Chronic hypothermia and energy expenditure in a neurodevelopmentally disabled patient: a case study

Hypothermia is defined as a core body temperature of \u3c35°C and results in a decrease in measured resting energy expenditure. A 51-year-old mentally disabled patient experienced chronic hypothermia from neurologic sequelae. Because of her continued weight gain and increased body fat in the presence of presumed hypocaloric nutrition, indirect calorimetry measurements were performed twice in a 3-month period. The resting energy expenditure measurements prompted a reduction of her daily caloric intake to prevent further overfeeding. Hypothermia reduces oxygen consumption and, as a consequence, decreases resting energy expenditure. In patients for whom chronic hypothermia is a problem, nutritional intake must be adjusted to prevent overfeeding, excessive weight gain, and the long-term complications of an excess of total calories

Co-Localization of the Oncogenic Transcription Factor MYCN and the DNA Methyl Binding Protein MeCP2 at Genomic Sites in Neuroblastoma

MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma. MeCP2 is a CpG methyl binding protein which has been associated with a number of cancers and developmental disorders, particularly Rett syndrome.Using an integrative global genomics approach involving chromatin immunoprecipitation applied to microarrays, we have determined that MYCN and MeCP2 co-localize to gene promoter regions, as well as inter/intragenic sites, within the neuroblastoma genome (MYCN amplified Kelly cells) at high frequency (70.2% of MYCN sites were also positive for MeCP2). Intriguingly, the frequency of co-localization was significantly less at promoter regions exhibiting substantial hypermethylation (8.7%), as determined by methylated DNA immunoprecipitation (MeDIP) applied to the same microarrays. Co-immunoprecipitation of MYCN using an anti-MeCP2 antibody indicated that a MYCN/MeCP2 interaction occurs at protein level. mRNA expression profiling revealed that the median expression of genes with promoters bound by MYCN was significantly higher than for genes bound by MeCP2, and that genes bound by both proteins had intermediate expression. Pathway analysis was carried out for genes bound by MYCN, MeCP2 or MYCN/MeCP2, revealing higher order functions.Our results indicate that MYCN and MeCP2 protein interact and co-localize to similar genomic sites at very high frequency, and that the patterns of binding of these proteins can be associated with significant differences in transcriptional activity. Although it is not yet known if this interaction contributes to neuroblastoma disease pathogenesis, it is intriguing that the interaction occurs at the promoter regions of several genes important for the development of neuroblastoma, including ALK, AURKA and BDNF

Inhibition of Neuroblastoma Tumor Growth by Targeted Delivery of MicroRNA-34a Using Anti-Disialoganglioside GD2 Coated Nanoparticles

Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2)), providing a target for tumor-specific delivery.Nanoparticles encapsulating miR-34a and conjugated to a GD(2) antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors.These novel findings highlight the potential of anti-GD(2)-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2)-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth

Changing Patterns of Microhabitat Utilization by the Threespot Damselfish, Stegastes planifrons, on Caribbean Reefs

Background: The threespot damselfish, Stegastes planifrons (Cuvier), is important in mediating interactions among corals, algae, and herbivores on Caribbean coral reefs. The preferred microhabitat of S. planifrons is thickets of the branching staghorn coral Acropora cervicornis. Within the past few decades, mass mortality of A. cervicornis from white-band disease and other factors has rendered this coral a minor ecological component throughout most of its range. Methodology/Principal Findings: Survey data from Jamaica (heavily fished), Florida and the Bahamas (moderately fished), the Cayman Islands (lightly to moderately fished), and Belize (lightly fished) indicate that distributional patterns of S. planifrons are positively correlated with live coral cover and topographic complexity. Our results suggest that speciesspecific microhabitat preferences and the availability of topographically complex microhabitats are more important than the abundance of predatory fish as proximal controls on S. planifrons distribution and abundance. Conclusions/Significance: The loss of the primary microhabitat of S. planifrons—A. cervicornis—has forced a shift in the distribution and recruitment of these damselfish onto remaining high-structured corals, especially the Montastraea annulari

Childhood Predictors of Desistance and Level of Persistence in Offending in Early Onset Offenders

Childhood predictors of adolescent offending careers were studied in 310 boys from the longitudinal Pittsburgh Youth Study who started offending prior to age 12. Three main groups were distinguished: serious persisters (n = 95), moderately serious persisters (n = 117), desisters (n = 63), and an intermittent group (n = 35). Group membership was predicted using risk and promotive factors measured in childhood. Serious and moderately serious persisters could be distinguished well from desisters (29.2% and 32.3% explained variance). Distinction between the two persister groups proved somewhat more difficult (20.9% explained variance). More serious persisters than desisters showed disruptive behavior, while moderately serious persisters fell in between. Further, more moderately serious persisters were marked by social disadvantage. Family involvement, small family and positive peer relationships were promotive of desistance. Concluding, early onset offenders show considerable heterogeneity in their adolescent offending careers which seem to some extent to be predicted by different sets of risk and promotive factors

Carpal tunnel syndrome and the "double crush" hypothesis: a review and implications for chiropractic

