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Distribution of Serotypes, Vaccine Coverage, and Antimicrobial Susceptibility Pattern of Streptococcus Pneumoniae in Children Living in SAARC Countries: A Systematic Review. |
INTRODUCTION: Each SAARC nation falls in the zone of high incidence of pneumococcal disease but there is a paucity of literature estimating the burden of pneumococcal disease in this region. OBJECTIVE: To identify the prevalent serotypes causing invasive pneumococcal disease in children of SAARC countries, to determine the coverage of these serotypes by the available vaccines, and to determine the antibiotic resistance pattern of Streptococcus pneumoniae. METHODS: We searched major electronic databases using a comprehensive search strategy, and additionally searched the bibliography of the included studies and retrieved articles till July 2014. Both community and hospital based observational studies which included children aged </=12 years as/or part of the studied population in SAARC countries were included. RESULTS: A total of 17 studies were included in the final analysis. The period of surveillance varied from 12-96 months (median, 24 months). The most common serotypes country-wise were as follows: serotype 1 in Nepal; serotype 14 in Bangladesh and India; serotype 19F in Sri Lanka and Pakistan. PCV-10 was found to be suitable for countries like India, Nepal, Bangladesh, and Sri Lanka, whereas PCV-13 may be more suitable for Pakistan. An increasing trend of non-susceptibility to antibiotics was noted for co-trimoxazole, erythromycin and chloramphenicol, whereas an increasing trend of susceptibility was noted for penicillin. CONCLUSION: Due to paucity of recent data in majority of the SAARC countries, urgent large size prospective studies are needed to formulate recommendations for specific pneumococcal vaccine introduction and usage of antimicrobial agents in these regions. |
Effects of Human Parvovirus B19 and Bocavirus VP1 Unique Region on Tight Junction of Human Airway Epithelial A549 Cells. |
As is widely recognized, human parvovirus B19 (B19) and human bocavirus (HBoV) are important human pathogens. Obviously, both VP1 unique region (VP1u) of B19 and HBoV exhibit the secreted phospholipase A2 (sPLA2)-like enzymatic activity and are recognized to participate in the pathogenesis of lower respiratory tract illnesses. However, exactly how, both VP1u from B19 and HBoV affect tight junction has seldom been addressed. Therefore, this study investigates how B19-VP1u and HBoV-VP1u may affect the tight junction of the airway epithelial A549 cells by examining phospholipase A2 activity and transepithelial electrical resistance (TEER) as well as performing immunoblotting analyses. Experimental results indicate that TEER is more significantly decreased in A549 cells by treatment with TNF-alpha (10 ng), two dosages of B19-VP1u and BoV-VP1u (400 ng and 4000 ng) or bee venom PLA2 (10 ng) than that of the control. Accordingly, more significantly increased claudin-1 and decreased occludin are detected in A549 cells by treatment with TNF-alpha or both dosages of HBoV-VP1u than that of the control. Additionally, more significantly decreased Na+/K+ ATPase is observed in A549 cells by treatment with TNF-alpha, high dosage of B19-VP1u or both dosages of BoV-VP1u than that of the control. Above findings suggest that HBoV-VP1u rather than B19 VP1u likely plays more important roles in the disruption of tight junction in the airway tract. Meanwhile, this discrepancy appears not to be associated with the secreted phospholipase A2 (sPLA2)-like enzymatic activity. |
Proton Pump Inhibitors and Hospitalization with Hypomagnesemia: A Population-Based Case-Control Study. |
BACKGROUND: Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. METHODS AND FINDINGS: We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06-1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11-2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81-1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54-2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of hypomagnesemia, and generalizability of our findings to younger patients. CONCLUSIONS: PPIs are associated with a small increased risk of hospitalization with hypomagnesemia among patients also receiving diuretics. Physicians should be aware of this association, particularly for patients with hypomagnesemia. Please see later in the article for the Editors' Summary. |
Testosterone Trajectories and Reference Ranges in a Large Longitudinal Sample of Male Adolescents. |
PURPOSE: Pubertal dynamics plays an important role in physical and psychological development of children and adolescents. We aim to provide reference ranges of plasma testosterone in a large longitudinal sample. Furthermore, we describe a measure of testosterone trajectories during adolescence that can be used in future investigations of development. METHODS: We carried out longitudinal measurements of plasma testosterone in 2,216 samples obtained from 513 males (9 to 17 years of age) from the Avon Longitudinal Study of Parents and Children. We used integration of a model fitted to each participant's testosterone trajectory to calculate a measure of average exposure to testosterone over adolescence. We pooled these data with corresponding values reported in the literature to provide a reference range of testosterone levels in males between the ages of 6 and 19 years. RESULTS: The average values of total testosterone in the ALSPAC sample range from 0.82 nmol/L (Standard Deviation [SD]: 0.09) at 9 years of age to 16.5 (SD: 2.65) nmol/L at 17 years of age; these values are congruent with other reports in the literature. The average exposure to testosterone is associated with different features of testosterone trajectories such as Peak Testosterone Change, Age at Peak Testosterone Change, and Testosterone at 17 years of age as well as the timing of the growth spurt during puberty. CONCLUSIONS: The average exposure to testosterone is a useful measure for future investigations using testosterone trajectories to examine pubertal dynamics. |
The interplay between inflammatory cytokines and the endocannabinoid system in the regulation of synaptic transmission. |
Excessive glutamate-mediated synaptic transmission and secondary excitotoxicity have been proposed as key determinants of neurodegeneration in many neurological diseases. Soluble mediators of inflammation have recently gained attention owing to their ability to enhance glutamate transmission and affect synaptic sensitivity to neurotransmitters. In the complex crosstalk between soluble immunoactive molecules and synapses, the endocannabinoid system (ECS) plays a central role, exerting an indirect neuroprotective action by inhibiting cytokine-dependent synaptic alterations, and a direct neuroprotective effect by limiting glutamate transmission and excitotoxic damage. On the other hand, the endocannabinoid (eCB)-mediated control of synaptic transmission is altered by proinflammatory cytokines with consequent effects in central nervous system (CNS) disorders. In this review, we summarize the interactions, at the pre- and postsynaptic level, between major inflammatory cytokines and the ECS. In addition, the behavioral and clinical consequences of the modulation of synaptic transmission during neuroinflammation are discussed. |
Hepatic Resection Is Safe and Effective for Patients with Hepatocellular Carcinoma and Portal Hypertension. |
BACKGROUND & AIMS: Official guidelines do not recommend hepatic resection (HR) for patients with hepatocellular carcinoma (HCC) and portal hypertension (PHT). This study aims to investigate the safety and efficacy of HR for patients with HCC and PHT. METHODS: Mortality and survival after HR were analyzed retrospectively in a consecutive sample of 1738 HCC patients with PHT (n = 386) or without it (n = 1352). To assess the robustness of findings, we repeated the analysis using propensity score-matched analysis. We also comprehensively searched the PubMed database for studies evaluating the efficacy and safety of HR for patients with HCC and PHT. RESULTS: The 90-day mortality rate was 6.7% among those with PHT and 2.1% among those without it (P<.001). Patients without PHT had a survival benefit over those with PHT at 1, 3, and 5 years (96% vs 90%, 75% vs 67%, 54% vs 45%, respectively; P = .001). In contrast, PHT was not associated with worse short- or long-term survival when only propensity score-matched pairs of patients and those with early-stage HCC or those who underwent minor hepatectomy were included in the analysis (all P>.05). Moreover, the recurrence rates were similar between the two groups. Consistent with our findings, all 9 studies identified in our literature search reported HR to be safe and effective for patients with HCC and PHT. CONCLUSIONS: HR is safe and effective in HCC patients with PHT and preserved liver function. This is especially true for patients who have early-stage HCC or who undergo minor hepatectomy. |
A Suitable Streptomycin-Resistant Mutant for Constructing Unmarked In-Frame Gene Deletions Using rpsL as a Counter-Selection Marker. |
