). There were significant negative correlations of blood lead levels with delta-ALAD (r=-0.612, p<0.01), hematocrit (r=-0.427, p<0.05), iron (r=-0.552, p<0.05) zinc (r=-0.427, p<0.05), and calcium (r=-0.324, p<0.05). CONCLUSION: Results indicate that elevated blood lead levels (>or=10 microg/dl) in children were significantly associated with risk of anemia and that blood lead levels also influenced the status of essential trace metals. However, results of this study may be limited due to limited sample size but certainly form the basis of a larger sample size study, taking into account all the known potential confounders of anemia in children.

Biomonitoring of organochlorines, glutathione, lipid peroxidation and cholinesterase activity among pesticide sprayers in mango orchards.

BACKGROUND: Pesticide sprayers in mango orchards of Malihabad, Lucknow (India) are generally exposed to organophosphate (OP) and pyrethroid pesticides. We determined the pesticide exposure levels along with their biochemical and clinical effects in 31 sprayers, compared with 18 controls. METHODS: Assay of acetyl and butyrylcholinesterases (AChE, BChE respectively) as an indirect measurement of OP exposure and levels of malondialdehyde (MDA) and glutathione (GSH) were estimated in blood samples to determine their impact on redox potential. Organochlorines were estimated by GLC-ECD. RESULTS: Significantly inhibited AChE, BChE activities and higher MDA level were found among sprayers compared to controls (p<0.05). Mean of total organochlorines were surprisingly higher (97.65+/-13.38 ppb) in sprayers than in those of controls (20.42+/-3.56 ppb) (p<0.05). Respiratory morbidity (32.4%), ocular problems (8.8%), gastrointestinal (17.6%) and skin problems (23.5%) were found in sprayers. There was significant correlation between AChE and GSH (r=0.29, p<0.05) and AChE with MDA (r=-0.34, p<0.05). CONCLUSION: Results indicated the significantly enhanced lipid peroxidation in sprayers correlated with cholinesterases inhibition. A small sample size limits the significance of this study. However, it paves the way for a larger Indian study with extended practical significance.

Childhood aplastic anaemia in Lucknow, India: incidence, organochlorines in the blood and review of case reports following exposure to pesticides.

OBJECTIVES: A hospital-based case-control study, the first in India, was conducted to determine the incidence of childhood aplastic anaemia in and around Lucknow in the backdrop of organochlorine levels in the blood and review the database for any association between the disease and exposure to pesticides. DESIGN AND METHODS: A total of 25 cases of childhood aplastic anaemia were identified as per established criteria and enrolled over the study period of 1 year. Their blood organochlorine levels were determined using a gas-liquid chromatograph equipped with an electron capture detector. RESULTS: The annual incidence of childhood aplastic anaemia in and around Lucknow was found to be 6.8 cases per million which is higher than many countries (e.g., France, Brazil, UK, and United States) but lower than those reported in Sweden, China and an European-Israeli collaborative study. Blood levels of alpha-HCH, gamma-HCH, delta-HCH, total-HCH, and p, p'-DDE were higher in children with aplastic anaemia than in those of controls; only alpha-HCH differed significantly (P < 0.05). CONCLUSIONS: Although this pilot study, with limited statistical power, did not support any association between exposure to organochlorines and risk of childhood aplastic anaemia, a possible association between the two could not be ruled out in view of several cases identified following exposure to pesticides.

Comparison of some trace elements concentration in blood, tumor free breast and tumor tissues of women with benign and malignant breast lesions: an Indian study.

Fifty women residing in and around New Delhi, India and identified to have benign (25 nos.) and malignant (25 nos.) breast lesions were studied for the first time to access the association between environmental exposure to lead and risk of breast cancer and to determine the potential of changes in trace elements concentration as a diagnostic marker and/or its etiological involvement in the disease. Blood, tumor tissue and breast adipose tissue from tumor free area from each patient of the two groups, collected at the time of lumpectomy or mastectomy (only blood sample was collected from disease free control group), were analyzed to determine the concentration of Pb, Zn, Cu, Fe and Ca using Atomic Absorption Spectrometry. Blood lead was significantly higher in malignant cases than in those of benign and control (p<0.05 each). Lead level was also higher in tumor tissue when compared with their respective normal tumor free breast tissue, though non-significant, in both benign and malignant cases. Interestingly, Zn, Fe, and Ca levels were higher in blood of malignant cases than in those of their benign counterparts. Furthermore, these metals were also higher in tumor of malignant and benign cases as compared to normal tumor free breast tissue, many of them statistically significant (p<0.05/0.01/0.001). However, Cu level was insignificantly lower in the blood and tumor tissue of malignant cases when compared with their benign counterparts while it was significantly higher (p<0.05) in tumor of benign cases when compared with those of their respective normal tumor free breast tissue. There were statistically significant correlations between lead and trace element levels only in normal tumor free breast tissue of benign and malignant cases (r=0.41-0.73; p<0.05-0.001) but neither in blood nor tumor tissue of the two groups. These results suggest that in the backdrop of existing experimental and epidemiological evidences exposure to lead may be one of the risk factors for breast lesions; though it warrants further investigation. Further, modulation of trace elements level in both benign and malignant breast diseases patients may be of potential to be used as diagnostic marker of the disease process and its possible relationship etiologically.

