The effects of bracing on sagittal spinopelvic parameters and Cobb angle in adolescents with idiopathic scoliosis: A before-after clinical study.
This study aims to evaluate the effects of bracing on the Cobb angle and sagittal spinopelvic parameters in adolescent idiopathic scoliosis (AIS) patients. A total of 25 adolescents (2 males, 23 females; mean age 12.7±1.6; range, 10-15 years) with AIS who received bracing between January 2000 and June 2017 were retrospectively analyzed. The initial and final out-of-brace radiographs of 25 AIS patients were analyzed with regard to the spinopelvic parameters. The pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), Cobb angle, thoracic kyphosis (TK), and lumbar lordosis (LL) were measured. The mean age at the initiation of bracing was 12.7±1.6 years. The mean initial Cobb angle was 31.8°±5.9°. There were no statistically significant differences between the baseline and the final measurements of the PI, PT, and SS. However, there were statistically significant differences between the baseline and the final measurements of the TK, LL, and Cobb angle. A significant correlation was observed between the PI and Cobb angle and TK and between the LL and SS. Our study results show significant associations between the sagittal pelvic parameters and the spinal parameters during the brace treatment of adolescents with idiopathic scoliosis.


Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo.
The microbiome dysbiosis caused by antibiotic treatment has been associated with both susceptibility to and relapse of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on its use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. While it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage, lysing 18 and 62 of the ribotypes and strains tested, respectively. Single-phage treatments of ribotype 076, 014/020, and 027 strains showed an initial reduction in the bacterial load followed by the emergence of phage-resistant colonies. However, these colonies remained susceptible to infection with an unrelated phage. In contrast, specific phage combinations caused the complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, the oral delivery of optimized phage combinations resulted in reduced C. difficile colonization at 36 h postinfection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to the time of onset of symptoms in untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.


Tailoring peptidomimetics for targeting protein-protein interactions.
Protein-protein interactions (PPI) are a hallmark of cellular signaling. Such interactions occur abundantly within the cellular milieu and encompass interactions involved in vital cellular processes. Understanding the various types, mechanisms, and consequences of PPIs with respect to cellular signaling and function is vital for targeted drug therapy. Various types of small-molecule drugs and targeted approaches to drug design have been developed to modulate PPIs. Peptidomimetics offer an exciting class of therapeutics as they can be designed to target specific PPIs by mimicking key recognition motifs found at critical points in the interface of PPIs (e.g., hotspots). In contrast to peptides, peptidomimetics do not possess a natural peptide backbone structure but present essential functional groups in a required three-dimensional pattern complimentary to the protein-binding pocket. This design feature overcomes many limitations of peptide therapeutics including limited stability toward peptidases, poor transport across biologic membranes, and poor target specificity. Equally important is deciphering the structural requirements and amino acid residues critical to PPIs. This review provides an up-to-date perspective of the complexity of cellular signaling and strategies for targeting PPIs in disease states, particularly in cancer, using peptidomimetics, and highlights that the rational design of agents that target PPIs is not only feasible but is of the utmost clinical importance.


Experience with using second life for medical education in a family and community medicine education unit.
The application of new technologies to the education of health professionals is both a challenge and a necessity. Virtual worlds are increasingly being explored as a support for education. The aim of this work is to study the suitability of Second Life (SL) as an educational tool for primary healthcare professionals. Qualitative study of accredited clinical sessions in SL included in a continuing professional development (CPD) programme for primary healthcare professionals. Zaragoza I Zone Family and Community Medicine Education Unit (EU) and 9 health centres operated by the Aragonese Health Service, Aragon, Spain. The EU held two training workshops in SL for 16 healthcare professionals from 9 health centres by means of two workshops, and requested them to facilitate clinical sessions in SL. Attendance was open to all personnel from the EU and the 9 health centres. After a trail period of clinical sessions held at 5 health centres between May and November 2010, the CPD-accredited clinical sessions were held at 9 health centres between February and April 2011. 76 healthcare professionals attended the CPD-accredited clinical sessions in SL. Questionnaire on completion of the clinical sessions. Response rate: 42-100%. Questionnaire completed by each health centre on completion of the CPD-accredited clinical sessions: Access to SL: 2 centres were unable to gain access. Sound problems: 0% (0/9). Image problems: 0% (0/9). Voice/text chat: used in 100% (10/9); 0 incidents. Questionnaire completed by participants in the CPD-accredited clinical sessions: Preference for SL as a tool: 100% (76/76). Strengths of this method: 74% (56/76) considered it eliminated the need to travel; 68% (52/76) believed it made more effective use of educational resources; and 47% (36/76) considered it improved accessibility. Weaknesses: 91% (69/76) experienced technical problems, while; 9% (7/76) thought it was impersonal and with little interaction. 65.79% (50/76) believed it was better than other distance learning methods and 38.16% (29/76) believed it was better than face-to-face learning. SL is a tool that allows educational activities to be designed that involve a number of health centres in different geographical locations, consequently eliminating the need to travel and making more effective use of educational resources.


Resistance exercise: an effective strategy to reverse muscle wasting in hemodialysis patients?
Muscle wasting is a common complication afflicting maintenance hemodialysis (HD) patients, and it is associated with decreased muscle function, exercise performance, physical function, and quality of life. Meanwhile, numerous epidemiologic studies have consistently shown that greater muscle mass (ascertained by body anthropometry surrogates, body composition tests such as dual x-ray absorptiometry, and/or serum creatinine in patients with little to no residual kidney function) is associated with increased survival in this population. The pathophysiology of muscle wasting in HD patients is complex and may be caused by poor dietary intake, catabolic effects of dialysis therapy, hormonal alterations (e.g., decreased levels or resistance to anabolic hormones, increased levels of catabolic hormones), inflammation, metabolic acidosis, and concurrent comorbidities. Muscle disuse resulting from low physical activity is an important yet under-appreciated risk factor for muscle wasting. Intra-dialytic resistance exercise training has been suggested as a potential strategy to correct and/or prevent this complication in HD patients, but prior studies examining this exercise modality as an anabolic intervention have shown mixed results. In a recently published 12-week randomized controlled trial of a novel intra-dialytic progressive resistance exercise training (PRET) program vs. control therapy conducted in HD and non-HD patients, PRET resulted in increased muscle volume and strength in both groups. At this time, further study is needed to determine if anabolic improvements imparted by resistance exercise translates into improved physical function and quality of life, decreased hospitalization and mortality risk, and greater cost-effectiveness in HD patients.


Effect of airline travel on performance: a review of the literature.
The need for athletes to travel long distances has spurred investigation into the effect of air travel across multiple time zones on athletic performance. Rapid eastward or westward travel may negatively affect the body in many ways; therefore, strategies should be employed to minimise these effects which may hamper athletic performance. In this review, the fundamentals of circadian rhythm disruption are examined along with additional effects of airline travel including jet lag, sleep deprivation, travel at altitude and nutritional considerations that negatively affect performance. Evidence-based recommendations are provided at the end of the manuscript to minimise the effects of airline travel on performance.


Microchip-based engineering of super-pancreatic islets supported by adipose-derived stem cells.
Type 1 diabetes mellitus (T1DM) is a chronic disorder characterized by targeted autoimmune-mediated destruction of the β cells of Langerhans within pancreatic islets. Currently, islet transplantation is the only curative therapy; however, donor shortages and cellular damage during the isolation process critically limit the use of this approach. Here, we describe a method for creating viable and functionally potent islets for successful transplantation by co-culturing single primary islet cells with adipose-derived stem cells (ADSCs) in concave microwells. We observed that the ADSCs segregated from the islet cells, eventually yielding purified islet spheroids in the three-dimensional environment. Thereafter, the ADSC-exposed islet spheroids showed significantly different ultrastructural morphologies, higher viability, and enhanced insulin secretion compared to mono-cultured islet spheroids. This suggests that ADSCs may have a significant potential to protect islet cells from damage during culture, and may be employed to improve islet cell survival and function prior to transplantation. In vivo experiments involving xenotransplantation of microfiber-encapsulated spheroids into a mouse model of diabetes revealed that co-culture-transplanted mice maintained their blood glucose levels longer than mono-culture-transplanted mice, and required less islet mass to reverse diabetes. This method for culturing islet spheroids could potentially help overcome the cell shortages that have limited clinical applications and could possibly be developed into a bioartificial pancreas.