The streptomycin counter-selection system is a useful tool for constructing unmarked in-frame gene deletions, which is a fundamental approach to study bacteria and their pathogenicity at the molecular level. A prerequisite for this system is acquiring a streptomycin-resistant strain due to rpsL mutations, which encodes the ribosomal protein S12. However, in this study no streptomycin resistance was found to be caused by rpsL mutations in all 127 clinical strains of Klebsiella pneumoniae isolated from liver abscess patients. By screening 107 spontaneous mutants of streptomycin resistance from a clinical strain of K. pneumoniae, nucleotide substitution or insertion located within the rpsL was detected in each of these strains. Thirteen different mutants with varied S12 proteins were obtained, including nine streptomycin-dependent mutants. The virulence of all four streptomycin-resistant mutants was further evaluated. Compared with the parental strain, the K42N, K42T and K87R mutants showed a reduction in growth rate, and the K42N and K42T mutants became susceptible to normal human serum. In the mice LD50 (the bacterial dose that caused 50% death) assay, the K42N and K42T mutants were approximately 1,000-fold less lethal ( approximately 2x105 CFU) and the K87R mutant was approximately 50-fold less lethal ( approximately 1x104 CFU) than the parental strain ( approximately 2x102 CFU). A K42R mutant showed non-observable effects on the above assays, while this mutant exhibited a small cost (P<0.01) in an in vitro growth competition experiment. In summary, most of the K. pneumoniae strains with streptomycin resistance caused by rpsL mutations are less virulent than their parental strain in the absence of streptomycin. The K42R mutant showed similar pathogenicity to its parental strain and should be one of the best choices when using rpsL as a counter-selection marker. |
Association between Combined Lifestyle Factors and Non-Restorative Sleep in Japan: A Cross-Sectional Study Based on a Japanese Health Database. |
BACKGROUND: Although lifestyle factors such as cigarette smoking, excessive drinking, obesity, low or no exercise, and unhealthy dietary habits have each been associated with inadequate sleep, little is known about their combined effect. The aim of this study was to quantify the overall impact of lifestyle-related factors on non-restorative sleep in the general Japanese population. METHODS AND FINDINGS: A cross-sectional study of 243,767 participants (men, 39.8%) was performed using the Specific Health Check and Guidance System in Japan. A healthy lifestyle score was calculated by adding up the number of low-risk lifestyle factors for each participant. Low risk was defined as (1) not smoking, (2) body mass index<25 kg/m2, (3) moderate or less alcohol consumption, (4) regular exercise, and (5) better eating patterns. Logistic regression analysis was used to examine the relationship between the score and the prevalence of non-restorative sleep, which was determined from questionnaire responses. Among 97,062 men (mean age, 63.9 years) and 146,705 women (mean age, 63.7 years), 18,678 (19.2%) and 38,539 (26.3%) reported non-restorative sleep, respectively. The prevalence of non-restorative sleep decreased with age for both sexes. Compared to participants with a healthy lifestyle score of 5 (most healthy), those with a score of 0 (least healthy) had a higher prevalence of non-restorative sleep (odds ratio, 1.59 [95% confidence interval, 1.29-1.97] for men and 2.88 [1.74-4.76] for women), independently of hypertension, hypercholesterolemia, diabetes, and chronic kidney disease. The main limitation of the study was the cross-sectional design, which limited causal inferences for the identified associations. CONCLUSIONS: A combination of several unhealthy lifestyle factors was associated with non-restorative sleep among the general Japanese population. Further studies are needed to establish whether general lifestyle modification improves restorative sleep. |
The role of FeS clusters for molybdenum cofactor biosynthesis and molybdoenzymes in bacteria. |
Molybdenum is the only second row transition metal essential for biological systems, which is biologically available as molybdate ion. In eukarya, bacteria and archaea, molybdenum is bound to either to a tricyclic pyranopterin, thereby forming the molybdenum cofactor (Moco), or in some bacteria to the FeS cluster based iron-molybdenum cofactor (FeMoco), which forms the active site of nitrogenase. To date more than 50 Moco-containing enzymes have been purified and biochemically or structurally characterized. The physiological role of molybdenum in these enzymes is fundamental to organisms, since the reactions include the catalysis of key steps in carbon, nitrogen and sulfur metabolism. The catalyzed reactions are in most cases oxo-transfer reactions or the hydroxylation of carbon centers. The biosynthesis of Moco has been intensively studied, in addition to its insertion into molybdoenzymes. In particular, a link between the biosynthesis and maturation of molybdoenzymes and the biosynthesis and distribution of FeS clusters has been identified in the last years: 1) The synthesis of the first intermediate in Moco biosynthesis requires an FeS-cluster containing protein, 2) The sulfurtransferase for the dithiolene group in Moco is common also for the synthesis of FeS clusters, thiamin and thiolated tRNAs, 3) the modification of the active site with a sulfur atom additionally involves a sulfurtransferase, 4) most molybdoenzymes in bacteria require FeS clusters as additional redox active cofactors. In this review we will focus on the biosynthesis of the molybdenum cofactor in bacteria, its modification and insertion into molybdoenzymes, with an emphasis to its link to FeS cluster biosynthesis and sulfur transfer. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. |
Decline in cellular clearance systems induces inflammasome signaling in human ARPE-19 cells. |
Retinal pigment epithelium (RPE) plays a major role in the maintenance of photoreceptors, and degeneration of RPE results in the development of age-related macular degeneration (AMD). Accumulation of intracellular protein aggregates, increased oxidative stress, and chronic inflammation are all factors damaging the functionality of aged RPE cells. Here, we report that inhibition of proteasomal degradation with MG-132 and autophagy with bafilomycin A1 resulted in the release of IL-1beta but not that of IL-18 in human ARPE-19 cells. NLRP3 receptor became upregulated, and caspase-1, the functional component of an inflammasome complex, was activated. In addition to accumulating intracellular protein aggregates, inhibition of degradation systems induced oxidative stress which was demonstrated by elevated amounts of intracellular 4-hydroxynonenal (HNE)-protein adducts. Along with IL-1beta, exposure to MG-132 and bafilomycin A1 resulted in the secretion of IL-8. A low concentration (1pg/ml) of IL-1beta was capable of triggering significant IL-8 production which also became attenuated by treatment with a specific caspase-1 inhibitor. These results suggest that decline in intracellular degradation systems results not only in increased amounts of intracellular protein aggregates and oxidative stress but also in the activation of NLRP3 inflammasomes, arisen as a result of elevated production of biologically active IL-1beta. |
miR-34a Inhibits Migration and Invasion of Tongue Squamous Cell Carcinoma via Targeting MMP9 and MMP14. |
BACKGROUND: miR-34a is an important tumor suppressor gene in various cancer types. But little is known about the dysregulation of miR-34a in tongue squamous cell carcinoma (TSCC). In this study, we investigate the expression and potential role of miR-34a in TSCC. METHODS: We evaluated miR-34a expression and its relationship with clinicopathological characters in 75 pairs of TSCC samples, and confirmed the role of miR-34a for predicting lymph node metastases from a further 15 pairs of paraffin-embedded TSCC specimens with stringent clinicopathological recruitment criteria using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of miR-34a on cell proliferation, migration and invasion were examined in TSCC cell lines using Cell Counting Kit-8 assay, wound healing assay and transwell assay, respectively. The effects of miR-34a on the expression of matrix metalloproteinase (MMP) 9 and 14 were detected by luciferase reporter assays and Western blot analysis. The expression of miR-34a, MMP9 and MMP14 were also confirmed in TSCC samples by in situ hybridization and immunohistochemistry. RESULTS: miR-34a expression in tumor tissues from TSCC patients with positive lymph node metastases was significantly lower than that with negative lymph node metastases. Overexpression of miR-34a significantly suppressed migration and invasion in TSCC cells and simultaneously inhibited the expression of MMP9 and MMP14 through targeting the coding region and the 3'untranslated region, respectively. Moreover, miR-34a expression in TSCC was inversely correlated with protein expression of MMP9 and MMP14 in the TSCC samples. CONCLUSIONS: miR-34a plays an important role in lymph node metastases of TSCC through targeting MMP9 and MMP14 and may have potential applications in prognosis prediction and gene therapy for lymph node metastases of TSCC patients. |
Carotid Intima-Media Thickness Is Predicted by Combined Eotaxin Levels and Severity of Hepatic Steatosis at Ultrasonography in Obese Patients with Nonalcoholic Fatty Liver Disease. |
BACKGROUND: Non-Alcoholic Fatty Liver Disease (NAFLD) is a distinct coronary artery disease (CAD) risk factor. The atherosclerotic process predisposing to CAD includes altered lipid profile and inflammatory processes. The available evidence suggests that increased circulating levels of eotaxin, an eosinophil chemoattractant cytokine implicated in allergic responses, are detected in the serum of patients with CAD. Relationships were sought between serum eotaxin on the one hand, and intima-media thickness-an early predictor of the atherosclerotic process, hepatic steatosis, arterial blood pressure values, as well as inflammation/immune markers and angiogenetic factors-on the other. METHODS: Eighty obese patients with NAFLD, diagnosed at ultrasonography, without evident cytolysis, formed our study population. Anthropometric measures, metabolic profile, serum concentrations of interleukin-1beta, C-reactive protein, interleukin-6, fibrinogen, ferritin, TNF-alpha, spleen size, vascular endothelial growth factor, platelet-derived growth factor-BB and heat shock protein-70 were evaluated. RESULTS: Serum eotaxin concentrations were distinctly associated with TNF alpha, IL-6, IL-1beta, VEGF and PDGF-BB levels but not with CRP, fibrinogen, heat shock protein-70 or spleen size. Among the metabolic and anthropometric parameters, a significant predictive power emerged when comparing eotaxin to insulin resistance, expressed as HOMA. NAFLD was distinctly associated with HOMA (P = 0.0005). Intima-media thickness was well predicted by both eotaxin levels and severity of NAFLD at ultrasonography, although no relation was detected between these last two variables. DISCUSSION AND CONCLUSION: A role for insulin resistance in mediating the interplay between eotaxin and other inflammation/immune parameters could be evidenced in the induction/maintenance of atherosclerosis of obese patients with NAFLD. |
