Rapid identification of somatic mutations in colorectal and breast cancer tissues using mismatch repair detection (MRD)

Mismatch repair detection (MRD) was used to screen 93 matched tumor-normal sample pairs and 22 cell lines for somatic mutations in 30 cancer relevant genes. Using a starting amount of only 150 ng of genomic DNA, we screened 102 kb of sequence for somatic mutations in colon and breast cancer. A total of 152 somatic mutations were discovered, encompassing previously reported mutations, such as BRAF V600E and KRAS G12S, G12V, and G13D, as well as novel mutations, including some in genes in which somatic mutations have not previously been reported, such as MAP2K1 and MAP2K2. The distribution of mutations ranged widely within and across tumor types. The functional significance of many of these mutations is not understood, with patterns of selection only evident in KRAS and BRAF in colon cancer. These results present a novel approach to high-throughput mutation screening using small amounts of starting material and reveal a mutation spectrum across 30 genes in a large cohort of breast and colorectal cancers.     

Low-Level Lead Exposure and Blood Lead Levels in Children: A Cross-Sectional Survey

The authors studied 53 girls (44.5%) and 66 (55.5%) boys in Karachi, Pakistan, to determine their blood lead levels. The association between blood lead levels/water lead levels and the possible risk factors and symptoms associated with lead toxicity was explored. The mean lead level for the entire group was 7.9 μg/dl (standard deviation = 4.5 μg/dl). Thirty (25.2%) of the children had lead levels that exceeded 10 μg/dl; 12 (10.0%) of these had lead levels that exceeded 15 μg/dl. Thirteen (20.9%) of the children under the age of 6 yr (n = 62) had lead levels greater than 10 μg/dl, and 6 (9.6%) had levels in excess of 15 μg/dl. The authors found no association (p > .05) between high lead levels in water and blood lead levels in children. Mean blood lead levels were highest in the group of children exposed to various risk factors for lead absorption (e.g., exposure to paint, remodeling, and renovation; use of lead utensils; pica). There was a significant association between a history of exposure to paint/renovation activities and a history of pica. High blood lead levels in the children in Karachi stress the urgency for actions that control lead pollution. Screening programs should be instituted by the state. Individuals must become aware of lead's toxicity, and they must avoid substances that contain lead.     

Toxico-pathological changes induced by cypermethrin in broiler chicks: Their attenuation with Vitamin E and selenium

Ninety 1-day old broiler chicks of mixed gender (as hatched) procured from a local hatchery were randomly divided into five equal groups. All the treatments were given through crop tubing. Groups 1–4 received cypermethrin (CY) (600 mg kg^?1 b. wt.) daily for 30 days. In addition to CY (group 1), groups 2–4 received Vit E (150 mg kg^?1 b. wt.), Se (0.25 mg kg^?1 b. wt.), and Vit E (150 mg kg^?1 b. wt.)+Se (0.25 mg kg^?1 b. wt.), respectively. Group 5 served as control andreceived normal saline (2 ml kg^?1 b. wt.) for 30 days. Randomly selected six broiler chicks from each group were slaughtered at experimental days 10, 20 and 30 for the collection of serum/plasma and morbid tissues. Absolute organ weights were recorded. Total plasma proteins, fibrinogen and creatinine were significantly (P<0.05) increased while alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and urea decreased significantly (P<0.05) in CY-treated group when compared with the control group. Kidneys were swollen grossly in treated broiler chicks. In liver, necrosis of hepatocytes, cytoplasmic vacuolation, bile duct hyperplasia and mononuclear cellular infiltration were observed. In kidneys, necrosis of tubular epithelial cells, cytoplasmic vacuolation, cellular infiltration and atrophy of glomeruli were observed. Sub-arachnoid space was much dilated in CY-treated broiler chicks. It can be concluded that CY induces biochemical and histopathological alterations in broilers chicks; however, these toxic effects can be ameliorated by Vit E or Se. Combination of Vit E and Se was more effective in ameliorating toxic effects of cypermethrin in broilers chicks.     

