An update on the biology and physiology of resistin.
Resistin is a newly discovered adipocyte hormone. It is related to resistin-like molecules alpha, beta and gamma in structure and function. Resistin is produced by white and brown adipose tissues but has also has been identified in several other tissues, including the hypothalamus, pituitary and adrenal glands, pancreas, gastrointestinal tract, myocytes, spleen, white blood cells and plasma. The tissue level of resistin is decreased by insulin, cytokines such as tumour necrosis factor alpha, endothelin-1 and increased by growth and gonadal hormones, hyperglycaemia, male gender and some proinflammatory cytokines, such as interleukin-6 and lipopolysaccharide. Resistin antagonizes insulin action, and it is downregulated by rosiglitazone and peroxisome proliferator-activated receptor gamma agonists. Since evidence of a direct link between resistin genotype and human diabetes is still weak, more molecular, physiological and clinical studies are needed to determine the role of resistin in the aetiology of type 2 diabetes.


Adjuvant liver perfusion in colorectal cancer: initial results of a clinical trial.
Fifty consecutive patients with colorectal cancer but no evidence of secondary deposits in the liver were included in an ongoing controlled clinical trial of adjuvant liver perfusion aimed at reducing the incidence of hepatic metastases. All patients had their primary tumour resected in the standard way. Twenty-six of the patients served as controls, and 24 received fluorouracil, 1 g daily, as a continuous infusion into the portal venous system during the first seven days after operation. The patients were matched for age, sex, and site and stage of the disease. The immediate postoperative mortality and morbidity did not differ significantly between the two groups. During the follow-up period (mean duration 15.5 months), however, six deaths occurred in the control group and only one in the perfusion group. At necropsy four of the controls had multiple liver metastases. Two of the surviving controls developed evidence of liver metastases, and two had a local recurrence. No patient in the perfusion group developed evidence of hepatic metastases. These initial results suggest that adjuvant portal venous perfusion with fluorouracil may reduce the incidence of liver metastases in colorectal cancer.


[Recent data on hemorrhagic fevers in West Africa].
Among the viruses which can provoke human haemorrhagic fevers, the Congo-Crimean Haemorrhagic Fever and Rift Valley Fever viruses have been discovered relatively recently in West Africa. Two human cases of severe haemorrhagic fever have been connected with Congo-CHF, in Mauritania and Burkina-Faso. The epidemiological enquiry performed in Mauritania, consequent to the appearance of the first case, has demonstrated that the patient had been contaminated by contact with camels. Twelve strains of Congo-CHF virus have been isolated from ticks taken on bovines and dromedaries in that area. The serological enquiries realized on man show that the incidence is relatively feeble; on the other hand, among animals, one finds a large distribution among small ruminants in Mauritania as well as in Senegal. The recent realization of a complete identity between the Zinga and Rift Valley Fever viruses has broadened the geographical distribution of this virus to the whole of inter-tropical Africa including Madagascar. The serological enquiries realized among men and animals in areas where the virus has been isolated from wild vectors show that the presence of antibodies is faintly superior. On the other hand, in southern Mauritania, the virus prevails among men, who get antibodies of the IGM type, which proves a recent circulation. The immunological enquiries on camels seem to corroborate these data. The Rift Valley Fever epidemic which broke out in 1978 among the human and animal populations of Egypt has, apparently, been connected with the passage of camels coming from Sudan through the intermediary halting-place of the Assuan dam.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical course and prognosis in ulcerative colitis: results from population-based and observational studies.
The clinical course of ulcerative colitis (UC) may range from a quiescent course with prolonged periods of remission to fulminant disease requiring intensive medical treatment or surgery. Disease outcome is often determined by relapse rates, the development of colorectal cancer (CRC) and mortality rates. Early patient classification, identifying those with a high risk of developing complicated disease, is essential for choosing appropriate treatment. This paper reviews the clinical outcomes of UC patients as reported in population-based and observational studies representative of the whole patient population. Extensive colitis, a high level of systemic symptoms and young age at diagnosis are factors associated with a high risk of colectomy. Patients with distal disease who progress to extensive colitis seem to be a subgroup with an especially high risk of colectomy. Some prognostic factors of severe disease have been identified which could be used to optimize treatment and possibly reduce future complications. The overall risk of CRC and mortality was not significantly different from that of the background population. These results may have implications for follow-up strategies, especially regarding endoscopic surveillance of UC patients.


Transcriptome analyses of primitively eusocial wasps reveal novel insights into the evolution of sociality and the origin of alternative phenotypes.
Understanding how alternative phenotypes arise from the same genome is a major challenge in modern biology. Eusociality in insects requires the evolution of two alternative phenotypes - workers, who sacrifice personal reproduction, and queens, who realize that reproduction. Extensive work on honeybees and ants has revealed the molecular basis of derived queen and worker phenotypes in highly eusocial lineages, but we lack equivalent deep-level analyses of wasps and of primitively eusocial species, the latter of which can reveal how phenotypic decoupling first occurs in the early stages of eusocial evolution. We sequenced 20 Gbp of transcriptomes derived from brains of different behavioral castes of the primitively eusocial tropical paper wasp Polistes canadensis. Surprisingly, 75% of the 2,442 genes differentially expressed between phenotypes were novel, having no significant homology with described sequences. Moreover, 90% of these novel genes were significantly upregulated in workers relative to queens. Differential expression of novel genes in the early stages of sociality may be important in facilitating the evolution of worker behavioral complexity in eusocial evolution. We also found surprisingly low correlation in the identity and direction of expression of differentially expressed genes across similar phenotypes in different social lineages, supporting the idea that social evolution in different lineages requires substantial de novo rewiring of molecular pathways. These genomic resources for aculeate wasps and first transcriptome-wide insights into the origin of castes bring us closer to a more general understanding of eusocial evolution and how phenotypic diversity arises from the same genome.


Construction of a RFLP genetic linkage map for oil palm (Elaeis guineensis Jacq.).
We have developed a restriction fragment length polymorphism (RFLP) genetic map in oil palm (Elaeis guineensis Jacq.) for use in breeding programmes. A segregating population of 98 individuals was probed with 84 informative low copy clones (mainly PstI genomics). This yielded 103 scorable loci, of which 97 could be linked into 24 groups of two or more markers (n = 16 for oil palm), encompassing a total of 860 cM. The high level of linkage between markers (95%) suggests good genome coverage and very little segregation distortion of markers was observed. The mapping population, which was generated by the selfing of an important breeding palm (A 137/30), also segregated for the shell thickness character (Sh), enabling mapping of the gene conferring this major commercial trait. The nearest RFLP marker (pOPgSP1282) was located 9.8 cM from Sh in the mapping population and 6.6 cM away in a related (A137/30 x E80/29) smaller population (45 palms). Strategies for conversion of RFLP markers to a PCR format were explored and two important markers were shown to generate allelic variants following PCR amplification and restriction digestion of PCR products. The application of this map to oil palm breeding programmes is discussed.


Self-harm on roads: Register-based study of methods and characteristics of individuals involved.
Suicide on roads is receiving increased attention. However, there has been little research on non-fatal road-related self-harm. This study was conducted in order to investigate the characteristics of such acts. Information on non-fatal road self-harm was extracted from a self-harm monitoring system database of self-harm presentations to a major general hospital in England during 2005-2017. Patients were identified through being referred for psychosocial assessment by a clinical service and through scrutiny of medical records. During the 13-year study period 110 individuals (67 males, 43 females) presented to the hospital with road-related self-harm: 38 (34.5%) jumped from bridges, 34 (30.9%) jumped or lay in front of vehicles, 27 (24.5%) crashed vehicles and 11 (10.0%) jumped from moving vehicles. Crashing vehicles was more common in males and jumping from vehicles more common in females. In patients who received a psychosocial assessment, their most frequent problems were with a partner, employment and family members. Over half had been in psychiatric care and nearly two-thirds had a history of previous self-harm. Suicide intent was often high, especially in those who crashed a vehicle or jumped from a bridge. The study was based on presentations to a single hospital. Some data were not available for non-assessed patients. Road-related self-harm, while not common, more frequently involves males and the acts are often of high suicidal intent. The range of problems preceding this method of self-harm indicates that there needs to be a variety of aftercare interventions, adapted to each individual's situation.


A national fundamentals curriculum for neurosurgery PGY1 residents: the 2010 Society of Neurological Surgeons boot camp courses.
In July 2009, the Accreditation Council for Graduate Medical Education (ACGME) incorporated postgraduate year 1 (PGY1 intern) level training into all U.S. neurosurgery residency programs. To provide a fundamentals curriculum for all incoming neurosurgery PGY1 residents in ACGME-accredited programs, including skills, knowledge, and attitudes that promote quality, patient safety, and professionalism. The Society of Neurological Surgeons organized 6 regional "boot camp" courses for incoming neurosurgery PGY1 residents in July 2010 that consisted of 9 lectures on clinical and nonclinical competencies plus 10 procedural and 6 surgical skills stations. Resident and faculty participants were surveyed to assess knowledge and course effectiveness. A total of 186 of 197 U.S. neurosurgical PGY1 residents (94%) and 75 neurosurgical faculty from 36 of 99 programs (36%) participated in the inaugural boot camp courses. All residents and 83% of faculty participants completed course surveys. All resident and faculty respondents thought that the boot camp courses fulfilled their purpose and objectives and imparted skills and knowledge that would improve patient care. PGY1 residents' knowledge of information taught in the courses improved significantly in postcourse testing (P < .0001). Residents and faculty particularly valued simulated and other hands-on skills training. Regional organization facilitated an unprecedented degree of participation in a national fundamental skills program for entering neurosurgery residents. One hundred percent of resident and faculty respondents positively reviewed the courses. The boot camp courses may provide a model for enhanced learning, professionalism, and safety at the inception of training in other procedural specialties.


