Sustained esophageal longitudinal smooth muscle contraction may not be a cause of noncardiac chest pain.

BACKGROUND: The etiology of noncardiac chest pain (NCCP) is poorly understood. Some evidence suggests that it may be related to sustained esophageal contractions (SECs) of longitudinal smooth muscle. This study attempts to evaluate whether SECs play a role in symptom production in NCCP patients. METHODS: This was a prospective double-blind study comparing NCCP patients to healthy controls. Subjects underwent high-resolution esophageal manometry followed by infusions of normal saline and 0.1N hydrochloric acid into the esophagus. Pain intensity was recorded during each minute of the infusion using a visual analog scale between 0 and 10. Two blinded investigators measured the esophageal length at the end of the saline and acid infusion periods as well as the point at which esophageal shortening began using the computer based manometry software. KEY RESULTS: Seventeen NCCP patients and 16 controls completed the study. 64% of study subjects demonstrated esophageal shortening in response to acid infusion with mean shortening of 0.4 ± 0.54 cm. The mean decrease in esophageal length with acid was similar between the groups (1.9% ± 2.6% for NCCP patients vs 1.7% ± 2.4% for controls, P = .82). There was no correlation between pain onset and esophageal shortening. CONCLUSIONS AND INFERENCES: NCCP patients did not appear to have an exaggerated esophageal shortening response to intraluminal acid. As well, there was poor temporal correlation between esophageal shortening and symptoms. Thus, acid-induced SECs may not play a significant role in pain production in NCCP patients.

HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease.

BACKGROUND: Azathioprine (AZA)-induced pancreatitis is an unpredictable and dose-independent adverse event affecting 2%-7% of patients with inflammatory bowel disease (IBD) patients treated with AZA. There are no tools in clinical practice to identify at-risk individuals; however, a genome wide association study (GWAS) identified a strong association between the Class II HLA gene region polymorphism (rs2647087) and thiopurine-induced pancreatitis. AIM: To independently confirm the findings of the GWAS in an IBD cohort, to evaluate its utility in clinical practice and to offer a novel AZA treatment algorithm for IBD based on pharmacogenomic principles. METHODS: A retrospective cohort study evaluated 373 AZA-exposed IBD patients from a tertiary care academic centre in London, Canada. Due to the limited number of patients taking mercaptopurine (MP), such patients were not included this cohort. All subjects underwent screening for the single nucleotide polymorphism (SNP) rs2647087 mapped to the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype and were sub-divided based on the presence (n = 13) or absence (n = 360) of an AZA-induced pancreatitis diagnosis. The risk of AZA-induced pancreatitis was assessed based on rs2647087 genotype. RESULTS: The risk of pancreatitis during AZA-therapy was highly predictable and genotype dependent: 0.53% for wild type (A/A), 4.25% (OR = 4.19, 95% CI 1.02-36.45, P = 0.044) for heterozygous (A/C), and 14.63% (OR = 15.83, 95% CI 3.80-145.26, P = 0.0001) for homozygous variant (C/C) patients. CONCLUSIONS: The class II HLA region (at rs2647087) is an important marker of AZA-induced pancreatitis risk. We propose a simple and clinically implementable algorithm based on rs2647087 and TPMT genotypes for AZA selection and dosing for patients with IBD.

Effects of school-wide positive behavioral interventions and supports and fidelity of implementation on problem behavior in high schools.

High school is an important time in the educational career of students. It is also a time when adolescents face many behavioral, academic, and social-emotional challenges. Current statistics about the behavioral, academic, and social-emotional challenges faced by adolescents, and the impact on society through incarceration and dropout, have prompted high schools to direct their attention toward keeping students engaged and reducing high-risk behavioral challenges. The purpose of the study was to examine the effects of School-Wide Positive Behavioral Interventions and Supports (SW-PBIS) on the levels of individual student problem behaviors during a 3-year effectiveness trial without random assignment to condition. Participants were 36,653 students in 12 high schools. Eight schools implemented SW-PBIS, and four schools served as comparison schools. Results of a multilevel latent growth model showed statistically significant decreases in student office discipline referrals in SW-PBIS schools, with increases in comparison schools, when controlling for enrollment and percent of students receiving free or reduced price meals. In addition, as fidelity of implementation increased, office discipline referrals significantly decreased. Results are discussed in terms of effectiveness of a SW-PBIS approach in high schools and considerations to enhance fidelity of implementation.

