Influence of medical school on medical students' opinions about primary care practice.
To compare first- and fourth-year medical students' opinions about primary care practice. A cross-sectional survey was made of medical students at New York Medical College (NYMC) and East Carolina University School of Medicine (ECUSOM) over three years (1993-94, 1994-95, and 1995-96). Three consecutive classes of first-year students from both schools (n = 807), two consecutive classes of fourth-year NYMC students (n = 373), and three consecutive classes of fourth-year ECUSOM students (n = 221) were given a self-administered questionnaire about professional aspects of primary care practice. Responses to ten items about primary care practice were the independent variables in a logistic regression analysis. Career choice, categorized as primary care or non-primary care, was the dependent variable. Independent, two-tailed t-tests were employed to compare the responses of the first-year students interested in primary care careers with those of the fourth-year students interested in primary care careers. In all, 639 (79%) of the first-year students and 396 (67%) of the fourth-year students returned completed questionnaires. The first-year students interested in primary care careers were significantly more likely to believe that primary care practice has more prestige, has more intellectual stimulation, needs a large knowledge base, and involves work that is more important than that of non-primary care physicians, and were significantly more likely to disagree with the assertion that in primary care practice, physicians have more control over their working hours. With one exception (prestige of primary care practice), all these independent variables were significant for the fourth-year students as well. The comparison of the first- and fourth-year students indicated that the fourth-year students were significantly more likely to believe that primary care practice has more intellectual stimulation, needs a large knowledge base, and requires knowledge that non-primary care practice may not; they were also significantly more likely to disagree with the assertions that primary care practice is adequately compensated, has more prestige, and allows more control over working hours. It appears that students' positive perceptions about primary care practice may change as realistic perceptions about the professional demands on primary care physicians develop during medical school.


Atmospheric trends in methylchloroform and the global average for the hydroxyl radical.
Frequent atmospheric measurements of the anthropogenic compound methylchloroform that were made between 1978 and 1985 indicate that this species is continuing to increase significantly around the world. Reaction with the major atmospheric oxidant, the hydroxyl radical (OH), is the principal sink for this species. The observed mean trends for methylchloroform are 4.8, 5.4, 6.4, and 6.9 percent per year at Aldrigole (Ireland) and Cape Meares (Oregon), Ragged Point (Barbados), Point Matatula (American Samoa), and Cape Grim (Tasmania), respectively, from July 1978 to June 1985. These measured trends, combined with knowledge of industrial emissions, were used in an optimal estimation inversion scheme to deduce a globally averaged methylchloroform atmospheric lifetime of 6.3 (+ 1.2, -0.9) years (1sigma uncertainty) and a globally averaged tropospheric hydroxyl radical concentration of (7.7 +/- 1.4) x 10(5) radicals per cubic centimeter (1sigma uncertainty). These 7 years of gas chromatographic measurements, which comprise about 60,000 individual calibrated real-time air analyses, provide the most accurate estimates yet of the trends and lifetime of methylchloroform and of the global average for tropospheric hydroxyl radical levels. Accurate determination of hydroxyl radical levels is crucial to understanding global atmospheric chemical cycles and trends in the levels of trace gases such as methane.


Affluence and Private Health Insurance Influence Treatment and Survival in Non-Hodgkin's Lymphoma.
The aim of this study was to investigate inequalities in survival for non-Hodgkin's lymphoma (NHL), distinguishing between direct and indirect effects of patient, social and process-of-care factors. All cases of NHL diagnosed in Ireland in 2004-2008 were included. Variables describing patient, cancer, stage and process of care were included in a discrete-time model of survival using Structural Equation Modelling software. Emergency admissions were more common in patients with co-morbid conditions or with more aggressive cancers, and less frequent for patients from more affluent areas. Aggressive morphology, female sex, emergency admission, increasing age, comorbidity, treatment in a high caseload hospital and late stage were associated with increased hazard of mortality. Private patients had a reduced hazard of mortality, mediated by systemic therapy, admission to high caseload hospitals and fewer emergency admissions. The higher rate of emergency presentation, and consequent poorer survival, of uninsured patients, suggests they face barriers to early presentation. Social, educational and cultural factors may also discourage disadvantaged patients from consulting with early symptoms of NHL. Non-insured patients, who present later and have more emergency admissions would benefit from better access to diagnostic services. Older patients remain disadvantaged by sub-optimal treatment, treatment in non-specialist centres and emergency admission.


Molecular complementarity and structural heterogeneity within co-assembled peptide β-sheet nanofibers.
Self-assembling peptides have garnered an increasing amount of interest as a functional biomaterial for medical and biotechnological applications. Recently, β-sheet peptide designs utilizing complementary pairs of peptides composed of charged amino acids positioned to impart co-assembly behavior have expanded the portfolio of peptide aggregate structures. Structural characterization of these charge-complementary peptide co-assemblies has been limited. Thus, it is not known how the complementary peptides organize on the molecular level. Through a combination of solid-state NMR measurements and discontinuous molecular dynamics simulations, we investigate the molecular organization of King-Webb peptide nanofibers. KW+ and KW- peptides co-assemble into near stoichiometric two-component β-sheet structures as observed by computational simulations and 13C-13C dipolar couplings. A majority of β-strands are aligned with antiparallel nearest neighbors within the β-sheet as previously suggested by Fourier transform infrared spectroscopy measurements. Surprisingly, however, a significant proportion of β-strand neighbors are parallel. While charge-complementary peptides were previously assumed to organize in an ideal (AB)n pattern, dipolar recoupling measurements on isotopically diluted nanofiber samples reveal a non-negligible amount of self-associated (AA and BB) pairs. Furthermore, computational simulations predict these different structures can coexist within the same nanofiber. Our results highlight structural disorder at the molecular level in a charge-complementary peptide system with implications on co-assembling peptide designs.


Healing under pressure: hyperbaric oxygen and myocutaneous flap repair for extreme persistent perineal sinus after proctectomy for inflammatory bowel disease.
Persistent perineal sinus (PPS) following proctectomy for inflammatory bowel disease affects about 50% of patients. Up to 33% of cases of PPS remain unhealed at 12 months and the most refractory cases are unhealed at 24 months despite optimal conventional therapy. Reports of hyperbaric oxygen therapy (HBOT) for chronic wounds and Crohn's perianal disease led us to explore perioperative HBOT with rectus abdominis myocutaneous (RAM) flap repair in a highly selected group of patients with extreme PPS who had failed all other interventions. Patients with extreme PPS received preoperative HBOT (a 90-min session at 2.2-2.4 atmospheres, five times per week for 5-6 weeks, for a total of up to 30 sessions), before abdominoperineal PPS excision and perineal reconstruction with vertical or transverse RAM flap repair within 2-4 weeks of completing HBOT. Postoperative HBOT (10 further 90-min sessions) was administered within 2 weeks where practicable. Between 2007 and 2011, four patients with extreme PPS underwent RAM flap repair with preoperative HBOT; two also received postoperative HBOT. The median (range) duration of PPS before HBOT was 88.5 (23-156) months. All patients had previously failed multiple (5 to > 35) surgical procedures. Complete healing occurred in all patients at a median (range) follow-up of 2.5 (2-3) months. There were no further hospital admissions for PPS at a median (range) follow-up of 35 (8-64) months. Hyperbaric oxygen therapy combined with PPS excision and perineal reconstruction with a RAM flap led to complete perineal healing in four patients with extreme PPS and appears a safe and effective extension to the therapeutic pathway for exceptionally treatment-refractory PPS.


Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study.
Even though recent studies suggest that a high intake of heme iron is associated with several types of cancer, epidemiological studies in relation to gastric cancer (GC) are lacking. Our previous results show a positive association between red and processed meat and non cardia gastric cancer, especially in Helicobacter pylori infected subjects. The aim of the study is to investigate the association between heme iron intake and GC risk in the European prospective investigation into cancer and nutrition (EURGAST-EPIC). Dietary intake was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat intake, derived from the literature. Antibodies of H. pylori infection and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control study within the cohort. The study included 481,419 individuals and 444 incident cases of GC that occurred during an average of 8.7 years of followup. We observed a statistically significant association between heme iron intake and GC risk (HR 1.13 95% CI: 1.01-1.26 for a doubling of intake) adjusted by sex, age, BMI, education level, tobacco smoking and energy intake. The positive association between heme iron and the risk of GC was statistically significant in subjects with plasma vitamin C <39 mmol/l only (log2 HR 1.54 95% CI (1.01-2.35). We found a positive association between heme iron intake and gastric cancer risk.


Successful tricuspid valvectomy in a septic patient with tricuspid valve endocarditis.
Endocarditis is characterized by vegetations, which is a mass of platelets, fibrin, micro-colonies of micro-organisms, and inflammatory cells, in the endocardium. Over the past three decades, the incidence of right-sided endocarditis has risen dramatically in Pakistan. We report a 36-year woman with a history of repeated intravenous analgesic injections for low back pain, presenting with high grade fever, sepsis and a white cell count of 44,000 with 90% neutrophils. Echocardiography showed large mobile vegetations on Tricuspid Valve (TV). Tricuspid Valve Endocarditis (TVE) is generally responsive to medical treatment; however, about 25% of TVE patients require surgical intervention. Long-term survival of a patient is possible without a prosthetic TV replacement, particularly if the pulmonary artery pressure is normal.


