Palatogenesis and potential mechanisms for clefting

This review concentrates on mechanisms of palatogenesis. This includes theories of shelf elevation, the role of matrix and identification of molecules and growth factors, which have key roles. The areas where failure to develop could potentially lead to clefting are highlighted. A key part of shelf fusion is the breakdown of the medial edge epithelium, a process that is probably dependent on enzymes involved in matrix turnover. There is good evidence that the matrix metalloproteinases may provide a common link to the multiple genetic and environmental factors that are known to cause clefting.     

Methylamine but not mafenide mimics insulin-like activity of the semicarbazide-sensitive amine oxidase-substrate benzylamine on glucose tolerance and on human adipocyte metabolism

It has been reported that benzylamine reduces blood glucose in rabbits, stimulates hexose uptake, and inhibits lipolysis in mouse, rabbit, and human adipocytes. In the presence of vanadate, benzylamine is also able to improve glucose disposal in normoglycaemic and diabetic rats. Such insulin-mimicking properties are the consequence of hydrogen peroxide production during benzylamine oxidation by semicarbazide-sensitive amine oxidase (SSAO). The aim of the study was to determine whether other SSAO-substrates could share such potential antidiabetic properties. Thus, mafenide, a synthetic antimicrobial sulfonamide structurally related to benzylamine, and which has been recently reported to interact with SSAO, was tested in the above mentioned models, in parallel with methylamine, a proposed endogenous SSAO-substrate. All tested amines stimulated glucose uptake and inhibited lipolysis in rat and mouse fat cells. Methylamine and benzylamine, but not mafenide, reduced the hyperglycaemic response during a glucose tolerance test in rabbits while the three amines tested were devoid of insulin-releasing activity under both in vivo and in vitro conditions. In human adipocytes, mafenide did not stimulate glucose transport since it was not a high-affinity substrate for SSAO and generated less hydrogen peroxide than benzylamine or methylamine. Therefore, mafenide could not be considered as an antidiabetic drug despite being oxidized and exhibiting insulin-mimicking effects in rat and mouse adipocytes. By contrast, the endogenous substrate methylamine improved glucose utilization in all in vitro and in vivo models, leading to consider novel SSAO substrates as drugs with potential anti-hyperglycaemic properties.     

The roles of transporters and enzymes in hepatic drug processing.

A simple, physiological model was used to illustrate the competing nature of transporters and metabolic enzymes in hepatic drug processing. Enalapril, a drug whose basolateral influx and canalicular efflux are mediated by rat organic anion-transporting polypeptide 1 (Oatp1) and rat multidrug resistance-associated protein 2 (Mrp2), respectively, and metabolism by the carboxylesterases, was enlisted as the example to illustrate how the transport and intrinsic clearances are inter-related in the estimation of the hepatic and metabolic, and excretion clearances. Moreover, simulations were performed to explore the effects of inhibitors or inducers of transporters/enzymes to unravel the compensatory changes of alternate pathways. Generally speaking, inhibition of one pathway led to an apparent increase in the alternate (competing) pathway and total hepatic clearance was decreased; induction would lead to an apparent decrease in the alternate pathway and an increase in total hepatic clearance. A reduction in influx clearance brought about parallel decreases in the biliary and metabolic clearances, whereas a reduction in efflux basolateral clearance evoked similar increases in biliary and metabolic clearances. However, the steady-state tissue concentration (C(L,ss)) or area under the tissue concentration-time curve (AUC(L)) was reliant only on the unbound fraction in liver, and the secretory and metabolic intrinsic clearances and not the influx and efflux clearances. Variations in the influx and efflux intrinsic clearances evoked temporal changes in the tissue concentration-time profile but not the AUC(L) or C(L,ss). The pharmacokinetic theory developed offers data interpretation from literature reports on P-glycoprotein and cytochrome P450 substrates with mdr1a/1b knockout versus wild-type mice, and rat liver perfusion studies, with and without the use of inhibitors. In some cases, critiques on data interpretation were made.     

Cytokine expression in response to bacterial antigens in preterm and term infant cord blood monocytes

BACKGROUND: Neonatal susceptibility to bacterial infection is associated with an immature immune system, but the role of different bacterial antigens in specific responses is largely unknown. OBJECTIVE: To evaluate differences in intracellular cytokine response to physiologically relevant bacterial antigens in term and preterm infants as compared with adults. METHODS: Cord blood samples from preterm and term neonates and adult peripheral blood samples were cultured ex vivo with and without whole heat-killed bacteria. Intracellular leukocyte production of interleukin (IL)-6, IL-10, IL-12, and IL-8 responses was assessed by flow cytometry. RESULTS: Monocytes were the primary producers of all mediators. Escherichia coli was the most potent stimulant. Lactobacillus plantarum 299v activated fewer monocytes as compared with E. coli for all responses (p < 0.05), except for IL-12 in term neonates. IL-6 response to Staphylococcus epidermidis was lower in both groups of neonates as compared with adults (p = 0.023 and p = 0.001). IL-8 response to S. epidermidis was lower in term as compared with preterm neonates and adults (p = 0.003). IL-10 response to group B streptococci was lower in term neonates as compared with adults and higher in preterm as compared with term neonates (p = 0.015). CONCLUSIONS: Monocytes from term neonates compared to preterm neonates show a downregulated anti-inflammatory response to specific bacteria. High neonatal response to pathogenic E. coli in the preterm infant could cause uncontrolled inflammatory response, while lower IL-6 response to S. epidermidis in neonates may indicate a basis for vulnerability to S. epidermidis infection.     