A study of var gene transcription in vitro using universal var gene primers.
The polymorphic multigene family, var, encodes the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), present on the surface of erythrocytes infected with the human malaria parasite, P. falciparum. PfEMP1 has been implicated in the pathology of malaria through its ability to bind to host endothelial receptors and uninfected erythrocytes. Understanding the relationship between host pathology, immune response and parasite variation is crucial, but requires a method of reliably detecting and differentiating all possible var genes. Several primer pairs used to date are biased and limited in their detection capacity. Here we describe a set of PCR primers that amplify the majority of var genes in the laboratory isolates 3D7 and A4, and appear to work equally well on all isolates tested. We use these universal primers to examine the relationship between var gene transcription as assessed by reverse transcriptase-PCR (RT-PCR) with that measured by Northern analysis of parasite RNA. Phenotypically selected young parasites have multiple transcripts detected by RT-PCR, but the full-length transcript appears to be homogeneous. In addition, we demonstrate that the choice of primers used for RT-PCR is crucial in data interpretation.


Trends of hematopoietic stem cell transplantation in the Eastern Mediterranean region, 1984-2007.
Hematopoietic stem cell transplantation (HSCT) activity was surveyed in the 9 countries in the World Health Organization Eastern Mediterranean region that reported transplantation activity. Between the years of 1984 and 2007, 7933 transplantations were performed. The number of HSCTs per year has continued to increase, with a plateau in allogeneic HSCT (allo-HSCT) between 2005 and 2007. Overall, a greater proportion of transplantations were allo-HSCT (n = 5761, 77%) compared with autologous HSCT (ASCT) (n = 2172, 23%). Of 5761 allo-HSCT, acute leukemia constituted the main indication (n = 2124, 37%). There was a significant proportion of allo-HSCT for bone marrow failures (n = 1001, 17%) and hemoglobinopathies (n = 885, 15%). The rate of unrelated donor transplantations remained low, with only 2 matched unrelated donor allo-HSCTs reported. One hundred umbilical cord blood transplantations were reported (0.017% of allo-HSCT). Peripheral blood stem cells were the main source of graft in allo-HSCT, and peripheral blood stem cells increasingly constitute the main source of hematopoietic stem cells overall. Reduced-intensity conditioning was utilized in 5.7% of allografts over the surveyed period. ASCT numbers continue to increase. There has been a shift in the indication for ASCT from acute leukemia to lymphoproliferative disorders (45%), followed by myeloma (26%). The survey reflects transplantation activity according to the unique health settings of this region. Notable differences in transplantation practices as reported to the European Group for Blood and Marrow Transplantation over recent years are highlighted.


A thirty year, fine-scale, characterization of area burned in Canadian forests shows evidence of regionally increasing trends in the last decade.
Fire as a dominant disturbance has profound implications on the terrestrial carbon cycle. We present the first ever multi-decadal, spatially-explicit, 30 meter assessment of fire regimes across the forested ecoregions of Canada at an annual time-step. From 1985 to 2015, 51 Mha burned, impacting over 6.5% of forested ecosystems. Mean annual area burned was 1,651,818 ha and varied markedly (σ = 1,116,119), with 25% of the total area burned occurring in three years: 1989, 1995, and 2015. Boreal forest types contained 98% of the total area burned, with the conifer-dominated Boreal Shield containing one-third of all burned area. While results confirm no significant national trend in burned area for the period of 1985 to 2015, a significant national increasing trend (α = 0.05) of 11% per year was evident for the past decade (2006 to 2015). Regionally, a significant increasing trend in total burned area from 1985 to 2015 was observed in the Montane Cordillera (2.4% increase per year), while the Taiga Plains and Taiga Shield West displayed significant increasing trends from 2006 to 2015 (26.1% and 12.7% increases per year, respectively). The Atlantic Maritime, which had the lowest burned area of all ecozones (0.01% burned per year), was the only ecozone to display a significant negative trend (2.4% decrease per year) from 1985 to 2015. Given the century-long fire return intervals in many of these ecozones, and large annual variability in burned area, short-term trends need to be interpreted with caution. Additional interpretive cautions are related to year used for trend initiation and the nature and extents of spatial regionalizations used for summarizing findings. The results of our analysis provide a baseline for monitoring future national and regional trends in burned area and offer spatially and temporally detailed insights to inform science, policy, and management.


Ventilation of patients with asthma and chronic obstructive pulmonary disease.
Ventilatory intervention is often life-saving when patients with asthma or chronic obstructive pulmonary disease (COPD) experience acute respiratory compromise. Although both noninvasive and invasive ventilation methods may be viable initial choices, which is better depends upon the severity of illness, the rapidity of response, coexisting disease, and capacity of the medical environment. In addition, noninvasive ventilation often relieves dyspnea and hypoxemia in patients with stable severe COPD. On the basis of current evidence, the general principles of ventilatory management common to patients with acutely exacerbated asthma/COPD are these: noninvasive ventilation is suitable for a relatively simple condition, but invasive ventilation is usually required in patients with more complex or more severe disease. It is crucial to provide controlled hypoventilation, longer expiratory time, and titrated extrinsic positive end-expiratory pressure to avoid dynamic hyperinflation and its attendant consequences. Controlled sedation helps achieve synchrony of triggering, power, and breath timing between patient and ventilator. When feasible, noninvasive ventilation often facilitates the weaning of ventilator-dependent patients with COPD and shortens the patient's stay in the intensive care unit.


Pathogenesis of dengue: challenges to molecular biology.
Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.


Antitumor immunity after vaccination with B lymphoma cells overexpressing a triad of costimulatory molecules.
The costimulatory molecules B7-1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3) play pivotal roles in the activation of T cells. We investigated whether in vivo vaccination with lymphoma cells infected with a recombinant, nonreplicating fowlpox (FP) virus encoding this triad of costimulatory molecules (TRICOM) could stimulate lymphoma-specific immunity. TRICOM-infected A20 B lymphoma cells were analyzed for expression of B7-1, ICAM-1, and LFA-3. Mice (10 per group) were vaccinated with irradiated A20 cells infected with either the TRICOM vector or the wild-type FP virus (WT-FP), challenged with live A20 tumor cells, and followed for survival. Mice with established A20 tumors were also treated with irradiated TRICOM-infected A20 cells. Survival curves were compared with the log-rank statistic. The mechanism of the antitumor effect was studied by in vivo depletion of CD4(+) and CD8(+) T cells and in vitro cytotoxicity assays. All statistical tests were two-sided. A20 tumor cells infected with TRICOM expressed high levels of B7-1, ICAM-1, and LFA-3. Mice vaccinated with irradiated TRICOM-infected A20 cells had prolonged survival relative to mice vaccinated with WT-FP-infected cells (80% versus 20% survival at 110 days; P<.001). In mice with established tumors, tumor growth was slower in those treated with TRICOM-infected tumor cells than in those treated with WT-FP-infected cells, and this treatment provided a survival advantage (P<.001). Depletion of CD4(+) or CD8(+) T cells reduced the antitumor immunity provided by the tumor cell-TRICOM vaccine, and lymphocytes from vaccinated mice displayed in vitro cytotoxic activity toward A20 cells. Increasing expression of costimulatory molecules on B lymphoma cells by infection with a recombinant FP virus encoding B7-1, ICAM-1, and LFA-3 stimulates antitumor immune responses in vivo and may provide a novel strategy for treating patients with B-cell malignancies.


Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway.
The methionine salvage pathway is widely distributed among some eubacteria, yeast, plants and animals and recycles the sulfur-containing metabolite 5-methylthioadenosine (MTA) to methionine. In eukaryotic cells, the methionine salvage pathway takes place in the cytosol and usually involves six enzymatic activities: MTA phosphorylase (MTAP, EC 184.108.40.206), 5'-methylthioribose-1-phosphate isomerase (mtnA, EC 188.8.131.52), 5'-methylthioribulose-1-phosphate dehydratase (mtnB, EC: 22.214.171.124), 2,3-dioxomethiopentane-1-phosphate enolase/phosphatase (mtnC, EC 18.104.22.168), aci-reductone dioxygenase (mtnD, EC 184.108.40.206) and 4-methylthio-2-oxo-butanoate (MTOB) transaminase (EC 2.6.1.-). The aim of this study was to complete the available information on the methionine salvage pathway in human by identifying the enzyme responsible for the dehydratase step. Using a bioinformatics approach, we propose that a protein called APIP could perform this role. The involvement of this protein in the methionine salvage pathway was investigated directly in HeLa cells by transient and stable short hairpin RNA interference. We show that APIP depletion specifically impaired the capacity of cells to grow in media where methionine is replaced by MTA. Using a Shigella mutant auxotroph for methionine, we confirm that the knockdown of APIP specifically affects the recycling of methionine. We also show that mutation of three potential phosphorylation sites does not affect APIP activity whereas mutation of the potential zinc binding site completely abrogates it. Finally, we show that the N-terminal region of APIP that is missing in the short isoform is required for activity. Together, these results confirm the involvement of APIP in the methionine salvage pathway, which plays a key role in many biological functions like cancer, apoptosis, microbial proliferation and inflammation.


Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects.
High fat, low carbohydrate (HFLC) diets have become popular tools for weight management. We sought to determine the effects of a HFLC diet compared to a low fat high carbohydrate (LFHC) diet on the change in weight loss, cardiovascular risk factors and inflammation in subjects with obesity. Obese subjects (29.0-44.6 kg/m2) recruited from Boston Medical Center were randomized to a hypocaloric LFHC (n=26) or HFLC (n=29) diet for 12 weeks. The age range of subjects was 21-62 years. As a percentage of daily calories, the HFLC group consumed 33.5% protein, 56.0% fat and 9.6% carbohydrate and the LFHC group consumed 22.0% protein, 25.0% fat and 55.7% carbohydrate. The change in percent body weight, lean and fat mass, blood pressure, flow mediated dilation, hip:waist ratio, hemoglobin A1C, fasting insulin and glucose, and glucose and insulin response to a 2h oral glucose tolerance test did not differ (P>0.05) between diets after 12 weeks. The HFLC group had greater mean decreases in serum triglyceride (P=0.07), and hs-CRP (P=0.03), and greater mean increases in HDL cholesterol (P=0.004), and total adiponectin (P=0.045) relative to the LFHC. Secreted adipose tissue adiponectin or TNF-α did not differ after weight loss for either diet. Relative to the LFHC group, the HFLC group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets.


Posttraumatic stress and depressive symptomatology in a sample of battered women from South Africa.
This study investigated the incidence of depression, posttraumatic stress symptomatology, anger, and guilt in a sample of 40 battered women in a shelter. Analysis indicated that 63% of the 40 scored moderate to severe on depression, 59% manifested high posttraumatic stress symptoms, while 38.4% and 54.5% reported problems with anger and guilt, respectively. Frequency and severity of physical abuse were not correlated with depressive or posttraumatic stress symptomatology.


The risk of extrapolation in neuroanatomy: the case of the Mammalian vomeronasal system.
The sense of smell plays a crucial role in mammalian social and sexual behaviour, identification of food, and detection of predators. Nevertheless, mammals vary in their olfactory ability. One reason for this concerns the degree of development of their pars basalis rhinencephali, an anatomical feature that has been considered in classifying this group of animals as macrosmatic, microsmatic or anosmatic. In mammals, different structures are involved in detecting odours: the main olfactory system, the vomeronasal system (VNS), and two subsystems, namely the ganglion of Grüneberg and the septal organ. Here, we review and summarise some aspects of the comparative anatomy of the VNS and its putative relationship to other olfactory structures. Even in the macrosmatic group, morphological diversity is an important characteristic of the VNS, specifically of the vomeronasal organ and the accessory olfactory bulb. We conclude that it is a big mistake to extrapolate anatomical data of the VNS from species to species, even in the case of relatively close evolutionary proximity between them. We propose to study other mammalian VNS than those of rodents in depth as a way to clarify its exact role in olfaction. Our experience in this field leads us to hypothesise that the VNS, considered for all mammalian species, could be a system undergoing involution or regression, and could serve as one more integrated olfactory subsystem.


Responding to climate change and the global land crisis: REDD+, market transformation and low-emissions rural development.
Climate change and rapidly escalating global demand for food, fuel, fibre and feed present seemingly contradictory challenges to humanity. Can greenhouse gas (GHG) emissions from land-use, more than one-fourth of the global total, decline as growth in land-based production accelerates? This review examines the status of two major international initiatives that are designed to address different aspects of this challenge. REDD+ is an emerging policy framework for providing incentives to tropical nations and states that reduce their GHG emissions from deforestation and forest degradation. Market transformation, best represented by agricultural commodity roundtables, seeks to exclude unsustainable farmers from commodity markets through international social and environmental standards for farmers and processors. These global initiatives could potentially become synergistically integrated through (i) a shared approach for measuring and favouring high environmental and social performance of land use across entire jurisdictions and (ii) stronger links with the domestic policies, finance and laws in the jurisdictions where agricultural expansion is moving into forests. To achieve scale, the principles of REDD+ and sustainable farming systems must be embedded in domestic low-emission rural development models capable of garnering support across multiple constituencies. We illustrate this potential with the case of Mato Grosso State in the Brazilian Amazon.


The regulation of proliferation and differentiation in oligodendrocyte progenitor cells by alphaV integrins.
We have previously shown that oligodendrocyte progenitor cells exhibit developmental switching between alphav-associated beta integrin subunits to sequentially express alphavbeta1, alphavbeta3 and alphavbeta5 integrins during differentiation in vitro. To understand the role that alphavveta3 integrin may play in regulating oligodendrocyte progenitor cell behaviour, cells of the rat cell line, CG-4, were genetically engineered to constitutively express alphavbeta3 integrin by transfection with full-length human beta3 integrin subunit cDNA. Time-lapse videomicroscopy showed no effect of beta3 expression on cell migration but revealed enhanced proliferation on vitronectin substrata. Comparison of mitotic indices, as measured by 5-bromo-2'-deoxyuridine incorporation, confirmed that human beta3 integrin-expressing cells exhibited enhanced proliferation, as compared to both vector-only transfected, and wild-type CG-4 cells when switched to differentiation medium from growth medium, but only in cultures grown on vitronectin and not on poly-D-lysine. The effects on proliferation were inhibited by a function-blocking antibody specifically directed against the human beta3 integrin subunit. Human beta3 integrin-expressing cells also exhibited reduced differentiation. This differentiation could be reduced still further by a function-blocking monoclonal antibody against alphavbeta5 integrin, as could differentiation in the wild-type CG-4 cells. Taken together, these results suggest that alphavbeta3 integrin may regulate oligodendroglial cell proliferation and that both downregulation of alphavbeta3 integrin expression and signalling through alphavbeta5 integrin may be critical to continued differentiation in vitro.


Aberrations in 4Pi Microscopy.
The combination of two opposing objective lenses in 4Pi fluorescence microscopy significantly improves the axial resolution and increases the collection efficiency. Combining 4Pi microscopy with other super-resolution techniques has resulted in the highest three-dimensional (3D) resolution in fluorescence microscopy to date. It has previously been shown that the performance of 4Pi microscopy is significantly affected by aberrations. However, a comprehensive description of 4Pi microscope aberrations has been missing. In this paper, we introduce an approach to describe aberrations in a 4Pi cavity through a new functional representation. We discuss the focusing properties of 4Pi systems affected by aberrations and discuss the implications for adaptive optics schemes for 4Pi microscopes based on this new insight.


Acupuncture for whiplash-associated disorder following road traffic collision: a physiotherapy service evaluation.
Whiplash-associated disorder (WAD) is a common musculoskeletal condition that frequently occurs following a road traffic collision. Physiotherapy is often prescribed to help with the symptoms and injuries. Research evidence has demonstrated that acupuncture may be beneficial, but no studies have examined the routine clinical use of acupuncture by physiotherapists for treatment of WAD. Therefore, a physiotherapy service evaluation was conducted to examine the effects of acupuncture on WAD following a road traffic collision. This study involved 87 patients who attended a private physiotherapy practice following a road traffic collision after referral by their solicitor as part of a personal injury claim. Patients were included if they had been diagnosed with WAD (grades I-III) and received acupuncture as part of their treatment. An average of three sessions of acupuncture were received, which primarily involved needling of traditional acupuncture points and/or myofascial trigger points of the neck and upper/lower back. Pain significantly reduced (p < 0.001). Musculoskeletal outcome measures including neck disability index, Oswestry low back pain scale and Quick disabilities of the arm, shoulder and hand (Quick-DASH) scale also significantly improved (all p < 0.001). Adverse events were minor. The majority of the patients (n = 66) were able to return to full-work duties following treatment. Acupuncture appears to be an effective clinical treatment for WAD following a road traffic collision and should be considered by physiotherapists working with such patient groups.


Impacts of climate variability and human colonization on the vegetation of the Galápagos Islands.
A high-resolution (2-9 year sampling interval) fossil pollen record from the Galápagos Islands, which spans the last 2690 years, reveals considerable ecosystem stability. Vegetation changes associated with independently derived histories of El Niño Southern Oscillation variability provided evidence of shifts in the relative abundance of individual species rather than immigration or extinction. Droughts associated with the Medieval Climate Anomaly induced rapid ecological change that was followed by a reversion to the previous state. The paleoecological data suggested nonneutral responses to climatic forcing in this ecosystem prior to the period of human influence. Human impacts on the islands are evident in the record. A marked decline in long-term codominants of the pollen record, Alternanthera and Acalypha, produced a flora without modern analogue before 1930. Intensified animal husbandry after ca. 1930 may have induced the local extinction of Acalypha and Alternanthera. Reductions in populations of grazing animals in the 1970s and 1980s did not result in the return of the native flora, but in invasions by exotic species. After ca. 1970 the trajectory of habitat change accelerated, continuously moving the ecosystem away from the observed range of variability in the previous 2690 years toward a novel ecosystem. The last 40 years of the record also suggest unprecedented transport of lowland pollen to the uplands, consistent with intensified convection and warmer wet seasons.