Systematic review and meta-analysis of maintenance of physical activity behaviour change in cancer survivors.
Physical activity can improve health and wellbeing after cancer and may reduce cancer recurrence and mortality. To achieve such long-term benefits cancer survivors must be habitually active. This review evaluates the effectiveness of interventions in supporting maintenance of physical activity behaviour change among adults diagnosed with cancer and explores which intervention components and contextual features are associated with effectiveness. Relevant randomised controlled trials (RCTs) were identified by a search of Ovid Medline, Ovid Embase and PsychINFO. Trials including adults diagnosed with cancer, assessed an intervention targeting physical activity and reported physical activity behaviour at baseline and ≥ 3 months post-intervention were included. The behaviour change technique (BCT) taxonomy was used to identify intervention components and the Template for Intervention Description and Replication to capture contextual features. Random effect meta-analysis explored between and within group differences in physical activity behaviour. Standardised mean differences (SMD) describe effect size. Twenty seven RCTs were included, 19 were pooled in meta-analyses. Interventions were effective at changing long-term behaviour; SMD in moderate to vigorous physical activity (MVPA) between groups 0.25; 95% CI = 0.16-0.35. Within-group pre-post intervention analysis yielded a mean increase of 27.48 (95% CI = 11.48-43.49) mins/wk. of MVPA in control groups and 65.30 (95% CI = 45.59-85.01) mins/wk. of MVPA in intervention groups. Ineffective interventions tended to include older populations with existing physical limitations, had fewer contacts with participants, were less likely to include a supervised element or the BCTs of 'action planning', 'graded tasks' and 'social support (unspecified)'. Included studies were biased towards inclusion of younger, female, well-educated and white populations who were already engaging in some physical activity. Existing interventions are effective in achieving modest increases in physical activity at least 3 months post-intervention completion. Small improvements were also evident in control groups suggesting low-intensity interventions may be sufficient in promoting small changes in behaviour that last beyond intervention completion. However, study samples are not representative of typical cancer populations. Interventions should consider a stepped-care approach, providing more intensive support for older people with physical limitations and others less likely to engage in these interventions.


Microstructure of Cu-Ag Uniform Nanoparticulate Films on Polyurethane 3D Catheters: Surface Properties.
The preparation, characterization, and antibacterial testing of Cu-Ag sputtered polyurethane (PU) catheters are addressed in this study. PU catheters with different atomic ratios Cu:Ag have been sputtered and led to different optical properties as followed by diffuse reflectance spectroscopy (DRS) and the surface redox properties were also different for different Cu-Ag ratios as observed by X-ray photoelectron spectroscopy (XPS). The surface atomic percentage concentration of the oxidized/reduced C-species originating from bacterial cultures before and after bacterial inactivation were determined on the Cu-Ag PU catheters. The crystallographic properties were determined by X-ray diffraction (XRD). The XRD-diffractogram showed the presence of Cu2O (111), Cu (200), CuO (020), and Ag (111) indicating that Cu nanoparticles present a more crystalline character compared to Ag nanoparticles. Increasing the percentage of Ag in the Cu-Ag films, bigger Ag-particle agglomerates were detected by scanning transmission electron microscopy (STEM) microanalysis confirming the results obtained by AFM. The bacterial inactivation kinetics of the sputtered Cu-Ag films on PU catheters was investigated in detail. Quasi-instantaneous bacterial inactivation kinetics was induced by the sputtered films on PU catheters after optimization of the Cu-Ag film thickness.


Specific Soft-Tissue Invasion and LMP1 Expression Are Potential Indicators of Extranodal NK/T Cell Lymphoma, Nasal Type.
BACKGROUND Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is difficult to distinguish from nasal polyps and inverted papilloma, leading to its high misdiagnosis ratio. The aim of this study was to investigate its potential prognostic indicators. MATERIAL AND METHODS Kaplan-Meier method was used to calculate overall survival (OS) rate. Cox proportional hazards regression was used to analyze risk ratios (ORs) with 95% confidence intervals (CIs). RESULTS Nasal ala infiltration and nasal floor thickness >2.0 mm or nasal septum thickness >2.5 mm were potential prognostic factors for OS (p=0.0323 and 0.0072, respectively). Cox proportional-hazards regression indicated that high LMP1 expression and the nasal floor thickness >2.0 mm or nasal septum thickness >2.5 mm were the independent risk factors for poor OS of ENKTL-NT (HR=3.0655, p=0.028; HR=2.3650, p=0.0452, respectively). In the subgroup analysis, the OS rate was lower when the nasal floor thickness >2.0 mm or nasal septum thickness >2.5 mm in the patients who had high expression of LMP1 (p=0.0651), whereas high LMP1 expression increased the risk of worse prognostic outcome in patients with deep infiltration thickness. Thus, high LMP1 expression may contribute to the tissue invasion of ENKTL-NT. CONCLUSIONS Any patient with nasal ala soft-tissue invasion, nasal floor thickness >2.0 mm/nasal septum thickness >2.5 mm on CT imaging or high LMP1 expression should prompt immediate histopathologic diagnosis to rule out ENKTL-NT in clinical practice.


Application of multiframe high-resolution image reconstruction to digital microscopy.
A high-resolution image reconstruction algorithm previously used to improve undersampled infrared airborne imagery was applied to two different sets of digital microscopy images. One set is that of medical pap smear images, and the second set contains metallurgical micrographs. Both the pap smear images and the metallurgical micrographs are undersampled, thus causing loss of detail and aliasing artifacts. The algorithm minimizes the effects of aliasing and restores detail unobtainable through simple interpolation techniques. Both applications demonstrate improvement by use of the image reconstruction algorithm.


CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells.
A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.


Large-scale functional network reorganization in 22q11.2 deletion syndrome revealed by modularity analysis.
The 22q11.2 deletion syndrome (22q11DS) is associated with cognitive impairments and a 41% risk of developing schizophrenia. While several studies performed on patients with 22q11DS showed the presence of abnormal functional connectivity in this syndrome, how these alterations affect large-scale network organization is still unknown. Here we performed a network modularity analysis on whole-brain functional connectomes derived from the resting-state fMRI of 40 patients with 22q11DS and 41 healthy control participants, aged between 9 and 30 years old. We then split the sample at 18 years old to obtain two age subgroups and repeated the modularity analyses. We found alterations of modular communities affecting the visuo-spatial network and the anterior cingulate cortex (ACC) in both age groups. These results corroborate previous structural and functional studies in 22q11DS that showed early impairment of visuo-spatial processing regions. Furthermore, as ACC has been linked to the development of psychotic symptoms in 22q11DS, the early impairment of its functional connectivity provide further support that ACC alterations may provide potential biomarkers for an increased risk of schizophrenia. Finally, we found an abnormal modularity partition of the dorsolateral prefrontal cortex (DLPFC) only in adults with 22q11DS, suggesting the presence of an abnormal development of functional network communities during adolescence in 22q11DS.


Host-symbiont interactions of the primary endosymbiont of human head and body lice.
The first mycetome was discovered more than 340 yr ago in the human louse. Despite the remarkable biology and medical and social importance of human lice, its primary endosymbiont has eluded identification and characterization. Here, we report the host-symbiont interaction of the mycetomic bacterium of the head louse Pediculus humanus capitis and the body louse P. h. humanus. The endosymbiont represents a new bacterial lineage in the gamma-Proteobacteria. Its closest sequenced relative is Arsenophonus nasoniae, from which it differs by more than 10%. A. nasoniae is a male-killing endosymbiont of jewel wasps. Using microdissection and multiphoton confocal microscopy, we show the remarkable interaction of this bacterium with its host. This endosymbiont is unique because it occupies sequentially four different mycetomes during the development of its host, undergoes three cycles of proliferation, changes in length from 2-4 microm to more than 100 microm, and has two extracellular migrations, during one of which the endosymbionts have to outrun its host's immune cells. The host and its symbiont have evolved one of the most complex interactions: two provisional or transitory mycetomes, a main mycetome and a paired filial mycetome. Despite the close relatedness of body and head lice, differences are present in the mycetomic provisioning and the immunological response.


Plants, microorganisms, and soil temperatures contribute to a decrease in methane fluxes on a drained Arctic floodplain.
As surface temperatures are expected to rise in the future, ice-rich permafrost may thaw, altering soil topography and hydrology and creating a mosaic of wet and dry soil surfaces in the Arctic. Arctic wetlands are large sources of CH4 , and investigating effects of soil hydrology on CH4 fluxes is of great importance for predicting ecosystem feedback in response to climate change. In this study, we investigate how a decade-long drying manipulation on an Arctic floodplain influences CH4 -associated microorganisms, soil thermal regimes, and plant communities. Moreover, we examine how these drainage-induced changes may then modify CH4 fluxes in the growing and nongrowing seasons. This study shows that drainage substantially lowered the abundance of methanogens along with methanotrophic bacteria, which may have reduced CH4 cycling. Soil temperatures of the drained areas were lower in deep, anoxic soil layers (below 30 cm), but higher in oxic topsoil layers (0-15 cm) compared to the control wet areas. This pattern of soil temperatures may have reduced the rates of methanogenesis while elevating those of CH4 oxidation, thereby decreasing net CH4 fluxes. The abundance of Eriophorum angustifolium, an aerenchymatous plant species, diminished significantly in the drained areas. Due to this decrease, a higher fraction of CH4 was alternatively emitted to the atmosphere by diffusion, possibly increasing the potential for CH4 oxidation and leading to a decrease in net CH4 fluxes compared to a control site. Drainage lowered CH4 fluxes by a factor of 20 during the growing season, with postdrainage changes in microbial communities, soil temperatures, and plant communities also contributing to this reduction. In contrast, we observed CH4 emissions increased by 10% in the drained areas during the nongrowing season, although this difference was insignificant given the small magnitudes of fluxes. This study showed that long-term drainage considerably reduced CH4 fluxes through modified ecosystem properties.