An objective method for assessing adherence to prophylaxis in adults with severe haemophilia.

Severe haemophilia is often managed by prophylactic factor infusions in developed countries. The benefits of secondary prophylaxis in adults are currently being studied and adherence to the prescribed prophylactic factor regimen is vital to decreasing bleeding episodes. The aim of this study was to measure discrepancy between the physicians' prescription for prophylactic factor usage, and the actual factor usage obtained through infusion logs. During this method subjects with severe haemophilia A or B (FVIII or FIX ≤2%), from a single haemophilia clinic with complete medical and infusion records from July 01, 2009 to June 30, 2011, were evaluated. Continuous prophylaxis ≥4 weeks were included in the analysis. A scoring system for adherence to prescribed dosing and frequency was developed. A global scale of adherence was performed by two independent nurses using visual analogue scale. Thirty-one subjects, all with haemophilia A, with a median age of 26 years (range 18-56) were included. Results showed that the median (IQR) adherence rate to prescribed frequency and dosage, respectively, was 76% (67;85) and 93% (73;97). In multivariate analysis, only the length of time on prophylaxis during the study period showed a positive correlation with adherence whereas age, number of co-infections, number of bleeds and number of joints with chronic arthropathy did not. Global nursing assessments were in general agreement with the score. In conclusion, we observed a moderately good level of adherence based on score and by the nurse global assessment. Better adherence was found in subjects with longer exposure to prophylaxis.

Decreased motor unit discharge rate in the potentiated human tibialis anterior muscle.

AIM: The purpose of this study was to examine the influence of post-activation potentiation (PAP), the transient increase in low-frequency isometric force observed after muscle activity, on motor unit discharge rates measured during submaximal contractions. METHODS: A quadrifilar needle electrode was inserted into the tibialis anterior muscle to determine discharge rate of individual motor units while monopolar electrodes were used to monitor the root-mean-square (RMS) and mean power frequency (MPF) of the surface EMG signal. Control (unpotentiated) and experimental (potentiated) measures were obtained during a 5 s voluntary contraction at 50% of maximal. In between these measures, subjects performed a 10 s maximal voluntary contraction (MVC) to induce PAP. RESULTS: All subjects data are reported as means ± SEM (n = 10). Compared to baseline values measured prior to the MVC, isometric twitch force measured immediately after the MVC was increased by 260 ± 16% (day 3). Motor unit discharge rate in the potentiated tibialis anterior muscle decreased by approx. 10%, from 20.3 ± 0.8 (before) to 18.3 ± 0.99 pps (P = 0.01) (after). Moreover, the MPF was decreased by approx. 9% (from 58.1 ± 2.84 to 53.6 ± 2.85 Hz; P = 0.01) in the potentiated tibialis anterior. On the other hand, consistent with the absence of fatigue during the MVC, the RMS signal was not altered in the potentiated tibialis anterior (0.29 ± 0.03 vs. 0.33 ± 0.04 mV; P = 0.07). CONCLUSION: Motor unit discharge rates determined during a brief, submaximal contraction were decreased in the potentiated human tibialis anterior muscle.

Antiretroviral regimens in pregnancy and breast-feeding in Botswana.

BACKGROUND: The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown. METHODS: We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, > or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine. RESULTS: The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group. CONCLUSIONS: All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.)

Dual heterologous porcine circovirus genogroup 2a/2b infection induces severe disease in germ-free pigs.

Our primary objectives were to determine: the relative virulence of porcine circovirus (PCV) 2a and PCV2b, if heterologous infection induces severe illness, and the relative concentration of PCV2a and PCV2b in tissues of heterologously infected pigs. In experiment 1, 18 germ-free piglets served as controls or were infected with PCV2a or PCV2b. Half were immune stimulated with keyhole limpet hemocyanin (KLH) emulsified in incomplete Freund's adjuvant (2aKLH, 2bKLH). No piglets demonstrated severe illness. Lesion severity did not differ, but PCV2 capsid staining was more intense in 2a- than 2b-infected pigs (P<.05). In experiment 2, 20 germ-free piglets were dual inoculated 7 days apart with PCV2a and PCV2b (2a2b, 2b2a), PCV2b twice (2b2b), or PCV2a (2a2a) twice. Five of 9 heterologous-infected pigs developed severe illness. All heterologously infected pigs demonstrated ascites or edema, and 8/9 developed thymic atrophy. By contrast, 1 of 5 2b2b-infected pigs developed bronchopneumonia and pleural effusion. No 2a2a-infected pig developed illness. Gross lesions were more severe in heterologously infected pigs than in 2b2b pigs (P<.05), and were more severe in 2b2b than 2a2a pigs (P<.05). PCV2 capsid staining intensity did not differ by group. In heterologously infected pigs, higher levels of PCV2 DNA reflective of the first inoculum compared to the second were found in mesenteric lymph node (P=.04), spleen (P=.004) and liver (P=.04). These results indicate that dual heterologous PCV2a/2b inoculation 7 days apart may induce severe clinical illness, but PCV2a and PCV2b when administered singularly or in combination with KLH appear to be of equivalent virulence.