A fluorophore's electron-deficiency does matter in designing high-performance near-infrared fluorescent probes.
The applications of most fluorescent probes available for Glutathione S-Transferases (GSTs), including NI3 which we developed recently based on 1,8-naphthalimide (NI), are limited by their short emission wavelengths due to insufficient penetration. To realize imaging at a deeper depth, near-infrared (NIR) fluorescent probes are required. Here we report for the first time the designing of NIR fluorescent probes for GSTs by employing the NIR fluorophore HCy which possesses a higher brightness, hydrophilicity and electron-deficiency relative to NI. Intriguingly, with the same receptor unit, the HCy-based probe is always more reactive towards glutathione than the NI-based one, regardless of the specific chemical structure of the receptor unit. This was proved to result from the higher electron-deficiency of HCy instead of its higher hydrophilicity based on a comprehensive analysis. Further, with caging of the autofluorescence being crucial and more difficult to achieve via photoinduced electron transfer (PET) for a NIR probe, the quenching mechanism of HCy-based probes was proved to be PET for the first time with femtosecond transient absorption and theoretical calculations. Thus, HCy2 and HCy9, which employ receptor units less reactive than the one adopted in NI3, turned out to be the most appropriate NIR probes with high-sensitivity and little nonenzymatic background noise. They were then successfully applied to detecting GST in cells, tissues and tumor xenografts in vivo. Additionally, unlike HCy2 with a broad isoenzyme selectivity, HCy9 is specific for GSTA1-1, which is attributed to its lower reactivity and the higher effectiveness of GSTA1-1 in stabilizing the active intermediate via H-bonds based on docking simulations.


The solution structure of a chimeric LEKTI domain reveals a chameleon sequence.
The conversion of an alpha-helical to a beta-strand conformation and the presence of chameleon sequences are fascinating from the perspective that such structural features are implicated in the induction of amyloid-related fatal diseases. In this study, we have determined the solution structure of a chimeric domain (Dom1PI) from the multidomain Kazal-type serine proteinase inhibitor LEKTI using multidimensional NMR spectroscopy. This chimeric protein was constructed to investigate the reasons for differences in the folds of the homologous LEKTI domains 1 and 6 [Lauber, T., et al. (2003) J. Mol. Biol. 328, 205-219]. In Dom1PI, two adjacent phenylalanine residues (F28 and F29) of domain 1 were substituted with proline and isoleucine, respectively, as found in the corresponding P4' and P5' positions of domain 6. The three-dimensional structure of Dom1PI is significantly different from the structure of domain 1 and closely resembles the structure of domain 6, despite the sequence being identical to that of domain 1 except for the two substituted phenylalanine residues and being only 31% identical to the sequence of domain 6. The mutation converted a short 3(10)-helix into an extended loop conformation and parts of the long COOH-terminal alpha-helix of domain 1 into a beta-hairpin structure. The latter conformational change occurs in a sequence stretch distinct from the region containing the substituted residues. Therefore, this switch from an alpha-helical structure to a beta-hairpin structure indicates a chameleon sequence of seven residues. We conclude that the secondary structure of Dom1PI is determined not only by the local protein sequence but also by nonlocal interactions.


Diagnosis and treatment of erectile dysfunction for reduction of cardiovascular risk.
We established erectile dysfunction as an often neglected but valuable marker of cardiovascular risk, particularly in younger men and men with diabetes. We also reviewed evidence that lifestyle change, combined with informed prescribing of pharmacotherapies used to mitigate cardiovascular risk, can improve overall vascular health and sexual functioning in men with erectile dysfunction. We performed a PubMed® search for articles and guidelines pertinent to relationships between erectile dysfunction and cardiovascular disease, cardiovascular and all cause mortality, and pharmacotherapies for dyslipidemia and hypertension. The clinical guidance presented incorporates the current literature and the expertise of the multispecialty investigator group. Numerous cardiovascular risk assessment tools exist but risk stratification remains challenging, particularly in patients at low or intermediate short-term risk. Erectile dysfunction has a predictive value for cardiovascular events that is comparable to or better than that of traditional risk factors. Interventional studies support lifestyle changes as a means of improving overall vascular health as well as sexual functioning. Statins, diuretics, β-blockers and renin-angiotensin system modifiers may positively or negatively affect erectile function. Furthermore, the phosphodiesterase type 5 inhibitors used to treat erectile dysfunction may have systemic vascular benefits. Erectile dysfunction treatment should be considered secondary to decreasing cardiovascular risk. However, informed prescribing may prevent worsening sexual function in men receiving pharmacotherapy for dyslipidemia and hypertension. As the first point of medical contact for men with erectile dysfunction symptoms, the primary care physician or urologist has a unique opportunity to identify those who require early intervention to prevent cardiovascular disease.


Disease associations and altered immune function in CD45 138G variant carriers.
The CD45 antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signalling in lymphocytes. Expression of different patterns of alternatively spliced CD45 isoforms is associated with distinct functions. We recently identified a polymorphism in exon 6 (A138G) of the gene encoding CD45 (PTPRC) that results in altered CD45 splicing. The 138G allele is present at a high frequency among Japanese (23.7%), with 5.1% individuals homozygous for the G allele. In this study we show that the A138G polymorphism is the cause of altered CD45 isoform expression, promoting splicing towards low molecular weight CD45 isoforms. We further report that the frequency of A138G heterozygotes is significantly reduced in number in cohorts of patients with autoimmune Graves' disease or hepatitis B infection, whereas G138G homozygotes are absent from a cohort of Hashimoto's thyroiditis patients. We also show that 138G individuals exhibit altered cytokine production in vitro and an increased proportion of memory T cells. These data suggest that the 138G variant allele strongly influences these diseases by modulation of immune mechanisms and may have achieved its high frequency as a result of a natural selection probably related to pathogen resistance.


Antigen spacing on protein nanoparticles influences antibody responses to vaccination.
Immunogen design approaches aim to control the specificity and quality of antibody responses elicited by next-generation vaccines. Here, we use computational protein design to generate a nanoparticle vaccine platform based on the receptor-binding domain (RBD) of influenza hemagglutinin (HA) that enables precise control of antigen conformation and spacing. HA RBDs are presented as either monomers or native-like closed trimers that are connected to the underlying nanoparticle by a rigid linker that is modularly extended to precisely control antigen spacing. Nanoparticle immunogens with decreased spacing between trimeric RBDs elicit antibodies with improved hemagglutination inhibition and neutralization potency as well as binding breadth across diverse H1 HAs. Our "trihead" nanoparticle immunogen platform provides insights into anti-HA immunity, establishes antigen spacing as an important parameter in structure-based vaccine design, and embodies several design features that could be used in next-generation vaccines against influenza and other viruses.


Functional consequences of subcortical white matter lesions and MRI-defined brain infarct in an elderly general population.
The impact of single and combined effects of subcortical white matter lesions (WMLs) and magnetic resonance imaging (MRI)-defined brain infarct on activities of daily living (ADL), depression, and health status perception was analyzed in community-dwelling elderly individuals. The study included 268 participants from the Memory and Morbidity in Augsburg Elderly (MEMO) project, a population-based study on individuals aged 65 to 83 years, conducted in Augsburg, Germany. Cerebral MRI was performed, and 2 geriatric performance tests, scales to assess ADL, depressive symptoms, and self-perceived health status were assessed. The prevalence of large (>10 mm) subcortical WML was 37.7% and of MRI-defined infarct-like lesions was 15.3%. Both vascular lesion types combined were found in 9% of the participants. Large WMLs were associated with significantly more impairments in basic ADL, inferior results in the performance tests, and a worse self-perceived health status compared to those without large WML. Magnetic resonance imaging-defined brain infarct was associated with impairments in performance tests. Participants with both lesion types were limited in all domains and were 2 to 3 times more likely to have impairments in all examined functions. Their risk of impairment in a specific function was considerably higher than the sum of the single risks associated with each lesion type alone. This study suggests that the single and especially the combined occurrence of common vascular brain lesions are associated with functional impairment. Identifying individuals with severe WML combined with MRI-defined brain infarct can help better understand the development of marked impairments in old age.