How operational research influenced the scale up of antiretroviral therapy in Malawi.
The national scale up of antiretroviral therapy in Malawi is based on a public health approach, with principles and practices borrowed from the successful World Health Organization "DOTS" tuberculosis control framework. The scale up of antiretroviral therapy was under-pinned by a very strong monitoring and evaluation system, which was used to audit the scale up approach and conduct operational research to answer relevant questions. Examples of research included:- i) access to antiretroviral therapy, populations and social groups served, and how the different groups fared with regard to outcomes; ii) determining whether the quality of data at antiretroviral therapy sites was adequate and whether external supervision was needed; iii) finding feasible ways of reducing the high early mortality in patients starting treatment in both Malawi and the sub-Saharan African region; iv) the causes of loss-to-follow-up, what happened to patients who transferred out of sites and whether transfer-out patients had outcomes comparable to those who did not transfer; and v) the important question of whether antiretroviral therapy scale up reduced population mortality. The answers to these questions had an important influence on how treatment was delivered in the country, and show the value of this work within a programme setting. Key generic lessons include the importance of i) research questions being relevant to programme needs, ii) studies being coordinated, designed and undertaken within a programme, iii) study findings being disseminated at national stakeholder meetings and through publications in peer-reviewed journals and iv) research being used to influence policy and practice, improve programme performance and ultimately patient treatment outcomes.


Chitosan-genipin nanohydrogel as a vehicle for sustained delivery of alpha-1 antitrypsin.
Alpha-1antitrypsin (A1AT) deficiency, an inherited disorder, has been shown to be the cause of lung diseases such as emphysema and chronic obstructive pulmonary disease. One of the treatment strategies to provide appropriate and adequate concentrations of A1AT in the lungsis the application of nanoparticles (NPs) in pulmonary drug delivery. In the current study, biocompatible nanohydrogels were prepared using chemically cross-linked chitosan with ginepin, a natural cross linker reagent, and used as a carrier to deposit A1AT into the lung tissue. Colloidal and monodispersed NPs were synthesized through reverse microemulsion. Nanohydrogels were characterized with TEM, LLS, FTIR, ZTEA potential, UV spectrum, and swelling test. Encapsulation efficacy was determined at different concentrations of A1AT using Bradford assay. Effect of processing variables such as pH, loading efficiency, and release media components on drug release profile was determined in simulated lung fluids. To evaluate the inhibitory activity of the A1AT after release from NPs, trypsin inhibitory capacity assay was carried out. Results from FTIR and UV spectrum confirmed the development of chitosan cross linkage. Spherical chitosan-genipin NPs were sized from 30-100 nm. NPs exhibited the ability to release 49% of the drug within 12-dayperiodatpH 7. However, there were variations with the drug release profile due to pH variations and loading efficacy. Drug release was higher in pseudo alveolar fluid in comparison with saline solution. These data indicate that application of chitosan nanohydrogels can be a useful tool for sustained release of A1AT in the lung tissue.


Serotonin reuptake inhibitors in pregnancy: can genes help us in predicting neonatal adverse outcome?
Lots has been written on use of SSRI during pregnancy and possible short and long term negative outcomes on neonates. the literature so far has described a various field of peripartum illness related to SSRI exposure during foetal life, such as increased incidence of low birth weight, respiratory distress, persistent pulmonary hypertension, poor feeding, and neurobehavioural disease. We know that different degrees of outcomes are possible, and not all the newborns exposed to SSRIs during pregnancy definitely will develop a negative outcome. So far, still little is known about the possible etiologic mechanism that could not only explain the adverse neonatal effects but also the degree of clinical involvement and presentation in the early period after birth. Pharmacogenetics and moreover pharmacogenomics, the study of specific genetic variations and their effect on drug response, are not widespread. This review describes possible relationship between SSRIs pharmacogenetics and different neonatal outcomes and summarizes the current pharmacogenetic inquiries in relation to maternal-foetal environment.


Fecal Markers of Environmental Enteropathy and Subsequent Growth in Bangladeshi Children.
Environmental enteropathy (EE), a subclinical intestinal disorder characterized by mucosal inflammation, reduced barrier integrity, and malabsorption, appears to be associated with increased risk of stunting in children in low- and middle-income countries. Fecal biomarkers indicative of EE (neopterin [NEO], myeloperoxidase [MPO], and alpha-1-antitrypsin [AAT]) have been negatively associated with 6-month linear growth. Associations between fecal markers (NEO, MPO, and AAT) and short-term linear growth were examined in a birth cohort of 246 children in Bangladesh. Marker concentrations were categorized in stool samples based on their distribution (< first quartile, interquartile range, > third quartile), and a 10-point composite EE score was calculated. Piecewise linear mixed-effects models were used to examine the association between markers measured quarterly (in months 3-21, 3-9, and 12-21) and 3-month change in length-for-age z-score (ΔLAZ). Children with high MPO levels at quarterly time points lost significantly more LAZ per 3-month period during the second year of life than those with low MPO (ΔLAZ = -0.100; 95% confidence interval = -0.167 to -0.032). AAT and NEO were not associated with growth; however, composite EE score was negatively associated with subsequent 3-month growth. In this cohort of children from an urban setting in Bangladesh, elevated MPO levels, but not NEO or AAT levels, were associated with decreases in short-term linear growth during the second year of life, supporting previous data suggesting the relevance of MPO as a marker of EE.


Associations between single nucleotide polymorphisms in multiple candidate genes and body weight in rabbits.
In this study, we examined parts of six growth genes (growth hormone [GH], melanocortin 4 receptor [MC4R], growth hormone receptor [GHR], phosphorglycerate mutase [PGAM], myostatin [MSTN], and fibroblast growth factor [FGF]) as specific primers for two rabbit lines (V-line, Alexandria) using nucleotide sequence analysis, to investigate association between detecting single nucleotide polymorphism (SNP) of these genes and body weight (BW) at market. Each line kits were grouped into high and low weight rabbits to identify DNA markers useful for association studies with high BW. DNA from blood samples of each group was extracted to amplify the six growth genes. SNP technique was used to study the associate polymorphism in the six growth genes and marketing BW (at 63 days) in the two rabbit lines. The purified polymerase chain reaction products were sequenced in those had the highest and lowest BW in each line. Alignment of sequence data from each group revealed the following SNPs: At nucleotide 23 (A-C) and nucleotide 35 (T-G) in MC4R gene (sense mutation) of Alexandria and V-line high BW. Furthermore, we detected the following SNPs variation between the two lines: A SNP (T-C) at nucleotide 27 was identified by MC4R gene (sense mutation) and another one (A-C) at nucleotide 14 was identified by GHR gene (nonsense mutation) of Alexandria line. The results of individual BW at market (63 days) indicated that Alexandria rabbits had significantly higher BW compared with V-line rabbits. MC4R polymorphism showed significant association with high BW in rabbits. The results of polymorphism demonstrate the possibility to detect an association between BW in rabbits and the efficiency of the used primers to predict through the genetic specificity using the SNP of MC4R.


Fortuitous encounters between seagliders and adult female northern fur seals (Callorhinus ursinus) off the Washington (USA) coast: upper ocean variability and links to top predator behavior.
Behavioral responses by top marine predators to oceanographic features such as eddies, river plumes, storms, and coastal topography suggest that biophysical interactions in these zones affect predators' prey, foraging behaviors, and potentially fitness. However, examining these pathways is challenged by the obstacles inherent in obtaining simultaneous observations of surface and subsurface environmental fields and predator behavior. In this study, migratory movements and, in some cases, diving behavior of 40 adult female northern fur seals (NFS; Callorhinus ursinus) were quantified across their range and compared to remotely-sensed environmental data in the Gulf of Alaska and California Current ecosystems, with a particular focus off the coast of Washington State (USA)--a known foraging ground for adult female NFS and where autonomous glider sampling allowed opportunistic comparison of seal behavior to subsurface biophysical measurements. The results show that in these ecosystems, adult female habitat utilization was concentrated near prominent coastal topographic, riverine, or inlet features and within 200 km of the continental shelf break. Seal dive depths, in most ecosystems, were moderated by surface light level (solar or lunar), mirroring known behaviors of diel vertically-migrating prey. However, seal dives differed in the California Current ecosystem due to a shift to more daytime diving concentrated at or below the surface mixed layer base. Seal movement models indicate behavioral responses to season, ecosystem, and surface wind speeds; individuals also responded to mesoscale eddies, jets, and the Columbia River plume. Foraging within small scale surface features is consistent with utilization of the inner coastal transition zone and habitats near coastal capes, which are known eddy and filament generation sites. These results contribute to our knowledge of NFS migratory patterns by demonstrating surface and subsurface behavioral responses to a spatially and temporally dynamic ocean environment, thus reflecting its influence on associated NFS prey species.


Tumour Expression of Histone Deacetylases in Uveal Melanoma.
To determine the expression of histone deacetylase enzymes in uveal melanoma tumour cells. This is an observational immunohistochemical study of 16 formalin-fixed, paraffin-embedded eyes enucleated for uveal melanoma between January 2001 and March 2002. Haematoxylin and eosin paraffin sections were reviewed for histopathological parameters according to the American Joint Committee on Cancer 7th edition. Sections were then immunohistochemically stained for histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2 using an automated Leica Bond II platform and Fast Red chromogen, then digitally scanned using Aperio software before assessment of staining. Nuclear expression of histone deacetylases 1, 2, 3, 4 and 6 and of sirtuin 2 was confirmed in uveal melanoma tumour cells. In addition, the tumour cells showed cytoplasmic expression of histone deacetylases 4 and 6 and sirtuin 2. Nuclear and cytoplasmic immunostaining was also seen in intraocular tissues uninvolved by the tumour. Uveal melanoma tumour cells express histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2, confirming potential tissue targets for histone deacetylase inhibitors.