Human diaphragm remodeling associated with chronic obstructive pulmonary disease: clinical implications.
Diaphragm remodeling associated with chronic obstructive pulmonary disease (COPD) consists of a fast-to-slow fiber type transformation as well as adaptations within each fiber type. To try to explain disparate findings in the literature regarding the relationship between fiber type proportions and FEV1, we obtained costal diaphragm biopsies on 40 subjects whose FEV1 ranged from 118 to 16% of the predicted normal value. First, we noted that our exponential regression model indicated that changes in FEV1 can account for 72% of the variation in the proportion of Type I fibers. Second, to assess the impact of COPD on diaphragm force generation, we measured maximal specific force generated by single permeabilized fibers prepared from the diaphragms of two patients with normal pulmonary function tests and two patients with severe COPD. We noted that fibers prepared from the diaphragms of severe COPD patients generated a lower specific force than control fibers (p < 0.001) and Type I fibers generated a lower specific force than Type II fibers (p < 0.001). Our finding of an exponential relationship between the proportion of Type I fibers and FEV1 accounts for discrepancies in the literature. Moreover, our single-fiber results suggest that COPD-associated diaphragm remodeling decreases diaphragmatic force generation by adaptations within each fiber type as well as by fiber type transformations.


Can your house keep you out of a nursing home?
We examine the impact of the accessibility of an older individual's house on her use of nursing home care. We link administrative data on the accessibility of all houses in the Netherlands to data on long-term care use of all older persons from 2011 to 2014. We find that older people living in more accessible houses are less likely to use nursing home care. The effects increase with age and are largest for individuals aged 90 or older. The effects are stronger for people with physical limitations than for persons with cognitive problems. We also provide suggestive evidence that older people living in more accessible houses substitute nursing home care by home care.


Yeast Eps15-like endocytic protein, Pan1p, activates the Arp2/3 complex.
Longstanding evidence supports a role for actin in endocytosis; an intact actin cytoskeleton is required for endocytosis in yeast, and drugs that inhibit actin polymerization inhibit endocytosis in both yeast and mammalian cells. The yeast Arp2/3 complex is required for the internalization step of endocytosis. In addition, some early endocytic events in mammalian cells are associated with the formation of actin tails similar to those generated by activated Arp2/3 complex. However, until now no Arp2/3 complex activator has been identified among proteins known to mediate early steps in endocytosis. Here we show that the yeast endocytic protein Pan1p binds to and activates the Arp2/3 complex. Genetic interactions between PAN1 and mutants of Arp2/3 subunits, or of the Arp2/3 activator LAS17, provide evidence for this activity in vivo. We suggest that Pan1p forms the core of an endocytic complex and physically couples actin polymerization nucleated by the Arp2/3 complex to the endocytic machinery, thus providing the forces necessary for endocytosis.


Characterization of MHz pulse repetition rate femtosecond laser-irradiated gold-coated silicon surfaces.
In this study, MHz pulse repetition rate femtosecond laser-irradiated gold-coated silicon surfaces under ambient condition were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS). The radiation fluence used was 0.5 J/cm2 at a pulse repetition rate of 25 MHz with 1 ms interaction time. SEM analysis of the irradiated surfaces showed self-assembled intermingled weblike nanofibrous structure in and around the laser-irradiated spots. Further TEM investigation on this nanostructure revealed that the nanofibrous structure is formed due to aggregation of Au-Si/Si nanoparticles. The XRD peaks at 32.2°, 39.7°, and 62.5° were identified as (200), (211), and (321) reflections, respectively, corresponding to gold silicide. In addition, the observed chemical shift of Au 4f and Si 2p lines in XPS spectrum of the irradiated surface illustrated the presence of gold silicide at the irradiated surface. The generation of Si/Au-Si alloy fibrous nanoparticles aggregate is explained by the nucleation and subsequent condensation of vapor in the plasma plume during irradiation and expulsion of molten material due to high plasma pressure.


In vitro Gram-positive antimicrobial activity of evernimicin (SCH 27899), a novel oligosaccharide, compared with other antimicrobials: a multicentre international trial.
The antimicrobial activity of evernimicin (formerly SCH 27899), a novel oligosaccharide antimicrobial of the everninomicin class, was evaluated against four groups of Gram-positive pathogens: (i) Streptococcus pneumoniae (n = 1452); (ii) methicillin- or oxacillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CoNS; n = 1427); (iii) enterococci (n = 1517); and (iv) non-pneumococcal streptococci (n = 1388), using the Etest method at each study centre throughout Eastern and Western Europe, Scandinavia, South Africa, Turkey and North America. Comparative MICs were determined for a variety of reference compounds, including vancomycin, quinupristin/dalfopristin, chloramphenicol, penicillin, ampicillin, oxacillin, ceftriaxone and ciprofloxacin. Evernimicin was highly active against all strains tested, with MIC90 values < or = 1.0 mg/L, ranging from 0.047 mg/L against S. pneumoniae to 1.0 mg/L against MRSA/MR-CoNS and enterococci. Compared with the reference agents, the MIC90 of evernimicin were lower against all species. Against MRSA and MR-CoNS the MIC90s of evernimicin, quinupristin/dalfopristin and vancomycin (the three most active agents) were 1.0, 1.5 and 3.0 mg/L, respectively. Against all species tested, the relative activities and spectra of these agents were: evernimicin > vancomycin > quinupristin/dalfopristin. The Etest proved to be reliable and reproducible, despite occasional interpretive difficulties caused by observer inexperience. Quality control results were excellent among the 33 participant sites. The results of this in vitro, multicentre, multinational study demonstrate that evernimicin possesses high antimicrobial activity against Gram-positive organisms that compares favourably with established antibacterial treatments and newer agents such as quinupristin/dalfopristin. Further clinical investigations of everninomicin class compounds appear warranted.


Investigating Helium Bubble Nucleation and Growth through Simultaneous In-Situ Cryogenic, Ion Implantation, and Environmental Transmission Electron Microscopy.
Palladium can readily dissociate molecular hydrogen at its surface, and rapidly accept it onto the octahedral sites of its face-centered cubic crystal structure. This can include radioactive tritium. As tritium β-decays with a half-life of 12.3 years, He-3 is generated in the metal lattice, causing significant degradation of the material. Helium bubble evolution at high concentrations can result in blister formation or exfoliation and must therefore be well understood to predict the longevity of materials that absorb tritium. A hydrogen over-pressure must be applied to palladium hydride to prevent hydrogen from desorbing from the metal, making it difficult to study tritium in palladium by methods that involve vacuum, such as electron microscopy. Recent improvements in in-situ ion implantation Transmission Electron Microscopy (TEM) allow for the direct observation of He bubble nucleation and growth in materials. In this work, we present results from preliminary experiments using the new ion implantation Environmental TEM (ETEM) at the University of Huddersfield to observe He bubble nucleation and growth, in-situ, in palladium at cryogenic temperatures in a hydrogen environment. After the initial nucleation phase, bubble diameter remained constant throughout the implantation, but bubble density increased with implantation time. β-phase palladium hydride was not observed to form during the experiments, likely indicating that the cryogenic implantation temperature played a dominating role in the bubble nucleation and growth behavior.


Signal reconstruction from noisy-phase and -magnitude data.
Signal reconstruction based on knowing either the magnitude or the phase of the Fourier transform of the signal is important in numerous applications, and the problem of signal reconstruction from noisy-phase and noisy-magnitude data is addressed. The proposed procedure relates to the deviations of the available magnitude and phase estimates from their exact values in the reconstruction algorithm by use of spectral prototype constraint sets. The properties of these new constraint sets for the magnitude and the phase of the Fourier transform are analyzed, and the corresponding projection operators are constructed. Simulation results indicate improvement of the performance of reconstructions from noisy-phase and -magnitude values based on these sets.


Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?
Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.


ProViz-a web-based visualization tool to investigate the functional and evolutionary features of protein sequences.
Low-throughput experiments and high-throughput proteomic and genomic analyses have created enormous quantities of data that can be used to explore protein function and evolution. The ability to consolidate these data into an informative and intuitive format is vital to our capacity to comprehend these distinct but complementary sources of information. However, existing tools to visualize protein-related data are restricted by their presentation, sources of information, functionality or accessibility. We introduce ProViz, a powerful browser-based tool to aid biologists in building hypotheses and designing experiments by simplifying the analysis of functional and evolutionary features of proteins. Feature information is retrieved in an automated manner from resources describing protein modular architecture, post-translational modification, structure, sequence variation and experimental characterization of functional regions. These features are mapped to evolutionary information from precomputed multiple sequence alignments. Data are displayed in an interactive and information-rich yet intuitive visualization, accessible through a simple protein search interface. This allows users with limited bioinformatic skills to rapidly access data pertinent to their research. Visualizations can be further customized with user-defined data either manually or using a REST API. ProViz is available at http://proviz.ucd.ie/.