Lowering the Bar for Mass Spectrometry: A Comparison between Immunoassay and Rapid Time-of-Flight for Presumptive Screening of Drugs in Urine.
Immunoassay-based techniques and creatinine quantification have historically been the methods of choice for urine drug screening. Positive presumptive drug screen results are reflexed to more specific, confirmatory testing using gas or liquid chromatography coupled to mass spectrometry. False positives and false negatives with immunoassay techniques are common problems that have substantial down-stream consequences for patient care, laboratory operations, and total costs. The final workflow included rapid enzymatic hydrolysis, rapid liquid chromatographic methods, and time-of-flight mass spectrometry for detection. In total, 84 drugs and metabolites were included and reported qualitatively using 11 isotopically labeled internal standards selected to represent compound classes, retention time, and expected abundances to control for method inefficiencies and matrix suppression/enhancement. The method performance validation included 420 individual urine specimens. Of the 420 samples screened by immunoassay, 117 failed to confirm by mass spectrometry and were immunoassay false positives. None of these 117 samples screened positive on the liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) assay. The LC-TOF-MS method failed to detect 1 sample in each of the following classes: buprenorphine, ethanol markers, and opiates owing to concentrations below the established cutoffs. Out of 579 samples, 275 (47.4%) screened positive by LC-TOF-MS for nicotine and at least 2 of its metabolites. Quantitative creatinine comparison to an existing Jaffe method yielded a slope of 0.91 and a correlation coefficient of 0.96. We investigated whether immunoassay-based drug screening and creatinine quantification could be sufficiently replaced by a rapid LC-TOF-MS screen with higher specificity and accuracy than existing methods. The LC-LC-TOF-MS method is a sensitive and more specific way to screen for drugs, providing creatinine quantification and potential novel specimen validity testing with the inclusion of nicotine metabolites.


Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome.
Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.


1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells.
The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3-dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclo-pentyl)xanthine (CPX), 1,3-dipropyl-8-(3-noradamantyl)xanthine (NAX) and (+/-)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A2a AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 microM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine-antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 +/- 0.19, 8.55 +/- 0.28 and 8.79 +/- 0.15, respectively. ENX (30 microM) and N-0861 (30 microM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 microM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A2a AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.


Characterization of cylindrical terahertz metallic hollow waveguide with multiple dielectric layers.
Dielectric-coated metallic hollow waveguides (DMHW) are drawing considerable attention for their application in terahertz (THz) waveguiding. This paper theoretically analyzes the multilayer structure to reduce the transmission and bending loss of DMHW. The efficiency of THz multilayer DMHW depends on a proper selection of dielectric materials and geometrical parameters. The low-loss properties are demonstrated by studying the multilayer gold waveguides with a stack of polypropylene (PP) and Si-doped polypropylene (PP(Si)). Comparisons are made with single-layer Au/PP and Au-only waveguides. The effect of dielectric absorption is discussed in detail. It is found that low index dielectric causes more additional loss than that of high index dielectric layers. Several design considerations for the THz multilayer DMHW are pointed out by studying the effects of multilayer structure parameters with a stack of polyethylene (PE) and TiO(2)-doped polyethylene (PE(TiO2)). We conclude that the inner radius of the waveguide and the refractive indices of the dielectrics tend to be larger in order to reduce the influence of material absorption. An optimal value exists for the total number of layers when the dielectrics are absorptive. The absorption tolerances are pointed out to guarantee a smaller loss for multilayer DMHW than that of metal-only waveguide. Finally, a fabrication method for THz multilayer DMHW Ag/PE/PE(TiO2) is proposed based on co-rolling technique.


Rapid diagnostic tests for plague.
Plague is a severe disease associated with high mortality. Late diagnosis leads to advance stage of the disease with worse outcomes and higher risk of spread of the disease. A rapid diagnostic test (RDT) could help in establishing a prompt diagnosis of plague. This would improve patient care and help appropriate public health response. To determine the diagnostic accuracy of the RDT based on the antigen F1 (F1RDT) for detecting plague in people with suspected disease. We searched the CENTRAL, Embase, Science Citation Index, Google Scholar, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov up to 15 May 2019, and PubMed (MEDLINE) up to 27 August 2019, regardless of language, publication status, or publication date. We handsearched the reference lists of relevant papers and contacted researchers working in the field. We included cross-sectional studies that assessed the accuracy of the F1RDT for diagnosing plague, where participants were tested with both the F1RDT and at least one reference standard. The reference standards were bacterial isolation by culture, polymerase chain reaction (PCR), and paired serology (this is a four-fold difference in F1 antibody titres between two samples from acute and convalescent phases). Two review authors independently selected studies and extracted data. We appraised the methodological quality of each selected studies and applicability by using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. When meta-analysis was appropriate, we used the bivariate model to obtain pooled estimates of sensitivity and specificity. We stratified all analyses by the reference standard used and presented disaggregated data for forms of plague. We assessed the certainty of the evidence using GRADE. We included eight manuscripts reporting seven studies. Studies were conducted in three countries in Africa among adults and children with any form of plague. All studies except one assessed the F1RDT produced at the Institut Pasteur of Madagascar (F1RDT-IPM) and one study assessed a F1RDT produced by New Horizons (F1RDT-NH), utilized by the US Centers for Disease Control and Prevention. We could not pool the findings from the F1RDT-NH in meta-analyses due to a lack of raw data and a threshold of the test for positivity different from the F1RDT-IPM. Risk of bias was high for participant selection (retrospective studies, recruitment of participants not consecutive or random, unclear exclusion criteria), low or unclear for index test (blinding of F1RDT interpretation unknown), low for reference standards, and high or unclear for flow and timing (time of sample transportation was longer than seven days, which can lead to decreased viability of the pathogen and overgrowth of contaminating bacteria, with subsequent false-negative results and misclassification of the target condition). F1RDT for diagnosing all forms of plague F1RDT-IPM pooled sensitivity against culture was 100% (95% confidence interval (CI) 82 to 100; 4 studies, 1692 participants; very low certainty evidence) and pooled specificity was 70.3% (95% CI 65 to 75; 4 studies, 2004 participants; very low-certainty evidence). The performance of F1RDT-IPM against PCR was calculated from a single study in participants with bubonic plague (see below). There were limited data on the performance of F1RDT against paired serology. F1RDT for diagnosing pneumonic plague Performed in sputum, F1RDT-IPM pooled sensitivity against culture was 100% (95% CI 0 to 100; 2 studies, 56 participants; very low-certainty evidence) and pooled specificity was 71% (95% CI 59 to 80; 2 studies, 297 participants; very low-certainty evidence). There were limited data on the performance of F1RDT against PCR or against paired serology for diagnosing pneumonic plague. F1RDT for diagnosing bubonic plague Performed in bubo aspirate, F1RDT-IPM pooled sensitivity against culture was 100% (95% CI not calculable; 2 studies, 1454 participants; low-certainty evidence) and pooled specificity was 67% (95% CI 65 to 70; 2 studies, 1198 participants; very low-certainty evidence). Performed in bubo aspirate, F1RDT-IPM pooled sensitivity against PCR for the caf1 gene was 95% (95% CI 89 to 99; 1 study, 88 participants; very low-certainty evidence) and pooled specificity was 93% (95% CI 84 to 98; 1 study, 61 participants; very low-certainty evidence). There were no data providing data on both F1RDT and paired serology for diagnosing bubonic plague. Against culture, the F1RDT appeared highly sensitive for diagnosing either pneumonic or bubonic plague, and can help detect plague in remote areas to assure management and enable a public health response. False positive results mean culture or PCR confirmation may be needed. F1RDT does not replace culture, which provides additional information on resistance to antibiotics and bacterial strains.


Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.
The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality. A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy. Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1-5 exercise PVCs, P<0.001) and HR, 1.3 (1-5 recovery PVCs, P<0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, P<0.001) and HR, 1.6 (>5 recovery PVCs, P<0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, P<0.001) and 1.5 (>5 recovery PVCs, P<0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs. In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy.


[Guanosine and inosine as natural geneprotectors for mice blood cells exposed to X-rays].
The radioprotective effects of guanosine and of inosine on bone marrow cells of mice exposed to acute X-rays (1.5 Gy) were studied by using the micronuclear test. The guanosine and inosine (riboxine) decrease the frequency of micronucleated polychromatic erythrocytes and significantly recover erythropoiesis. Also, radioprotective effects of the guanosine and of the inosine on the irradiated leucocytes of mice were tested by the alkaline comet assay. Was shown that purine ribonucleosides diminish quantity of DNA damage and activates repair processes in leucocytes under irradiation of blood and animals. The reactive oxygen species induced by ionizing radiation perform essential role in DNA damaging. Using a sensitive method of enhanced chemiluminescence in a peroxidase-luminol-p-iodophenol system for quantitative measurement of hydrogen peroxide and coumarin-3-carboxylic acid for quantitative measurement of hydroxyl radicals we have shown that guanosine and inosine essentially decrease the yield of hydrogen peroxide and hydroxyl radicals in X-ray-irradiated water. The results obtained indicate that radioprotective properties of guanosine and inosine (riboxine) in the blood cells are operative at the genome level.


Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3.
Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder characterized by the loss of language and motor skills during early childhood. We generated mice with a truncating mutation similar to those found in RTT patients. These mice appeared normal and exhibited normal motor function for about 6 weeks, but then developed a progressive neurological disease that includes many features of RTT: tremors, motor impairments, hypoactivity, increased anxiety-related behavior, seizures, kyphosis, and stereotypic forelimb motions. Additionally, we show that although the truncated MeCP2 protein in these mice localizes normally to heterochromatic domains in vivo, histone H3 is hyperacetylated, providing evidence that the chromatin architecture is abnormal and that gene expression may be misregulated in this model of Rett syndrome.