Factors predicting the total medical costs associated with first-ever ischemic stroke patients transferred to the rehabilitation ward. |
Objective: To investigate the predictors of total medical costs for first-ever ischaemic stroke patients transferred to the rehabilitation ward from the acute ward. Patients: A total of 311 first-ever ischaemic stroke patients (mean age 68.9 (standard deviation (SD) 12.2) years). Methods: Data, including common complications and medical events, from July 2002 to June 2012 were collected retrospectively from a regional hospital in Taiwan in order to study the potential predictors for medical costs. Significant variables from univariate analysis were included in a stepwise multivariate linear regression analysis. Results: The mean total medical cost per patient was USD 4,606.80 (SD 2,926.10). The significant predictors for cost were days of total stay (coefficient: 70.3; 95% confidence interval (CI) = 56.4-84.3), impaired consciousness (coefficient: 1,031.3; 95% CI = 490.8-1,571.8), hypoalbuminaemia in the acute ward (coefficient: 2,045.1; 95% CI = 1,054.6-3,035.7), fever (coefficient: 927.0; 95% CI = 193.3-1,660.7), hypokalaemia (coefficient: 2,698.4; 95% CI = 660.5-4,736.4), and hyponatraemia (coefficient: 1,123.3; 95% CI = 72.2-2,174.5) in the rehabilitation ward (R2 = 0.416). Conclusion: These findings can help clinicians to identify risk factors for total medical costs in these patients and reduce costs by minimizing some complications (hypoalbuminaemia, fever, hypokalaemia, and hyponatraemia). |
Cocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal. |
Cocaine self-administration disturbs intracellular signaling in prefrontal cortical neurons that regulate neurotransmission in the nucleus accumbens. The deficits in dorsomedial prefrontal cortex (dmPFC) signaling change over time, resulting in different neuroadaptations during early withdrawal from cocaine self-administration than after one or more weeks of abstinence. Within the first few hours of withdrawal, there is a marked decrease in tyrosine phosphorylation of critical intracellular and membrane-bound proteins in the dmPFC that include ERK/MAP kinase and the NMDA receptor subunits, GluN1 and GluN2B. These changes are accompanied by a marked increase in STEP tyrosine phosphatase activation. Simultaneously, ERK and PKA-dependent synapsin phosphorylation in presynaptic terminals of the nucleus accumbens is increased that may have a destabilizing impact on glutamatergic transmission. Infusion of brain-derived neurotrophic factor (BDNF) into the dmPFC immediately following a final session of cocaine self-administration blocks the cocaine-induced changes in phosphorylation and attenuates relapse to cocaine seeking for as long as three weeks. The intra-dmPFC BDNF infusion also prevents cocaine-induced deficits in prefronto-accumbens glutamatergic transmission that are implicated in cocaine seeking. Thus, intervention with BDNF in the dmPFC during early withdrawal has local and distal effects in target areas that are critical to mediating cocaine-induced neuroadaptations that lead to cocaine seeking. |
Evolution of the miR-290-295/miR-371-373 Cluster Family Seed Repertoire. |
Expression of the mouse miR-290-295 cluster and its miR-371-373 homolog in human is restricted to early embryos, primordial germ cells, the germ line stem cell compartment of the adult testis and to stem cell lines derived from the early embryonic lineages. Sequencing data suggest considerable seed diversification between the seven homologous pre-miRNAs of miR-290-295 but it is not clear if all of the implied miR-290-295 seeds are also conserved in the human miR-371-373 cluster, which consists of only three homologous pre-miRNAs. By employing miRNA target reporters we show that most, if not all, seeds in miR-290-295 are represented in miR-371-373. In the mouse, pre-miR-290, pre-miR-292 and pre-miR-293 express subsets of the miRNA isoforms processed from the single human pre-miR-371. Comparison of the possible miR-290-295/miR-371-373 seed repertoires in placental mammals suggests a model for the evolution of this miRNA cluster family, which would be otherwise difficult to deduce based solely on pre-miRNA sequence comparisons. The conservation of co-expressed seeds that is characteristic of miR-290-295/miR-371-373 should be taken into account in models of the corresponding miRNA-target interaction networks. |
Detection and Characterization of Cancer Cells and Pathogenic Bacteria Using Aptamer-Based Nano-Conjugates. |
Detection and characterization of cells using aptamers and aptamer-conjugated nanoprobes has evolved a great deal over the past few decades. This evolution has been driven by the easy selection of aptamers via in vitro cell-SELEX, permitting sensitive discrimination between target and normal cells, which includes pathogenic prokaryotic and cancerous eukaryotic cells. Additionally, when the aptamer-based strategies are used in conjunction with nanomaterials, there is the potential for cell targeting and therapeutic effects with improved specificity and sensitivity. Here we review recent advances in aptamer-based nano-conjugates and their applications for detecting cancer cells and pathogenic bacteria. The multidisciplinary research utilized in this field will play an increasingly significant role in clinical medicine and drug discovery. |
Validating and Calibrating the Nintendo Wii Balance Board to Derive Reliable Center of Pressure Measures. |
The Nintendo Wii balance board (WBB) has generated significant interest in its application as a postural control measurement device in both the clinical and (basic, clinical, and rehabilitation) research domains. Although the WBB has been proposed as an alternative to the "gold standard" laboratory-grade force plate, additional research is necessary before the WBB can be considered a valid and reliable center of pressure (CoP) measurement device. In this study, we used the WBB and a laboratory-grade AMTI force plate (AFP) to simultaneously measure the CoP displacement of a controlled dynamic load, which has not been done before. A one-dimensional inverted pendulum was displaced at several different displacement angles and load heights to simulate a variety of postural sway amplitudes and frequencies (<1 Hz). Twelve WBBs were tested to address the issue of inter-device variability. There was a significant effect of sway amplitude, frequency, and direction on the WBB's CoP measurement error, with an increase in error as both sway amplitude and frequency increased and a significantly greater error in the mediolateral (ML) (compared to the anteroposterior (AP)) sway direction. There was no difference in error across the 12 WBB's, supporting low inter-device variability. A linear calibration procedure was then implemented to correct the WBB's CoP signals and reduce measurement error. There was a significant effect of calibration on the WBB's CoP signal accuracy, with a significant reduction in CoP measurement error (quantified by root-mean-squared error) from 2-6 mm (before calibration) to 0.5-2 mm (after calibration). WBB-based CoP signal calibration also significantly reduced the percent error in derived (time-domain) CoP sway measures, from -10.5% (before calibration) to -0.05% (after calibration) (percent errors averaged across all sway measures and in both sway directions). In this study, we characterized the WBB's CoP measurement error under controlled, dynamic conditions and implemented a linear calibration procedure for WBB CoP signals that is recommended to reduce CoP measurement error and provide more reliable estimates of time-domain CoP measures. Despite our promising results, additional work is necessary to understand how our findings translate to the clinical and rehabilitation research domains. Once the WBB's CoP measurement error is fully characterized in human postural sway (which differs from our simulated postural sway in both amplitude and frequency content), it may be used to measure CoP displacement in situations where lower accuracy and precision is acceptable. |
A Sensorized Nuss Bar for Patient-Specific Treatment of Pectus Excavatum. |
Pectus Excavatum is an anatomical deformation characterized by a depression of the anterior chest wall. Nuss technique (representing the current clinical golden standard) consists in the introduction of a corrective metal bar, in order to raise the sternum in its anatomic natural position. Nowadays, the bar plays purely a mechanical/corrective action and is kept implanted for about three years, supporting up to a maximum force of 250 N. Our study aims at optimizing the procedure of correction, in terms of monitoring the bar effect, minimizing the body response, and facilitating the bar removal. The sensorized Nuss bar prototype inserted in a platform for telemedicine described in this article is able to monitor in vitro pressure data variations, with more than 150 discrete measurements during the operating period. This behavior is promising for future clinical applications, in which the device could be exploited to monitor the forces at work, thus, providing a customized therapeutic protocol, which in turn may optimize the period of implant. The sensorized bar was also provided with a polymeric coating, able to influence human dermal fibroblast behavior in vitro. This highlights the possibility to minimize, in future in vivo applications, tissue fibrotic responses. |