Adverse effects of arsenic exposure on uterine function and structure in female rat

The present investigation examined the adverse effects of arsenic exposure on uterine function and structure of female rat at 56 days of age, exposed to different doses (50, 100, and 200 ppm) of sodium arsenite in drinking water at immature age (28 days) for 28 days. Dose-dependent decrease (P<0.001) was observed in mean uterine weight and length in all treated groups compared to control. Higher arsenic deposition was found in uterine tissue against increased doses of arsenite. Arsenite treatment altered the histomormphology of the uterus. Uterine epithelium in 50 ppm group was lined by cuboidal cells instead of columnar cells observed in control epithelium. In 100 and 200 ppm groups, no demarcation was observed between epithelial cells and endometrial stroma. No basement membrane was seen in these groups; even in 50 ppm, basement membrane was disturbed. The endometrial stroma in 100 and 200 ppm groups was very dense in appearance and contained irregular-shaped cells. In myometrium, loosening of cells was observed in 100 and 200 ppm groups. Dose-dependent decrease (P<0.001) was observed in mean uterine diameter, epithelial height, thickness of endometrium, myometrium, and in plasma levels of estradiol, progesterone, FSH and LH in all the treatment groups compared to control. In summary, arsenic is a major threat to female reproductive health acting as a reproductive toxicant and as an endocrine disruptor, restricted the function and structure of uterus, by altering the gonadotrophins and steroid levels, not only at high dose concentration but also at low (50 ppm) levels, when they become mature.     

Antispasmodic and vasodilator activities of <Emphasis Type=Italic>Morinda citrifolia</Emphasis> root extract are mediated through blockade of voltage dependent calcium channels

Background  

Morinda citrifolia (Noni) is an edible plant with wide range of medicinal uses. It occurs exclusively in tropical climate zone from India through Southeast Asia and Australia to Eastern Polynesia and Hawaii. The objective of this study was to explore the possible mode(s) of action for its antispasmodic, vasodilator and cardio-suppressant effects to rationalize its medicinal use in gut and cardiovascular disorders.     

The expectant management of women with early pregnancy of unknown location.

OBJECTIVE: To assess the results of expectant management in women with pregnancy of unknown location and to identify diagnostic parameters that are predictive of spontaneous pregnancy resolution. DESIGN: Prospective, observational study. SUBJECTS: Women with a positive pregnancy test and suspected early pregnancy complications who were referred for ultrasound assessment. METHODS: Women were first examined by transvaginal ultrasound to establish the location and viability of pregnancy. All women with pregnancies that could not be located on the scan had a blood sample taken to quantify the serum human chorionic gonadotropin (hCG) and progesterone levels. Management was expectant until the pregnancy was identified, the condition resolved spontaneously or an intervention was required because clinical symptoms deteriorated or hCG levels did not decline. For each woman, age, clinical symptoms (pain and bleeding), menstrual dates, past gynecological history, endometrial thickness and levels of serum hCG and progesterone were recorded. All parameters were tested by univariate analysis and then analyzed in a stepwise procedure to form a logistic regression model for predicting spontaneous resolution of pregnancy. RESULTS: A total of 1625 women were included in the study. In 135 cases (8%) the location of pregnancy was unknown. Complete data sets were obtained in 127 cases. These included 34 (27%) normal intrauterine pregnancies, 11 (9%) miscarriages and 18 (14%) ectopic pregnancies. A total of 64 (50%) pregnancies resolved spontaneously. Stepwise analysis showed that four diagnostic parameters--vaginal bleeding, endometrial thickness, serum hCG level and progesterone level--contributed significantly to the predictive power of the logistic model. With the use of this model, spontaneous pregnancy resolution could be predicted at the initial visit with a sensitivity and specificity of 92%. CONCLUSIONS: The majority of pregnancies of unknown location are abnormal: many resolve spontaneously when managed expectantly. A logistic model may be used at the initial visit to identify those cases in which the pregnancy is likely to resolve without the need for intervention.     

No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics

OBJECTIVE: The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. METHOD: The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. RESULTS: Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. CONCLUSIONS: It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out.