Advances in the synthesis of nitroxide radicals for use in biomolecule spin labelling.
EPR spectroscopy is an increasingly useful analytical tool to probe biomolecule structure, dynamic behaviour, and interactions. Nitroxide radicals are the most commonly used radical probe in EPR experiments, and many methods have been developed for their synthesis, as well as incorporation into biomolecules using site-directed spin labelling. In this Tutorial Review, we discuss the most practical methods for the synthesis of nitroxides, focusing on the tunability of their structures, the manipulation of their sidechains into spin labelling handles, and their installation into biomolecules.


Public Opinions about Overdiagnosis: A National Community Survey.
Despite evidence about the "modern epidemic" of overdiagnosis, and expanding disease definitions that medicalize more people, data are lacking on public views about these issues. Our objective was to measure public perceptions about overdiagnosis and views about financial ties of panels setting disease definitions. We conducted a 15 minute Computer Assisted Telephone Interview with a randomly selected community sample of 500 Australians in January 2014. We iteratively developed and piloted a questionnaire, with a convenience sample (n=20), then with participants recruited by a research company (n=20). Questions included whether respondents had been informed about overdiagnosis; opinions on informing people; and views about financial ties among panels writing disease definitions. Our sample was generally representative, but included a higher proportion of females and seniors, typical of similar surveys. American Association for Public Opinion Research response rate was 20% and cooperation rate was 44%. Only 10% (95% CI 8%-13%) of people reported ever being told about overdiagnosis by a doctor. 18% (95% CI 11%-28%) of men who reported having prostate cancer screening, and 10% (95% CI 6%-15%) of women who reported having mammography said they were told about overdiagnosis. 93% (95% CI 90%-95%) agreed along with screening benefits, people should be informed about overdiagnosis. On panels setting disease definitions, 78% (95% CI 74%-82%) felt ties to pharmaceutical companies inappropriate, and 91% (95% CI 82%-100%) believed panels should have a minority or no members with ties. Limitations included questionnaire novelty and complexity. A small minority of Australians surveyed, including those reporting being screened for prostate or breast cancer, reported being informed of overdiagnosis; most believed people should be informed; and a majority felt it inappropriate that doctors with ties to pharmaceutical companies write disease definitions. Results suggest strategies to better inform people about overdiagnosis, and review disease definition processes, have significant public sympathy.


A phase II trial. Oral UFT and leucovorin in patients with advanced gastric carcinoma.
Thirty-nine patients with locally advanced or metastatic gastric carcinoma received oral UFT (tegafur and uracil) plus leucovorin. Treatment consisted of UFT 360 mg/m2/day plus leucovorin 25 mg/m2/day, given orally in divided daily doses for 21 days followed by a 7-day rest period. The median age of the patients was 64 years, and the median World Health Organization performance status was 2. Patients received a median of two courses of treatment (range, 1 to 25). Among 37 evaluable patients, two patients achieved a complete response, and eight had partial responses, for an overall response rate of 27% (95% confidence interval, 15.4% to 42.9%). Stable disease was reported in 12 patients (32%) and another 15 showed disease progression. The median duration of response was 30 weeks, and the median duration of survival was also 30 weeks (range, 8 to 111). All patients were evaluable for toxicity. Significant toxicity (World Health Organization grade 3 or 4) included diarrhea in seven patients (18%), oral mucositis in six (15%), and nausea/vomiting in six patients. We conclude that oral UFT plus leucovorin, an outpatient regimen, has favorable activity in patients with gastric carcinoma and has tolerable toxicities.


Prognostic Factors in Complex Regional Pain Syndrome Type 1 Occurring in the Korean Army.
In Korea, patients diagnosed with complex regional pain syndrome (CRPS) in the army are typically discharged from the army; however, the course of the disease after discharge is not known. The purpose of this study was to investigate the course of CRPS that occurred in the army and to identify the influences of various clinical and psychosocial factors immediately before discharge on the disease course. Clinical profiles and psychosocial status were collected from the medical records of 16 patients with CRPS type 1 who were discharged during the period between March 2017 and April 2018. The degree of improvement after discharge was assessed by follow-up evaluation through telephone contact. Cox proportional hazards regression was performed to identify clinical and psychosocial predictors for the rate of recovery. The median time to recovery after discharge was 39 weeks (95% confidence interval [CI] = 8.8-69.2 weeks). The sole predictor for time to recovery after discharge was the time period from the onset of pain to discharge. Each one-week increase in the duration of pain experienced in the military was associated with a 18.2% (95% CI = 5.3%-29.5%) reduction in the rate of recovery after discharge (P = 0.007). Patients who experienced a short period of pain in the military demonstrated a relatively good prognosis after discharge. This may show how prolonged pain in the army could affect the experience of pain from a social point of view, in that it shows the disease course after a change in the social environment.


Anal Cancer Risk Among People With HIV Infection in the United States.
Purpose People with HIV infection have an elevated risk of anal cancer. However, recent calendar trends are incompletely described, and which population subgroups might benefit from cancer screening is unknown. Methods We used linked data from HIV and cancer registries in nine US areas (1996 to 2012). We calculated standardized incidence ratios to compare anal cancer incidence in people with HIV infection with the general population, used Poisson regression to evaluate anal cancer incidence among subgroups of people with HIV and to assess temporal trends, and estimated the cumulative incidence of anal cancer to measure absolute risk. Results Among 447,953 people with HIV infection, anal cancer incidence was much higher than in the general population (standardized incidence ratio, 19.1; 95% CI, 18.1 to 20.0). Anal cancer incidence was highest among men who have sex with men (MSM), increased with age, and was higher in people with AIDS than in those without AIDS (ie, HIV only; adjusted incidence rate ratio, 3.82; 95% CI, 3.27 to 4.46). Incidence among people with HIV increased steeply during 1996 to 2000 (annual percentage change, 32.8%; 95% CI, -1.0% to 78.2%), reached a plateau during 2001 to 2008, and declined during 2008 to 2012 (annual percentage change, -7.2%; 95% CI, -14.4% to 0.6%). Cumulative incidence after a 5-year period was high for MSM with HIV only age 45 to 59 or ≥ 60 years (0.32% to 0.33%) and MSM with AIDS age 30 to 44, 45 to 59, or ≥ 60 years (0.29% to 0.65%). Conclusion Anal cancer incidence is markedly elevated among people with HIV infection, especially in MSM, older individuals, and people with AIDS. Recent declines may reflect delayed benefits of HIV treatment. Groups with high cumulative incidence of anal cancer may benefit from screening.


Clinical implications of the differences between diagnostic 123I and post-therapy 131I scans.
123I has been promoted for diagnostic imaging as a means of avoiding 'stunning'. It has also been suggested that the more favourable physical characteristics and consequent enhanced imaging resolution provided by 123I offers a more accurate diagnostic assessment of the extent of disease prior to therapy. This study evaluated pairs of diagnostic 123I and post-therapy 131I scans for differences in patterns of radioiodine uptake. Thirty-eight patients (31 women and seven men) with a history of differentiated thyroid cancer underwent 41 diagnostic 123I studies. 131I therapy was administered to 29 patients as soon as possible after positive diagnostic findings were confirmed (with one patient being treated twice during the study period, making 30 treatments). Post-treatment scans were obtained an average of 5.8 days after therapy. Qualitative comparison of diagnostic 123I and post-therapy 131I scans revealed a decrease in the extent of post-treatment uptake in four of the 30 treatments (13%). Seven patients (23%) demonstrated increased uptake on their post-therapy 131I scan. Because the physical characteristics of 123I make it inconceivable that it could cause stunning, the decrease in post-treatment uptake seen in 13% of patients from this series increases the likelihood that this pattern is due to factors other than stunning, such as differential rates of radioiodine turnover. In addition, the increase in extent of post-therapy uptake seen in 23% of patients suggests that diagnostic imaging with 123I is vulnerable to the same pre-therapy staging inaccuracies as is low-dose diagnostic imaging with 131I. Further work is needed to determine whether larger diagnostic doses of 123I might mitigate this problem.


The zygomatic implant perforated (ZIP) flap: a new technique for combined surgical reconstruction and rapid fixed dental rehabilitation following low-level maxillectomy.
This aim of this report is to describe the development and evolution of a new surgical technique for the immediate surgical reconstruction and rapid post-operative prosthodontic rehabilitation with a fixed dental prosthesis following low-level maxillectomy for malignant disease.The technique involves the use of a zygomatic oncology implant perforated micro-vascular soft tissue flap (ZIP flap) for the primary management of maxillary malignancy with surgical closure of the resultant maxillary defect and the installation of osseointegrated support for a zygomatic implant-supported maxillary fixed dental prosthesis.The use of this technique facilitates extremely rapid oral and dental rehabilitation within a few weeks of resective surgery, providing rapid return to function and restoring appearance following low-level maxillary resection, even in cases where radiotherapy is required as an adjuvant treatment post-operatively. The ZIP flap technique has been adopted as a standard procedure in the unit for the management of low-level maxillary malignancy, and this report provides a detailed step-by-step approach to treatment and discusses modifications developed over the treatment of an initial cohort of patients.