Virus-mediated archaeal hecatomb in the deep seafloor.
Viruses are the most abundant biological entities in the world's oceans, and they play a crucial role in global biogeochemical cycles. In deep-sea ecosystems, archaea and bacteria drive major nutrient cycles, and viruses are largely responsible for their mortality, thereby exerting important controls on microbial dynamics. However, the relative impact of viruses on archaea compared to bacteria is unknown, limiting our understanding of the factors controlling the functioning of marine systems at a global scale. We evaluate the selectivity of viral infections by using several independent approaches, including an innovative molecular method based on the quantification of archaeal versus bacterial genes released by viral lysis. We provide evidence that, in all oceanic surface sediments (from 1000- to 10,000-m water depth), the impact of viral infection is higher on archaea than on bacteria. We also found that, within deep-sea benthic archaea, the impact of viruses was mainly directed at members of specific clades of Marine Group I Thaumarchaeota. Although archaea represent, on average, ~12% of the total cell abundance in the top 50 cm of sediment, virus-induced lysis of archaea accounts for up to one-third of the total microbial biomass killed, resulting in the release of ~0.3 to 0.5 gigatons of carbon per year globally. Our results indicate that viral infection represents a key mechanism controlling the turnover of archaea in surface deep-sea sediments. We conclude that interactions between archaea and their viruses might play a profound, previously underestimated role in the functioning of deep-sea ecosystems and in global biogeochemical cycles.


Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells.
Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5+ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5+ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n=26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a half-maximal dose (IC(50)) of 2.35 microM. In healthy B cells a significantly higher mean IC(50) of 148.5 microM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; P<0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P=0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.


Self-reported effectiveness and physician consultation rate in users of over-the-counter histamine-2 receptor antagonists.
Decreased physician visits for dyspepsia were predicted with the histamine-2 receptor antagonists (H2RA) release to over-the-counter (OTC) status. The aim of this study was to examine the presentation frequency for dyspeptic complaints before and after the OTC release of the H2RA and the self-reported effectiveness of OTC H2RA. Two cross-sectional surveys were used in a community sample. The patients comprised a random age- and sex-stratified sample of 1600 ambulatory adults in 1993 and 1800 in 1997. Self-report, valid mail surveys gathered information on healthcare seeking and gastrointestinal symptoms in 1993 and 1997 and antisecretory use in 1997. Presentation frequency for dyspepsia was 22% in 1993 versus 23.5% in 1997. Only 16% of chronic users of the OTC H2RA obtained complete relief of symptomatic episodes. Use of an OTC H2RA was highly associated with presentation to a physician in the past year. OTC H2RA infrequently provided the complete relief desired by patients. Presentation frequency to physicians for dyspeptic complaints did not change with availability of H2RA OTC.


Intrahepatic cholangiocarcinoma: expert consensus statement.
An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions.


Isolated percutaneous thoracoplasty procedure for skeletally mature adolescent idiopathic scoliosis patients, with rib deformity as their only concern: short-term outcomes.
Prospective case series study. To study the effect of percutaneous thoracoplasty-only procedure on curve pattern in mature adolescent idiopathic scoliosis (AIS). The rib hump prominence on the convex side is the major cosmetic concern among patients with AIS. Thoracoplasty combined with spinal fusion is a commonly used procedure in scoliosis. However, there are no studies regarding the effect of isolated thoracoplasty procedure on curve pattern in skeletally matured patients with AIS. The study involved 7 skeletally matured female patients with AIS. The convex rib hump deformity was measured preoperatively using hump height and hump angle. We performed thoracoplasty without spinal fusion in patients with the Cobb angle less than 40° but with prominent hump deformity. Thoracoplasty was performed percutaneously using 1 or 2 transverse incisions along the rib hump, and apex portions of the deformed ribs were resected. The Cobb angle was measured before surgery, immediately after surgery, and at final follow-up visit. In all cases, clinical satisfaction was assessed using the Scoliosis Research Society Instrument (SRS-22 questionnaires) and trunk appearance perception scale before surgery and at final follow-up visit. The mean patient age was 20.24 years and an average of 4 ribs were resected. The mean preoperative hump height and hump angle of 38.14 mm and 14.14° improved to 11.70 mm and 11.42° respectively, after surgery (P = 0.018 and 0.042). Preoperative and the final follow-up mean Cobb angles were 35.43° and 45.00°, respectively (P = 0.028). On average, the mean thoracic curve progressed by 9.57°. Preoperative Scoliosis Research Society Instrument SRS-22 questionnaires and trunk appearance perception scale scores of 4.09 and 2.57 respectively improved to and 4.26 and 3.66 after surgery (P = 0.126 and 0.014). Percutaneous thoracoplasty-only procedure gives significant rib humps correction and satisfactory clinical outcome. However, progression of the curve was observed after surgery. This suggests that the convex ribs function as a buttress for curve progression.


Association between extremely low-frequency electromagnetic fields occupations and amyotrophic lateral sclerosis: a meta-analysis.
To estimate the relationship between exposure to extremely low-frequency electromagnetic fields (ELF-EMF) and the risk of amyotrophic lateral sclerosis (ALS) by a meta-analysis. Through searching PubMed databases (or manual searching) up to April 2012 using the following keywords: "occupational exposure", "electromagnetic fields" and "amyotrophic lateral sclerosis" or "motor neuron disease", seventeen studies were identified as eligible for this meta-analysis. The associations between ELF-EMF exposure and the ALS risk were estimated based on study design (case-control or cohort study), and ELF-EMF exposure level assessment (job title or job-exposure matrix). The heterogeneity across the studies was tested, as was publication bias. Occupational exposure to ELF-EMF was significantly associated with increased risk of ALS in pooled studies (RR = 1.29, 95%CI = 1.02-1.62), and case-control studies (OR = 1.39, 95%CI = 1.05-1.84), but not cohort studies (RR = 1.16, 95% CI = 0.80-1.69). In sub-analyses, similar significant associations were found when the exposure level was defined by the job title, but not the job-exposure matrix. In addition, significant associations between occupational exposure to ELF-EMF and increased risk of ALS were found in studies of subjects who were clinically diagnosed but not those based on the death certificate. Moderate heterogeneity was observed in all analyses. Our data suggest a slight but significant ALS risk increase among those with job titles related to relatively high levels of ELF-EMF exposure. Since the magnitude of estimated RR was relatively small, we cannot deny the possibility of potential biases at work. Electrical shocks or other unidentified variables associated with electrical occupations, rather than magnetic-field exposure, may be responsible for the observed associations with ALS.


Review article: the management of severe Crohn's disease.
The treatment of severe and active Crohn's disease is currently based on immunosuppression, but also involves the management of nutrition, appropriate selection of patients for surgery, and maintenance of remission in the long term. Corticosteroids remain the drug of the first choice, particularly in the acute setting. However, there is evolving understanding of the role of other immunosuppressants and immune modifiers, as major concerns regarding side-effects and efficacy of steroids in the medium to long-term drive the search for alternatives.


Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study.
Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM. Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed. From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis. The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.


Oxidation of lactate and acetate in rat skeletal muscle: analysis by 13C-nuclear magnetic resonance spectroscopy.
The balance between carbohydrate and fatty acid utilization in skeletal muscle previously has been studied in vivo by using a variety of methods such as arteriovenous concentration differences and radioactive isotope tracer techniques. However, these methodologies provide only indirect estimates of substrate oxidation. We used 13C-nuclear magnetic resonance (NMR) spectroscopy and non-steady-state isotopomer analysis to directly quantify the relative oxidation of two competing exogenous substrates in rat skeletal muscles. We infused [1,2-13C]acetate and [3-13C]lactate intravenously in anesthetized rats during the final 30 min of 35 (n = 10) or 95 (n = 10) min of intense, unilateral, rhythmic hindlimb contractions. 13C-NMR spectroscopy and isotopomer analysis were performed on extracts of gastrocnemius and soleus muscles from both the contracting and contralateral resting hindlimbs. We found that 1) [13C]lactate and [13C]acetate were taken up and oxidized by both resting and contracting skeletal muscles; and 2) high-intensity muscle contractions altered the pattern of substrate utilization such that the relative oxidation of acetate decreased while that of lactate remained unchanged or increased. Based on these findings, we propose that 13C-NMR spectroscopy in combination with isotopomer analysis can be used to study the general dynamics of substrate competition between carbohydrates and fats in rat skeletal muscle.


