Elevated pCO2 and Hypoxia Alter the Acid-Base Homeostasis of Developing Sheepshead Minnows, Cyprinodon variegatus.

Low dissolved oxygen and increased acidification are two environmental variables that concomitantly change in an estuarine environment, both of which are exacerbated by nutrient pollution and subsequent eutrophication. To better understand how estuarine residents compensate for daily fluctuations in these environmental variables, the interactive effects of acidification and hypoxia were assessed in developing sheepshead minnows (Cyprinodon variegatus) using a 2 by 2 factorial design over a 42-day exposure. Embryos were exposed to either acidic (partial pressure of CO2, pCO2, ~2000 µatm), hypoxic (reduced dissolved oxygen, ~2 mg l-1), or combined acidic and hypoxic conditions and monitored for development, hatch rate, and survival. Changes in oxygen consumption, anaerobic metabolism, oxidative stress, and acid-base balance were evaluated at three life stages (embryo, larval, and juvenile fish) to discern if and how fish compensate for these stressors during development. The combination of acidification and hypoxia delayed hatching in embryos and significantly decreased oxygen consumption (p<0.001) in all three life-stages. Neither acidification, hypoxia, nor the combination of the stressors impacted the anaerobic metabolism or oxidative stress of juvenile fish, but acid-base equilibrium was disrupted by all three treatments in larval fish. Elevated carbonic anhydrase activity was observed in the multi-stress treatment in embryos and larval fish, but not in juvenile fish. These results show that developing sheepshead minnows can re-establish cellular homeostasis in compensating to acidified and hypoxic waters.

Activation of C3a receptor is required in cigarette smoke-mediated emphysema.

Exposure to cigarette smoke can initiate sterile inflammatory responses in the lung and activate myeloid dendritic cells (mDCs) that induce differentiation of T helper type 1 (Th1) and Th17 cells in the emphysematous lungs. Consumption of complement proteins increases in acute inflammation, but the contribution of complement protein 3 (C3) to chronic cigarette smoke-induced immune responses in the lung is not clear. Here, we show that following chronic exposure to cigarette smoke, C3-deficient (C3(-/-)) mice develop less emphysema and have fewer CD11b(+)CD11c(+) mDCs infiltrating the lungs as compared with wild-type mice. Proteolytic cleavage of C3 by neutrophil elastase releases C3a, which in turn increases the expression of its receptor (C3aR) on lung mDCs. Mice deficient in the C3aR (C3ar(-/-)) partially phenocopy the attenuated responses to chronic smoke observed in C3(-/-) mice. Consistent with a role for C3 in emphysema, C3 and its active fragments are deposited on the lung tissue of smokers with emphysema, and smoke-exposed mice. Together, these findings suggest a critical role for C3a through autocrine/paracrine induction of C3aR in the pathogenesis of cigarette smoke-induced sterile inflammation and provide new therapeutic targets for the treatment of emphysema.

Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families.

The purpose of this study was to examine colonoscopy adherence and attitudes toward colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation negative and 26 mutation positive). While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. To conclude, adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence.

Interplay between polymorphisms and methylation in the H19/IGF2 gene region may contribute to obesity in Mexican-American children.

Imprinted genes often affect body size-related traits such as weight. However, the association of imprinting with obesity, especially childhood obesity, has not been well studied. Mexican-American children have a high prevalence, approaching 50%, of obesity and/or overweight. In a pilot study of 75 Mexican-American children, we analyzed the relationships among obese/overweight status, methylation status and single-nucleotide polymorphism (SNP) status at a CpG site in a differentially methylated region (DMR) of the imprinted H19/IGF2 locus. We observed a significant difference in SNP rs10732516 frequency between boys and girls among the overweight and obese children but not among the lean children. We also found that children with lower methylation of the polymorphic CpG site (CpG4) in the H19 DMR had higher birth weights than did children with higher methylation (P = 0.04). Our results suggest that CpG4 methylation status may be associated with childhood obesity in Mexican-American children in a sex-specific manner.

