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.

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.)

Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children.

The highly sensitive quantitation of virus-specific CD8(+) T cells using major histocompatibility complex-peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-gamma, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-gamma was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-gamma cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection.

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.

Induction of suppressor cells specific for AChR in experimental autoimmune myasthenia gravis.

Suppressor cells specific for acetylcholine receptor (AChR) were induced in a population of lymphocytes previously sensitized to AChR, obtained from rats with experimental autoimmune myasthenia gravis (EAMG). The lymphocytes were cultured with the immunosuppressive drug cyclosporin A plus purified AChR for 7 days. These cells, when mixed with lymphocytes from rats with EAMG in vitro, strongly suppressed the antibody response to AChR. They did not inhibit antibody responses to an unrelated antigen, an indication that suppression was specific for AChR. This approach should be a useful way to induce specific suppressor cells from sensitized populations of lymphocytes and may be applicable in the treatment of autoimmune diseases such as myasthenia gravis.

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.

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.

Vertical Transmission of HIV-1. Correlation with maternal viral load and plasma levels of CD4 binding site anti-gp120 antibodies.

Almost all childhood HIV-1 is now acquired through vertical transmission. Identifying factors that affect the rate of transmission may lead to the initiation of specific preventive strategies. In this study, antibody levels against different neutralizing epitopes on the envelope glycoprotein of HIV-1 (gp120) were measured in HIV-1-infected pregnant women that either transmitted HIV-1 to their infants (18 women) or did not (29 women). Differences in levels of antibodies directed against the monomeric gp120 molecule and against the V3 loop region of gp120 were not significantly different between the two groups studied. However, significant differences were observed in the levels of CD4 binding site antibodies, as determined by the ability of diluted maternal plasma to inhibit binding of the CD4 binding site monoclonal antibody F105 (mAb F105) to monomeric gp120. In addition, more nontransmitting mothers had low viral load as defined by having two or more negative HIV-1 viral cultures during pregnancy compared with transmitters. This pilot study suggests that in addition to higher viral load, low levels of CD4 binding site antibodies correlate with increased risk of HIV-1 vertical transmission. Passive immunotherapy with broadly neutralizing CD4 binding site antibodies should be considered as a strategy to reduce this risk.

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.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal--infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group.

OBJECTIVES: Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. METHODS: The reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. RESULTS: Twenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P= 0.0001) and higher plasma HIV-1 RNA (P=0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P=0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P= 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P=0.009] were independently associated with transmission in multivariate analysis. CONCLUSION: Maternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

Growth and body composition in children infected with the human immunodeficiency virus-1.

Anthropometric data were collected on 89 children born to human immunodeficiency virus (HIV)-infected women (37 who seroreverted and 52 who were HIV-infected). The main outcomes included birth weight, gestational age, weight, height, arm muscle circumference (AMC), and triceps skinfold thickness (TSF). Gestational age and birth weight were not different between the two groups. The earliest anthropometric evaluation on seroreverted children (age 19 mo) when compared with HIV-infected children (age 21 mo) revealed that weight and weight-for-height percentiles were significantly different (51% vs 33% and 66% vs 48%, respectively). Height and TSF percentiles were not different, although AMC percentiles were lower in infected children (64% vs 43%). In follow-up evaluations, the weight differences between infected and control children did not change. We conclude that HIV does not affect birth weight, but postnatal events result in altered weight gain in HIV-infected children. Lean body mass is lower than in an HIV-negative comparison group at early stages of HIV infection.

Antibodies to vaccinia and measles viruses in multiple sclerosis patients.

A virologic comparison was made of 144 patients with multiple sclerosis, 34 of their healthy siblings, and 40 patients with other neurologic diseases (OND). Antibodies in serum and cerebrospinal fluid (CSF) to vaccinia and measles viruses were measured, and these were correlated in the multiple sclerosis patients with the clinical characteristics of their disease. The CSF antibody to vaccinia virus was more frequent and at a higher titer in multiple sclerosis patients than in either control group. Moreover, a statistically significant increase was found in both frequency and titer of CSF vaccinia antibody in patients with the progressive form of the disease as compared with those classified as relapsing-remitting. Statistically significant differences between multiple sclerosis patients and their siblings were not observed for CSF or serum measles virus antibody, although both groups had significantly higher serum antibody titers than patients with OND.