Enhanced sulfide removal and bioelectricity generation in microbial fuel cells with anodes modified by vertically oriented nanosheets.
Anode materials and structures are of critical importance for microbial fuel cells (MFCs) recovering energy from toxic substrates. Carbon-fiber-felt anodes modified by layers of vertically oriented TiO2 and Fe2O3 nanosheets were applied in the present study. Enhanced sulfide removal efficiencies (both over 90%) were obtained after a 48-h operation, with maximum power densities improved by 1.53 and 1.36 folds compared with MFCs with raw carbon-fiber-felt anode. The modified anodes provided more active sites for microbial adhesion with increasing biomass densities. High-throughput 16S rRNA gene sequencing analysis also indicated the increase in microbial diversities. Bacteroidetes responsible for bioelectricity generation with Thiobacillus and Spirochaeta dominating sulfide removal were found in the MFCs with the modified anodes, with less anaerobic fermentative bacteria as Firmicutes appeared. This indicates that the proposed materials are competitive for applications of MFCs generating bioelectricity from toxic sulfide.


How to Design AI for Social Good: Seven Essential Factors.
The idea of artificial intelligence for social good (henceforth AI4SG) is gaining traction within information societies in general and the AI community in particular. It has the potential to tackle social problems through the development of AI-based solutions. Yet, to date, there is only limited understanding of what makes AI socially good in theory, what counts as AI4SG in practice, and how to reproduce its initial successes in terms of policies. This article addresses this gap by identifying seven ethical factors that are essential for future AI4SG initiatives. The analysis is supported by 27 case examples of AI4SG projects. Some of these factors are almost entirely novel to AI, while the significance of other factors is heightened by the use of AI. From each of these factors, corresponding best practices are formulated which, subject to context and balance, may serve as preliminary guidelines to ensure that well-designed AI is more likely to serve the social good.


Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.
Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.


Intake frequency of fish and serum levels of long-chain n-3 fatty acids: a cross-sectional study within the Japan Collaborative Cohort Study.
Several investigations have adopted self-reported intake frequency of fish as a surrogate for intake of long-chain n-3 fatty acids, for which protective effects against cancer have been suggested. Whether reported fish consumption reflects the fatty acid intake, however, has to be elucidated. We examined the association between intake frequency of fish and serum long-chain n-3 fatty acids (weight percentage of total fatty acids) among 1,257 control subjects (631 men and 626 women), aged 40-79 years, in case-control studies nested in the Japan Collaborative Cohort Study. All the subjects were not fasting when blood was drawn. Serum fatty acids were determined by gas chromatography. In men, intake frequency of fresh fish and dried or salted fish was significantly but weakly correlated with serum levels of eicosapentaenoic (EPA), docosapentaenoic (n-3) (DPA), and docosahexaenoic (DHA) acids; the age-adjusted Spearman correlation coefficients ranged from 0.11 to 0.18. In women, fresh fish consumption was somewhat associated with serum EPA (Spearman correlation coefficient = 0.12) as was dried or salted fish consumption with serum DPA (0.11). A rising trend in geometric means of serum EPA, DPA, and DHA was found with an increasing intake frequency of fresh or dried/salted fish in both sexes. The geometric means adjusted for age and participating institution in the highest intake category were higher than those in the lowest by 7% to 40%. A population with high self-reported frequency of fish intake, as a group, may have higher bioavailability of long-chain n-3 fatty acids than one with low frequency.


Isotopic evidence for age-related immigration to imperial Rome.
Oxygen stable isotope ratios (delta(18)O) have been determined in carbonate in paired first and third molar teeth from individuals (N = 61) who lived in the town of Portus Romae ("Portus") and who were buried in the necropolis of Isola Sacra (First to Third centuries AD) near Rome, Italy. We compare these analyses with data for deciduous teeth of modern Roman children. Approximately one-third of the archaeological sample has first molar (M1) values outside the modern range, implying a large rate of population turnover at that time, consistent with historical data. Delta (18)O(ap) values suggest that a group within the sample migrated to the area before the third molar (M3) crown had completely formed (i.e., between 10 and 17.5 years of age). This is the first quantitative assessment of population mobility in Classical antiquity. This study demonstrates that migration was not limited to predominantly single adult males, as suggested by historical sources, but rather a complex phenomenon involving families. We hypothesize that migrants most likely came from higher elevations to the East and North of Rome. One individual with a higher delta(18)O value may have come (as a child) from an area isotopically similar to North Africa.


Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion.
We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmer's test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmer's test values, fluorescein and rose bengal scores, and tear-film break-up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments.


Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.
Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.


Reprogramming the Tumor Microenvironment to Improve Immunotherapy: Emerging Strategies and Combination Therapies.
Emerging immunotherapeutic approaches have revolutionized the treatment of multiple malignancies. Immune checkpoint blockers (ICBs) have enabled never-before-seen success rates in durable tumor control and enhanced survival benefit in patients with advanced cancers. However, this effect is not universal, resulting in responder and nonresponder populations not only between, but also within solid tumor types. Although ICBs are thought to be most effective against tumors with more genetic mutations and higher antigen loads, this is not always the case for all cancers or for all patients within a cancer subtype. Furthermore, debilitating and sometimes deadly immune-related adverse events (irAEs) have resulted from aberrant activation of T-cell responses following immunotherapy. Thus, we must identify new ways to overcome resistance to ICB-based immunotherapies and limit irAEs. In fact, preclinical and clinical data have identified abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies such as ICBs. Here, we will discuss how reprogramming various facets of the TME (blood vessels, myeloid cells, and regulatory T cells [Tregs]) may overcome TME-instigated resistance mechanisms to immunotherapy. We will discuss clinical applications of this strategic approach, including the recent successful phase III trial combining bevacizumab with atezolizumab and chemotherapy for metastatic nonsquamous non-small cell lung cancer that led to rapid approval by the U.S. Food and Drug Administration of this regimen for first-line treatment. Given the accelerated testing and approval of ICBs combined with various targeted therapies in larger numbers of patients with cancer, we will discuss how these concepts and approaches can be incorporated into clinical practice to improve immunotherapy outcomes.


The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin.
Previously we reported that the variable heavy chain region (VH) of a human beta2 glycoprotein I-dependent monoclonal antiphospholipid antibody (IS4) was dominant in conferring the ability to bind cardiolipin (CL). In contrast, the identity of the paired variable light chain region (VL) determined the strength of CL binding. In the present study, we examine the importance of specific arginine residues in IS4VH and paired VL in CL binding. The distribution of arginine residues in complementarity determining regions (CDRs) of VH and VL sequences was altered by site-directed mutagenesis or by CDR exchange. Ten different 2a2 germline gene-derived VL sequences were expressed with IS4VH and the VH of an anti-dsDNA antibody, B3. Six variants of IS4VH, containing different patterns of arginine residues in CDR3, were paired with B3VL and IS4VL. The ability of the 32 expressed heavy chain/light chain combinations to bind CL was determined by ELISA. Of four arginine residues in IS4VH CDR3 substituted to serines, two residues at positions 100 and 100 g had a major influence on the strength of CL binding while the two residues at positions 96 and 97 had no effect. In CDR exchange studies, VL containing B3VL CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine. In contrast, arginine residues in VL CDR2 or VL CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding. Subsets of arginine residues at specific locations in the CDRs of heavy chains and light chains of pathogenic antiphospholipid antibodies are important in determining their ability to bind CL.


3-T MR-guided brachytherapy for gynecologic malignancies.
Gynecologic malignancies are a leading cause of death in women worldwide. Standard treatment for many primary and recurrent gynecologic cancer cases includes external-beam radiation followed by brachytherapy. Magnetic resonance (MR) imaging is beneficial in diagnostic evaluation, in mapping the tumor location to tailor radiation dose and in monitoring the tumor response to treatment. Initial studies of MR guidance in gynecologic brachytherapy demonstrate the ability to optimize tumor coverage and reduce radiation dose to normal tissues, resulting in improved outcomes for patients. In this article, we describe a methodology to aid applicator placement and treatment planning for 3 Tesla (3-T) MR-guided brachytherapy that was developed specifically for gynecologic cancers. This methodology has been used in 18 cases from September 2011 to May 2012 in the Advanced Multimodality Image Guided Operating (AMIGO) suite at Brigham and Women's Hospital. AMIGO comprises state-of-the-art tools for MR imaging, image analysis and treatment planning. An MR sequence using three-dimensional (3D)-balanced steady-state free precession in a 3-T MR scanner was identified as the best sequence for catheter identification with ballooning artifact at the tip. 3D treatment planning was performed using MR images. Items in development include software designed to support virtual needle trajectory planning that uses probabilistic bias correction, graph-based segmentation and image registration algorithms. The results demonstrate that 3-T MR image guidance has a role in gynecologic brachytherapy. These novel developments have the potential to improve targeted treatment to the tumor while sparing the normal tissues.


