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.

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.

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.

Environmental lead exposure as a risk for childhood aplastic anemia.

Concern about environmental lead exposure as a significant public health threat has increased as evidence has accumulated regarding adverse health effects at successively lower levels. Aplastic anemia is a hematological disorder of unknown etiology with a high lethality rate. Lead is a known toxicant for the hematopoietic system. Oxidative stress appears to be the possible mode of lead toxicity. We evaluated the effects of blood lead level on oxidative stress parameters in children suffering from aplastic anemia disease. Seventeen children with aplastic anemia disease (15 male and 2 female, age 3-12 y) were recruited in the study group. Fifty one healthy children (45 male and 6 female, age 3-12 y) having normal blood profiles and not suffering from any chronic disease(s) were used as controls. Blood lead level and oxidative stress parameters were determined. Mean blood lead level was significantly higher while δ-aminolevulinic acid dehydratase (δ-ALAD) activity, a biomarker for lead exposure was significantly lower in the study group as compared to the control group (p < 0.05 for each). Thiobarbituric acid reactive species (TBARS), a marker of lipid peroxidation, was significantly higher while the antioxidant glutathione (GSH) level was significantly lower in the study group as compared to the control group (p < 0.05 for each). Activity of the antioxidant enzyme catalase (CAT) was significantly higher in the study group than in the control group (p < 0.05). There was a significant negative correlation of blood lead levels with δ-ALAD (r = -0.45; p < 0.05) and GSH (r = -0.32; p < 0.05), and a positive correlation with TBARS (r = 0.41; p < 0.05) and CAT (r = 0.37; p < 0.05). Although a causal pathway cannot be determined from this study, our results indicated that lead induces oxidative stress in children suffering from aplastic anemia. Lead-induced oxidative stress as an underlying mechanism for aplastic anemia warrants further research.

Silver nanoparticle applications and human health.

Nanotechnology is rapidly growing with nanoparticles produced and utilized in a wide range of commercial products throughout the world. For example, silver nanoparticles (Ag NP) are used in electronics, bio-sensing, clothing, food industry, paints, sunscreens, cosmetics and medical devices. These broad applications, however, increase human exposure and thus the potential risk related to their short- and long-term toxicity. A large number of in vitro studies indicate that Ag NPs are toxic to the mammalian cells derived from skin, liver, lung, brain, vascular system and reproductive organs. Interestingly, some studies have shown that this particle has the potential to induce genes associated with cell cycle progression, DNA damage and apoptosis in human cells at non-cytotoxic doses. Furthermore, in vivo bio-distribution and toxicity studies in rats and mice have demonstrated that Ag NP administered by inhalation, ingestion or intra-peritoneal injection were subsequently detected in blood and caused toxicity in several organs including brain. Moreover, Ag NP exerted developmental and structural malformations in non-mammalian model organisms typically used to elucidate human disease and developmental abnormalities. The mechanisms for Ag NP induced toxicity include the effects of this particle on cell membranes, mitochondria and genetic material. This paper summarizes and critically assesses the current studies focusing on adverse effects of Ag NPs on human health.

Oxidative stress and neurological disorders in relation to blood lead levels in children.

Oxidative stress plays a pivotal role in the pathogenesis of neurological disorders. Free radical generation appears to be the mode of lead toxicity. We evaluated the effects of blood lead levels on oxidative stress parameters in children suffering from neurological disorders. Thirty children (aged 3-12 years) with neurological disorders (cerebral palsy [n = 12], seizures [n = 11], and encephalopathy [n = 7]) were recruited in the study group. Sixty healthy children (aged 3-12 years) from similar socio-economic environments and not suffering from any chronic disease were taken as the controls. Blood lead levels and oxidant/antioxidant status were determined. Mean blood lead level was significantly higher while delta-aminolevulinic acid dehydratase (delta-ALAD) activity, a biomarker for lead exposure, was significantly lower in the study group as compared to the control group (P < 0.05 for each). Malondialdehyde (MDA) levels, an end-product of lipid peroxidation, were significantly higher while the antioxidant glutathione (GSH) levels were significantly lower in the study group as compared to the control group (P < 0.05 for each). Activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were significantly higher in the study group than those of the control group (P < 0.05 for each). There were significant negative correlations of blood lead levels with delta-ALAD (r = -0.35; P < 0.05) and GSH (r = -0.31; P < 0.05), and positive correlations with MDA (r = 0.37; P < 0.05), SOD (r = 0.53; P < 0.05), and CAT (r = 0.31; P < 0.05). In turn, delta-ALAD had significant negative correlations with MDA (r = -0.29; P < 0.05), SOD (r = -0.28; P < 0.05) and CAT (r = -0.34; P < 0.05), but positive correlation with GSH (r = 0.32; P < 0.05). Although a causal pathway can not be determined from the present study, our findings indicate lead-induced oxidative stress in blood of children with neurological disorders. Lead-induced oxidative stress as an underlying mechanism for neurological diseases in children warranted further investigation.

Blood levels of polycyclic aromatic hydrocarbons in children of Lucknow, India.