Optimizing expiratory flows during mechanical cough in a pediatric neuromuscular lung model.
Mechanical insufflation-exsufflation (MI-E) is recommended for subjects of all ages with neuromuscular disorders (NMDs) and weak cough. There is a lack of knowledge on the optimal treatment settings for young children. This study aims to determine the MI-E settings providing high expiratory airflow while using safe inspiratory volumes, and to identify possible limits where the benefit of incrementing the MI-E settings to achieve a higher expiratory airflow, decreased. Using an MI-E device and a lung model imitating a 1-year-old child with NMD, we explored the impact of 120 combinations of MI-E pressure and time settings on maximal expiratory airflow and inspiratory volume. High expiratory airflows were achieved with several pressure and time combinations where the exsufflation pressure, followed by insufflation pressure and time, had the greatest impact. The benefit of incrementing the settings to increase the expiratory airflow leveled off for the insufflation pressure and time, but not for the exsufflation pressure. Given exsufflation pressure of -40 or -50 cmH2 O and insufflation time longer than 1 second, a plateau in the expiratory airflow curve was present at insufflation pressures from 25 cmH2 O, whereas a plateau in the inspired volume curve occurred at insufflation pressures from 35 cmH2 O. The present neuromuscular pediatric lung model study showed that expiratory pressure impacts expiratory airflow more than inspiratory pressure and time. An inspiratory and expiratory pressure set between 20 to 30 and -40 cmH2 O, respectively, and an inspiratory time longer than 1 second may be considered as a basis when titrating MI-E settings in young children with NMD. The findings must be confirmed in clinical trials.


The orientation and charge of water at the hydrophobic oil droplet-water interface.
We established the charge and structure of the oil/water interface by combining ζ-potential measurements, sum frequency scattering (SFS) and molecular dynamics simulations. The SFS experiments show that the orientation of water molecules can be followed on the oil droplet/water interface. The average water orientation on a neat oil droplet/water interface is the same as the water orientation on a negatively charged interface. pH dependent experiments show, however, that there is no sign of selective adsorption of hydroxide ions. Molecular dynamics simulations, both with and without intermolecular charge transfer, show that the balance of accepting and donating hydrogen bonds is broken in the interfacial layer, leading to surface charging. This can account for the negative surface charge that is found in experiments.


Separating signal from noise: the challenge of identifying useful biomarkers in sepsis.
Sepsis diagnosis remains based largely on clinical presentation despite significant advances in the understanding of underlying pathophysiology and host-pathogen interactions. The systematic review article by Zonneveld and colleagues in the previous issue of Critical Care describes another potential avenue of study for using biomarkers for sepsis diagnosis and prognostication. Soluble leukocyte adhesion molecules and their associated sheddase enzymes vary in detectable levels and activity in patients in relation to immunologic status, age, and systemic inflammation, including in the setting of sepsis. Unfortunately, studies of these molecules as diagnostic or prognostic aids (or both) in sepsis have thus far been disappointing. Zonneveld and colleagues propose two potential avenues to enhance the performance characteristics of soluble adhesion molecules and their sheddases in sepsis diagnosis and prognosis: (a) identifying age-adjusted normal values for soluble leukocyte adhesion molecules and their sheddases and (b) investigating simultaneous measurement of both soluble adhesion molecules and sheddases in integrated sepsis evaluation schema. This commentary discusses the proposed solutions of Zonneveld and colleagues in more detail and outlines additional considerations that should be addressed in order to develop robust and valid diagnostic and prognostic tools for clinicians managing patients with sepsis.


Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis.
Recent studies suggest that M. tuberculosis lineage and host genetics interact to impact how active tuberculosis presents clinically. We determined the phylogenetic lineages of M. tuberculosis isolates from participants enrolled in the Tuberculosis Trials Consortium Study 28, conducted in Brazil, Canada, South Africa, Spain, Uganda and the United States, and secondarily explored the relationship between lineage, clinical presentation and response to treatment. Large sequence polymorphisms and single nucleotide polymorphisms were analyzed to determine lineage and sublineage of isolates. Of 306 isolates genotyped, 246 (80.4%) belonged to the Euro-American lineage, with sublineage 724 predominating at African sites (99/192, 51.5%), and the Euro-American strains other than 724 predominating at non-African sites (89/114, 78.1%). Uneven distribution of lineages across regions limited our ability to discern significant associations, nonetheless, in univariate analyses, Euro-American sublineage 724 was associated with more severe disease at baseline, and along with the East Asian lineage was associated with lower bacteriologic conversion after 8 weeks of treatment. Disease presentation and response to drug treatment varied by lineage, but these associations were no longer statistically significant after adjustment for other variables associated with week-8 culture status.


Effect of an after-school intervention on increases in children's physical activity.
Evaluate the effect of an after-school intervention on physical activity program changes and individual behaviors among children. A quasi-experimental evaluation of a YMCA-driven environmental change intervention with 16 intervention and 16 control sites in four metropolitan areas in the United States. Intervention sites participated in learning collaboratives designed to promote physical activity and nutrition through environmental change, educational activities, and parent engagement. Behavioral foci included increasing overall physical activity levels as well as combined moderate and vigorous physical activity and vigorous physical activity. Outcomes were assessed longitudinally using preintervention and follow-up surveys of program implementation and accelerometer measures of physical activity. ActiGraph accelerometer data were collected from a sample of 212 children, ages 5-11 yr, attending the programs. On average, 3 d of data were gathered per child. Reliability of the accelerometer counts averaged 0.78. Multivariate regression models were used to control for potential confounding variables and to account for clustering of observations. Data indicate greater physical activity increases in children in intervention versus control sites after modest intervention implementation. Controlling for baseline covariates, children in intervention sites showed greater increases in average physical activity level than in control sites (76 counts per minute, P = 0.037, 95% confidence interval (CI) = 8.1-144) and more minutes of moderate and vigorous physical activity (10.5 min·d(-1), P = 0.017, 95% CI = 1.5-18.6), minutes of moderate physical activity (5.6 min·d(-1), P = 0.020, 95% CI = 0.99-10.2), and minutes of vigorous physical activity (5.1 min·d(-1), P = 0.051, 95% CI = 0.21-9.93). Results indicate significant increases in daily physical activity among children in intervention versus control sites. This study documents the effectiveness of an environmental change approach in an applied setting.


Comparative value of four measures of retention in expert care in predicting clinical outcomes and health care utilization in HIV patients.
This study compared the ability of four measures of patient retention in HIV expert care to predict clinical outcomes. This retrospective study examined Veterans Health Administration (VHA) beneficiaries with HIV (ICD-9-CM codes 042 or V08) receiving expert care (defined as HIV-1 RNA viral load and CD4 cell count tests occurring within one week of each other) at VHA facilities from October 1, 2006, to September 30, 2008. Patients were ≥18 years old and continuous VHA users for at least 24 months after entry into expert care. Retention measures included: Annual Appointments (≥2 appointments annually at least 60 days apart), Missed Appointments (missed ≥25% of appointments), Infrequent Appointments (>6 months without an appointment), and Missed or Infrequent Appointments (missed ≥25% of appointments or >6 months without an appointment). Multivariable nominal logistic regression models were used to determine associations between retention measures and outcomes. Overall, 8,845 patients met study criteria. At baseline, 64% of patients were virologically suppressed and 37% had a CD4 cell count >500 cells/mm3. At 24 months, 82% were virologically suppressed and 46% had a CD4 cell count >500 cells/mm3. During follow-up, 13% progressed to AIDS, 48% visited the emergency department (ED), 28% were hospitalized, and 0.3% died. All four retention measures were associated with virologic suppression and antiretroviral therapy initiation at 24 months follow-up. Annual Appointments correlated positively with CD4 cell count >500 cells/mm3. Missed Appointments was predictive of all primary and secondary outcomes, including CD4 cell count ≤500 cells/mm3, progression to AIDS, ED visit, and hospitalization. Missed Appointments was the only measure to predict all primary and secondary outcomes. This finding could be useful to health care providers and public health organizations as they seek ways to optimize the health of HIV patients.


Morphological alterations of mouse skeletal muscles during early ageing are muscle specific.
One of the hallmarks of ageing is muscle wasting that may be preceded by morphological changes, such as capillary rarefaction. Muscle-specific changes in morphology in early ageing may differ between locomotor and respiratory muscles. To investigate this, we compared capillarization, fiber type composition, fiber cross-sectional area (FCSA) and oxidative capacity of individual fibers of the soleus (n = 6/5 for 20- and 79 weeks, respectively), extensor digitorum longus (EDL: n = 3/3) and diaphragm (n = 7/5) muscles in 20- (mature) and 79-week-old (early ageing) CD-1 female mice. There was no significant loss of soleus and EDL mass. The FCSA was larger and the capillary density lower at 79 than 20 weeks in the diaphragm, while in the EDL the opposite was found (both p ≤ 0.002) with no significant ageing-related differences in the soleus. The heterogeneity in capillary spacing, which may negatively impact on muscle oxygenation, was highest in muscles from 20-week-old mice, irrespective of muscle (p ≤ 0.011). Succinate dehydrogenase activity, indicative of oxidative capacity, and capillary to fiber ratio did not significantly change with age in any muscle. At all ages, the capillary supply to a fiber was positively related to FCSA in each muscle. We conclude that despite previously reported early age-related reductions in specific tension in both locomotor and respiratory muscles, morphological changes show a muscle-specific pattern in early ageing CD-1 mice. Specifically, early ageing was associated with 1) diaphragm hypertrophy 2) and fiber atrophy in the EDL that was not accompanied by angiogenesis, capillary rarefaction or reductions in oxidative capacity.