Experimental melanin-induced uveitis in the Fischer 344 rat is inhibited by anti-CD4 monoclonal antibody, but not by mannose-6-phosphate.
Experimental melanin-induced uveitis (EMIU) is a rodent model of acute anterior uveitis which was described in 1993. We investigated strain susceptibility, and age and gender characteristics of the model, undertook histological and immunohistochemical studies to investigate underlying cellular mechanisms, and examined several treatment options. Rats were immunized with bovine ocular melanin (250 microg), and disease was followed by slit lamp examination. Lewis, Fischer 344 and Porton rats were found to be susceptible to EMIU, whereas Wistar-Furth, DA, and Hooded Wistar strains were resistant. EMIU was neither age- nor gender-dependent. In Fischer 344 rats, EMIU was characterized clinically by florid anterior segment inflammation. Histopathological findings included infiltration of ciliary body and iris with mononuclear cells and neutrophils. Both CD4+ and CD8+ T lymphocytes were prominent. Rats were then treated with intraperitoneal injections of anti-CD4, anti-CD8 or irrelevant isotype-matched MoAb on days -3, 0, 3, 6 and 9 with respect to melanin immunization. Incidence of uveitis was significantly reduced in rats treated with a non-depleting cocktail of anti-CD4 MoAbs (P = 0.007), whereas a depleting anti-CD8 antibody had no effect on the disease. Mannose-6-phosphate inhibits lymphocyte migration in some models of T cell-mediated inflammation. This simple sugar was administered to additional rats via intraperitoneal osmotic pumps for 14 days following disease induction, but did not influence the uveitis. We conclude that EMIU is controlled by CD4+ T cells, and disease may be abrogated by treatment with anti-CD4 MoAbs.


Dynamic Nuclear Polarization NMR of Low-γ Nuclei: Structural Insights into Hydrated Yttrium-Doped BaZrO3.
We demonstrate that solid-state NMR spectra of challenging nuclei with a low gyromagnetic ratio such as yttrium-89 can be acquired quickly with indirect dynamic nuclear polarization (DNP) methods. Proton to (89)Y cross polarization (CP) magic angle spinning (MAS) spectra of Y(3+) in a frozen aqueous solution were acquired in minutes using the AMUPol biradical as a polarizing agent. Subsequently, the detection of the (89)Y and (1)H NMR signals from technologically important hydrated yttrium-doped zirconate ceramics, in combination with DFT calculations, allows the local yttrium and proton environments present in these protonic conductors to be detected and assigned to different hydrogen-bonded environments.


Epigenomics, Pharmacoepigenomics, and Personalized Medicine in Cervical Cancer.
Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events. Recent studies have also mapped these epigenetic modification and pathways leading to carcinogenesis. Discovery of drugs that target proteins/enzymes in the epigenetic pathways may provide better therapeutic opportunities, and identification of such modulators for DNA methylation, histone modifications, and expression of noncoding RNAs for several cancer types is underway. In this review, we provide a detailed description of recent developments in the field of epigenetics and its impact on personalized medicine to manage cervical cancer.


Validity of data-derived algorithms for ascertaining causes of adult death in two African sites using verbal autopsy.
background Verbal autopsy (VA) is used to ascertain causes of death using information obtained from bereaved relatives. Causes of death can be ascertained from VA questionnaires by a panel of physicians or from predefined algorithms. In a previous study, we developed data-derived algorithms using VA data from 796 adult deaths in hospitals in Tanzania, Ethiopia, and Ghana (primary sites). These computerized algorithms accurately estimated the cause-specific mortality fractions (CSMFs) for deaths due to injuries, meningitis, TB/AIDS and diarrhoeal diseases in the primary sites. Since the same data were used to generate and to validate the algorithms, the accuracy of our algorithms may have been overestimated. We report here on the validity of the algorithms when they were applied to VA data from two secondary sites in Ghana and Tanzania. Here, 'validity' is taken to mean the degree to which the algorithms replicated the physician-generated CSMF for major causes of death, when applied to the same VA data. methods VA interviews were conducted in two secondary sites: in Navrongo, Ghana, on 406 adult deaths, where three local physicians independently reviewed the questionnaires and assigned a cause of death. In Morogoro, Tanzania, VA interviews were conducted on 209 adult deaths, and a panel of physicians independently reviewed the VA questionnaires together with the hospital death certificates or hospital records to determine the cause of death. The CSMF obtained using each algorithm was compared with the CSMF obtained using physician review. results For injuries and meningitis, the algorithms and physician review estimated a similar CSMF in the Morogoro and Navrongo data. For TB/AIDS, the algorithm estimated a similar CSMF as the physicians in Morogoro. The algorithm for diarrhoeal diseases did not agree closely with the physicians in Morogoro or Navrongo. conclusions In general, our data-derived algorithms for assigning causes of death due to injuries, meningitis, and TB/AIDS estimated a similar CSMF as the physicians in the secondary sites. Recommendations for further validation and refinement are discussed. Computerized algorithms offer a potentially quick, affordable, and feasible method for assigning causes of death in mortality surveillance or studies using VA.


Association between menopause and lumbar disc degeneration: an MRI study of 1,566 women and 1,382 men.
The aim of this study was to revisit and further investigate the association between menopause and disc degeneration in the lumbar spine using a magnetic resonance imaging-based eight-level grading system. This study cohort comprised of 1,566 women and 1,382 age-matched men who were admitted for low back pain from June 2013 to October 2016. Data on age, weight, height, body mass index, age at natural menopause, and years since menopause (YSM) were obtained. Lumbar disc degeneration was assessed using a magnetic resonance imaging-based eight-level grading system. After adjustment for the confounding factors of age, height, and weight, young age-matched men were more susceptible to disc degeneration than premenopausal women (P < 0.05). However, after menopause, postmenopausal women had a significant tendency to develop more severe disc degeneration than their age-matched men (P < 0.05), and also compared with premenopausal and perimenopausal women (P < 0.01). Postmenopausal women were divided into nine subgroups by every 5 YSM. When YSM was less than 15 years, a positive trend was observed between YSM and severity of disc degeneration, respectively, at L1/L2 (r = 0.241), L2/L3 (r = 0.193), L3/L4 (r = 0.191), L4/L5 (r = 0.165), L5/S1 (r = 0.153), and all lumbar discs (r = 0.237) (P < 0.05 or 0.01). The analysis of covariance indicated a significant difference in each disc level (P < 0.05 or 0.01) between every two groups. When YSM was more than 15 years, the significant difference, however, disappeared in each disc level (P > 0.05). Menopause is associated with lumbar disc degeneration. The association occurred in the first 15 YSM, suggesting estrogen deficiency might be a risk factor of disc degeneration of the lumbar spine. Further studies need to be carried out for deciding whether age or menopause plays a more important role in the progression of disc degeneration in the lumbar spine.


Dislocation density-dependent photorefractive effect in (001)-cut GaAs.
We present studies of the photorefractive effect in nonphotorefractive orientations of liquid-encapsulated Czochralski-grown GaAs crystals. Picosecond diffraction experiments conducted in different samples show that a forbidden photorefractive signal correlates well with dislocation density, which points out that the effect arises from strain fields and growth defects.


Postoperative MRI evaluation of anorectal malformations with clinical correlation.
Sixteen postoperative patients with anorectal malformation were evaluated by MRI, and the results compared with the clinical assessment. Patients were classified into three groups--good (group 1, n = 10), fair (group 2, n = 3) and poor (group 3, n = 3)--on the basis of Kelly's clinical score of incontinence. The degree of development of the puborectalis and external sphincter muscles and the levator hammock was evaluated on MRI in comparison with patients without anorectal disease. The proportions of fair or poor development of the muscles were 37% in group 1,22% in group 2 and 67% in group 3. Although fair or poor development of the muscles was seen more frequently in group 3, there was no statistically significant difference between groups. However, poorly developed muscles were seen only in patients with fair or poor clinical scores. The difference in the anorectal angle measured on sagittal MRI images between patients in group 1 and groups 2 or 3 was significant. Our study indicates that MRI evaluation based solely on muscle development can be misleading, and measurement of the anorectal angle should be included in the MRI evaluation.