Polycyclic aromatic hydrocarbons (PAHs) are compounds with two or more fused benzene rings produced by incomplete combustion of organic substances involved in natural and anthropogenic processes. Children are exposed to these compounds through inhalation, dietary ingestion, and, also, soil at the playground. It has been well established that PAHs have carcinogenic, mutagenic, and teratogenic effects. Considering possible health risks due to PAHs exposure among children, the present study was carried out in collaboration with the Pediatrics Department, King George's Medical University (KGMU), Lucknow, to determine its exposure in children by estimating blood PAHs levels. Due to the variable composition of PAHs mixtures emitted from different environmental sources, any single compound or metabolite may not be representative of all exposure conditions. For these reasons, the measurement of blood PAHs levels as a possible biomarker, especially of the EPA (Environmental Protection Agency, USA) priority list, has been proposed. Acenaphthylene, anthracene, phenanthrene, fluoranthene, naphthalene, pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, and benzo(a)pyrene were determined by HPLC-FD/UV. On the basis of the individual compound, the median (50th percentile) of naphthalene (19 ppb) was highest, however, benzo(a)pyrene (4.0 ppb) level was found to be lowest among all detected PAHs. The median level of total noncarcinogenic PAHs (113.55 ppb) was higher than the total carcinogenic PAHs (32.35 ppb) in blood samples of children. A significant correlation was found between period of time spent in the surrounding breathing zone of the cooking place and total noncarcinogenic PAHs (p < 0.05), while the blood carcinogenic PAHs level in children was found to be associated with lower status of their families (p < 0.05). It is speculated that there may be chances of health hazards through exposure to PAHs, those not yet declared hazardous and present at higher concentrations in the Indian environment. Further study with a larger sample size and accompanying environmental data is desired to validate the findings of this pilot study and strengthen the database of PAHs exposure in India.

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.

Monitoring of plasma butyrylcholinesterase activity and hematological parameters in pesticide sprayers.

To evaluate the health impact of spraying organophosphorus insecticides (OPs), 34 male sprayers in the mango belt of Malihabad, a small town located 27 km from Lucknow in North India was selected. Plasma butyryl cholinesterase (PBChE) and complete blood count were assessed among sprayers after spraying pesticides and the findings obtained were compared with those determined in a reference group (n = 18). The most common symptoms observed were burning sensation in the eyes (8.82%), itching/skin irritation (23.52%) and chest symptoms (32.35%) in the exposed workers. Plasma butyrylcholinesterase (PBChE) was significantly decreased in workers. The results indicated significant decrease in the mean value of hemoglobin, hematocrit and platelets count; however, significantly higher count of leukocytes was also observed in the exposed group (sprayers) compared to that observed in the control group (P < 0.05). Monitoring of PBChE in pesticide sprayers could be useful to predict and prevent health hazards of OPs.

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.

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.

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.

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.

Possible mechanism of pesticide toxicity-related oxidative stress leading to airway narrowing.

The study was conducted to assess the magnitude of oxidative stress and lung function abnormalities in 34 male pesticide sprayers on exposure to pesticides in mango plantations. Biochemical studies on blood antioxidant enzymes revealed an unchanged glutathione level and increased level of malondialdehyde (P < 0.001), which indicates that pesticide sprayers may have suffered from oxidative stress. Decreased acetyl-cholinesterase levels (P < 0.001) in sprayers compared to the controls suggest inhibition of cholinesterase activity. The present study shows that pesticide toxicity might lead to oxidative stress and airway narrowing resulting in decreased peak expiratory flow rate.

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.

Hematological and clinical chemistry changes induced by subchronic dosing of a novel phosphorothionate (RPR-V) in Wistar male and female rats.

A novel phosphorothionate [2-butenoic acid-3-(diethoxy phosphinothioyl)-ethyl ester; RPR-V] synthesized at Indian Institute of Chemical Technology (Hyderabad, India) was studied using subchronic doses of 0.033 (low), 0.066 (medium), and 0.099 (high) mg kg(- 1) in male and female rats daily for 90 days. Continuous treatment with RPR-V caused significant (p < 0.05) decreases in body-weight gain, feed intake, hemoglobin (Hb), hematocrit (Hct), and total erythrocyte count (TEC), whereas total leukocyte count (TLC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were increased. Similarly, RPR-V caused significant elevation in serum clinical chemistry parameters calcium, phosphorus, creatinine, and chloride contents, whereas protein and glucose levels were depressed in both male and female treated rats after 45 and 90 days of treatment. These alterations were significant when compared with two-way ANOVA showing that these changes were dose- and time-dependent. The effects of low dose were generally not statistically significant, whereas medium and high doses caused significant effects. The changes in male rats were not significant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days post-treatment (withdrawal study), indicating that the compound entered into the system was eliminated from the body, and the blood parameters were improved. Hematological and clinical chemistry parameters can be detected rapidly and hence can be used for prediction and diagnosis of pesticide toxicity. Alterations in these parameters show toxic stress in the treated animals especially on blood and blood-forming organs.

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.