Polymerase chain reaction in detecting HIV infection among seropositive infants: relation to clinical status and age and to results of other assays.

The polymerase chain reaction (PCR) for human immunodeficiency virus (HIV) was evaluated using coded blood specimens from infants whose clinical status is now known. A micromethod for the efficient isolation of mononuclear cells from small volumes of blood, and definitions of PCR positivity that took into account the number and purity of these mononuclear cells, were established in an attempt to define parameters for quality assurance. Results of HIV culture, p-24 antigen, and HIV-specific IgA obtained on the same specimens were compared to PCR results. PCR had a specificity of 100% among 83 specimens from 50 babies known to be uninfected. Sensitivity among 26 HIV-infected infants older than 3 months was 98% (44 of 45 specimens); the one negative specimen, which had also been culture negative, gave a positive PCR result on the remaining aliquot when tested after decoding. Among infected infants less than 3 months old, which is an age when diagnosis by other assays is most problematic, PCR identified 10 of 10 patients (10 of 11 specimens) including two younger than one month. Viral culture showed the best concordance with PCR; however, in three infants, positive PCR results were observed several months before positive results were observed by viral culture.

Decreased lymphocyte transformation to vaccinia virus in multiple sclerosis.

Lymphocyte transformation to vaccinia virus was measured in multiple sclerosis (MS) patients and normal controls. There was a significant reduction of lymphocyte transformation to vaccinia virus in multiple sclerosis patients compared with the control group. In addition, a positive correlation existed between the degree of disability of the multiple sclerosis patients and the extent of lymphocyte transformation in the presence of vaccinia virus. There was no correlation between cell-mediated immunity to vaccinia virus and either serum or cerebrospinal fluid (CSF) antibody levels to vaccinia in multiple sclerosis patients or controls, all of whom had been previously vaccinated. In conjunction with other studies, all of whom had been previously vaccinated. In conjunction with other studies that have demonstrated elevated antibody titers to vaccinia virus in the CSF of multiple sclerosis patients, these results support the possibility that vaccinia virus may play a role in the pathogenesis of multiple sclerosis.

Short-segment incremental studies to localize ulnar nerve entrapment at the wrist.

Precise electrophysiologic localization of ulnar neuropathy at the wrist (UNW) is often problematic. In the last year, we evaluated only two patients who presented clinically with UNW. Routine electrophysiologic techniques were nondiagnostic for UNW. In contrast, short-segment incremental studies (SSIS) across the wrist demonstrated conduction block and segmental slowing of nerve conduction across the wrist in both patients. We conclude that SSIS is a valuable tool for diagnosis, precise localization, and prognosis of UNW.

Monoclonal capture antibody ELISA for respiratory syncytial virus: detection of individual viral antigens and determination of monoclonal antibody specificities.

An enzyme-linked immunosorbent assay (ELISA) for respiratory syncytial virus (RSV) that employs solid-phase monoclonal antibodies was developed. RSV antigens bound by these monoclonal capture antibodies were detected by addition of a polyclonal bovine antiserum, followed anti-bovine enzyme conjugate and enzyme substrate. The sensitivity and specific of the assay were determined by titrations of the solid-phase antibodies and by antigen titrations with both unpurified RSV-infected cell culture material and purified RSV nucleocapsids. The addition of a competitive binding step prior to the addition of antigen to the solid-phase antibody provides further evidence of the assay's specificity. Furthermore, the competitive binding assay enables the antigen specificity of monoclonal antibodies to be determined or compared without the use of purified antigens. Monoclonal capture ELISA is a convenient, rapid, and sensitive assay that can be used to measure specific RSV antigens in unpurified preparations as well as to determine anti-RSV antibody specificity and should prove useful in examining other complex antigen-antibody systems.