Arsenic removal from groundwater of the Chaco-Pampean plain (Argentina) using natural geological materials as adsorbents.
Use of natural geological materials for arsenic (As) removal is an emerging solution at a household level for poor people in remote rural settlements, especially when the materials are locally available and can be collected by the local population. Their low or zero cost makes these materials very attractive compared with synthetic or commercial materials. Sometimes, this may be the only option to provide safe water to very poor settlements. Their suitability for As removal from water is mainly due to adsorption, co-precipitation and ion exchange processes involving Fe- and Al-rich minerals and clay minerals present in the soils or sediments. In the present study, various clay-rich soils from the Santiago del Estero province (SDE, NW Argentina) and, for comparison, a laterite from the Misiones province have been tested as adsorbents for As in shallow naturally contaminated groundwaters of the Río Dulce alluvial aquifer in SDE. Batch adsorption experiments showed higher As(V) removal for the Misiones laterite sample (99 %) as compared with the soils from SDE (40-53 %), which can be related to lower contents of water-soluble and oxalate extractable Al and Fe in the last samples. These results suggest the application of the Misiones laterite soil as an alternative for As removal. However, high transportation costs from Misiones to SDE can be an economical restriction for the low-income population of SDE.


Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial.
This study was conducted to determine the effects of folate supplementation on metabolic profiles in obese women with polycystic ovary syndrome (PCOS). This randomized double-blind placebo-controlled clinical trial was conducted among 81 obese women (weight range: 65-110 kg) aged 18-40 year old diagnosed with PCOS. Participants were randomly assigned to three groups receiving: (1) Folate-1: 1 mg/day folate supplements (n = 27); (2) Folate-5: 5 mg/day folate supplements (n = 27), and (3) placebo (n = 27) for 8 weeks. Fasting blood samples were taken at baseline and after 8 weeks' intervention to quantify glucose metabolism and lipid concentrations. Folate supplementation (5 mg), compared with folate-1 and placebo, resulted in reduced plasma homocysteine (p-interaction = 0.009), homeostasis model of assessment-insulin resistance score (p-interaction = 0.01), and total cholesterol/HDL-C ratio (p-interaction = 0.01). Furthermore, we found a significant difference in mean change of serum total cholesterol (p-interaction = 0.01), LDL- (p-interaction = 0.007), and non-HDL-cholesterol levels (p = 0.01) in the folate-5 group compared with folate-1 and placebo. 5 mg/day folate supplementation for 8 weeks among women with PCOS had beneficial effects on metabolic profiles.


Analysis of somatic mutation in five B cell subsets of human tonsil.
Using a series of phenotypic markers that include immunoglobulin (Ig)D, IgM, IgG, CD23, CD44, Bcl-2, CD38, CD10, CD77, and Ki67, human tonsillar B cells were separated into five fractions representing different stages of B cell differentiation that included sIgD+ (Bm1 and Bm2), germinal center (Bm3 and Bm4), and memory (Bm5) B cells. To establish whether the initiation of somatic mutation correlated with this phenotypic characterization, we performed polymerase chain reaction and subsequent sequence analysis of the Ig heavy chain variable region genes from each of the B cell subsets. We studied the genes from the smallest VH families (VH4, VH5, and VH6) in order to facilitate the mutational analysis. In agreement with previous reports, we found that the somatic mutation machinery is activated only after B cells reach the germinal center and become centroblasts (Bm3). Whereas 47 independently rearranged IgM transcripts from the Bm1 and Bm2 subsets were nearly germline encoded, 57 Bm3-, and Bm4-, and Bm5-derived IgM transcripts had accumulated an average of 5.7 point mutations within the VH gene segment. gamma transcripts corresponding to the same VH gene families were isolated from subsets Bm3, Bm4, and Bm5, and had accumulated an average of 9.5 somatic mutations. We conclude that the molecular events underlying the process of somatic mutation takes place during the transition from IgD+, CD23+ B cells (Bm2) to the IgD-, CD23-, germinal center centroblast (Bm3). Furthermore, the analysis of Ig variable region transcripts from the different subpopulations confirms that the pathway of B cell differentiation from virgin B cell throughout the germinal center up to the memory compartment can be traced with phenotypic markers. The availability of these subpopulations should permit the identification of the functional molecules relevant to each stage of B cell differentiation.


Fabrication of Biomimetic Bone Tissue Using Mesenchymal Stem Cell-Derived Three-Dimensional Constructs Incorporating Endothelial Cells.
The development of technologies to promote vascularization of engineered tissue would drive major developments in tissue engineering and regenerative medicine. Recently, we succeeded in fabricating three-dimensional (3D) cell constructs composed of mesenchymal stem cells (MSCs). However, the majority of cells within the constructs underwent necrosis due to a lack of nutrients and oxygen. We hypothesized that incorporation of vascular endothelial cells would improve the cell survival rate and aid in the fabrication of biomimetic bone tissues in vitro. The purpose of this study was to assess the impact of endothelial cells combined with the MSC constructs (MSC/HUVEC constructs) during short- and long-term culture. When human umbilical vein endothelial cells (HUVECs) were incorporated into the cell constructs, cell viability and growth factor production were increased after 7 days. Furthermore, HUVECs were observed to proliferate and self-organize into reticulate porous structures by interacting with the MSCs. After long-term culture, MSC/HUVEC constructs formed abundant mineralized matrices compared with those composed of MSCs alone. Transmission electron microscopy and qualitative analysis revealed that the mineralized matrices comprised porous cancellous bone-like tissues. These results demonstrate that highly biomimetic bone tissue can be fabricated in vitro by 3D MSC constructs incorporated with HUVECs.


Improved Method for Estimating Reaction Rates During Push-Pull Tests.
The breakthrough curve obtained from a single-well push-pull test can be adjusted to account for dilution of the injection fluid in the aquifer fluid. The dilution-adjusted breakthrough curve can be analyzed to estimate the reaction rate of a solute. The conventional dilution-adjusted method assumes that the ratios of the concentrations of the nonreactive and reactive solutes in the injection fluid vs. the aquifer fluid are equal. If this assumption is invalid, the conventional method will generate inaccurate breakthrough curves and may lead to erroneous conclusions regarding the reactivity of a solute. In this study, a new method that generates a dilution-adjusted breakthrough curve was theoretically developed to account for any possible combination of nonreactive and reactive solute concentrations in the injection and aquifer fluids. The newly developed method was applied to a field-based data set and was shown to generate more accurate dilution-adjusted breakthrough curves. The improved dilution-adjusted method presented here is simple, makes no assumptions regarding the concentrations of the nonreactive and reactive solutes in the injection and aquifer fluids, and easily allows for estimating reaction rates during push-pull tests.


Diagnosis of pulmonary lymphangioleiomyomatosis by HMB45 in surgically treated spontaneous pneumothorax.
Pulmonary lymphangioleiomyomatosis (PLAM) is a rare disease with poor prognosis, characterized by an abnormal proliferation of smooth muscle. The patients are females and recurrent pneumothorax is a frequent complication. HMB45 is a monoclonal antibody with specific immunoreactivity for malignant melanoma. Recently, it was reported that some of the smooth muscle cells in PLAM had reactivity for HMB45. The aim of this study was to assess the sensitivity and specificity of HMB45 for the diagnosis of PLAM in cystic pulmonary diseases that cause recurrent pneumothorax. We compared immunoreactivity of the specimens obtained by open lung biopsy at surgical resection of bullae in 72 patients. The specimens of five females with PLAM, one female with suspected PLAM, 49 patients with primary spontaneous pneumothorax (19 females and 30 males), four with pulmonary eosinophilic granuloma (2 females and 2 males), seven with pulmonary emphysema (7 males), and six with idiopathic pulmonary fibrosis with apical bullous change (2 females and 4 males) were stained with HMB45 and anti-smooth muscle actin. All PLAM cases had HMB45 positive cells, which also stained with anti-smooth muscle actin. The biopsy specimens of a PLAM suspected case also stained with HMB45. None of the specimens from other diseases reacted with HMB45. HMB45 appears to provide a highly specific and highly sensitive diagnosis for PLAM in females. It may also be useful in patients with subtle smooth muscle proliferation. where the diagnosis of PLAM is difficult to confirm by conventional histological examination.


Cancer survival in five continents: a worldwide population-based study (CONCORD).
Cancer survival varies widely between countries. The CONCORD study provides survival estimates for 1.9 million adults (aged 15-99 years) diagnosed with a first, primary, invasive cancer of the breast (women), colon, rectum, or prostate during 1990-94 and followed up to 1999, by use of individual tumour records from 101 population-based cancer registries in 31 countries on five continents. This is, to our knowledge, the first worldwide analysis of cancer survival, with standard quality-control procedures and identical analytic methods for all datasets. To compensate for wide international differences in general population (background) mortality by age, sex, country, region, calendar period, and (in the USA) ethnic origin, we estimated relative survival, the ratio of survival noted in the patients with cancer, and the survival that would have been expected had they been subject only to the background mortality rates. 2800 life tables were constructed. Survival estimates were also adjusted for differences in the age structure of populations of patients with cancer. Global variation in cancer survival was very wide. 5-year relative survival for breast, colorectal, and prostate cancer was generally higher in North America, Australia, Japan, and northern, western, and southern Europe, and lower in Algeria, Brazil, and eastern Europe. CONCORD has provided the first opportunity to estimate cancer survival in 11 states in USA covered by the National Program of Cancer Registries (NPCR), and the study covers 42% of the US population, four-fold more than previously available. Cancer survival in black men and women was systematically and substantially lower than in white men and women in all 16 states and six metropolitan areas included. Relative survival for all ethnicities combined was 2-4% lower in states covered by NPCR than in areas covered by the Surveillance Epidemiology and End Results (SEER) Program. Age-standardised relative survival by use of the appropriate race-specific and state-specific life tables was up to 2% lower for breast cancer and up to 5% lower for prostate cancer than with the census-derived national life tables used by the SEER Program. These differences in population coverage and analytical method have both contributed to the survival deficit noted between Europe and the USA, from which only SEER data have been available until now. Until now, direct comparisons of cancer survival between high-income and low-income countries have not generally been available. The information provided here might therefore be a useful stimulus for change. The findings should eventually facilitate joint assessment of international trends in incidence, survival, and mortality as indicators of cancer control.