Social disruption induced priming of CNS inflammatory response to Theiler's virus is dependent upon stress induced IL-6 release.

Chronic social disruption stress (SDR) exacerbates acute and chronic phase Theiler's murine encephalomyelitis virus (TMEV) infection, a mouse model of multiple sclerosis. However, the precise mechanism by which this occurs remains unknown. The present study suggests that SDR exacerbates TMEV disease course by priming virus-induced neuroinflammation. It was demonstrated that IL-1ß mRNA expression increases following acute SDR; however, IL-6 mRNA expression, but not IL-1ß, is upregulated in response to chronic SDR. Furthermore, this study demonstrated SDR prior to infection increases infection related central IL-6 and IL-1ß mRNA expression, and administration of IL-6 neutralizing antibody during SDR reverses this increase in neuroinflammation.

Evolutionary evidence of the effect of rare variants on disease etiology.

The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.

Surgical treatment of partial distal biceps tendon ruptures.

PURPOSE: To demonstrate that surgical repair of partial distal biceps tendon ruptures allows return of supination and flexion strength nearly equal to the contralateral side without compromising range of motion. METHODS: We performed a retrospective study of 17 patients with unilateral partial biceps tendon ruptures who underwent surgical repair between 2003 and 2009, and who returned for further evaluation and strength testing. The follow-up examination included questionnaires, x-rays, strength testing, and range of motion with comparison to the opposite side. We used the Baltimore Therapeutic Equipment work simulator to objectively test isometric and dynamic elbow flexion and forearm supination strength of both extremities. RESULTS: A total of 17 patients returned for additional testing, 14 of whom had failed nonsurgical treatment. One patient had asymptomatic heterotopic ossification. Two patients reported mild lateral antebrachial cutaneous nerve dysesthesias. There was one partial re-rupture 4 years after the original surgery. The second repair consisted of suture anchor fixation; 15 months after re-repair, the patient remains asymptomatic. Average postoperative Disabilities of the Arm, Shoulder, and Hand score was 9 (range, 0-33). One patient had limited pronation (50 degrees degrees). The average isometric and dynamic elbow flexion was 3% and 11% stronger, respectively, compared with the opposite side. Average isometric supination was 6% and average dynamic supination was 10% weaker. CONCLUSIONS: After surgical treatment of partial distal biceps tendon tears, most patients achieved good return of strength with full motion. Surgical treatment of partial distal biceps tendon tears is a viable option after failed nonsurgical treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Work stressors, role-based performance, and the moderating influence of organizational support.

As a test of the 2-dimensional model of work stressors, the present study proposed differential relationships between challenge stressors and hindrance stressors and role-based performance, which were expected to be moderated by organizational support. In a sample of 215 employees across 61 offices of a state agency, the authors obtained a positive relationship between challenge stressors and role-based performance and a negative relationship between hindrance stressors and role-based performance. In addition, organizational support moderated the relationship between challenge stressors and role-based performance but did not moderate the relationship between hindrance stressors and role-based performance. This suggests that organizations would benefit from increasing challenges in the workplace as long as they are supportive of employees and removing hindrances. Further implications for organizational theory and practice are discussed. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Post-resuscitation complications in term neonates.

OBJECTIVE: It has been recommended that all newborn babies who have received substantial resuscitation be cared for in an environment where post-resuscitation care can be provided. To test this recommendation, we examined whether infants who received delivery room resuscitation and seemingly recovered by 5 min age are at increased risk of short-term morbidity. STUDY DESIGN: We undertook a retrospective analysis of the outcomes of babies who received delivery room resuscitation, and who had seemingly recovered by 5 min age, over a 1 year time period at a single academic institution. The 33 babies were compared with outcomes of 33 controls who received no resuscitation with normal 1 and 5 min Apgar scores. Complication rates and admissions to the neonatal intensive care unit (NICU) were compared between the two groups using the chi2 test. RESULTS: Fifty-two percent of the study group and three percent of the control group were admitted to the NICU (P<0.01). Short-term complications were noted in 61% of the study group and three percent of the control group (P<0.01). CONCLUSION: Increased short-term morbidity is demonstrated in neonates who receive delivery room resuscitation and are seemingly recovered at 5 min, when compared to a group of infants with normal Apgar scores at one and 5 min; and these infants should be cared for in an environment where ongoing evaluation can be provided.