Changes in Catastrophizing and Depressed Mood During and After Early Cognitive Behaviorally Oriented Interventions for Pain. |
Catastrophizing and depressed mood are risk factors for poor outcome in treatments for pain and appear to act as mediators for favorable outcome. However, little is known about how catastrophizing and depressed mood co-occur within individuals and how these patterns change during treatment, which is the focus of the current study. The study uses data from a randomized controlled trial about early cognitive behaviorally oriented interventions for patients with nonspecific spinal pain (N = 84). Cluster analyses were used to extract subgroups of individuals with similar scoring patterns on catastrophizing and depressed mood at pretreatment, mid-treatment, posttreatment, and at 6 months' follow-up. To track individual progress, the clusters were linked over time. The analyses revealed four clusters: "low depression and catastrophizing", "high depression and catastrophizing", "high depression", and "high catastrophizing". There was little individual transition from one scoring pattern to another across time, not at least for those scoring high on both depressed mood and catastrophizing. Moreover, high stability within this cluster was related to low levels of psychological flexibility at baseline. It is concluded that catastrophizing and depressed mood at the start of treatment were likely to remain high despite a cognitive behavioral intervention and that a lack of psychological flexibility may have a role. |
Association between DAPK1 Promoter Methylation and Cervical Cancer: A Meta-Analysis. |
BACKGROUND: Death-associated protein kinase1 (DAPK1) is an important tumor suppressor gene. DNA methylation can inactivate genes, which has often been observed in the carcinogenesis of cervical cancer. During the past several decades, many studies have explored the association between DAPK1 promoter methylation and cervical cancer. However, many studies were limited by the small samples size and the findings were inconsistent among them. Thus, we conducted a meta-analysis to assess the association between DAPK1 promoter methylation and cervical cancer. METHODS: We systematically searched eligible studies in the PubMed, Web of Science, EMBASE and CNKI databases. Using meta-regression, subgroup analysis and sensitivity analysis, we explored the potential sources of heterogeneity. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated by Meta-Analysis in R. RESULTS: A total of 15 studies from 2001 to 2012, comprising 818 tumor tissues samples and 671 normal tissues samples, were analyzed in this meta-analysis. The frequencies of DAPK1 promoter methylation ranged from 30.0% to 78.6% (median, 59.3%) in cervical cancer tissue and 0.0% to 46.7% (median, 7.8%) in normal cervical tissue. The pooled OR was 19.66 (95%CI = 8.72-44.31) with the random effects model, and heterogeneity was found through the sensitivity analysis. The I2 = 60% (P = 0.002) decreased to I2 = 29.2% (P = 0.144) when one heterogeneous study was excluded, and the pooled OR increased to 21.80 (95%CI = 13.44-35.36) with the fixed effects model. CONCLUSION: The results suggested a strong association between DAPK1 promoter methylation and cervical cancer. This study also indicated that DAPK1 promoter methylation may be a biomarker during cervical carcinogenesis that might serve as an early indication of cervical cancer. |
Retention and Risk Factors for Attrition in a Large Public Health ART Program in Myanmar: A Retrospective Cohort Analysis. |
BACKGROUND: The outcomes from an antiretroviral treatment (ART) program within the public sector in Myanmar have not been reported. This study documents retention and the risk factors for attrition in a large ART public health program in Myanmar. METHODS: A retrospective analysis of a cohort of adult patients enrolled in the Integrated HIV Care (IHC) Program between June 2005 and October 2011 and followed up until April 2012 is presented. The primary outcome was attrition (death or loss-follow up); a total of 10,223 patients were included in the 5-year cumulative survival analysis. Overall 5,718 patients were analyzed for the risk factors for attrition using both logistic regression and flexible parametric survival models. RESULT: The mean age was 36 years, 61% of patients were male, and the median follow up was 13.7 months. Overall 8,564 (84%) patients were retained in ART program: 750 (7%) were lost to follow-up and 909 (9%) died. During the 3 years follow-up, 1,542 attritions occurred over 17,524 person years at risk, giving an incidence density of 8.8% per year. The retention rates of participants at 12, 24, 36, 48 and 60 months were 86, 82, 80, 77 and 74% respectively. In multivariate analysis, being male, having high WHO staging, a low CD4 count, being anaemic or having low BMI at baseline were independent risk factors for attrition; tuberculosis (TB) treatment at ART initiation, a prior ART course before program enrollment and literacy were predictors for retention in the program. CONCLUSION: High retention rate of IHC program was documented within the public sector in Myanmar. Early diagnosis of HIV, nutritional support, proper investigation and treatment for patients with low CD4 counts and for those presenting with anaemia are crucial issues towards improvement of HIV program outcomes in resource-limited settings. |
An evidence-based method for examining and reporting cognitive processes in nutrition research. |
Cognitive outcomes are frequently implemented as endpoints in nutrition research. To reduce the number of statistical comparisons it is commonplace for nutrition researchers to combine cognitive test results into a smaller number of broad cognitive abilities. However, there is a clear lack of understanding and consensus as to how best execute this practice. The present paper reviews contemporary models of human cognition and proposes a standardised, evidence-based method for grouping cognitive test data into broader cognitive abilities. Both Carroll's model of human cognitive ability and the Cattell-Horn-Carroll (CHC) model of intelligence provide empirically based taxonomies of human cognition. These models provide a cognitive 'map' that can be used to guide the handling and analysis of cognitive outcomes in nutrition research. Making use of a valid cognitive nomenclature can provide the field of clinical nutrition with a common cognitive language enabling efficient comparisons of cognitive outcomes across studies. This will make it easier for researchers, policymakers and readers to interpret and compare cognitive outcomes for different interventions. Using an empirically derived cognitive nomenclature to guide the creation of cognitive composite scores will ensure that cognitive endpoints are theoretically valid and meaningful. This will increase the generalisability of trial results to the general population. The present review also discusses how the CHC model of cognition can also guide the synthesis of cognitive outcomes in systematic reviews and meta-analysis. |
Contribution of Psychosocial Factors to the Association between Socioeconomic Position and Takeaway Food Consumption. |
OBJECTIVE: To examine whether psychosocial factors mediate (explain) the association between socioeconomic position and takeaway food consumption. DESIGN: A cross-sectional postal survey conducted in 2009. SETTING: Participants reported their usual consumption of 22 takeaway food items, and these were grouped into a "healthy" and "less healthy" index based on each items' nutritional properties. Principal Components Analysis was used to derive three psychosocial scales that measured beliefs about the relationship between diet and health (alpha = 0.73), and perceptions about the value (alpha = 0.79) and pleasure (alpha = 0.61) of takeaway food. A nutrition knowledge index was also used. Socioeconomic position was measured by highest attained education level. SUBJECTS: Randomly selected adults (n = 1,500) aged between 25-64 years in Brisbane, Australia (response rate = 63.7%, N = 903). RESULTS: Compared with those with a bachelor degree or higher, participants with a diploma level of education were more likely to consume "healthy" takeaway food (p = 0.023) whereas the least educated (high school only) were more likely to consume "less healthy" choices (p = 0.002). The least educated were less likely to believe in a relationship between diet and health (p<0.001), and more likely to have lower nutritional knowledge compared with their highly educated counterparts (p<0.001). Education differences in beliefs about the relationship between diet and health partly and significantly mediated the association between education and "healthy" takeaway food consumption. Diet- and health-related beliefs and nutritional knowledge partly and significantly mediated the education differences in "less healthy" takeaway food consumption. CONCLUSIONS: Interventions that target beliefs about the relationship between diet and health, and nutritional knowledge may reduce socioeconomic differences in takeaway food consumption, particularly for "less healthy" options. |
Long-term follow-up of adult men born with hypospadias: Urological and cosmetic results. |