Modeling fixation locations using spatial point processes.
Whenever eye movements are measured, a central part of the analysis has to do with where subjects fixate and why they fixated where they fixated. To a first approximation, a set of fixations can be viewed as a set of points in space; this implies that fixations are spatial data and that the analysis of fixation locations can be beneficially thought of as a spatial statistics problem. We argue that thinking of fixation locations as arising from point processes is a very fruitful framework for eye-movement data, helping turn qualitative questions into quantitative ones. We provide a tutorial introduction to some of the main ideas of the field of spatial statistics, focusing especially on spatial Poisson processes. We show how point processes help relate image properties to fixation locations. In particular we show how point processes naturally express the idea that image features' predictability for fixations may vary from one image to another. We review other methods of analysis used in the literature, show how they relate to point process theory, and argue that thinking in terms of point processes substantially extends the range of analyses that can be performed and clarify their interpretation.


Developing concurrency messages for the black community in Seattle, Washington.
In the United States, Blacks are disproportionately impacted by HIV/AIDS. Sexual networks and concurrent relationships have emerged as important contributors to the heterosexual transmission of HIV. To date, Africa is the only continent where an understanding of the impact of sexual concurrency has been conveyed in HIV prevention messaging. This project was developed by researchers and members of the Seattle, Washington, African American and African-Born communities, using the principles of community-based participatory research (CBPR). Interest in developing concurrency messaging came from the community and resulted in the successful submission of a community-academic partnership proposal to develop and disseminate HIV prevention messaging around concurrency. The authors describe (a) the development of concurrency messaging through the integration of collected formative data and findings from the scientific literature; (b) the process of disseminating the message in the local Black community; and (c) important factors to consider in the development of similar campaigns.


Effect of protein restriction in insulin dependent diabetics at risk of nephropathy.
Persistent proteinuria is strongly associated with increased mortality in insulin dependent diabetes, and risk of this condition can be predicted many years in advance by subclinical increases in albumin excretion rate (microalbuminuria). Eight normotensive insulin dependent diabetics with microalbuminuria who had overnight albumin excretion rates of between 15 and 200 micrograms/min underwent a three week randomised crossover study of their normal protein diet (median 92 (range 55-117) g/day) and a low protein diet (47 (38-57) g/day). Both diets were isoenergetic, and the low protein diet was supplemented with calcium and phosphate. Median overnight albumin excretion rate fell from 23.0 (15.0-170.1) micrograms/min during the normal diet to 15.4 (4.1-97.8) micrograms/min during the low protein diet. No consistent change was found in urinary excretion of beta 2 microglobulin during the two diets. The reduction in albumin excretion rate was accompanied by a significant fall in median glomerular filtration rate and fractional renal clearance of albumin. Kidney volume remained unchanged. There were no significant changes in glycaemic control or arterial blood pressure. In these few patients restriction of dietary protein had a beneficial effect on microalbuminuria, independent of changes in glucose concentrations and arterial blood pressure.


Risk factors for the development of posttraumatic stress disorder following combat trauma: a semiprospective study.
When positioned in a combat situation, soldiers may be subjected to extreme stress. However, only a few combat-exposed soldiers develop long-term disturbance, namely, posttraumatic stress disorder (PTSD). This study aimed to explore risk factors for developing PTSD in order to improve the psychiatric screening process of new recruits. In a semiprospective design, we compared 2,362 war veterans who developed PTSD (according to DSM-IV criteria) with an equal number of war veterans who did not develop PTSD. Controls were matched on the basis of sequential army identification numbers, that is, the soldier drafted immediately after the index PTSD veteran (usually on the same day). This method ensured similar demographic variables such as socioeconomic level and education. Data were collected from the Israeli Defense Force database and used in a comprehensive survey conducted between January 2000 and March 2001. Comparisons were made on predrafting personal factors (behavioral assessment, cognitive assessment, linguistic ability, and education) and pretrauma army characteristics (ie, rank and training). Neither behavioral assessment nor training were found to predict PTSD. The predictive factors that were found were essentially nonspecific, such as cognitive functioning, education, rank, and position during the trauma, with little effect from training. In an armed force that uses universal recruitment, carefully structured predrafting psychological assessment of social and individual qualifications (including motivation) failed to identify increased risk factors for PTSD. However, nonspecific factors were found to be associated with an increased risk for PTSD. This study suggests that the focus of future research on risk factors for PTSD should incorporate other domains rather than behavioral assessment alone. clinicaltrials.gov Identifier: NCT00229359.


Impact of total body water errors on Kt/V estimates in children on peritoneal dialysis.
Determining Kt/V in peritoneal dialysis (PD) requires estimation of total body water (TBW). The Dialysis Outcomes Quality Initiative (DOQI) guidelines recommend use of the Mellits and Cheek (MC) formulas for the estimation of TBW in children. However, the MC formulas were developed from healthy children and may not apply to children on PD. Re-evaluating the MC data with additional, recent data from healthy infants has led to the development of new formulas. In addition, and as part of a prospective study of children initiating PD, the Pediatric Peritoneal Dialysis Study Consortium (PPDSC) has directly measured TBW using H2[18O]. To assess the impact of various TBW estimates, KPDt/V values prospectively collected in 24 children were calculated using H2[18O]-measured TBW (O18), MC-derived TBW (MCD), and new-formula TBW (NEW). The mean weekly KPDt/V by O18 was 2.2; by MCD, it was 2.0; and by NEW, it was 2.0. The results derived using the O18 method varied from both the MCD and the NEW results (p < 0.001). The mean deviation from the measured KPDt/V using O18 was 9.5% (maximum: 16%) using the MCD estimate and 7.8% (maximum: 18%) using the NEW formulas. Determinations of KPDt/V are significantly affected by the method of estimating TBW. The PPDSC formulas for children on PD based on the use of H2[18O] offer the most accurate means of calculating TBW and should replace formulas derived from healthy children. The use of Kt/V itself as a marker of adequacy in children will be validated only in prospective studies.


Fecal microbiota imbalance in Mexican children with type 1 diabetes.
Dysbiosis of the intestinal microbiota affecting the gut barrier could be triggering Type 1 Diabetes (T1D), the second most frequent autoimmune disease in childhood. This study compared the structure of the fecal microbiota in 29 mestizo children aged 7-18 years, including 8 T1D at onset, 13 T1D after 2 years treatment, and 8 healthy controls. Clinical information was collected, predisposing haplotypes were determined; the fecal DNA was extracted, the V4 region of the 16S rRNA gene amplified and 454-pyrosequenced. The newly diagnosed T1D cases had high levels of the genus Bacteroides (p < 0.004), whereas the control group had a gut microbiota dominated by Prevotella. Children with T1D treated for ≥2 years had levels of Bacteroides and Prevotella compared to those of the control group. The gut microbiota of newly diagnosed T1D cases is altered, but whether it is involved in disease causation or is a consequence of host selection remains unclear.


Associations of multimorbidity and patient-reported experiences of care with conservative management among elderly patients with localized prostate cancer.
Many elderly localized prostate cancer patients could benefit from conservative management (CM). This retrospective cohort study examined the associations of patient-reported access to care and multimorbidity on CM use patterns among Medicare Fee-for-Service (FFS) beneficiaries with localized prostate cancer. We used linked Surveillance, Epidemiology, and End Results cancer Registry, Medicare Claims, and the Medicare Consumer Assessment of Healthcare Providers and Systems (MCAHPS) survey files. We identified FFS Medicare Beneficiaries (age ≥ 66; continuous enrollment in Parts A & B) with incident localized prostate cancer from 2003 to 2013 and a completed MCAHPS survey measuring patient-reported experiences of care within 24 months after diagnosis (n = 496). We used multivariable models to examine MCAHPS measures (getting needed care, timeliness of care, and doctor communication) and multimorbidity on CM use. Localized prostate cancer patients with multimorbidity were less likely to use CM (adjusted odds ratio (AOR)=0.42 (0.27- 0.66), P < .001); those with higher scores on timeliness of care (AOR = 1.21 (1.09, 1.35), P < .001), higher education attainment (3.21 = AOR (1.50,6.89), P = .003), and impaired mental health status (4.32 = AOR (1.86, 10.1) P < .001) were more likely to use CM. Patient-reported experience with timely care was significantly and positively associated with CM use. Multimorbidity was significantly and inversely associated with CM use. Addressing specific modifiable barriers to timely care along the cancer continuum for elderly localized prostate cancer patients with limited life expectancy could reduce the adverse effects of overtreatment on health outcomes and costs.


Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation.
Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are "pervasive developmental disorders" and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism.