The use of total lymphocyte count as a surrogate for low CD4+ T lymphocyte cell counts among HIV-1-infected women in Tanzania.

BACKGROUND: Human Immunodeficiency Virus type 1 (HIV-1) infection leads to a progressive decline in CD4+ T-lymphocyte (CD4) cells. Initiation of prophylaxis against Opportunistic infections in adults (CD4% used for children) and antiretroviral therapy is usually based on CD4 cell counts, but CD4 cell counts measurement is not affordable in most African countries. OBJECTIVE: To examine whether total lymphocyte counts (TLC) may be used as proxies for low CD4 cell counts. DESIGN: Cross-sectional at baseline when women were pregnant and at least six months postpartum. METHODS: 1,078 HIV-1-infected pregnant women from Dar es Salaam, Tanzania were enrolled in a randomized clinical trial. A series of receiver operator characteristic (ROC) curves were created at baseline and at least 6 months postpartum and among women in WHO Stage 3 and above. The sensitivity and specificity of TLC and hemoglobin in predicting an absolute CD4 count < 200 cells/mm3 were determined for various clinically relevant cut points. RESULTS: TLC was not a good predictor of low CD4 cell counts during pregnancy or at least six months postpartum as exhibited by low ROC Area Under the Curve (AUCs) of .57 and .62 respectively. No other variable had the ability to predict CD4 < 200 cells/mm3. CONCLUSIONS: The use of TLC as a proxy for the estimation of low CD4 cell counts in a population of HIV-1-infected adults from sub-Saharan Africa was not substantiated. Inexpensive methods to quantify CD4 cell counts in Africa are needed.

The surface EMG-force relationship during isometric dorsiflexion in males and females.

This study compared the tibialis anterior (TA) surface electromyographic (sEMG) to force relationship for males and females. One-hundred participants (50 males and 50 females) performed three isometric contractions at 20, 40, 60, 80, and 100% of maximal voluntary contraction (MVC) in an apparatus designed to isolate the action of the dorsiflexors. The sEMG signal was amplified (1000x), band-pass filtered (10-500 Hz), and sampled at 2048 Hz. The load cell signal was low-pass filtered at 100 Hz and sampled at the same rate. Males were stronger than females (p < 0.05). However, there was no significant difference in the root-mean-square (RMS) amplitude of the sEMG signal between males and females (p < 0.05). Both groups exhibited a quadratic increase in the RMS across force levels (p < 0.05). The mean power frequency (MNF) of the sEMG signal for males was greater than for females (p < 0.05). Males and females exhibited a linear increase in MNF means up to 80% of MVC (p < 0.05). Between 80 and 100% MVC, the frequency values for the females plateaued while males showed a decrease (p < 0.05). The magnitude of the difference in MNF between males and females was consistent with the observation that males have greater type II muscle fiber diameters. In general, the pattern of means for RMS and MNF between males and females revealed no differences between groups in the sEMG-force relationship. We therefore conclude that there are no differences between males and females in the gradation of muscle force.

Financial benefits for child health and well-being in low income or socially disadvantaged families in developed world countries.