Delta-aminolevulinic acid dehydratase inhibition and oxidative stress in relation to blood lead among urban adolescents.

To explore lead-induced oxidative stress among urban adolescents, the present study, the first from India, was designed to determine the proportion of urban adolescents with blood lead >10 microg/dL and its impact on selected oxidative stress parameters and delta-aminolevulinic acid dehydratase (delta-ALAD) inhibition, which could be used as biomarkers of lead intoxication. A total of 39, urban, male adolescents, drawn from Lucknow and adjoining areas, were recruited to determine lead, delta-ALAD, malondialdehyde (MDA) and glutathione (GSH) in blood and catalase (CAT) in RBCs. Mean level of blood lead was 9.96 +/- 3.63 microg/dL (4.62-18.64); 43% of adolescents crossed the Centre for Disease Control (CDC) intervention level of 10 pg/dL blood lead. On the basis of blood lead levels (BLLs), adolescents were categorized into two groups: Group I and Group II had a blood lead <10 microg/dL (7.40 +/- 1.62) and >10 microg/dL (13.27 +/- 2.67), respectively, with significantly different mean values (P <0.001). Age, sex, body mass index (BMI), Hb level (malnutrition), and area of living as confounders of lead exposure and toxicity were not statistically different between the two groups. However, delta-ALAD activity was significantly lower (P <0.001), while CAT activity was higher in Group II than in Group I (P <0.01). MDA level was also significantly higher in Group II compared to Group I (P <0.001). There were significant negative correlation of BLL with 6-ALAD (r= -0.592, P <0.001), and positive correlations with CAT (r=0.485, P <0.01) and MDA (r=0.717, P <0.001). Interestingly, delta-ALAD, in turn, had significant negative correlations with CAT (r= -0.456, P <0.01) and MDA (r= -0.507, P <0.01). Results of the present pilot study provide clues to the possible low level of lead-induced oxidative stress in urban adolescents, suggesting that lead-induced 6-ALAD inhibition can also be an indicator of oxidative stress. The potential of oxidative stress parameters to be used as biomarkers of lead toxicity warranted further investigation.

Environmental exposure to lead and its correlation with biochemical indices in children.

Lead is a global concern because of its ubiquity in the environment and known to be associated with abnormal neurobehavioral and cognitive development of young children. There is no study from India to describe a composite profile of blood lead and its biochemical influences in children. The present study was aimed at determining the proportion of children with >10 mug/dL blood lead levels (BLLs), association between BLLs, and sociodemographic characteristics, if any, and alterations in biochemical indices in the blood as an underlying mechanism of lead intoxication. A total of 62 children (4--12 y) of Lucknow and nearby areas were recruited to determine BLLs, delta-amimolevulinic acid dehydratase (delta-ALAD) activity, catalase (CAT) activity, and malondialdehyde (MDA) and glutathione (GSH) levels in the blood. Mean level of blood lead was 7.47+/-3.06 microg/dL (2.78--15.0) and 29%-exceeded 10 microg/dL, CDC intervention level. The BLLs were found to be significantly influenced by social status, area of residence, source of water supply, maternal educational status (p<0.001), type of house, and proximity to traffic density (p<0.01). delta-ALAD was significantly lower in the group of children with BLLs 11.39+/-1.39 microg/dL when compared to children with BLLs 7.11+/-1.25 microg/dL and 3.93+/-0.61 microg/dL (p=0.0007, 0.0005, respectively). However, CAT activity was higher in the groups of children with higher blood levels than with lower BLLs (p=0.0159, 0.0001, respectively). There was an increase in MDA level with a concomitant decrease of GSH in children with BLLs 11.39+/-1.39 microg/dL compared with those of children with BLLs 7.11+/-1.25 microg/dL and 3.93+/-0.61 microg/dL (p=0.0001, 0.0002, and p=0.0001, respectively). There was statistically significant correlation of BLLs with delta-ALAD (r=-0.44, p=0.00035), MDA (r=0.46, p=0.00018), GSH (r=-0.62, p=0.00001), and CAT (r=0.44, p=0.00035). Significantly, CAT activity, MDA, and GSH levels were in turn, found to be correlated with delta-ALAD (r=-0.45, p=0.00024; r=-0.43, p=0.00053; r=0.43, p=0.00053, respectively). Results of the present study indicate a declining trend of BLLs in children when compared with those reported from metropolitan cities of India when leaded gasoline was in practice and that the BLLs were significantly associated with biochemical indices in the blood which have the potential to be used as biomarkers of lead intoxication.