The production and application of carbon nanomaterials from high alkali silicate herbaceous biomass.
Herein, value-added materials such as activated carbon and carbon nanotubes were synthesized from low-value Miscanthus × giganteus lignocellulosic biomass. A significant drawback of using Miscanthus in an energy application is the melting during the combustion due to its high alkali silicate content. An application of an alternative approach was proposed herein for synthesis of activated carbon from Miscanthus × giganteus, where the produced activated carbon possessed a high surface area and pore volume of 0.92 cm3.g-1 after two activation steps using phosphoric acid and potassium hydroxide. The SBET of the raw biomass, after first activation and second activation methods showed 17, 1142 and 1368 m2.g-1, respectively. Transforming this otherwise waste material into a useful product where its material properties can be utilized is an example of promoting the circular economy by valorising waste lignocellulosic biomass to widely sought-after high surface area activated carbon and subsequently, unconventional multi-walled carbon nanotubes. This was achieved when the activated carbon produced was mixed with nitrogen-based material and iron precursor, where it produced hydrophilic multi-wall carbon nanotubes with a contact angle of θ = 9.88°, compared to the raw biomass. synthesised materials were tested in heavy metal removal tests using a lead solution, where the maximum lead absorption was observed for sample AC-K, with a 90% removal capacity after the first hour of testing. The synthesis of these up-cycled materials can have potential opportunities in the areas of wastewater treatment or other activated carbon/carbon nanotube end uses with a rapid cycle time.


Cost of joint replacement surgery for osteoarthritis: the patients' perspective.
To address costs of total joint replacement surgery from the patients' perspective by determining patient out-of-pocket costs during the first year following joint replacement, and to explore whether health status presurgery or in the immediate 3 months postsurgery were determinants of costs. In light of the different outcomes experienced by patients with total knee replacement (TKR) and total hip replacement (THR), any differences in costs between the 2 groups were also explored. Patients with osteoarthritis (OA) scheduled for primary unilateral TKR or THR surgery at 3 Sydney hospitals were approached. Patients completed questionnaires preoperatively to record expenses during the previous 3 months and health status immediately prior to surgery. Patients then maintained detailed prospective cost diaries and completed SF-36 and WOMAC Index every 3 months for the first postoperative year. Arthritis-specific cost inforrmation obtained in the diary included medications (prescription and nonprescription), visits to health professionals, tests (radiographs, scans, blood tests, etc), special equipment, alterations to house, and the use of private or community services. Ninety-eight TKR and 76 THR patients provided cost details for their first postoperative year. For both THR and TKR patients, out-of-pocket costs fell considerably over the first postoperative year, and during the year the proportion of patients who experienced no out-of-pocket costs increased, as did the proportion who made no use of health services such as medical tests or visits to health professionals. Regression analysis for THR patients showed that pension status, preoperative SF-36 Physical Component Score, and 3-month postoperative WOMAC Function were significant independent predictors of postoperative costs. Regression analysis for TKR patients showed that presurgery WOMAC Stiffness and pension status were significant independent predictors of postoperative costs, indicating that those with greater stiffness had greater postsurgery costs and those on a pension had lower costs. OA patients undergoing THR and TKR have substantial out-of-pocket costs presurgery, which fall dramatically over the first postoperative year. Poorer presurgery health status predicted greater expenditure during the first postoperative year, which might be taken into consideration when patients are making a choice about the timing of joint surgery.


From "Sooo excited!!!" to "So proud": using language to study development.
We introduce a new method, differential language analysis (DLA), for studying human development in which computational linguistics are used to analyze the big data available through online social media in light of psychological theory. Our open vocabulary DLA approach finds words, phrases, and topics that distinguish groups of people based on 1 or more characteristics. Using a data set of over 70,000 Facebook users, we identify how word and topic use vary as a function of age and compile cohort specific words and phrases into visual summaries that are face valid and intuitively meaningful. We demonstrate how this methodology can be used to test developmental hypotheses, using the aging positivity effect (Carstensen & Mikels, 2005) as an example. While in this study we focused primarily on common trends across age-related cohorts, the same methodology can be used to explore heterogeneity within developmental stages or to explore other characteristics that differentiate groups of people. Our comprehensive list of words and topics is available on our web site for deeper exploration by the research community.


Pseudoelastic intramedullary nailing for tibio-talo-calcaneal arthrodesis.
Tibio-talo-calcaneal (TTC) arthrodesis is a procedure to treat severe ankle arthropathy by providing a pain-free and stable fusion. Intramedullary (IM) nails offer a method of internal fixation for TTC arthrodesis by providing compressive stability, as well as shear and torsional rigidity. IM nails have been developed to apply compression to the TTC complex during installation; however, current designs are highly susceptible to a loss of compression when exposed to small amounts of bone resorption and cyclic loading. Nickel titanium (NiTi) is a shape-memory alloy capable of recovering large amounts of deformation via shape-memory or pseudoelasticity. Currently, the next generation of IM nails is being developed to utilize the adaptive, pseudoelastic properties of NiTi and provide a fusion nail that is resistant to loss of compression or loosening. Specifically, the pseudoelastic IM nail contains an internal NiTi compression element that applies sustained compression during the course of fusion, analogous to external fixators.


Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty.
Mammary gland development begins with the appearance of epithelial placodes that invaginate, sprout, and branch to form small arborized trees by birth. The second phase of ductal growth and branching is driven by the highly invasive structures called terminal end buds (TEBs) that form at ductal tips at the onset of puberty. Ectodysplasin (Eda), a tumor necrosis factor-like ligand, is essential for the development of skin appendages including the breast. In mice, Eda regulates mammary placode formation and branching morphogenesis, but the underlying molecular mechanisms are poorly understood. Fibroblast growth factor (Fgf) receptors have a recognized role in mammary ductal development and stem cell maintenance, but the ligands involved are ill-defined. Here we report that Fgf20 is expressed in embryonic mammary glands and is regulated by the Eda pathway. Fgf20 deficiency does not impede mammary gland induction, but compromises mammary bud growth, as well as TEB formation, ductal outgrowth and branching during puberty. We further show that loss of Fgf20 delays formation of Eda-induced supernumerary mammary buds and normalizes the embryonic and postnatal hyperbranching phenotype of Eda overexpressing mice. These findings identify a hitherto unknown function for Fgf20 in mammary budding and branching morphogenesis.


Dynamics of stimulus-evoked spike timing correlations in the cat lateral geniculate nucleus.
Precisely synchronized neuronal activity has been commonly observed in the mammalian visual pathway. Spike timing correlations in the lateral geniculate nucleus (LGN) often take the form of phase synchronized oscillations in the high gamma frequency range. To study the relations between oscillatory activity, synchrony, and their time-dependent properties, we recorded activity from multiple single units in the cat LGN under stimulation by stationary spots of light. Autocorrelation analysis showed that approximately one third of the cells exhibited oscillatory firing with a mean frequency ∼80 Hz. Cross-correlation analysis showed that 30% of unit pairs showed significant synchronization, and 61% of these pairs consisted of synchronous oscillations. Cross-correlation analysis assumes that synchronous firing is stationary and maintained throughout the period of stimulation. We tested this assumption by applying unitary events analysis (UEA). We found that UEA was more sensitive to weak and transient synchrony than cross-correlation analysis and detected a higher incidence (49% of cell pairs) of significant synchrony (unitary events). In many unit pairs, the unitary events were optimally characterized at a bin width of 1 ms, indicating that neural synchrony has a high degree of temporal precision. We also found that approximately one half of the unit pairs showed nonstationary changes in synchrony that could not be predicted by the modulation of firing rates. Population statistics showed that the onset of synchrony between LGN cells occurred significantly later than that observed between retinal afferents and LGN cells. The synchrony detected among unit pairs recorded on separate tetrodes tended to be more transient and have a later onset than that observed between adjacent units. These findings show that stimulus-evoked synchronous activity within the LGN is often rhythmic, highly nonstationary, and modulated by endogenous processes that are not tightly correlated with firing rate.


Trichomoniasis: clinical manifestations, diagnosis and management.
Trichomonas vaginalis was originally considered a commensal organism until the 1950s when the understanding of its role as a sexually transmitted infection (STI) began to evolve. Trichomoniasis has been associated with vaginitis, cervicitis, urethritis, pelvic inflammatory disease (PID), and adverse birth outcomes. Infection with T vaginalis could have an important role in transmission and acquisition of HIV. T vaginalis is site specific for the genitourinary tract and has been isolated from virtually all genitourinary structures. Asymptomatic disease is common in both men and women, thus screening for disease is important. Various sociodemographic factors have been correlated with presence of T vaginalis, and may be used to predict infection. Diagnosis is usually made from wet mount microscopy and direct visualisation, which are insensitive. DNA amplification techniques perform with good sensitivity, but are not yet approved for diagnostic purposes. In areas where diagnostic methods are limited, management of trichomoniasis is usually as part of a clinical syndrome; vaginal discharge for women and urethral discharge for men. A single dose of metronidazole is effective in the majority of cases. Outside of the United States, other nitroimidazoles may be used and are as effective as metronidazole. Metronidazole resistance is an emerging problem, but its clinical importance is not yet clear. Concomitant treatment of sexual partners is recommended.


Reduced reactivity and enhanced negative feedback sensitivity of the hypothalamus-pituitary-adrenal axis in chronic whiplash-associated disorder.
Dysregulations of the hypothalamus-pituitary-adrenal (HPA) axis have been discussed as a physiological substrate of chronic pain and fatigue. The aim of the study was to investigate possible dysregulations of the HPA axis in chronic whiplash-associated disorder (WAD). In 20 patients with chronic WAD and 20 healthy controls, awakening cortisol responses as well as a short circadian free cortisol profile were assessed before and after administration of 0.5mg dexamethasone. In comparison to the controls, chronic WAD patients had attenuated cortisol responses to awakening, normal cortisol levels during the day, and showed enhanced and prolonged suppression of cortisol after the administration of 0.5mg dexamethasone. Dysregulations of the HPA axis in terms of reduced reactivity and enhanced negative feedback suppression exist in chronic WAD. The observed endocrine abnormalities could serve as a systemic mechanism of symptoms experienced by chronic WAD patients.