BACKGROUND: A strong and consistent relationship has been observed between relative poverty and poor child health and wellbeing even among rich nations. This review set out to examine evidence that additional monies provided to poor or disadvantaged families may benefit children by reducing relative poverty and thereby improving children's health, well-being and educational attainment. OBJECTIVES: To assess the effectiveness of direct provision of additional monies to socially or economically disadvantaged families in improving children's health, well-being and educational attainment SEARCH STRATEGY: In total 10 electronic databases were searched including the Cochrane library searched 2006 (Issue 1), Medline searched 1966 to May 2006 , Econlit searched 1969 to June 2006 and PsycINFO searched 1872 to June 2006, together with 3 libraries of working papers (MDRC, SSRN, SRDC). The general search strategy was [terms for income and financial benefits] and [paediatric terms] and [RCT filter] SELECTION CRITERIA: Studies selected provided money to relatively poor families (which included a child under the age of 18 or a pregnant woman), were randomised or quasi-randomised, measured outcomes related to child health or wellbeing and were conducted in a high income country. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified in the search were independently assessed for eligibility by two reviewers. Data were extracted and entered into RevMan, synthesised and presented in both written and graphical form (forest plots). MAIN RESULTS: Nine trials including more than 25,000 participants were included in this review. No effect was observed on child health, measures of child mental health or emotional state. Non-significant effects favouring the intervention group were seen for child cognitive development and educational achievement, and a non-significant effect favouring controls in rates of teenage pregnancy. AUTHORS' CONCLUSIONS: The review set out to examine the potential of financial support to poor families to improve circumstances for children. However, on the basis of current evidence we can not state unequivocally whether financial benefits delivered as an intervention are effective at improving child health or wellbeing in the short term. Our conclusions are limited by the fact that most of the studies had small effects on total household income and that while no conditions were attached to how money was spent, all studies included strict conditions for receipt of payments. We note particular concerns by some authors that sanctions and conditions (such as working hours) placed on families may increase family stress.

Topiramate and physiologic measures of nerve function in polyneuropathy.

OBJECTIVE: To evaluate topiramate treatment on nerve function using electrophysiologic methods and a non-inferiority clinical trial design. METHODS: A double-blind, multicenter, placebo-controlled trial was conducted in patients with painful diabetic polyneuropathy (n = 67). Change in peroneal motor nerve conduction velocity (NCV) was the primary outcome. NCVs of sural sensory and ulnar nerves, and amplitude and latency changes were measured secondarily. Peripheral nerve function was also evaluated in a patient subgroup reporting treatment-emergent paresthesias. RESULT: Least squares mean decrease in NCV was greater for placebo (-0.2 m/s) than for topiramate treatment (-0.1 m/s) (95% CI: -1.30, 1.42). Secondary measures showed no decrease in nerve function for topiramate-treated patients. Neurophysiologic measures were similar in patients with and without paresthesias. The most common adverse events with topiramate were paresthesias, anorexia, weight decrease, and taste perversion. CONCLUSION: This nerve conduction study found no evidence that topiramate is associated with deterioration of nerve function.

Predictors of incident tuberculosis among HIV-1-infected women in Tanzania.

SETTING: The development of tuberculosis (TB) in HIV-1-infected individuals is associated with accelerated HIV-1 disease progression. OBJECTIVE: To examine the predictors of incident TB in HIV-1-infected Tanzanian women. DESIGN: A prospective cohort of 1078 HIV-1-infected pregnant women was enrolled in a randomized clinical trial to examine the role of vitamin supplements in HIV-1 disease progression and fetal outcomes. RESULTS: Of 1008 women evaluated for TB, 88 (8.7%) developed TB. After controlling for age, education and hemoglobin concentration, in multivariate analysis, low CD4 cell count, elevated erythrocyte sedimentation rate (ESR), decreased mid-upper arm circumference, and high viremia were associated with an increased risk of TB. CD4 <200 vs. > or = 500 cells/mm3 was associated with a 4.44-fold increase in risk of TB (95%CI 2.10-9.40). Individuals with high viremia (> or = 50,000 copies/ml) had a 2.43-fold increase in risk of TB (95%CI 1.24-4.76). Elevated malarial parasite density was slightly associated with a 65% (95%CI 19-85) decreased risk of TB. CONCLUSIONS: The risk of developing TB was elevated among women with low CD4 cell counts, elevated ESR, coinfections with other pathogens, poor nutrition and high viremia. There is a slight inverse association between malarial infection and TB, possibly because treating malaria may reduce the risk of TB.

Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child.

The emergence of cytotoxic T-lymphocyte (CTL) escape mutations in human immunodeficiency virus type 1 (HIV-1) proteins has been anecdotally associated with progression to AIDS, but it has been difficult to determine whether viral mutation is the cause or the result of increased viral replication. Here we describe a perinatally HIV-infected child who maintained a plasma viral load of <400 copies/ml for almost a decade until a nonbinding escape mutation emerged within the immunodominant CTL epitope. The child subsequently experienced a reemergence of HIV-1 viremia accompanied by a marked increase in the number of CTL epitopes targeted. This temporal pattern suggests that CD8 escape can play a causal role in the loss of immune control.