Perceived stigma and quality of life in Parkinson’s disease with additional health conditions

BackgroundParkinson’s disease (PD) is associated with perceived stigma and affects quality of life (QoL). Additional health conditions may influence these consequences of PD.AimsThis study assessed the impact of health conditions on perceived stigma and QoL in persons with PD. We hypothesised that individuals with more health conditions would report more stigma and poorer QoL. We also examined the contributions of demographic and clinical characteristics to the correlations between health conditions and perceived stigma/QoL.MethodsWe identified 196 eligible participants from the Boston University Online Survey Study of Parkinson’s Disease and examined their health history, performance on multiple stigma measures, and scores on the 39-item Parkinson’s Disease Questionnaire assessing QoL.ResultsAt least one health condition was reported by 79% of the sample, with a median of 2 and a range of 0–7 health conditions. More perceived stigma and poorer QoL were associated with thyroid disease, depression, anxiety, and the total number of health conditions. These correlations were related to younger age, less education, and earlier disease onset. Other health conditions (high blood pressure, back/leg surgery, headache, cancer/tumours, and heart disease) were not significantly correlated with stigma or QoL.ConclusionsHaving more health conditions, or thyroid disease, depression, or anxiety, was associated with more perceived stigma and poorer QoL, with younger age, less education, and earlier disease onset affecting the associations. It is important to consider the burden of health conditions and how they affect persons with PD with specific clinical characteristics.     

Protectiveness of species sensitivity distribution hazard concentrations for acute toxicity used in endangered species risk assessment

A primary objective of threatened and endangered species conservation is to ensure that chemical contaminants and other stressors do not adversely affect listed species. Assessments of the ecological risks of chemical exposures to listed species often rely on the use of surrogate species, safety factors, and species sensitivity distributions (SSDs) of chemical toxicity; however, the protectiveness of these approaches can be uncertain. We comprehensively evaluated the protectiveness of SSD first and fifth percentile hazard concentrations (HC1, HC5) relative to the application of safety factors using 68 SSDs generated from 1,482 acute (lethal concentration of 50%, or LC50) toxicity records for 291 species, including 24 endangered species (20 fish, four mussels). The SSD HC5s and HCls were lower than 97 and 99.5% of all endangered species mean acute LC50s, respectively. The HC5s were significantly less than the concentrations derived from applying safety factors of 5 and 10 to rainbow trout (Oncorhynchus mykiss) toxicity data, and the HCls were generally lower than the concentrations derived from a safety factor of 100 applied to rainbow trout toxicity values. Comparison of relative sensitivity (SSD percentiles) of broad taxonomic groups showed that crustaceans were generally the most sensitive taxa and taxa sensitivity was related to chemical mechanism of action. Comparison of relative sensitivity of narrow fish taxonomic groups showed that standard test fish species were generally less sensitive than salmonids and listed fish. We recommend the use of SSDs as a distribution-based risk assessment approach that is generally protective of listed species.     

Association between state physical education (PE) requirements and PE participation,physical activity,and body mass index change

Objective

To determine if state physical education (PE) laws are associated with student physical education attendance and physical activity (PA), and whether physical education and competitive food laws, in conjunction, are associated with lower BMI change.

Method

State laws regarding physical education time requirements and competitive foods in 2003 and 2006 were classified as strong, weak, or none, based on codified law ratings obtained from the Classification of Laws Associated with School Students. Laws were linked to student data on PE attendance and physical activity (8th grade, Spring 2007) and BMI change (5th–8th grade, 2004–2007), obtained from the Early Childhood Longitudinal Study (n = 5510 students in 40 states).

Results

Girls reported 0.31 more days of activity (95% CI: 0.02, 0.61) and were more likely to attend physical education ≥ 3 days/week (74.1% versus 52.1%, difference = 22.0, 95% CI: 2.1, 42.0) if they resided in states with strong physical education laws compared to no physical education laws. Weak physical education laws had modest associations with PE and activity, and there was no evidence that weak laws reduce BMI gain regardless of competitive food laws.

Conclusion

Strong physical education laws with specific time requirements may increase physical education attendance and activity in girls. There is insufficient evidence that physical education laws reduce student weight gain.     

Measuring health outcomes of adolescents: report from a pilot study

There is a need to understand the practicality, validity and reliability of using utility measures with children and adolescents. We designed a pilot study in order to help guide the selection of an appropriate health-related quality-of-life (HRQoL) questionnaire for adolescents to be used in the context of a large randomised controlled trial (RCT) of family therapy versus standard treatment for adolescents aged 11–17 years. The pilot study was carried out on a school sample of adolescents in the same age range as the RCT. Adolescents were asked to fill in three HRQoL questionnaires: the standard EQ-5D, the licensed Health Utilities Index HUI, and the child-friendly version of the standard EQ-5D: the EQ-5D for youth (EQ-5D-Y). This report explores the problems with the language and concepts embodied within those HRQoL questionnaires and open discussion regarding how we can value the health of adolescents for cost-utility analysis in a larger study.