Ophthalmomyiasis caused by the sheep bot fly Oestrus ovis in northern Iraq.
Myiasis is the feeding of fly larvae on vertebrates. The sheep bot fly larva of Oestrus ovis is a mammalian parasite of the skin, nose, ears, and eyes. When the larvae infest and feed on the structures of the eye, the condition is termed ophthalmomyiasis. Most often this infestation is limited to the external structures of the eye and is referred to as ophthalmomyiasis externa. The features of this condition are severe local inflammation, positive foreign body sensation, erythema, and lacrimation. Vision may or may not be reduced, depending on involvement of the cornea. A 20-year-old white male soldier sought treatment for an inflamed eye and an irritated cornea OS. His eyelids were swollen with marked periorbital edema and conjunctival erythema OS. On slitlamp examination, small whitish organisms were viewed on the conjunctiva OS. The organisms were removed, preserved, and sent to Nova Southeastern University where they were identified as O. ovis first-stage larvae. The patient was treated with antibiotic ointment, and the inflammation resolved within 1 week. O. ovis has a worldwide distribution, and although sheep are the preferred host, humans may also serve as an intermediate host in the organism's life cycle. This case represents one of several reports of ophthalmomyiasis in the Middle East caused by O. ovis. U.S. troops stationed in Iraq and surrounding areas are vulnerable to eye infestation by fly larvae, and health care providers need to include this condition in their differential diagnosis of anterior segment inflammatory disorders.


Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood-brain barrier.
Neisseria meningitidis is a commensal bacterium of the human nasopharynx. Occasionally, this bacterium reaches the bloodstream and causes meningitis after crossing the blood-brain barrier by an unknown mechanism. An immunohistological study of a meningococcal sepsis case revealed that neisserial adhesion was restricted to capillaries located in low blood flow regions in the infected organs. This study led to the hypothesis that drag forces encountered by the meningococcus in the bloodstream determine its attachment site in vessels. We therefore investigated the ability of N. meningitidis to bind to endothelial cells in the presence of liquid flow mimicking the bloodstream with a laminar flow chamber. Strikingly, average blood flows reported for various organs strongly inhibited initial adhesion. As cerebral microcirculation is known to be highly heterogeneous, cerebral blood velocity was investigated at the level of individual vessels using intravital imaging of rat brain. In agreement with the histological study, shear stress levels compatible with meningococcal adhesion were only observed in capillaries, which exhibited transient reductions in flow. The flow chamber assay revealed that, after initial attachment, bacteria resisted high blood velocities and even multiplied, forming microcolonies resembling those observed in the septicemia case. These results argue that the combined mechanical properties of neisserial adhesion and blood microcirculation target meningococci to transiently underperfused cerebral capillaries and thus determine disease development.


Economic evidence for the clinical management of major depressive disorder: a systematic review and quality appraisal of economic evaluations alongside randomised controlled trials.
The aim of this systematic review of economic evaluations alongside randomised controlled trials (RCTs) was to provide a comprehensive overview of the evidence concerning cost-effectiveness analyses of common treatment options for major depression. An existing database was used to identify studies reporting cost-effectiveness results from RCTs. This database has been developed by a systematic literature search in the bibliographic databases of PubMed, PsychINFO, Embase and Cochrane library from database inception to December 2014. We evaluated the quality of economic evaluations using a 10-item short version of the Drummond checklist. Results were synthesised narratively. The risk of bias of the included RCTs was assessed, based on the Cochrane risk of bias assessment tool. Fourteen RCTs were included from the 5580 articles screened on titles and abstracts. The methodological quality of the health economic evaluations was relatively high and the majority of the included RCTs had low risk of bias in most of Cochrane items except blinding of participants and personnel. Cognitive behavioural therapy was examined in seven trials as part of a variety of treatment protocols and seems cost-effective compared with pharmacotherapy in the long-term. However cost-effectiveness results for the combination of psychotherapy with pharmacotherapy are conflicting and should be interpreted with caution due to limited comparability between the examined trials. For several treatments, only a single economic evaluation was reported as part of a clinical trial. This was the case for comparisons between different classes of antidepressants, for several types of psychotherapy (behavioural activation, occupational therapy, interpersonal psychotherapy, short-term psychotherapy, psychodynamic psychotherapy, rational emotive behavioural therapy, solution focused therapy), and for transcranial magnetic stimulation v. electroconvulsive therapy. The limited evidence base for these interventions means generalisations, based on economic evaluation alongside clinical trials, cannot easily be made. There is some economic evidence underpinning many of the common treatment options for major depression. Wide variability was observed in study outcomes, probably attributable to differences in population, interventions or follow-up periods. For many interventions, only a single economic evaluation alongside clinical trials was identified. Thus, significant economic evidence gaps remain in the area of major depressive disorder.


Purification/annealing of graphene with 100-MeV Ag ion irradiation.
Studies on interaction of graphene with radiation are important because of nanolithographic processes in graphene-based electronic devices and for space applications. Since the electronic properties of graphene are highly sensitive to the defects and number of layers in graphene sample, it is desirable to develop tools to engineer these two parameters. We report swift heavy ion (SHI) irradiation-induced annealing and purification effects in graphene films, similar to that observed in our studies on fullerenes and carbon nanotubes (CNTs). Raman studies after irradiation with 100-MeV Ag ions (fluences from 3 × 10(10) to 1 × 10(14) ions/cm(2)) show that the disorder parameter α, defined by I D/I G ratio, decreases at lower fluences but increases at higher fluences beyond 1 × 10(12) ions/cm(2). This indicates that SHI induces annealing effects at lower fluences. We also observe that the number of graphene layers is reduced at fluences higher than 1 × 10(13) ions/cm(2). Using inelastic thermal spike model calculations, we estimate a radius of 2.6 nm for ion track core surrounded by a halo extending up to 11.6 nm. The transient temperature above the melting point in the track core results in damage, whereas lower temperature in the track halo is responsible for annealing. The results suggest that SHI irradiation fluence may be used as one of the tools for defect annealing and manipulation of the number of graphene layers. 60.80.x; 81.05.ue.


Human locomotion on ice: the evolution of ice-skating energetics through history.
More than 3000 years ago, peoples living in the cold North European regions started developing tools such as ice skates that allowed them to travel on frozen lakes. We show here which technical and technological changes determined the main steps in the evolution of ice-skating performance over its long history. An in-depth historical research helped identify the skates displaying significantly different features from previous models and that could consequently determine a better performance in terms of speed and energy demand. Five pairs of ice skates were tested, from the bone-skates, dated about 1800 BC, to modern ones. This paper provides evidence for the fact that the metabolic cost of locomotion on ice decreased dramatically through history, the metabolic cost of modern ice-skating being only 25% of that associated with the use of bone-skates. Moreover, for the same metabolic power, nowadays skaters can achieve speeds four times higher than their ancestors could. In the range of speeds considered, the cost of travelling on ice was speed independent for each skate model, as for running. This latter finding, combined with the accepted relationship between time of exhaustion and the sustainable fraction of metabolic power, gives the opportunity to estimate the maximum skating speed according to the distance travelled. Ice skates were probably the first human powered locomotion tools to take the maximum advantage from the biomechanical properties of the muscular system: even when travelling at relatively high speeds, the skating movement pattern required muscles to shorten slowly so that they could also develop a considerable amount of force.


Substitution of Human Papillomavirus Type 16 L2 Neutralizing Epitopes Into L1 Surface Loops: The Effect on Virus-Like Particle Assembly and Immunogenicity.
Cervical cancer caused by infection with human papillomaviruses (HPVs) is the fourth most common cancer in women globally, with the burden mainly in developing countries due to limited healthcare resources. Current vaccines based on virus-like particles (VLPs) assembled from recombinant expression of the immunodominant L1 protein are highly effective in the prevention of cervical infection; however, these vaccines are expensive and type-specific. Therefore, there is a need for more broadly protective and affordable vaccines. The HPV-16 L2 peptide sequences 108-120, 65-81, 56-81, and 17-36 are highly conserved across several HPV types and have been shown to elicit cross-neutralizing antibodies. To increase L2 immunogenicity, L1:L2 chimeric VLPs (cVLP) vaccine candidates were developed. The four L2 peptides mentioned above were substituted into the DE loop of HPV-16 L1 at position 131 (SAC) or in the C-terminal region at position 431 (SAE) to generate HPV-16-derived L1:L2 chimeras. All eight chimeras were transiently expressed in Nicotiana benthamiana via Agrobacterium tumefaciens-mediated DNA transfer. SAC chimeras predominantly assembled into higher order structures (T = 1 and T = 7 VLPs), whereas SAE chimeras assembled into capsomeres or formed aggregates. Four SAC and one SAE chimeras were used in vaccination studies in mice, and their ability to generate cross-neutralizing antibodies was analyzed in HPV pseudovirion-based neutralization assays. Of the seven heterologous HPVs tested, cross-neutralization with antisera specific to chimeras was observed for HPV-11 (SAE 65-18), HPV-18 (SAC 108-120, SAC 65-81, SAC 56-81, SAE 65-81), and HPV-58 (SAC 108-120). Interestingly, only anti-SAE 65-81 antiserum showed neutralization of homologous HPV-16, suggesting that the position of the L2 epitope display is critical for maintaining L1-specific neutralizing epitopes.