PURPOSE: To present data on long-term functional and cosmetic results after hypospadias surgery. MATERIAL AND METHODS: Men > 18 years of age with hypospadias treated in Sweden were asked to participate in the study as well as age-matched controls and circumcised men. All participants answered questionnaires and a subgroup was examined during an outpatient visit. Relationships with outcome were analysed using analysis of variance and regression analysis. RESULTS: 167 patients (mean age: 34 years, 63% distal, 24% mid and 13% proximal hypospadias) and 169 controls (mean age: 33 years), answered the questionnaire and 46 patients and 49 controls came for physical examinations. Patients were significantly less satisfied with the penile cosmetic outcome regarding all parameters in the Penile Perception Score (PPS). There was a difference in penile length between the two groups, 9.7 cm and 11.6 cm, respectively (p < 0.001). More patients than controls reported voiding dysfunction symptoms (p = 0.003). Patients had a lower maximum urinary flow rate (ml/sec) (p=0.001) than controls. These differences were most prominent between patients with proximal hypospadias and controls. CONCLUSIONS: Men operated on for hypospadias were less satisfied with the cosmetic result than controls. Their penile length was shorter. They presented with more symptoms of voiding dysfunction and displayed a lower maximum urinary flow rate. Patients with proximal hypospadias were more affected than those with milder hypospadias. Our results indicate that hypospadias could be sub grouped and that the severe phenotypes should be followed more during childhood as well as later in adulthood. |
To Be or Want to Be: Disentangling the Role of Actual versus Ideal Self in Implicit Self-Esteem. |
A growing body of work suggests that both depressed and non-depressed individuals display implicit positivity towards the self. In the current study, we examined whether this positivity can be underpinned by two qualitatively distinct propositions related to actual ('I am good') or ideal ('I want to be good') self-esteem. Dysphoric and non-dysphoric participants completed a self-esteem Implicit Association Test (IAT) as well an Implicit Relational Assessment Procedure (IRAP) targeting their actual self-esteem and an IRAP targeting ideal self-esteem. Both groups demonstrated similar and positive IAT effects. A more complex picture emerged with regard to the IRAP effects. Whereas non-dysphorics did not differ in their actual and ideal self-esteem, their dysphoric counterparts demonstrated lower actual than ideal self-esteem. Our results suggest that closer attention to the role of propositional processes in implicit measures may unlock novel insight into the relationship between implicit self-esteem and depression. |
Mitochondrial disturbances in HIV pregnancies. |
BACKGROUND:: Mitochondrial consequences from foetal exposure to HIV infection and antiretrovirals could be further investigated. OBJECTIVE:: The main objective of this study was to evaluate maternofoetal mitochondrial disturbances in HIV infection and antiretroviral administration in human pregnancies as the aetiopathogenic basis of suboptimal perinatal-clinical features. DESIGN:: Cross-sectional, prospective, observational, exploratory and controlled study. METHODS:: Clinical/epidemiological data of 35 HIV-infected pregnant women and 17 controls were collected. Mitochondrial DNA (mtDNA) and RNA (mtRNA) content (RT-PCR), enzymatic activities and content (spectrophotometry) were measured in leucocytes. Genetic-functional, maternofoetal and molecular-clinical correlations were assessed. RESULTS:: Birth weight was lower in infants from HIV-infected mothers compared with controls. MtDNA values were slightly decreased in HIV cases, although not reaching statistical significance. MtRNA values were lower in HIV-infected mothers. Similarly, binary complex II+III enzymatic activity decreased to 50% in both HIV-infected mothers (44.45 +/- 3.77%) and their infants (48.79 +/- 3.41%) (P = 0.001 and P < 0.001). Global CI+III+IV enzymatic activity was lower in HIV-infected mothers and infants (90.43 +/- 2.39% and 51.16 +/- 9.30%) (P < 0.005 and P < 0.05). MtDNA content correlated with function in mothers and infants. Maternofoetal parameters correlated at genetic and functional levels. CONCLUSION:: HAART toxicity caused mitochondrial damage in HIV-infected pregnant women and their newborns, being present at a genetic and functional level with a maternofoetal correlation. |
Persistent HIV-related stigma in rural Uganda during a period of increasing HIV incidence despite treatment expansion. |
OBJECTIVE:: Programme implementers have argued that the increasing availability of antiretroviral therapy (ART) will reduce the stigma of HIV. We analyzed data from Uganda to assess how HIV-related stigma has changed during a period of ART expansion. DESIGN:: Serial cross-sectional surveys. METHODS:: We analyzed data from the Uganda AIDS Rural Treatment Outcomes study during 2007-2012 to estimate trends in internalized stigma among people living with HIV (PLHIV) at the time of treatment initiation. We analyzed data from the Uganda Demographic and Health Surveys from 2006 to 2011 to estimate trends in stigmatizing attitudes and anticipated stigma in the general population. We fitted regression models adjusted for sociodemographic characteristics, with year of data collection as the primary explanatory variable. RESULTS:: We estimated an upward trend in internalized stigma among PLHIV presenting for treatment initiation [adjusted b = 0.18; 95% confidence interval (CI), 0.06-0.30]. In the general population, the odds of reporting anticipated stigma were greater in 2011 compared with 2006 [adjusted odds ratio (OR) = 1.80; 95% CI, 1.51-2.13], despite an apparent decline in stigmatizing attitudes (adjusted OR = 0.62; 95% CI, 0.52-0.74). CONCLUSION:: Internalized stigma has increased over time among PLHIV in the setting of worsening anticipated stigma in the general population. Further study is needed to better understand the reasons for increasing HIV-related stigma in Uganda and its impact on HIV prevention efforts. |
Detection of Colorectal Cancer (CRC) by Urinary Volatile Organic Compound Analysis. |
Colorectal cancer (CRC) is a leading cause of cancer related death in Europe and the USA. There is no universally accepted effective non-invasive screening test for CRC. Guaiac based faecal occult blood (gFOB) testing has largely been superseded by Faecal Immunochemical testing (FIT), but sensitivity still remains poor. The uptake of population based FOBt testing in the UK is also low at around 50%. The detection of volatile organic compounds (VOCs) signature(s) for many cancer subtypes is receiving increasing interest using a variety of gas phase analytical instruments. One such example is FAIMS (Field Asymmetric Ion Mobility Spectrometer). FAIMS is able to identify Inflammatory Bowel disease (IBD) patients by analysing shifts in VOCs patterns in both urine and faeces. This study extends this concept to determine whether CRC patients can be identified through non-invasive analysis of urine, using FAIMS. 133 patients were recruited; 83 CRC patients and 50 healthy controls. Urine was collected at the time of CRC diagnosis and headspace analysis undertaken using a FAIMS instrument (Owlstone, Lonestar, UK). Data was processed using Fisher Discriminant Analysis (FDA) after feature extraction from the raw data. FAIMS analyses demonstrated that the VOC profiles of CRC patients were tightly clustered and could be distinguished from healthy controls. Sensitivity and specificity for CRC detection with FAIMS were 88% and 60% respectively. This study suggests that VOC signatures emanating from urine can be detected in patients with CRC using ion mobility spectroscopy technology (FAIMS) with potential as a novel screening tool. |
Soyasaponins Prevent HO-Induced Inhibition of Gap Junctional Intercellular Communication by Scavenging Reactive Oxygen Species in Rat Liver Cells. |
It appears to be more practical and effective to prevent carcinogenesis by targeting the tumor promotion stage. Gap junctional intercellular communication (GJIC) is strongly involved in carcinogenesis, especially the tumor promotion stage. Considerable interest has been focused on the chemoprevention activities of soyasaponin (SS), which are major phytochemicals found in soybeans and soy products. However, less is known about the preventive effects of SS (especially SS with different chemical structures) against tumor promoter-induced inhibition of GJIC. We investigated the protective effects of SS-A1, SS-A2, and SS-I against hydrogen peroxide (H2O2)-induced GJIC inhibition and reactive oxygen species (ROS) production in Buffalo rat liver (BRL) cells. The present results clearly show for the first time that SS-A1, SS-A2, and SS-I prevent the H2O2-induced GJIC inhibition by scavenging ROS in BRL cells in a dose-dependent manner at the concentration range of from 25 to 100 mug/mL. Soyasaponins attenuated the H2O2-induced ROS through potentiating the activities of superoxide dismutase and glutathione peroxidase. This may be an important mechanism by which SS protects against tumor promotion. In addition, various chemical structures of SS appear to exhibit different protective abilities against GJIC inhibition. This may partly attribute to their differences in ROS-scavenging activities. |
Short-term Curcuminoid Supplementation for Chronic Pulmonary Complications due to Sulfur Mustard Intoxication: Positive Results of a Randomized Double-blind Placebo-controlled Trial. |
Pulmonary problems are among the most frequent chronic complications of sulfur mustard (SM) intoxication and are often accompanied by deregulated production of pro-inflammatory cytokines. Curcuminoids, comprising curcumin, demethoxycurcumin and bisdemethoxycurcumin, are phytochemicals with remarkable anti-inflammatory properties that are derived from dried rhizomes of the plant Curcuma longa L. (turmeric). The present pilot study aimed to investigate the clinical effects of supplementation with curcuminoids on markers of pulmonary function and systemic inflammation in SM-intoxicated subjects. In a randomized double-blind placebo-controlled trial, 89 male subjects who were suffering from chronic SM-induced pulmonary complications were recruited and assigned to either curcuminoids (500 mg TID per oral; n=45) or placebo (n=44) for a period of 4 weeks. Efficacy measures were changes in the spirometric parameters (FVC, FEV1, FEV1/FVC) and serum levels of inflammatory mediators including interleukins 6 (IL-6) and 8 (IL-8), tumor necrosis factor-alpha (TNFalpha), transforming growth factor-beta (TGFbeta), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). 78 subjects completed the trial. Although FEV1 and FVC remained comparable between the groups, there was a greater effect of curcuminoids vs. placebo in improving FEV1/FVC (p=0.002). Curcuminoids were also significantly more efficacious compared to placebo in modulating all assessed inflammatory mediators: IL-6 (p<0.001), IL-8 (p=0.035), TNFalpha (p<0.001), TGFbeta (p<0.001), substance P (p=0.016), hs-CRP (p<0.001), CGRP (p<0.001) and MCP-1 (p<0.001). Curcuminoids were safe and well-tolerated throughout the trial. Short-term adjunctive therapy with curcuminoids can suppress systemic inflammation in patients suffering from SM-induced chronic pulmonary complications. |