Interaction of monocrotophos and its novel thion analogues with microsomal cytochrome P-450: in vivo and in vitro studies in rat.

The binding of monocrotophos (MCP) and its two thion analogues (coded as RPR-II and RPR-V) to rat hepatic microsomal cytochrome P-450 (HMC) were investigated in vitro by difference spectroscopy. These three organophosphorus insecticides were found to bind stoichiometrically to HMC with very high affinity (Ks 34-50 microM). RPR-V showed the highest binding affinity followed by RPR-II and MCP. Association of these compounds with HMC occurred within 2 min of addition in the cuvette and therefore, appeared to be tight binding ligands of cytochrome P-450. In vivo studies at equitoxic doses of the three compounds 24 h after oral treatment in rats revealed that they all caused reduction in MC content in liver, lung, kidney and brain, as against induction in cardiac and splenic cytochrome P-450. These in vivo results suggest organ specificity in modulating the microsomal cytochrome P-450 (MC) content of hepatic and extra-hepatic tissues by the three compounds. Apparently, their binding affinity with HMC is strongly correlated with their LD50 value and has a substantial co-relationship with the cytochrome P-450 level in the liver.

Hepatic and extra hepatic glutathione depletion and glutathione-S-transferase inhibition by monocrotophos and its two thiol analogues.

Effect of monocrotophos (MCP) and its thiol analogues (coded as RPR-2 and RPR-5) on hepatic and extra-hepatic glutathione (GSH) depletion and glutathione-S-transferase (GST) inhibition was studied at 0.96, 1.23 and 3.0 mg/kg respectively 24 h after medication in rats. All the three compounds caused tissue specific depletion of GSH from hepatic and extra-hepatic tissues. Cytosolic GST activity was significantly inhibited in all the tissues, MCP being the most potent inhibitor. Both in vitro and in vivo data indicate that hepatic GST inhibiting potential of the three compounds lies in the order MCP greater than RPR-5 greater than RPR-2. In vitro effect of 3 compounds on GSH activation kinetics of GST demonstrate competitive inhibition by MCP and non-competitive inhibition by the two analogues. However, CDNB activation kinetics of the enzymes revealed mixed inhibition by all 3 compounds. The present study suggests that monocrotophos and its thiol analogues may bring about physiological upsets by altering GSH and GST dependent events in different tissues of exposed organisms.

Role of chlorinated hydrocarbon pesticides in abortions and premature labour.

Premature labour and abortion possibly due to the high concentration of organochlorine pesticides have been investigated. Considerably higher amounts of organochlorine pesticide residues have been detected by gas liquid chromatography in the circulating blood and placental tissue of the women undergoing abortion or premature labour as compared with pregnant women in full term labour. The differences are highly significant for all pesticides estimated.

Toxicity of endosulfan: distribution of alpha- and beta-isomers of racemic endosulfan following oral administration in rats.

Endosulfan was administered orally (2.5 and 7.5 mg/kg) daily to male rats for a period of 60 days. The distribution pattern of alpha and beta-isomers was studied using a gas-liquid chromatograph equipped with an electron capture detector. There was a significant increase in liver and lung weights. The testes weight was slightly decreased. No significant change in weights of other tissues was observed. At both dose levels, the concentration of alpha-isomer was highest in kidney (574 and 1655 ng/g, respectively), followed by lung, ventral prostate, spleen, testes and brain. In the seminal vesicle, epididymis, heart and liver, the concentration of beta-isomer was higher than the alpha-isomer. The results of the study indicated a differential ability to accumulate the two isomers of endosulfan which may help to explain the difference in the toxic potential of the alpha- and beta-isomers.

Biological monitoring of environmental contaminants: chlorinated hydrocarbons in eggs of hens.

High concentrations of persistent chlorinated hydrocarbon pesticide residues were detected by gas-liquid chromatography with an electron capture detector (3H), in eggs of hens collected from Lucknow under the pesticide monitoring programme. The present study reveals extremely high contamination of eggs, particularly with DDT and HCH residues. The eggs may be an important source of DDT and HCH build-up in the human body. Residue levels of p,p'-DDT and its metabolites p,p'-DDE and alpha, beta and gamma-isomers of HCH were higher in eggs of poultry-farm hens compared to those of domestic hens. Egg yolk contained higher levels compared with egg white, because of the lipophilic nature of pesticides and the high lipid content in the yolk. Average levels of total DDT and HCH residues in the yolk and white in the whole egg of a poultry-farm hen were found to be 18.5 and 4.6 micrograms respectively, whereas the average levels were 7.4 and 4.1 micrograms, respectively, in the whole egg of a domestic hen.