Measuring research capacity development in healthcare workers: a systematic review.
A key barrier in supporting health research capacity development (HRCD) is the lack of empirical measurement of competencies to assess skills and identify gaps in research activities. An effective tool to measure HRCD in healthcare workers would help inform teams to undertake more locally led research. The objective of this systematic review is to identify tools measuring healthcare workers' individual capacities to conduct research. Systematic review and narrative synthesis using Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for reporting systematic reviews and narrative synthesis and the Critical Appraisals Skills Programme (CASP) checklist for qualitative studies. 11 databases were searched from inception to 16 January 2020. The first 10 pages of Google Scholar results were also screened. We included papers describing the use of tools/to measure/assess HRCD at an individual level among healthcare workers involved in research. Qualitative, mixed and quantitative methods were all eligible. Search was limited to English language only. Two authors independently screened and reviewed studies using Covidence software, and performed quality assessments using the extraction log validated against the CASP qualitative checklist. The content method was used to define a narrative synthesis. The titles and abstracts for 7474 unique records were screened and the full texts of 178 references were reviewed. 16 papers were selected: 7 quantitative studies; 1 qualitative study; 5 mixed methods studies; and 3 studies describing the creation of a tool. Tools with different levels of accuracy in measuring HRCD in healthcare workers at the individual level were described. The Research Capacity and Culture tool and the 'Research Spider' tool were the most commonly defined. Other tools designed for ad hoc interventions with good generalisability potential were identified. Three papers described health research core competency frameworks. All tools measured HRCD in healthcare workers at an individual level with the majority adding a measurement at the team/organisational level, or data about perceived barriers and motivators for conducting health research. Capacity building is commonly identified with pre/postintervention evaluations without using a specific tool. This shows the need for a clear distinction between measuring the outcomes of training activities in a team/organisation, and effective actions promoting HRCD. This review highlights the lack of globally applicable comprehensive tools to provide comparable, standardised and consistent measurements of research competencies. CRD42019122310.


Methylated HBHA produced in M. smegmatis discriminates between active and non-active tuberculosis disease among RD1-responders.
A challenge in tuberculosis (TB) research is to develop a new immunological test that can help distinguish, among subjects responsive to QuantiFERON TB Gold In tube (QFT-IT), those who are able to control Mtb replication (remote LTBI, recent infection and past TB) from those who cannot (active TB disease). IFN-γ response to the Heparin-binding-hemagglutinin (HBHA) of Mtb has been associated with LTBI, but the cumbersome procedures of purifying the methylated and immunological active form of the protein from Mtb or M. bovis Bacillus Calmette et Guerin (BCG) have prevented its implementation in a diagnostic test. Therefore, the aim of the present study was to evaluate the IFN-γ response to methylated HBHA of Mtb produced in M. smegmatis (rHBHAms) in individuals at different stages of TB who scored positive to QFT-IT. 87 individuals at different stages of TB who scored positive to QFT-IT were selected. IFN-γ response to in vitro whole blood stimulation with rHBHAms was evaluated by short-term and long-term tests and detected by ELISA or flow cytometry. We demonstrated that the IFN-γ response to rHBHAms is mediated by CD4(+) T-cells with an effector-memory phenotype. This response, evaluated by short-term-tests, is significantly lower in active TB than in remote LTBI (p = 0.0010) and past TB (p = 0.0152). These results were confirmed by long-term tests. The qualitative data confirmed that IFN-γ responses higher than the cut-off point identified by ROC analysis are associated with the status of non-active disease. In this study we show that the T-cell response to a recombinant and methylated HBHA of Mtb produced in M. smegmatis is useful to discriminate between active and non-active TB disease among those responsive to QFT-IT in a whole blood system. Further studies are needed to improve the accuracy of the assay.


Intracellular Zn2+ accumulation enhances suppression of synaptic activity following spreading depolarization.
Spreading depolarization (SD) is a feed-forward wave that propagates slowly throughout brain tissue and recovery from SD involves substantial metabolic demand. Presynaptic Zn(2+) release and intracellular accumulation occurs with SD, and elevated intracellular Zn(2+) ([Zn(2+) ]i ) can impair cellular metabolism through multiple pathways. We tested here whether increased [Zn(2+) ]i could exacerbate the metabolic challenge of SD, induced by KCl, and delay recovery in acute murine hippocampal slices. [Zn(2+) ]i loading prior to SD, by transient ZnCl2 application with the Zn(2+) ionophore pyrithione (Zn/Pyr), delayed recovery of field excitatory post-synaptic potentials (fEPSPs) in a concentration-dependent manner, prolonged DC shifts, and significantly increased extracellular adenosine accumulation. These effects could be due to metabolic inhibition, occurring downstream of pyruvate utilization. Prolonged [Zn(2+) ]i accumulation prior to SD was required for effects on fEPSP recovery and consistent with this, endogenous synaptic Zn(2+) release during SD propagation did not delay recovery from SD. The effects of exogenous [Zn(2+) ]i loading were also lost in slices preconditioned with repetitive SDs, implying a rapid adaptation. Together, these results suggest that [Zn(2+) ]i loading prior to SD can provide significant additional challenge to brain tissue, and could contribute to deleterious effects of [Zn(2+) ]i accumulation in a range of brain injury models.


Ecological and evolutionary genomics of marine photosynthetic organisms.
Environmental (ecological) genomics aims to understand the genetic basis of relationships between organisms and their abiotic and biotic environments. It is a rapidly progressing field of research largely due to recent advances in the speed and volume of genomic data being produced by next generation sequencing (NGS) technologies. Building on information generated by NGS-based approaches, functional genomic methodologies are being applied to identify and characterize genes and gene systems of both environmental and evolutionary relevance. Marine photosynthetic organisms (MPOs) were poorly represented amongst the early genomic models, but this situation is changing rapidly. Here we provide an overview of the recent advances in the application of ecological genomic approaches to both prokaryotic and eukaryotic MPOs. We describe how these approaches are being used to explore the biology and ecology of marine cyanobacteria and algae, particularly with regard to their functions in a broad range of marine ecosystems. Specifically, we review the ecological and evolutionary insights gained from whole genome and transcriptome sequencing projects applied to MPOs and illustrate how their genomes are yielding information on the specific features of these organisms.


Coping with drought: stress and adaptive responses in potato and perspectives for improvement.
Potato (Solanum tuberosum L.) is often considered as a drought sensitive crop and its sustainable production is threatened due to frequent drought episodes. There has been much research aiming to understand the physiological, biochemical, and genetic basis of drought tolerance in potato as a basis for improving production under drought conditions. The complex phenotypic response of potato plants to drought is conditioned by the interactive effects of the plant's genotypic potential, developmental stage, and environment. Effective crop improvement for drought tolerance will require the pyramiding of many disparate characters, with different combinations being appropriate for different growing environments. An understanding of the interaction between below ground water uptake by the roots and above ground water loss from the shoot system is essential. The development of high throughput precision phenotyping platforms is providing an exciting new tool for precision screening, which, with the incorporation of innovative screening strategies, can aid the selection and pyramiding of drought-related genes appropriate for specific environments. Outcomes from genomics, proteomics, metabolomics, and bioengineering advances will undoubtedly compliment conventional breeding strategies and presents an alternative route toward development of drought tolerant potatoes. This review presents an overview of past research activity, highlighting recent advances with examples from other crops and suggesting future research directions.


Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells.
This study first investigates the anticancer effect of asiatic acid in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Asiatic acid exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclinB1, cyclinA, Cdc2, and Cdc25C in a p53-independent manner. Asiatic acid also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the level of inactivated phospho-Cdc2 and phospho-Cdc25C. Asiatic acid treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8. We also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), and p38, but not c-Jun NH2-terminal kinase (JNK), are critical mediators in asiatic acid-induced cell growth inhibition. U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], specific inhibitors of mitogen-activated protein kinase kinase and p38 kinase activities, significantly decreased or delayed apoptosis. Asiatic acid was likely to confine the breast cancer cells in the S-G2/M phase mainly through the p38 pathway, because both SB203580 and p38 small interfering RNA (siRNA) inhibition significantly attenuated the accumulation of inactive phospho-Cdc2 and phospho-Cdc25C proteins and the cell numbers of S-G2/M phase. Moreover, U0126 and ERK siRNA inhibition completely suppressed asiatic acid-induced Bcl-2 phosphorylation and Bax up-regulation, and caspase-9 activation. Together, these results imply a critical role for ERK1/2 and p38 but not JNK, p53, and Fas/Fas ligand in asiatic acid-induced S-G2/M arrest and apoptosis of human breast cancer cells.


Transnational policy migration, interdisciplinary policy transfer and decolonization: Tracing the patterns of research ethics regulation in Taiwan.
Research ethics regulation in parts of the Global North has sometimes been initiated in the face of biomedical scandal. More recently, developing and recently developed countries have had additional reasons to regulate, doing so to attract international clinical trials and American research funding, publish in international journals, or to respond to broader social changes. In Taiwan, biomedical research ethics policy based on 'principlism' and committee-based review were imported from the United States. Professionalisation of research ethics displaced other longer-standing ways of conceiving ethics connected with Taiwanese cultural traditions. Subsequently, the model and its discursive practices were extended to other disciplines. Regulation was also shaped by decolonizing discourses associated with asserting Indigenous peoples' rights. Locating research ethics regulation within the language and practices of public policy formation and transfer as well as decolonization, allows analysis to move beyond the self-referential and attend to the social, economic and political context within which regulation operates.


CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment.
Expression of CD44, especially the variant isoforms (CD44v) of this major cancer stem cell marker, contributes to reactive oxygen species (ROS) defense through stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38(MAPK) (a major ROS target) expression in Opisthorchis viverrini-induced hamster CCA tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho-p38(MAPK) signal, whereas the CD44v signal was increased during bile duct transformation. Patients with CCA showed CD44v overexpression and negative-phospho-p38(MAPK) patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38(MAPK) patients (P = 0.030). Knockdown of CD44 showed that xCT and glutathione levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v cancer stem cell therapy using sulfasalazine. Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38(MAPK) in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug (e.g. gemcitabine) by blocking the mechanism of the cell's ROS defensive system.