Use of the paired-comparison technique to determine the most valued qualities of the McMaster Medical Programme Admissions Process.

The Undergraduate Medical Programme at McMaster University selects students using a comprehensive set of tools. Attempts to modify the selection process over many years have been impeded by an inability to reconcile very strongly held views among stakeholders as to the importance of the selection tools and, indeed, the very purposes of the admission process. The objective of this study was to identify key 'qualities' of the selection process and to measure their relative importance to admissions process assessors. Through a qualitative review of internal research documents, Medical Programme Admissions Committee meeting minutes, memos and accreditation surveys eight qualities of the admissions process were identified: validity, fairness, accessibility, comprehensiveness, affordability, legal defensibility, contribution to class diversity and the role of the process as a public statement of the Programme's values. Faculty, students and community admissions assessors were surveyed, by mail, using a paired-comparisons technique. The overall response rate was 58%. By a wide margin, all three groups of admissions assessors valued validity and fairness most highly. The least valued qualities were affordability and the role of the process as a statement of our values. Possible applications of this approach to the admissions process deliberations are discussed.

Bending-related faulting and mantle serpentinization at the Middle America trench.

The dehydration of subducting oceanic crust and upper mantle has been inferred both to promote the partial melting leading to arc magmatism and to induce intraslab intermediate-depth earthquakes, at depths of 50-300 km. Yet there is still no consensus about how slab hydration occurs or where and how much chemically bound water is stored within the crust and mantle of the incoming plate. Here we document that bending-related faulting of the incoming plate at the Middle America trench creates a pervasive tectonic fabric that cuts across the crust, penetrating deep into the mantle. Faulting is active across the entire ocean trench slope, promoting hydration of the cold crust and upper mantle surrounding these deep active faults. The along-strike length and depth of penetration of these faults are also similar to the dimensions of the rupture area of intermediate-depth earthquakes.

Comprehensive screening reveals strong and broadly directed human immunodeficiency virus type 1-specific CD8 responses in perinatally infected children.

Advances in antiviral therapy have dramatically shifted the demographics of pediatric human immunodeficiency virus type 1 (HIV-1) infection in the developed world, and a growing proportion of perinatally HIV-1-infected children are now entering their second or even third decade of life. Although cellular immune responses to HIV are known to be weak in early infancy, the magnitude, breadth, and specificity of responses later in childhood have not been characterized in detail. We performed a comprehensive characterization of HIV-1-specific CD8 responses in 18 perinatally infected children (age range, 6 to 17 years), most of whom were on antiviral therapy, using both previously defined HIV-1 epitopes and overlapping peptides spanning all HIV-1 proteins. Multispecific responses were detected in all subjects and accounted for a median of 0.25 to 0.3% of all peripheral blood mononuclear cells that was similar to the magnitude seen in HIV-infected adults. CD8 responses were broadly directed at an average of 11 epitopes (range, 2 to 27 epitopes) and targeted nearly all HIV-1 proteins, with the highest proportion in Gag. Responses were readily detected even in those children with suppressed viremia on highly active antiretroviral therapy, although the breadth (P = 0.037) and the magnitude (P = 0.021) were significantly lower in these subjects. Each child recognized only a small minority of the HIV-1 optimal epitopes defined for his or her class I HLA alleles. Together, these data indicate that perinatally infected children who survive infancy mount a robust HIV-1-specific CD8 response that is much stronger than previously thought and is comparable in magnitude and breadth to that of adults. Moreover, this response has the potential to be broadened to target more epitopes, making these children attractive candidates for immunotherapeutic interventions.

Mesenchymal stem cells combined with biphasic calcium phosphate ceramics promote bone regeneration.

The reconstruction and repair of large bone defects, resulting from trauma, cancer or metabolic disorders, is a major clinical challenge in orthopaedics. Clinically available biological and synthetic grafts have clear limitations that necessitate the development of new graft materials and/or strategies. Human mesenchymal stem cells (MSCs), obtained from the adult bone marrow, are multipotent cells capable of differentiating into various mesenchymal tissues. Of particular interest is the ability of these cells to differentiate into osteoblasts, or bone-forming cells. At Osiris, we have extensively characterized MSCs and have demonstrated MSCs can induce bone repair when implanted in vivo in combination with a biphasic calcium phosphate, specifically hydroxyapatite/tricalcium phosphate. This article reviews previous and current studies utilizing mesenchymal stem cells and biphasic calcium phosphates in bone repair.