Comorbid psychiatric disorders in 201 cases of encopresis.
Although encopresis is a common and complex disorder, relatively few studies have evaluated the comorbid psychiatric disorders in this condition. This study was performed to investigate the comorbid psychiatric disorders in encopresis. One hundred and sixty boys (79.6%) and 41 girls (20.4%) fulfilled the diagnostic criteria for encopresis according to DSM-IV. There was at least one comorbid diagnosis in 149 (74.1%) patients. The most frequent comorbid diagnosis was enuresis (55.2%). Clinical and demographical data were compared between patients with comorbid disorders and others. Primary encopresis was significantly more frequent in patients with comorbid disorders, and the mean age at admission was lower in these patients. The mean interval between the onset of symptoms and the diagnosis was significantly shorter in secondary encopretic patients with comorbid disorders. Furthermore, there were significantly more psychiatric disorders in the first-degree relatives of patients with comorbid disorders. Encopresis is frequently accompanied with a psychiatric disorder. Clinicians need to inquire about symptoms of other psychiatric disorders in patients who present with encopresis and vice versa.


Initiators and promoters for the occurrence of screen-detected breast cancer and the progression to clinically-detected interval breast cancer.
The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m2) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99-1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51-0.82). Dense breast (aRR 1.46; 95% CI, 1.12-1.91), triple-negative (aRR 2.07; 95% CI, 1.37-3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19-2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56-7.02) compared with the Luminal A subtype. We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individually-tailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage.


Development of scaffold-free vascularized pancreatic beta-islets in vitro models by the anchoring of cell lines to a bioligand-functionalized gelatine substrate.
Bioengineered pancreatic β-islets have been widely advocated for the research and treatment of diabetes by offering both suitable cell culture models for the study of the pathology and the testing of new drugs and a therapy in those patients no longer responding to insulin administration and as an alternative to the shortage of donors for organ and islet transplantation. Unlike most of the studies published so far where pancreatic islets of pancreatic β-cells are encapsulated in hydrogels, this study demonstrate the formation of bioengineered pancreatic islets through cell anchoring to a gelatine-based biomaterial, PhenoDrive-Y, able to mimic the basement membrane of tissues. Through simple culture conditions, PhenoDrive-Y led human pancreatic β-cell lines and human umbilical endothelial cell lines to form organized structures closely resembling the natural vascularized pancreatic islets. When compared to gelatine, the cultures in presence of PhenoDrive-Y show higher degree of organization in tissue-like structures, a more pronounced endothelial sprouting and higher expression of typical cell markers. Noticeably, when challenged by hyperglycaemic conditions, the cells embedded in the PhenoDrive-Y assembled spheroids responded with higher levels of insulin production. In conclusion, the present work demonstrates the potential of PhenoDrive-Y as substrate for the development of bioengineered vascularized pancreatic islets and to be particularly suitable as a model for in vitro studies and testing of new therapeutics. Graphical abstract.


Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2.
Toll like receptors (TLRs) are pattern-recognition molecules that initiate the innate immune response to pathogens. Pulmonary surfactant protein (SP)-A is an endogenously produced ligand for TLR2 and TLR4. SP-A has been proposed as a fetally produced signal for the onset of parturition in the mouse. We examined the effect of interactions between SP-A and the pathogenic TLR agonists lipopolysaccharide (LPS), peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C)) (ligands for TLR4, TLR2 and TLR3, respectively) on the expression of inflammatory mediators and preterm delivery. Three types of mouse macrophages (the cell line RAW 264.7, and fresh amniotic fluid and peritoneal macrophages, including macrophages from TLR4 and TLR2 knockout mice) were treated for up to 7 hours with pathogenic TLR agonists with or without SP-A. SP-A alone had no effect upon inflammatory mediators in mouse macrophages and did not independently induce preterm labor. SP-A significantly suppressed TLR ligand-induced expression of inflammatory mediators (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the chemokine CCL5) via a TLR2 dependent mechanism. In a mouse inflammation-induced preterm delivery model, intrauterine administration of SP-A significantly inhibited preterm delivery, suppressed the expression of proinflammatory mediators and enhanced the expression of the CXCL1 and anti-inflammatory mediator IL-10. We conclude that SP-A acts via TLR2 to suppress TLR ligand-induced preterm delivery and inflammatory responses.


A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of Invasive Bacterial Infection.
To derive and internally validate a prediction model for the identification of febrile infants ≤60 days old at low probability of invasive bacterial infection (IBI). We conducted a case-control study of febrile infants ≤60 days old who presented to the emergency departments of 11 hospitals between July 1, 2011 and June 30, 2016. Infants with IBI, defined by growth of a pathogen in blood (bacteremia) and/or cerebrospinal fluid (bacterial meningitis), were matched by hospital and date of visit to 2 control patients without IBI. Ill-appearing infants and those with complex chronic conditions were excluded. Predictors of IBI were identified with multiple logistic regression and internally validated with 10-fold cross-validation, and an IBI score was calculated. We included 181 infants with IBI (155 [85.6%] with bacteremia without meningitis and 26 [14.4%] with bacterial meningitis) and 362 control patients. Twenty-three infants with IBI (12.7%) and 138 control patients (38.1%) had fever by history only. Four predictors of IBI were identified (area under the curve 0.83 [95% confidence interval (CI): 0.79-0.86]) and incorporated into an IBI score: age <21 days (1 point), highest temperature recorded in the emergency department 38.0-38.4°C (2 points) or ≥38.5°C (4 points), absolute neutrophil count ≥5185 cells per μL (2 points), and abnormal urinalysis results (3 points). The sensitivity and specificity of a score ≥2 were 98.8% (95% CI: 95.7%-99.9%) and 31.3% (95% CI: 26.3%-36.6%), respectively. All 26 infants with meningitis had scores ≥2. Infants ≤60 days old with fever by history only, a normal urinalysis result, and an absolute neutrophil count <5185 cells per μL have a low probability of IBI.


Why is the definition of life so elusive? Epistemological considerations.
A central question of astrobiology concerns the origin and distribution of life in the Universe. For this reason, astrobiology can be considered to fall within the science called transitional biology. If we accept that life originated by a process of prebiotic chemical evolution, the next question concerns the nature of the transitional pathway from inanimate chemical systems to the first forms of life on Earth. These possible transitional states are the subject matter of transitional biology as a discipline. A related question concerns attempts to synthesize living systems in the laboratory. In contrast to traditional biology, the definition of life has an important methodological role in transitional biology, yet we still do not have a generally accepted definition despite the immense accumulation of empirical data in the life sciences. This review analyzes three approaches to defining life and concludes that all three are problematic in that they attempt to define life with undefined terms, confuse a description with a definition, or define life arbitrarily in terms of minimal living systems.


Attitudes and behaviour regarding deep dentin caries removal: a survey among German dentists.
Incomplete removal of deep caries has been shown to reduce the risks of pulp exposure and postoperative pulpal complications. It is therefore of interest whether dentists perform one- or two-step incomplete excavation, and which criteria and methods they use to assess and provide removal of deep caries. This study investigated the attitudes and behaviour of dentists in northern Germany using a new, validated questionnaire. The survey included 2,346 practitioners, 821 (35%) of whom responded. Demographic and sensitivity analysis did not indicate selection bias. 50% of dentists considered only complete excavation, even if pulp exposure was likely. If caries was to be removed incompletely, 77% considered two-step excavation. Hardness was the most important criterion to assess excavation. To treat an exposed pulp, 75% of dentists considered direct capping, 70% refused incomplete excavation fearing caries progression or pulp damage, and 59% reported to prefer more invasive treatment to facilitate restoration longevity. Over 50% recognised an influence of professional regulations on their treatment decisions. There was a moderate correlation between attitudes and behaviour of dentists, with dentists who suspected residual caries to be harmful rejecting incomplete excavation and vice versa. Cluster analysis identified two groups of dentists with opposite attitudes and behaviour, independently from dentist's age or gender. In conclusion, the majority of surveyed dentists was sceptical about leaving caries during excavation and does not practice incomplete caries removal. Therefore, benefits of partial excavation should be highlighted in under- and postgraduate education and regulatory incentives modified to promote minimally invasive techniques.