Respiratory Syncytial Virus: Pathology, therapeutic drugs and prophylaxis. |
Human Respiratory Syncytial Virus (hRSV) is the leading cause of lower respiratory tract diseases, affecting particularly newborns and young children. This virus is able to modulate the immune response, generating a pro-inflammatory environment in the airways that causes obstruction and pulmonary alterations in the infected host. To date, no vaccines are available for human use and the first vaccine that reached clinical trials produced an enhanced hRSV-associated pathology 50 years ago, resulting in the death of two children. Currently, only two therapeutic approaches have been used to treat hRSV infection in high risk children: 1. Palivizumab, a humanized antibody against the F protein that reduces to half the number of hospitalized cases and 2. Ribavirin, which fails to have a significant therapeutic effect. A major caveat for these approaches is their high economical cost, which highlights the need of new and affordable therapeutic or prophylactic tools to treat or prevents hRSV infection. Accordingly, several efforts are in progress to understand the hRSV-associated pathology and to characterize the immune response elicited by this virus. Currently, preclinical and clinical trials are being conducted to evaluate safety and efficacy of several drugs and vaccines, which have shown promising results. In this article, we discuss the most important advances in the development of drugs and vaccines, which could eventually lead to better strategies to treat or prevent the detrimental inflammation triggered by hRSV infection. |
Regional fibrocartilage variations in human anterior cruciate ligament tibial insertion: a histological three-dimensional reconstruction. |
Abstract Purpose: We studied anterior cruciate ligament (ACL) tibial insertion architecture in humans and investigated regional differences that could suggest unequal force transmission from ligament to bone. Materials and Methods: ACL tibial insertions were processed histologically. With Photoshop software, digital images taken from the histological slides were collaged, contour lines were drawn, and different gray values were filled based on the structure. The data were exported to Amira software for three-dimensional reconstruction. Results: The uncalcified fibrocartilage (UF) layer was divided into 3 regions: lateral, medial and posterior according to the architecture. The UF zone was significantly thicker laterally than medially or posteriorly (P < 0.05). Similarly, the calcified fibrocartilage (CF) thickness was significantly greater in the lateral part of the enthesis compared to the medial and posterior parts (P < 0.05). Conclusions: The UF quantity (more UF laterally) corresponding to the CF quantity (more CF laterally) at the ACL tibial insertion provides further evidence suggesting that the load transferred from the ACL to the tibia was greater laterally than medially and posteriorly. |
Multiprofessional teamwork in work-related medical rehabilitation for patients with chronic musculoskeletal disorders. |
Objective: Systematic reviews indicate the effectiveness of multimodal rehabilitation. In Germany this has been shown, in particular, for work-related medical rehabilitation. A recently published guideline on work-related medical rehabilitation support the dissemination of these programmes. The feasibility of this guideline was examined in a multicentre study. This paper presents findings on the relevance of multiprofessional teamwork for the implementation of successful work-related medical rehabilitation. Methods: Focus groups were conducted with 7 inpatient orthopaedic rehabilitation teams and examined using qualitative content analysis. Results: Multiprofessional teamwork emerged inductively as a meaningful theme. All teams described multiprofessional teamwork as a work-related medical rehabilitation success factor, referring to its relevance for holistic treatment of multifactorially impaired patients. Although similar indicators of successful multiprofessional teamwork were named, the teams realized multiprofessional teamwork differently. We found 3 team types, corresponding to multidisciplinary, interdisciplinary and transdisciplinary team models. These types and models constitute a continuum of collaborative practice, which seems to be affected by context-related factors. Conclusion: The significance of multiprofessional teamwork for successful multimodal rehabilitation was underlined. Indicators of ideal multiprofessional teamwork and contextual facilitators were specified. The contingency approach to teamwork, as well as the assumption of multiprofessional teamwork as a continuum of collaborative practice, is supported. Stronger consideration of multiprofessional teamwork in the work-related medical rehabilitation guideline is indicated. |
High Uptake of Systematic HIV Counseling and Testing and TB Symptom Screening at a Primary Care Clinic in South Africa. |
BACKGROUND: Timely diagnosis and treatment of tuberculosis (TB) and HIV is important to reduce morbidity and mortality, and break the cycle of ongoing transmission. METHODS: We performed an implementation research study to develop a model for systematic TB symptom screening and HIV counseling and testing (HCT) for all adult clients at a primary care clinic and prospectively evaluate the 6-month coverage and yield, and 18-month sustainability at a primary care clinic in Johannesburg, South Africa. RESULTS: During the first 6 months, 26,515 visits occurred among 12,078 adults. The proportion of adults aware of their HIV status was 43.7% at the start of the first visit, increased to 84.6% at the end of the first visit, and to 90% at end of any visit during the first 6 months. During these 6 months, 1042 clients were newly diagnosed with HIV. HIV prevalence was 22.9% among those newly tested, and 58.9% among all adult clinic clients. High coverage of systematic HCT was sustained across all 18 months. Coverage of systematic HIV-stratified TB symptom screening during first 6-months was also high (89.6%) but only 35.0% of those symptomatic were screened by sputum. During these 6-months, 90 clients had a positive Xpert MTB/RIF assay, corresponding to a TB prevalence of 0.4% among all 23,534 clients TB symptom-screened and 2.8% among the 3,284 clients with a positive TB symptom screen. The initial high coverage of TB symptom screening was not sustained, with coverage of TB symptom screening dropping after the first six months to 70% and assessment by sputum dropping to 15%. CONCLUSION: Routine, systematic HCT and HIV-stratified TB symptom screening is feasible at primary care level. Systematic HCT doubled the proportion of clients with known HIV status. While HCT was sustainable, coverage of systematic TB screening dropped significantly after the first 6 months of implementation. |
Surface-assisted laser desorption/ionization mass spectrometry using ordered silicon nanopillar arrays. |
Surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) is ideally suited for the high-throughput analysis of small molecules in bodily fluids (e.g. saliva, urine, and blood plasma). A key application for this technique is the testing of drug consumption in the context of workplace, roadside, athlete sports and anti-addictive drug compliance. Here, we show that vertically-aligned ordered silicon nanopillar (SiNP) arrays fabricated using nanosphere lithography followed by metal-assisted chemical etching (MACE) are suitable substrates for the SALDI-MS detection of methadone and small peptides. Porosity, length and diameter are fabrication parameters that we have explored here in order to optimize analytical performance. We demonstrate the quantitative analysis of methadone in MilliQ water down to 32 ng mL-1. Finally, the capability of SiNP arrays to facilitate the detection of methadone in clinical samples is also demonstrated. |
Lung tissue engineering and preservation of alveolar microstructure using a novel casting method. |
We used a rat model to decellularize and seed alveolar cells on a three-dimensional lung scaffold to preserve alveolar microarchitecture. We verified the preservation of terminal respiratory structure by casting and by scanning electron microscopy (SEM) of the casts after decellularization. Whole lungs were obtained from 12 healthy Sprague-Dawley rats, cannulated through the trachea under sterile conditions, and decellularized using a detergent-based method. Casting of both natural and decellularized lungs was performed to verify preservation of the inner microstructure of scaffolds for further cell seeding. Alveolar cell seeding was performed using green fluorescent protein (GFP) lung cells and non-GFP lung cells, and a peristaltic pump. We assessed cell seeding using histological and immunohistochemical staining, and enzymatic evaluation. All cellular components were removed completely from the scaffolds, and histological staining and SEM of casts were used to verify the preservation of tissue structure. Tensile tests verified conservation of biomechanical properties. The hydroxyproline content of decellularized lungs was similar to native lung. Histological and immunohistochemical evaluations showed effective cell seeding on decellularized matrices. Enzymatic measurement of trypsin and alpha 1 antitrypsin suggested the potential functional properties of the regenerated lungs. Casts produced by our method have satisfactory geometrical properties for further cell seeding of lung scaffolds. Preservation of micro-architecture and terminal alveoli that was confirmed by SEM of lung casts increases the probability of an effective cell seeding process. |