Reduced recovery of dieldrin residues-a shortcoming of sulfuric cleanup of biological samples.

Reduced quantitative recovery of dieldrin (1, 2, 3, 4, 10, -10-hexachloro-6, 7-epoxy-1, 4, 4a, 5, 6, 7, 8, 8a-octahydro-1, 4-endo, exo-5, 8-dimethanoaphthalene) while using concentrated sulfuric acid for the cleanup of the extracted samples, has been investigated by gas-liquid chromatography and infrared (IR) spectroscopy. In vitro studies have shown that the servere breakdown in the recovery of dieldrin can be checked if 65% (v/v) H2SO4 is used as opposed to the concentrations greater than 70% sulfuric acid, the epoxide ring attached to the norbornene nucleus of dieldrin undergoes rearrangement to form keto-dihydroaldrin.

Blood lead and zinc in pregnant women and their offspring in intrauterine growth retardation cases.

As part of our program to investigate the possible role of environmental pollutants in the incidence of intrauterine-growth retardation (IUGR) in India, we determined the lead and zinc levels in mothers and neonatal blood, collected at parturition, in cases with normal and IUGR babies. Both maternal and cord blood lead levels were significantly higher in IUGR cases than in normal cases (p < 0.05). The mean level of zinc was also higher in maternal blood of IUGR cases. Significantly, the mean cord blood lead level was > 10 microg/dL, which is greater than Centers for Disease Control's intervention level, in 54% of newborns. A good correlation (r = 0.53, p < 0.01) between maternal and cord blood lead levels confirmed the transfer of lead from mother to the fetus. There was a weak but significant relationhsip between cord blood lead levels and birth weight of newborns (r = -0.22, p < 0.05). The study may serve as a pointer to the perils of in utero exposure to chemical contaminants and a call for measures by the public health authorities for a continuous bio-monitoring program to evaluate impact of environmental pollutants on women and children's health.

Organochlorine pesticides in specimens from women undergoing spontaneous abortion, premature of full-term delivery.

Organochlorine insecticides (BHC, aldrin, p,p'-DDE, p,p'-DDD, p,p'-DDT) were measured in the blood, placenta and fetus of women experiencing spontaneous abortions, preterm labor or full-term labor using an electron-capture gas chromatographic method. The following trend was found for insecticide concentrations in each of the specimens tested: spontaneous abortions greater than preterm greater than full-term. One conclusion of this work is that the organochlorine insecticides act as antagonists to pregnancy. A plausible explanation for the facilitory role of organochlorine insecticides in the initiation of preterm labor/abortion is hypothesized.

The Association of Begomovirus with Bitter Melon in India.

Bitter melon, Momordica charantia (Cucurbitaceae), is a vegetable of nutritive and medicinal value that is cultivated throughout India and other tropical countries. In September 2001, a severe disease of bitter melon with virus-like symptoms was observed at Lucknow, India. Symptoms consisted of upward curling, shortening, and distortion of leaves. Diseased melon fruits were stunted and deformed. Disease incidence was as high as 100%. Whitefly (Bemicia tabaci) can transmit the associated virus from diseased bitter melon to Nicotiana tabacum cv. White burley. The development of leaf curl symptoms in N. tabacum indicated the pathogen could be a begomovirus. Total nucleic acids were extracted from diseased bitter melon leaves, and polymerase chain reaction (PCR) tests were performed. Three pairs of primers, AV494 and AC1048 (1), CL-CR/F2 and CL-CR/R2, CL/11F and CL10/R (2), specific to DNA-A of begomoviruses were used in PCR. Virus-specific DNA-A fragments of expected sizes were identified (≈0.5, 0.7 and 1.2 kb, respectively). The presence of a begomovirus in all PCR-amplified DNA fragments was confirmed by Southern hybridization. Cloned DNA-A fragments of Tomato leaf curl virus and Cotton leaf curl virus (both begomoviruses) cross-hybridized with the PCR products gave strong signals under high stringency conditions. These data suggest that a begomovirus is associated with this bitter melon disease. Watermelon mosaic 1 virus is the only virus previously reported to naturally infect bitter melon; however, this virus has not been identified in India. Bitter melon is also an experimental host of Ribgrass mosaic virus (genus Tobamovirus) and Trichosanthes mottle virus (genus Potyvirus). To our knowledge, this is the first report of the occurrence of begomovirus infecting bitter melon. References: (1) S. D. Wyatt and J. K. Brown. Phytopathology 86:1288, 1996. (2). X. Zhou et al. J. Gen. Virol. 79:915, 1998.