Proline-rich antimicrobial peptides targeting protein synthesis.
Covering: up to 2017The innate immune system employs a broad array of antimicrobial peptides (AMPs) to attack invading microorganisms. While most AMPs act by permeabilizing the bacterial membrane, specific subclasses of AMPs have been identified that pass through membranes and inhibit bacterial growth by targeting fundamental intracellular processes. One such subclass is the proline-rich antimicrobial peptides (PrAMPs) that bind to the ribosome and interfere with the process of protein synthesis. A diverse range of PrAMPs have been identified in insects, such as bees, wasps and beetles, and crustaceans, such as crabs, as well as in mammals, such as cows, sheep, goats and pigs. Mechanistically, the best-characterized PrAMPs are the insect oncocins, such as Onc112, and bovine bactenecins, such as Bac7. Biochemical and structural studies have revealed that these PrAMPs bind within the ribosomal exit tunnel with a reverse orientation compared to a nascent polypeptide chain. The PrAMPs allow initiation but prevent the transition into the elongation phase of translation. Insight into the interactions of PrAMPs with their ribosomal target provides the opportunity to further develop these peptides as novel antimicrobial agents.


Acoustic telemetry reveals large-scale migration patterns of walleye in Lake Huron.
Fish migration in large freshwater lacustrine systems such as the Laurentian Great Lakes is not well understood. The walleye (Sander vitreus) is an economically and ecologically important native fish species throughout the Great Lakes. In Lake Huron walleye has recently undergone a population expansion as a result of recovery of the primary stock, stemming from changing food web dynamics. During 2011 and 2012, we used acoustic telemetry to document the timing and spatial scale of walleye migration in Lake Huron and Saginaw Bay. Spawning walleye (n = 199) collected from a tributary of Saginaw Bay were implanted with acoustic tags and their migrations were documented using acoustic receivers (n = 140) deployed throughout U.S. nearshore waters of Lake Huron. Three migration pathways were described using multistate mark-recapture models. Models were evaluated using the Akaike Information Criterion. Fish sex did not influence migratory behavior but did affect migration rate and walleye were detected on all acoustic receiver lines. Most (95%) tagged fish migrated downstream from the riverine tagging and release location to Saginaw Bay, and 37% of these fish emigrated from Saginaw Bay into Lake Huron. Remarkably, 8% of walleye that emigrated from Saginaw Bay were detected at the acoustic receiver line located farthest from the release location more than 350 km away. Most (64%) walleye returned to the Saginaw River in 2012, presumably for spawning. Our findings reveal that fish from this stock use virtually the entirety of U.S. nearshore waters of Lake Huron.


Transfer RNA-pseudouridine synthetase Pus1 of Saccharomyces cerevisiae contains one atom of zinc essential for its native conformation and tRNA recognition.
RNA:pseudouridine synthetase (Pus1) from Saccharomyces cerevisiae is a multisite specific enzyme that catalyzes the formation of pseudouridine at positions 34 and 36 of intron-containing precursor tRNAIle and at positions 27 and/or 28 of several yeast tRNAs. In this paper we demonstrate that the purified recombinant Pus1, expressed in Escherichia coli, contains one atom of zinc per 63-kDa monomer, as determined by atomic absorption spectroscopy. This zinc ion could not be removed by treatment with EDTA or urea. However, a zinc-depleted enzyme was obtained after prolonged dialysis against the specific chelating agent 1,10-phenanthroline. Removal of the zinc ion resulted in inactivation of the enzyme with concomitant loss of its ability to bind tRNA. Dialysis of the zinc-depleted inactive enzyme against buffer containing zinc ions led to recovery of up to 25% of bound zinc in parallel with 25% of its initial activity. Removal of the tightly bound zinc atom resulted in a conformational change of the protein, as determined by analytical ultracentrifugation, with minor changes in the internal structure of the protein, as evidenced by circular dichroism and infrared and fluorescence spectroscopy. Our results are consistent with a structural role for the zinc in the tRNA-pseudouridine synthetase Pus1; zinc ion could maintain the association between domains structurally organized around the coordinated metal ion. Zinc chelation was never demonstrated for any of the tRNA-pseudouridine synthetases characterized so far.


Phenolic content, antioxidant effect and cytotoxic activity of Leea indica leaves.
The leaves of Leea indica (Vitaceae), commonly known as 'Huo Tong Shu' in Malaysia, have been traditionally used as natural remedy in folk medicine by the locals. The current study reports the outcome of antioxidant and cytotoxic investigation of L. indica leaves. To the best of our knowledge, this is the first report of L. indica leaf crude ethanol and its fractionated extracts (hexane, ethyl acetate and water) for evaluation of total phenolic content, antioxidant effect and cytotoxic activity against colon cancer cell lines. In the present study, L. indica leaf crude ethanol and its fractionated extracts (hexane, ethyl acetate and water) were firstly prepared prior to phenolic content, antioxidant effect and cytotoxic activity assessment. Folin-Ciocalteau's method was used for the measurement of total phenolic content of the extracts. The antioxidant activity was measured by employing three different established testing systems, such as scavenging activity on DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals, reducing power assay and SOD (superoxide dismutase) activity assay. The cytotoxic activity of the extracts were evaluated against three colon cancer cell lines with varying molecular characteristics (HT-29, HCT-15 and HCT-116) by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The total phenolic content and antioxidant capabilities differed significantly among the L. indica leaf extracts. A strong correlation between total phenolic content and antioxidant properties was found, indicating that phenolic compounds are the major contributor to the antioxidant properties of these extracts. Among the crude ethanol and its fractionated extracts, fractionated water extract showed significantly the highest total phenolic content and strongest antioxidant effect in all the antioxidant testing systems employed in this study. All the four extracts exert no damage to the selected colon cancer cells. The data obtained in these testing systems clearly establish the antioxidant potency of the fractionated water extract of L. indica leaves. Additional studies should be carried out to isolate and identify the bioactive compounds in the fractionated water extract, in order to provide more convincing evidence.


Aprepitant for postoperative nausea and vomiting: a systematic review and meta-analysis.
Postoperative nausea and vomiting (PONV) is an important clinical problem. Aprepitant is a relatively new agent for this condition which may be superior to other treatment. A systematic review was performed after searching a number of medical databases for controlled trials comparing aprepitant with conventional antiemetics published up to 25 April 2015 using the following keywords: 'Aprepitant for PONV', 'Aprepitant versus 5-HT3 antagonists' and 'NK-1 versus 5-HT3 for PONV'. The primary outcome for the pooled analysis was efficacy of aprepitant in preventing vomiting on postoperative day (POD) 1 and 2. 172 potentially relevant papers were identified of which 23 had suitable data. For the primary outcome, 14 papers had relevant data. On POD1, 227/2341 patients (9.7%) patients randomised to aprepitant had a vomiting episode compared with 496/2267 (21.9%) controls. On POD2, the rate of vomiting among patients receiving aprepitant was 6.8% compared with 12.8% for controls. The OR for vomiting compared with controls was 0.48 (95% CI 0.34 to 0.67) on POD1 and 0.54 (95% CI 0.40 to 0.72) on POD2. Aprepitant also demonstrated a better profile with a lower need for rescue antiemetic and a higher complete response. Efficacy for vomiting prevention was demonstrated for 40 mg, 80 mg and 125 mg without major adverse effects. For vomiting comparison there was significant unexplainable heterogeneity (67.9% and 71.5% for POD1 and POD2, respectively). We conclude that (1) aprepitant reduces the incidence of vomiting on both POD1 and POD2, but there is an unexplained heterogeneity which lowers the strength of the evidence; (2) complete freedom from PONV on POD1 is highest for aprepitant with minimum need for rescue; and (3) oral aprepitant (80 mg) provides an effective and safe sustained antivomiting effect.


Shifts in tree functional composition amplify the response of forest biomass to climate.
Forests have a key role in global ecosystems, hosting much of the world's terrestrial biodiversity and acting as a net sink for atmospheric carbon. These and other ecosystem services that are provided by forests may be sensitive to climate change as well as climate variability on shorter time scales (for example, annual to decadal). Previous studies have documented responses of forest ecosystems to climate change and climate variability, including drought-induced increases in tree mortality rates. However, relationships between forest biomass, tree species composition and climate variability have not been quantified across a large region using systematically sampled data. Here we use systematic forest inventories from the 1980s and 2000s across the eastern USA to show that forest biomass responds to decadal-scale changes in water deficit, and that this biomass response is amplified by concurrent changes in community-mean drought tolerance, a functionally important aspect of tree species composition. The amplification of the direct effects of water stress on biomass occurs because water stress tends to induce a shift in tree species composition towards species that are more tolerant to drought but are slower growing. These results demonstrate concurrent changes in forest species composition and biomass carbon storage across a large, systematically sampled region, and highlight the potential for climate-induced changes in forest ecosystems across the world, resulting from both direct effects of climate on forest biomass and indirect effects mediated by shifts in species composition.