Baicalein inhibits agonist- and tumor cell-induced platelet aggregation while suppressing pulmonary tumor metastasis via cAMP-mediated VASP phosphorylation along with impaired MAPKs and PI3K-Akt activation. |
Recently, the importance of platelet activation in cancer metastasis has become generally accepted. As a results, the development of new platelet inhibitors with minimal adverse effects is now a promising area of targeted cancer therapy. Baicalein is a functional ingredient derived from the root of Scutellaria baicalensis Georgi, a plant used intraditional medicine. The pharmacological effects of this compound including anti-oxidative and anti-inflammatory activities have already been demonstrated. However, its effects on platelet activation are unknown. We therefore investigated the effects of baicalein on ligand-induced platelet aggregation and pulmonary cancer metastasis. In the present study, baicalein inhibited agonist-induced platelet aggregation, granule secretion markers (P-selectin expression and ATP release), [Ca2+]i mobilization, and integrin alphaIIbbeta3 expression. Additionally, baicalein attenuated ERK2, p38, and Akt activation, and enhanced VASP phosphorylation. Indeed, baicalein was shown to directly inhibit PI3K kinase activity. Moreover, baicalein attenuated the platelet aggregation induced by C6 rat glioma tumor cells in vitro and suppressed CT26 colon cancer metastasis in mice. These features indicate that baicalein is a potential therapeutic drug for the prevention of cancer metastasis. |
Effects of Perioperative Supplementation with Omega-3 Fatty Acids on Leukotriene B4 and Leukotriene B5 Production by Stimulated Neutrophils in Patients with Colorectal Cancer: A Randomized, Placebo-Controlled Intervention Trial. |
Omega-3 fatty acids (n-3 FA) may have beneficial clinical and immune-modulating effects in surgical patients. In a randomized, double-blind, prospective, placebo-controlled trial, 148 patients referred for elective colorectal cancer surgery received an n-3 FA-enriched oral nutritional supplement (ONS) providing 2.0 g of eicosapentaenoic acid (EPA) and 1.0 g of docosahexaenoic acid (DHA) per day or a standard ONS for seven days before surgery. On the day of operation, there was a significant increase in the production of leukotriene B5 (LTB5) (p < 0.01) and 5-hydroxyeicosapentaenoic acid (5-HEPE) (p < 0.01), a significant decrease in the production of leukotriene B4 (LTB4) (p < 0.01) and a trend for a decrease in the production of 5-hydroxyeicosatetraenoic acid (5-HETE) (p < 0.1) from stimulated neutrophils in the active group compared with controls. There was no association between LTB4 values and postoperative complications. In conclusion, oral n-3 FA exerts anti-inflammatory effects in surgical patients, without reducing the risk of postoperative complications. |
Green Tea Consumption Affects Cognitive Dysfunction in the Elderly: A Pilot Study. |
Green tea is known to have various health benefits for humans. However, the effect of green tea consumption on cognitive dysfunction remains to be clinically verified. We conducted a clinical study to investigate the effects of green tea consumption on cognitive dysfunction. Twelve elderly nursing home residents with cognitive dysfunction (Mini-Mental State Examination Japanese version (MMSE-J) score: <28) participated in the study (2 men, 10 women; mean age, 88 years). The participants consumed green tea powder 2 g/day for 3 months. After three months of green tea consumption, the participants' MMSE-J scores were significantly improved (before, 15.3 +/- 7.7; after, 17.0 +/- 8.2; p = 0.03). This result suggests that green tea consumption may be effective in improving cognitive function or reducing the progression of cognitive dysfunction; however, long-term large-scale controlled studies are needed to further clarify the effect. |
Utility of cystatin C-derived equations for evaluation of residual renal function in peritoneal dialysis patients. |
Abstract Background: Residual renal function (RRF) plays a key role in the follow-up of the patients undergoing chronic ambulatory peritoneal dialysis (CAPD). Available methods for measurement of RRF are cumbersome and rarely used, and alternatively, cystatin C-derived equations have been proposed. Methods: Seventy-six adult CAPD patients were recruited. RRF was measured using the 24-hour urea-creatinine clearance method. Serum concentrations of cystatin C were determined. Glomerular filtration rate (GFR) was estimated using the two published equations of Hoek and colleagues, and Yang and colleagues. GFR was also estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Results: Patients (age range 18-86 years) were on CAPD for a median of 24 months. Average serum concentrations of cystatin C was 5 +/- 1.2 mg/L. Average RRF was 0.7 +/- 1.6 mL/min/1.73 m2. All three methods significantly overestimated the measured RRF values (Hoek: 4 +/- 1.4; Yang: 4.5 +/- 1.5; 7.4 +/- 4 mL/min/1.73 m2). Based on Bland-Altman plots, all three methods yielded poor agreement with RRF (p < 0.001 for all tests), with Hoek's equation providing the narrowest limits of agreement [mean difference (limits of agreement): 3.4 (2.9-3.9)] and CKD-EPI the widest [6.7 (5.9-7.5)]. Although the Hoek's method outperformed CKD-EPI, the within 30 and 50% accuracy rates were unsatisfactory (10.5 and19.7 %, respectively). Conclusions: Cystatin C-derived equations outperform the CKD-EPI formula in approximating the RRF values. Yet, these methods still significantly overestimate the measured RRF and their routine application in clinical practice is not advised. |
The Effect and Mechanism of Growth Hormone Replacement on Cognitive Function in Rats with Traumatic Brain Injury. |
OBJECTIVE: The effects of growth hormone on cognitive dysfunction were observed in a controlled cortical impact (CCI) rat model and the underlying mechanism was explored. METHOD: Three-month-old male SD rats were randomly divided into sham (n = 10), control (n = 10), and CCI groups (n = 40) The parameters were set as follows: striking speed, 3.5 m/s; impact depth, 1.5 mm; and dwell time, 400 msec. Eight and ten weeks post-injury, the GH levels were measured the water maze test and novel object recognition test were performed. CCI rats were divided into normal and decreased GH groups, and further randomly divided into two sub-groups (rhGH treatment and saline vehicle groups). All rats were tested for SYN, BDNF, and TrkB mRNA in the prefrontal cortex and hippocampus by RT-PCR. RESULTS: CCI rats 8 weeks post-injury had cognitive dysfunction regardless of the GH level (P<0.05). rhGH treatment improved cognitive function in CCI rats. There was a positive correlation between the expression of prefrontal BDNF and SYN mRNA in CCI rats after rhGH therapy and the water maze test score (r = 0.773 and 0.534, respectively; P<0.05). Furthermore, the expression of BDNF, TrkB, and SYN mRNA in the hippocampus was negatively correlated with the water maze test score (r = 0.602, 0.773, 0.672, and 0.783, respectively; P<0.05). There was a difference in the expression of hippocampal and prefrontal BDNF, TrkB, and SYN mRNA (P<0.05). CONCLUSION: rhGH treatment had a positive effect on cognitive function, which was more evident in GH-deficient rats. The increased expression of hippocampal and prefrontal BDNF and TrkB mRNA is implicated in rhGH therapy to improve cognitive function. Changes in the expression of hippocampal SYN mRNA following rhGH therapy may also play a role in improving cognitive function. |
Comparison of Combined and Sequential Surgery for Proliferative Diabetic Retinopathy: A Single Surgeon Study. |
PURPOSE: To compare the results of combined and consecutive surgeries to treat proliferative diabetic retinopathy and cataract. METHODS: Retrospective comparative study. Forty-one patients with proliferative diabetic retinopathy (PDR) were enrolled. Twenty-nine eyes for the combined surgery group and twelve eyes for the sequential group were included. All surgeries were performed by one surgeon. Phacoemulsification was performed using a clear cornea incision. The vitrectomy was performed using a 20-gauge vitreous cutter. RESULTS: The best corrected visual acuity (BCVA) and intra- and post-operative complications were the main outcome measures. In the combined surgery group, the BCVA increased in 18 (62.1%) eyes, while eight (27.6%) eyes remained stable and three (10.3%) eyes decreased. Postoperative complications included fibrinous exudation in nine eyes, macular edema in three eyes and vitreous hemorrhage in three eyes. In the sequential surgery group, the BCVA increased in seven (58.3%) eyes, remained the same in four (33.3%) eyes and was reduced in one (8.3%) eye. Postoperative complications included macular edema in two eyes, neovascular glaucoma in two eyes and vitreous hemorrhage in one eye. CONCLUSIONS: Both combined and sequential surgeries are safe and effective for treating PDR and cataracts. The combined surgery had a higher incidence of fibrinous exudation. |
Editorial: Oral Delivery of Biotechnology based Drugs: Dream or Reality? |