Thermodynamics constrains the evolution of insect population growth rates: "warmer is better".

Diverse biochemical and physiological adaptations enable different species of ectotherms to survive and reproduce in very different temperature regimes, but whether these adaptations fully compensate for the thermodynamically depressing effects of low temperature on rates of biological processes is debated. If such adaptations are fully compensatory, then temperature-dependent processes (e.g., digestion rate, population growth rate) of cold-adapted species will match those of warm-adapted species when each is measured at its own optimal temperature. Here we show that cold-adapted insect species have much lower maximum rates of population growth than do warm-adapted species, even when we control for phylogenetic relatedness. This pattern also holds when we use a structural-equation model to analyze alternative hypotheses that might otherwise explain this correlation. Thus, although physiological adaptations enable some insects to survive and reproduce at low temperatures, these adaptations do not overcome the "tyranny" of thermodynamics, at least for rates of population increase. Indeed, the sensitivity of population growth rates of insects to temperature is even greater than predicted by a recent thermodynamic model. Our findings suggest that adaptation to temperature inevitably alters the population dynamics of insects. This result has broad evolutionary and ecological consequences.

Genotype-phenotype correlations in Peutz-Jeghers syndrome.

BACKGROUND AND AIMS: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated. METHODS: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. RESULTS: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. CONCLUSION: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1.

Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1.

Interactive effects of rearing temperature and oxygen on the development of Drosophila melanogaster.

Although higher temperatures strongly stimulate ectothermic metabolic rates, they only slightly increase oxygen diffusion rates and decrease oxygen solubility. Consequently, we predicted that insect gas exchange systems would have more difficulty meeting tissue oxygen demands at higher temperatures. In this study, Drosophila melanogaster were reared from egg to adult in hyperoxic (40%), hypoxic (10%), and normoxic (21%) conditions and in temperatures ranging from 15 degrees -31.5 degrees C to examine the interactive effect of temperature and oxygen on development. Hyperoxia generally increased mass and growth rate at higher rearing temperatures. At lower rearing temperatures, however, hyperoxia had a very small effect on mass, did not affect growth rate, and lengthened time to eclosion. Relative to normoxia, flies reared in hypoxic conditions were generally smaller (mass and thorax length), had longer eclosion times, slower growth rates, and reduced survival. At cooler temperatures, hypoxia had relatively modest or nonsignificant effects on development, while at higher temperatures, the effects of hypoxia were large. These results suggest that higher temperatures reduce oxygen delivery capacity relative to tissue oxygen needs, which may partially explain why ectotherms are smaller when development occurs at higher temperatures.

Cyclin D1 polymorphism and risk for squamous cell carcinoma of the head and neck: a case-control study.

A G-->A polymorphism (G870A) in exon 4 of the cyclin D1 (CCND1) gene creates an alternative splice site in its mRNA, encoding a protein with an altered C-terminal domain. It has been suggested that DNA damage in cells with the A allele bypasses the G(1)/S checkpoint of the cell cycle more easily than damage in cells without the A allele. Because CCND1 plays a critical role in cell cycle control and reduced DNA repair capacity is associated with an increased risk for squamous cell carcinoma of the head and neck (SCCHN), we hypothesize that this CCND1 polymorphism modulates individual susceptibility to SCCHN. To test this hypothesis we evaluated the frequency of the polymorphism in a hospital-based case-control study of 233 newly diagnosed SCCHN patients and 248 non-cancer controls. The cases and controls were frequency matched by age (+/-5 years), sex and tobacco use. All subjects were non-Hispanic whites. We found that the A allele frequency was slightly higher in the cases (0.485) than in the controls (0.425), but the difference was borderline statistically significant (P = 0.064). The frequencies of the CCND1 AA, GA and GG genotypes were 23.6, 49.8 and 26.6%, respectively, in cases and 16.5, 52.5 and 31.5%, respectively, in controls. Multivariate logistic regression analysis adjusting for age (in years), sex, smoking and alcohol use was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Compared with the wild-type CCND1 GG, the CCND1 A G genotype was associated with a non-significantly increased risk (adjusted OR 1.15, 95% CI 0.75-1.76), but the CCND1 AA genotype was associated with a significantly increased risk (adjusted OR 1.77, 95% CI 1.04-3.02) for SCCHN. Results from a trend test using a logistic regression model were statistically significant (P = 0.044). Among the cases the mean age of onset was 59.0, 56.8 and 55.5 years for the GG, GA and AA genotypes, respectively. In the stratification analysis the CCND1 AA variant genotype was associated with a >3-fold increased risk in individuals who were

Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes.

Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects.

Human pancreatic ribonuclease 1: expression and distribution in pancreatic adenocarcinoma.

BACKGROUND: Human pancreatic ribonuclease (RNase 1) is a pancreatic enzyme that is present at high levels in the serum of most patients with pancreatic adenocarcinoma. For this reason, the authors studied its patterns of expression at the single-cell level in pancreatic adenocarcinoma tissues by immunohistochemical analysis and in situ hybridization (ISH). METHODS: Immunohistochemical analysis with polyclonal antibodies against RNase 1 and by ISH with digoxigenin-labeled RNase 1 probe were used to detect RNase 1 in the neoplastic cells of ductal type pancreatic adenocarcinomas. RESULTS: Fifteen of 18 carcinoma samples were positive for RNase 1, demonstrating that the expression of ribonuclease that the authors observed previously in human pancreatic adenocarcinoma cell lines was not an artifact of cell culture. The authors also found RNase 1 in some of the metaplastic ducts and atrophic islets in 4 of 6 chronic pancreatitis samples, and they observed RNase 1 immunostaining in hyperplastic ducts adjacent to one of the well-differentiated adenocarcinomas. CONCLUSIONS: The expression levels of RNase 1 by tumor cells from pancreatic adenocarcinomas are consistent with the high RNase 1 levels found in the serum of most patients with pancreatic adenocarcinoma. This expression of RNase 1, which is an acinar protein, demonstrates that the patterns of gene expression in pancreatic adenocarcinoma are distinct from those of normal pancreatic duct cells. Conversely, RNase 1 expression levels in altered ductal cells from some chronic pancreatitis tissues and hyperplastic ducts from carcinoma tissues suggest that abnormal expression levels may be an early event in pancreatic tumorigenesis.

A sequential sampling scheme for detecting infestation levels of tracheal mites (Heterostigmata: Tarsonemidae) in honey bee (Hymenoptera: Apidae) colonies.

The introduction of parasitic honey bee mites, the tracheal mite, Acarapis woodi (Rennie) in 1984 and the Varroa mite, Varroa jacobsoni, in 1987, has dramatically increased the winter mortality of honey bee, Apis mellifera L., colonies in many areas of the United States. Some beekeepers have minimized their losses by routinely treating their colonies with menthol, currently the only Environmental Protection Agency-approved and available chemical for tracheal mite control. Menthol is also expensive and can interfere with honey harvesting. Because of inadequate sampling techniques and a lack of information concerning treatment, this routine treatment strategy has increased the possibility that tracheal mites will develop resistance to menthol. It is important to establish economic thresholds and treat colonies with menthol only when treatment is warranted rather than treating all colonies regardless of infestation level. The use of sequential sampling may reduce the amount of time and effort expended in examining individual colonies and determining if treatment is necessary. Sequential sampling also allows statistically based estimates of the percentage of bees in standard Langstroth hives infested with mites while controlling for the possibility of incorrectly assessing the amount of infestation. On the average, sequential sampling plans require fewer observations (bees) to reach a decision for specified probabilities of type I and type II errors than are required for fixed sampling plans, especially when the proportion of infested bees is either very low or very high. We developed a sequential sampling decision plan to allow the user to choose specific economic injury levels and the probability of making type I and type II errors which can result inconsiderable savings in time, labor and expense.