Upton and McComas claimed that most patients with carpal tunnel syndrome not only have compressive lesions at the wrist, but also show evidence of damage to cervical nerve roots. This "double crush" hypothesis has gained some popularity among chiropractors because it seems to provide a rationale for adjusting the cervical spine in treating carpal tunnel syndrome. Here I examine use of the concept by chiropractors, summarize findings from the literature, and critique several studies aimed at supporting or refuting the hypothesis. Although the hypothesis also has been applied to nerve compressions other than those leading to carpal tunnel syndrome, this discussion mainly examines the original application – "double crush" involving both cervical spinal nerve roots and the carpal tunnel. I consider several categories: experiments to create double crush syndrome in animals, case reports, literature reviews, and alternatives to the original hypothesis. A significant percentage of patients with carpal tunnel syndrome also have neck pain or cervical nerve root compression, but the relationship has not been definitively explained. The original hypothesis remains controversial and is probably not valid, at least for sensory disturbances, in carpal tunnel syndrome. However, even if the original hypothesis is importantly flawed, evaluation of multiple sites still may be valuable. The chiropractic profession should develop theoretical models to relate cervical dysfunction to carpal tunnel syndrome, and might incorporate some alternatives to the original hypothesis. I intend this review as a starting point for practitioners, educators, and students wishing to advance chiropractic concepts in this area

Does smoking among friends explain apparent genetic effects on current smoking in adolescence and young adulthood?

We used data from a prospective cohort study of twins to investigate the influence of unmeasured genetic and measured and unmeasured environmental factors on the smoking behaviour of adolescents and young adults. Twins were surveyed in 1988 (aged 11–18 years), 1991, 1996 and 2004 with data from 1409, 1121, 732 and 758 pairs analysed from each survey wave, respectively. Questionnaires assessed the smoking behaviour of twins and the perceived smoking behaviour of friends and parents. Using a novel logistic regression analysis, we simultaneously modelled individual risk and excess concordance for current smoking as a function of zygosity, survey wave, parental smoking and peer smoking. Being concordant for having peers who smoked was a predictor of concordance for current smoking (P<0.001). After adjusting for peer smoking, monozygotic (MZ) pairs were no more alike than dizygotic pairs for current smoking at waves 2, 3 and 4. Genetic explanations are not needed to explain the greater concordance for current smoking among adult MZ pairs. However, if they are invoked, the role of genes may be due to indirect effects acting through the social environment. Smoking prevention efforts may benefit more by targeting social factors than attempting to identify genetic factors associated with smoking

Phospholipase C Isozymes Are Deregulated in Colorectal Cancer – Insights Gained from Gene Set Enrichment Analysis of the Transcriptome

Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer

Improving educational achievement and anaemia of school children: design of a cluster randomised trial of school-based malaria prevention and enhanced literacy instruction in Kenya

BACKGROUND: Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence on the benefits of school-based malaria prevention or how health interventions interact with other efforts to improve education quality. This study aims to evaluate the impact of school-based malaria prevention and enhanced literacy instruction on the health and educational achievement of school children in Kenya. DESIGN: A factorial, cluster randomised trial is being implemented in 101 government primary schools on the coast of Kenya. The interventions are (i) intermittent screening and treatment of malaria in schools by public health workers and (ii) training workshops and support for teachers to promote explicit and systematic literacy instruction. Schools are randomised to one of four groups: receiving either (i) the malaria intervention alone; (ii) the literacy intervention alone; (iii) both interventions combined; or (iv) control group where neither intervention is implemented. Children from classes 1 and 5 are randomly selected and followed up for 24 months. The primary outcomes are educational achievement and anaemia, the hypothesised mediating variables through which education is affected. Secondary outcomes include malaria parasitaemia, school attendance and school performance. A nested process evaluation, using semi-structured interviews, focus group discussion and a stakeholder analysis will investigate the community acceptability, feasibility and cost-effectiveness of the interventions. DISCUSSION: Across Africa, governments are committed to improve health and education of school-aged children, but seek clear policy and technical guidance as to the optimal approach to address malaria and improved literacy. This evaluation will be one of the first to simultaneously evaluate the impact of health and education interventions in the improvement of educational achievement. Reflection is made on the practical issues encountered in conducting research in schools in Africa. TRIAL REGISTRATION: National Institutes of Health NCT00878007

Large-Scale Absence of Sharks on Reefs in the Greater-Caribbean: A Footprint of Human Pressures

BACKGROUND: In recent decades, large pelagic and coastal shark populations have declined dramatically with increased fishing; however, the status of sharks in other systems such as coral reefs remains largely unassessed despite a long history of exploitation. Here we explore the contemporary distribution and sighting frequency of sharks on reefs in the greater-Caribbean and assess the possible role of human pressures on observed patterns. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 76,340 underwater surveys carried out by trained volunteer divers between 1993 and 2008. Surveys were grouped within one km2 cells, which allowed us to determine the contemporary geographical distribution and sighting frequency of sharks. Sighting frequency was calculated as the ratio of surveys with sharks to the total number of surveys in each cell. We compared sighting frequency to the number of people in the cell vicinity and used population viability analyses to assess the effects of exploitation on population trends. Sharks, with the exception of nurse sharks occurred mainly in areas with very low human population or strong fishing regulations and marine conservation. Population viability analysis suggests that exploitation alone could explain the large-scale absence; however, this pattern is likely to be exacerbated by additional anthropogenic stressors, such as pollution and habitat degradation, that also correlate with human population. CONCLUSIONS/SIGNIFICANCE: Human pressures in coastal zones have lead to the broad-scale absence of sharks on reefs in the greater-Caribbean. Preventing further loss of sharks requires urgent management measures to curb fishing mortality and to mitigate other anthropogenic stressors to protect sites where sharks still exist. The fact that sharks still occur in some densely populated areas where strong fishing regulations are in place indicates the possibility of success and encourages the implementation of conservation measures