Biotechnology has provided a wide array of therapeutic agents such as peptide, protein, vaccine and gene products that are currently mainly administered by means of injections. Therapeutic agents produced by biotechnological processes such as recombinant DNA technology, fermentation, tissue and cell culture technology as well as genetic engineering are usually large, hydrophilic molecules facing delivery challenges, for example, these drugs are susceptible to degradation and are generally poorly membrane permeable. Since successful delivery of any drug is a pre-requisite to achieve the therapeutic goal, novel strategies have emerged in the late 20th century to overcome challenges associated with the oral route of drug administration. These strategies include, but are not restricted to micro- and nanotechnology including self-emulsifying lipid based formulations, dendrimers and devices, permeability enhancing technology, targeting of active transporters and membrane receptors, use of cell penetrating peptides, chemical modifications of peptides such as inclusion complex formation and peptide conjugates, site-specific delivery systems, muco-adhesive systems and polymeric hydrogels. Despite the initial excitement regarding the potential of these technologies to provide effective oral delivery, few have advanced from the pre-clinical stage into clinical trials and very few, if any, resulted so far in registered medicinal products. Moreover, most literature provides information on effectiveness and mechanisms based on in vitro investigations without revealing the viability of these technologies in clinical practice. Although this topic of oral peptide delivery has gone through different phases in terms of attracting attention from the scientific community, it remains a timely research subject. The therapeutic benefits to patients and potential economic benefits to the producer serve as the driving forces behind finding an effective oral delivery system for biotechnology derived drugs. This special issue aims at assessing some of the latest developments in the field of oral delivery of biotechnological therapeutic agents. The reader will not only gain an understanding of the challenges associated with oral delivery of protein and peptide based drugs, but certain strategies that emerged to overcome these drawbacks are also discussed. From the discussions it is clear that scientific research has contributed to a deeper understanding of older drug delivery strategies, while new discoveries keep the vision of producing an effective oral peptide drug delivery system alive. |
Mycobacterium tuberculosis Requires the ECF Sigma Factor SigE to Arrest Phagosome Maturation. |
SigE represents one of the best characterized alternative sigma factors of Mycobacterium tuberculosis, playing a major role in the response to several environmental stresses and essential for growth in macrophages and virulence. In previous work we demonstrated that a mutant of M. tuberculosis in which the sigE gene was disrupted by a cassette conferring hygromycin resistance is a promising vaccine candidate conferring better protection than Mycobacterium bovis BCG in a mouse model of infection. In this work we describe the construction of a new unmarked mutant in which the entire sigE gene was disrupted in order to fulfill the requirements of the Geneva consensus to enter clinical trials. After showing that the phenotype of this mutant is superimposable to that of the previous one, we further characterized the role of SigE in the M tuberculosis intracellular behavior showing that it is dispensable for replication in human pneumocytes, while it is essential for the arrest of phagosome maturation in THP-1-derived macrophages. |
Symptomatic and asymptomatic secondary transmission of Cryptosporidium parvum following two related outbreaks in schoolchildren. |
SUMMARY Two related outbreaks (in 2009 and 2012) of cryptosporidiosis in Norwegian schoolchildren during a stay at a remote holiday farm provided us with a natural experiment to investigate possible secondary transmission of Cryptosporidium parvum IIa A19G1R1. After the children had returned home, clinical data and stool samples were obtained from their household contacts. Samples were investigated for the presence of Cryptosporidium oocysts by immunofluorescence antibody test. We found both asymptomatic and symptomatic infections, which are likely to have been secondary transmission. Laboratory-confirmed transmission rate was 17% [4/23, 95% confidence interval (CI) 7.0-37.1] in the 2009 outbreak, and 0% (95% CI 0-16.8) in the 2012 outbreak. Using a clinical definition, the probable secondary transmission rate in the 2012 outbreak was 8% (7/83, 95% CI 4.1-16.4). These findings highlight the importance of hygienic and public health measures during outbreaks or individual cases of cryptosporidiosis. We discuss our findings in light of previous studies reporting varying secondary transmission rates of Cryptosporidium spp. |
Developing a Follow-Up Strategy for Patients with PSA Ranging from 4 to 10 ng/ml via a New Model to Reduce Unnecessary Prostate Biopsies. |
OBJECTIVE: The aim of this study was to develop a follow-up strategy based on the new model to reduce unnecessary prostate biopsies in patients with prostate specific antigen (PSA) ranging from 4 to 10 ng/ml. METHODS: A total of 436 patients with PSA ranging from 4 to 10 ng/ml who had undergone transrectal ultrasound (TRUS)-guided prostate biopsy were evaluated during the first stage. Age, PSA, free PSA (fPSA), digital rectal examination (DRE) findings, ultrasonic hypoechoic mass, ultrasonic microcalcifications, prostate volume (PV) and PSA density (PSAD) were considered as predictive factors. A multiple logistic regression analysis involving a backward elimination selection procedure was applied to select independent predictors. After a comprehensive analysis of all results, we developed a new model to assess the risk of prostate cancer and an effective follow-up strategy. RESULTS: Age, PSA, PV, fPSA, rate of abnormal DRE findings and rate of hypoechoic masses detected by TRUS were included in our model. A significantly greater area under the receiver-operating characteristic curve was obtained in our model when compared with using PSA alone (0.782 vs. 0.566). Patients were grouped according to the value of prostate cancer risk (PCaR). In the second stage of our study, patients with PCaR>0.52 were recommended to undergo biopsies immediately while the rest of the patients continued close follow-up observation. Compared with the first stage, the detection rate of PCa in the second stage was significantly increased (33.0% vs 21.1%, p = 0.012). There was no significant difference between the two stages in distribution of the Gleason score (p = 0.808). CONCLUSIONS: We developed a follow-up strategy based on the new model, which reduced unnecessary prostate biopsies without delaying patients' diagnoses and treatments. |
Voluntary Exercise Prevents Cisplatin-Induced Muscle Wasting during Chemotherapy in Mice. |
Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P<0.001), lean body mass (20.6%, P = 0.001), as well as anorexia, impaired muscle strength (22.5% decrease, P<0.001) and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P<0.001), maintained lean body mass (P<0.001) and muscle strength (P<0.001), reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival. |
The Effects of Orally Administered Beta-Glucan on Innate Immune Responses in Humans, a Randomized Open-Label Intervention Pilot-Study. |
RATIONALE: To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. beta-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral beta-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. METHODS: We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the beta -glucan (n = 10) or the control group (n = 5). Subjects in the beta-glucan group ingested beta-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine beta-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. RESULTS: beta-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered beta-glucan. CONCLUSION: The present study does not support the use of oral beta-glucan to enhance innate immune responses in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01727895. |
Combining MK626, a Novel DPP-4 Inhibitor, and Low-Dose Monoclonal CD3 Antibody for Stable Remission of New-Onset Diabetes in Mice. |
Combining immune intervention with therapies that directly influence the functional state of the beta-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support beta-cell survival and possibly stimulate beta-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of beta-cell secretory function with resolution of destructive insulitis and preservation of beta-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials. |
Effects of Intra-Aortic Balloon Counterpulsation Pump on Mortality of Acute Myocardial Infarction. |
BACKGROUND: Several randomized controlled trials (RCTs) have evaluated the effect of intra-aortic balloon counterpulsation pump(IABP) on the mortality of acute myocardial infarction (AMI). OBJECTIVES: To analyze the relevant RCT data on the effect of IABP on mortality and the occurrence of bleeding in AMI. DATA SOURCES: Published RCTs on the treatment of AMI by IABP were retrieved in searches of Medline, EMBASE, Cochrane and other related databases. The last search was conducted on July 20, 2014. STUDY ELIGIBILITY CRITERIA: Randomized clinical trials comparing IABP to controls as treatment for AMI. PARTICIPANTS: Patients with AMI. SYNTHESIS METHODS: The primary endpoint was mortality, and the secondary endpoint was bleeding events. To account for to heterogeneity, a random-effects model was used to analyze the study data. RESULTS: Ten trials with a total population of 973 patients that were included in the analysis showed no significant difference in 2-month mortality between the IABP and the control groups. The 6-month mortality in the IABP group was not significantly lower than in the control group in the four RCTs that enrolled 59 AMI patients with CS. But in the four that enrolled AMI 66 patients without CS, the data showed opposite conclusion. CONCLUSIONS: IABP cannot reduce within 2 months and 6-12 months mortality of AMI patients with CS as well as within 2 months mortality of AMI patients without CS, but can reduce 6-12 months mortality of AMI patients without CS. In addition, IABP can increase the risk of bleeding. |