The relative importance of family socioeconomic status and school-based peer hierarchies for morning cortisol in youth: an exporatory study.
This paper examines the relative importance of family socioeconomic status (SES) and school-based peer hierarchies for young people's psychoneuroendocrine response, represented by cortisol level. Data are drawn from a study of 2824, 15-year-olds in 22 Scottish secondary schools in 2006 who provided information on family SES (parental occupation, material deprivation and family affluence) and social position in school hierarchies, together with two morning salivary cortisol samples. School social position was assessed by participants placing themselves on seven 'ladders', from which three factors were derived, termed scholastic, peer and sports hierarchies. Controlling for confounds, there was little or no variation in cortisol by any SES measure. By contrast, each school hierarchy was independently associated with cortisol, but in different ways. For the scholastic hierarchy, an inverse linear relationship was found for females, cortisol increasing with lower position. For peer hierarchy, an opposite (direct) linear relationship occurred for males, while for females elevated cortisol was associated only with 'top' position. For sports, elevated cortisol among males was associated with 'bottom' position, among females with all except the 'top'. These results are interpreted in the context of Sapolsky's (Sapolsky, 2005) predictions for stress responses to hierarchical position in stable and unstable social systems, the former represented by the scholastic hierarchy involving elevated cortisol in lower positions, the latter by peer hierarchy with elevated cortisol in higher positions. Overall, the results highlight the greater importance of school-based peer groups than family SES for young people's psychoneuroendocrine response.


Ethical Challenges in Promoting the Implementation of Preventive Interventions: Report of the SPR Task Force.
Prevention science researchers and practitioners are increasingly engaged in a wide range of activities and roles to promote evidence-based prevention practices in the community. Ethical concerns invariably arise in these activities and roles that may not be explicitly addressed by university or professional guidelines for ethical conduct. In 2015, the Society for Prevention Research (SPR) Board of Directors commissioned Irwin Sandler and Tom Dishion to organize a series of roundtables and establish a task force to identify salient ethical issues encountered by prevention scientists and community-based practitioners as they collaborate to implement evidence-based prevention practices. This article documents the process and findings of the SPR Ethics Task Force and aims to inform continued efforts to articulate ethical practice. Specifically, the SPR membership and task force identified prevention activities that commonly stemmed from implementation and scale-up efforts. This article presents examples that illustrate typical ethical dilemmas. We present principles and concepts that can be used to frame the discussion of ethical concerns that may be encountered in implementation and scale-up efforts. We summarize value statements that stemmed from our discussion. We also conclude that the field of prevention science in general would benefit from standards and guidelines to promote ethical behavior and social justice in the process of implementing evidence-based prevention practices in community settings. It is our hope that this article serves as an educational resource for students, investigators, and Human Subjects Review Board members regarding some of the complexity of issues of fairness, equality, diversity, and personal rights for implementation of preventive interventions.


Functional domains of CCN1 (Cyr61) regulate breast cancer progression.
CCN1 plays diverse roles in cellular proliferation, survival, migration and angiogenesis. We determined the relationship between CCN1 protein expression and clinical factors that are important for the classification of breast cancer. CCN1 contains four functional domains; the contribution of each of the structural domains to the biological properties of CCN1 in breast cancer was investigated. We performed immunohistochemistry for CCN1 on a breast cancer tissue array, and conducted a detailed statistical analysis on the relationship between CCN1 protein expression and clinical factors that are important for the classification of breast cancer. The structure-function relationship was examined using four mutant constructs in which one of the modules (DM1-DM4) had been deleted. MCF-7 breast cancer cells were stably transfected with these constructs and their biological activity was tested in comparison to full-length CCN1. Staining of CCN1 in tumors was positively correlated with AJCC disease stage. A strong association also was found between lymph node involvement and high CCN1 expression in patients with invasive breast cancer; there was a significant increase in the breast cancer expression of CCN1 in patients with positive lymph nodes (P=0.004), and the levels of CCN1 correlated with the number of positive lymph nodes (P=0.0006). Deletion of module 4 rendered CCN1 unable to either bind heparin or associate with the extracellular matrix. Furthermore, MCF-7/DM4 cells demonstrated reduced cell spreading, migration and proliferation, indicating that module 4 of the protein is important for its ability to promote these activities. These findings indicate that CCN1 is involved throughout the clinical progression of breast cancer to an invasive phenotype. The multimodular structure of CCN1 enables it to fulfill multiple functions that may contribute to the different stages of cancer development, raising the prospect that specific regions of CCN1 could be targeted for therapeutic benefit to inhibit particular aspects of malignancy in breast cancer.


Osteopathic manipulative treatment for nonspecific low back pain: a systematic review and meta-analysis.
Nonspecific back pain is common, disabling, and costly. Therefore, we assessed effectiveness of osteopathic manipulative treatment (OMT) in the management of nonspecific low back pain (LBP) regarding pain and functional status. A systematic literature search unrestricted by language was performed in October 2013 in electronic and ongoing trials databases. Searches of reference lists and personal communications identified additional studies. Only randomized clinical trials were included; specific back pain or single treatment techniques studies were excluded. Outcomes were pain and functional status. Studies were independently reviewed using a standardized form. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) and overall effect size were calculated at 3 months posttreatment. GRADE was used to assess quality of evidence. We identified 307 studies. Thirty-one were evaluated and 16 excluded. Of the 15 studies reviewed, 10 investigated effectiveness of OMT for nonspecific LBP, 3 effect of OMT for LBP in pregnant women, and 2 effect of OMT for LBP in postpartum women. Twelve had a low risk of bias. Moderate-quality evidence suggested OMT had a significant effect on pain relief (MD, -12.91; 95% CI, -20.00 to -5.82) and functional status (SMD, -0.36; 95% CI, -0.58 to -0.14) in acute and chronic nonspecific LBP. In chronic nonspecific LBP, moderate-quality evidence suggested a significant difference in favour of OMT regarding pain (MD, -14.93; 95% CI, -25.18 to -4.68) and functional status (SMD, -0.32; 95% CI, -0.58 to -0.07). For nonspecific LBP in pregnancy, low-quality evidence suggested a significant difference in favour of OMT for pain (MD, -23.01; 95% CI, -44.13 to -1.88) and functional status (SMD, -0.80; 95% CI, -1.36 to -0.23), whereas moderate-quality evidence suggested a significant difference in favour of OMT for pain (MD, -41.85; 95% CI, -49.43 to -34.27) and functional status (SMD, -1.78; 95% CI, -2.21 to -1.35) in nonspecific LBP postpartum. Clinically relevant effects of OMT were found for reducing pain and improving functional status in patients with acute and chronic nonspecific LBP and for LBP in pregnant and postpartum women at 3 months posttreatment. However, larger, high-quality randomized controlled trials with robust comparison groups are recommended.


Functional conservation of Mei4 for meiotic DNA double-strand break formation from yeasts to mice.
Meiotic recombination is initiated by the programmed induction of DNA double-strand breaks (DSBs) catalyzed by the evolutionarily conserved Spo11 protein. Studies in yeast have shown that DSB formation requires several other proteins, the role and conservation of which remain unknown. Here we show that two of these Saccharomyces cerevisiae proteins, Mei4 and Rec114, are evolutionarily conserved in most eukaryotes. Mei4(-/-) mice are deficient in meiotic DSB formation, thus showing the functional conservation of Mei4 in mice. Cytological analyses reveal that, in mice, MEI4 is localized in discrete foci on the axes of meiotic chromosomes that do not overlap with DMC1 and RPA foci. We thus propose that MEI4 acts as a structural component of the DSB machinery that ensures meiotic DSB formation on chromosome axes. We show that mouse MEI4 and REC114 proteins interact directly, and we identify conserved motifs as required for this interaction. Finally, the unexpected, concomitant absence of Mei4 and Rec114, as well as of Mnd1, Hop2, and Dmc1, in some eukaryotic species (particularly Neurospora crassa, Drosophila melanogaster, and Caenorhabditis elegans) suggests the existence of Mei4-Rec114-dependent and Mei4-Rec114-independent mechanisms for DSB formation, and a functional relationship between the chromosome axis and DSB formation.


Vascular perfusion of choroidal melanoma by 3.0 tesla magnetic resonance imaging.
Because signal-to-noise performance improves with increased magnetic field strength, the quality of magnetic resonance images is greater at 3.0 tesla (T) than at 1.5 T. Because of the longer T1 values at higher field strength, intravenously administered magnetic resonance contrast agents provide improved T1 enhancement at 3.0 T. We have used these factors to obtain high-quality contrast-enhanced imaging of small intraocular lesions using a standard head radiofrequency volume coil. Specifically, we have examined lesion size and magnitude of maximum contrast enhancement in a series of intraocular melanomas before and during therapy. Eighteen patients with intraocular masses were examined by 3.0 T magnetic resonance imaging (MRI) including intravenous contrast enhancement. Precontrast images were acquired through the orbits followed by sequential postcontrast images at 1-minute intervals for 5 minutes. The magnitude of contrast enhancement of the lesion, extraocular muscles, and brain parenchyma was measured as a percentage increase in magnetic resonance signal over the preenhancement signal intensity. Lesions demonstrated different levels of enhancement ranging up to 130%. Three patterns of enhancement--0% to 20%, 20% to 50%, and >50%-were identified. Brain parenchyma, benign lesions, and responsive tumors following brachytherapy with 125I demonstrated enhancement of less than 20%. Four choroidal melanomas showed intermediate (20% to 50%) levels of enhancement. Four malignant lesions (three melanomas, one metastatic tumor), as well as the extraocular muscles, showed strong, rapid enhancement (>50%). Four patients who had MRI studies before and following plaque brachytherapy ultimately demonstrated a decline in the contrast enhancement following treatment. Contrast enhancement of intraocular lesions measured by 3.0 T MRI demonstrates different patterns of enhancement that may be useful for indicating the degree of malignancy and in monitoring response to therapy.