[A case of cerebellar degeneration with schizophrenia-like psychosis, severe iron deficiency, hypoceruloplasminemia and abnormal electroretinography: a new syndrome?].
A 33-year-old male patient began to develop schizophrenia-like symptoms and slowly progressive cerebellar ataxia. He was 170 cm tall and he had mild frontal baldness. Psychiatrically he was aconative, only willing to do nothing all day long after admission. He had neither hallucinations nor delusions, and his mental acuity was normal. Neurological examination revealed positive cerebellar signs including clumsiness in F-N-T and K-H-T and dysdiadochokinesis. He could neither stand up nor walk because of ataxia. The brain MRI showed severe cerebellar atrophy with normal basal ganglia. His EEG and the value of NCV were within normal range, whereas electroretinography showed a notable abnormality, pointing to the extremely small b-wave, resulting in a negative shape of the ERG. Although he was eating sufficiently, the level of serum iron and ferritin remained constantly low. The serum copper level was within normal range, whereas the serum ceruloplasmin level was mildly decreased. A hepatic biopsy indicated no accumulation of copper or iron. This case suggests the importance of the investigation of the serum iron and ceruloplasmin levels in patients who have cerebellar degeneration with psychosis.


Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial.
Emergency medical services (EMS) personnel have already made substantial contributions to improving care for patients with time-dependent illnesses, such as trauma and myocardial infarction. Patients with sepsis could also benefit from timely prehospital care. After training EMS personnel in recognising sepsis, we did a randomised controlled open-label trial in ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands. We compared the effects of early administration of antibiotics in the ambulance with usual care. Eligible patients were randomly assigned (1:1) using block-randomisation with blocks of size 4 to the intervention (open-label intravenous ceftriaxone 2000 mg in addition to usual care) or usual care (fluid resuscitation and supplementary oxygen). Randomisation was stratified per region. The primary outcome was all-cause mortality at 28 days and analysis was by intention to treat. To assess the effect of training, we determined the average time to antibiotics (TTA) in the emergency department and recognition of sepsis by EMS personnel before and after training. The trial is registered at ClinicalTrials.gov, number NCT01988428. 2698 patients were enrolled between June 30, 2014, and June 26, 2016. 2672 patients were included in the intention-to-treat analysis: 1535 in the intervention group and 1137 in the usual care group. The intervention group received antibiotics a median of 26 min (IQR 19-34) before arriving at the emergency department. In the usual care group, median TTA after arriving at the emergency department was 70 min (IQR 36-128), compared with 93 min (IQR 39-140) before EMS personnel training (p=0·142). At day 28, 120 (8%) patients had died in the intervention group and 93 (8%) had died in the usual care group (relative risk 0·95, 95% CI 0·74-1·24). 102 (7%) patients in the intervention group and 119 (10%) in the usual care group were re-admitted to hospital within 28 days (p=0·0004). Seven mild allergic reactions occurred, none of which could be attributed to ceftriaxone. In patients with varying severity of sepsis, EMS personnel training improved early recognition and care in the whole acute care chain. However, giving antibiotics in the ambulance did not lead to improved survival, regardless of illness severity. The NutsOhra Foundation, Netherlands Society of Internal Medicine (NIV).


Phase diagram of Hertzian spheres.
We report the phase diagram of interpenetrating Hertzian spheres. The Hertz potential is purely repulsive, bounded at zero separation, and decreases monotonically as a power law with exponent 5/2, vanishing at the overlapping threshold. This simple functional describes the elastic interaction of weakly deformable bodies and, therefore, it is a reliable physical model of soft macromolecules, like star polymers and globular micelles. Using thermodynamic integration and extensive Monte Carlo simulations, we computed accurate free energies of the fluid phase and a large number of crystal structures. For this, we defined a general primitive unit cell that allows for the simulation of any lattice. We found multiple re-entrant melting and first-order transitions between crystals with cubic, trigonal, tetragonal, and hexagonal symmetries.


Comparison of two tDCS protocols on pain and EEG alpha-2 oscillations in women with fibromyalgia.
Transcranial Direct Current Stimulation (tDCS) has been used as an alternative treatment for pain reduction in fibromyalgia. In this study, in addition to behavioral measures, we analyzed oscillations in alpha 2 frequency band in the frontal, occipital, and parietal regions, in response to the application of two neuromodulation protocols in fibromyalgia. The study was a randomized, double-blind, placebo-controlled clinical trial with 31 women diagnosed with fibromyalgia. The participants were allocated to three groups with the anodic stimulation applied on the left motor cortex: Group 1, for five consecutive days; Group 2, for 10 consecutive days; and Group 3, sham stimulation for five consecutive days. Statistical analysis showed a reduction in pain intensity after treatment for groups in general [F (1.28) = 8.02; p = 0.008; η2 = 0.223], in addition to a reduction in alpha 2 in the frontal (p = 0.039; d = 0.384) and parietal (p = 0.021; d = 0.520) regions after the treatment on five consecutive days. We conclude that neuromodulation protocols produced similar effects on pain reduction, but differed with respect to the changes in the alpha 2 frequency band in the frontal and parietal regions.


Effect of orientation in translocation of polymers through nanopores.
The motion of polymers with inhomogeneous structure through nanopores is discussed theoretically. Specifically, we consider the translocation dynamics of polymers consisting of double-stranded and single-stranded blocks. Since only the single-stranded chain can go through the nanopore the double-stranded segment has to unzip before the translocation. Utilizing a simple analytical model, translocation times are calculated explicitly for different polymer orientations, i.e., when the single-stranded block enters the pore first and when the double-stranded segment is a leading one. The dependence of the translocation dynamics on external fields, energy of interaction in the double-stranded segment, size of the polymer, and the fraction of double-stranded monomers is analyzed. It is found that the order of entrance into the pore has a significant effect on the translocation dynamics. The theoretical results are discussed using free-energy landscape arguments.


Polymorphisms in the tumor necrosis factor alpha (TNF-alpha) gene correlate with murine resistance to development of toxoplasmic encephalitis and with levels of TNF-alpha mRNA in infected brain tissue.
Murine resistance to development of toxoplasmic encephalitis (TE) has recently been mapped to the D region of the major histocompatibility complex (H-2). Since the gene for tumor necrosis factor alpha (TNF-alpha) is located 5' of the D region and TNF-alpha has been implicated as playing a role in neurological diseases, we were interested in determining the relationship of TNF-alpha production to TE resistance. We have demonstrated that resistance to TE in inbred mice can be correlated with specific restriction fragment length polymorphisms and microsatellite variants in the TNF-alpha gene. Mice that are susceptible to TE express elevated levels of TNF-alpha mRNA in brain tissue 6 wk after infection with the ME49 strain of Toxoplasma gondii. Resistant mice and all mice that are uninfected show no detectable TNF-alpha mRNA expression in brain tissue. Differences in the TNF-alpha gene between susceptible and resistant mice have been localized to the first intron, the promoter, and the 3' end of the TNF-alpha gene. These data implicate differences in regulation of TNF-alpha production in brain tissue as contributing to differences in susceptibility to development of TE.


The critical needs and challenges for genetic architecture studies in Africa.
Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.


Research Advancements in Porcine Derived Mesenchymal Stem Cells.
In the present era of stem cell biology, various animals such as Mouse, Bovine, Rabbit and Porcine have been tested for the efficiency of their mesenchymal stem cells (MSCs before their actual use for stem cell based application in humans. Among them pigs have many similarities to humans in the form of organ size, physiology and their functioning, therefore they have been considered as a valuable model system for in vitro studies and preclinical assessments. Easy assessability, few ethical issues, successful MSC isolation from different origins like bone marrow, skin, umbilical cord blood, Wharton's jelly, endometrium, amniotic fluid and peripheral blood make porcine a good model for stem cell therapy. Porcine derived MSCs (pMSCs have shown greater in vitro differentiation and transdifferention potential towards mesenchymal lineages and specialized lineages such as cardiomyocytes, neurons, hepatocytes and pancreatic beta cells. Immunomodulatory and low immunogenic profiles as shown by autologous and heterologous MSCs proves them safe and appropriate models for xenotransplantation purposes. Furthermore, tissue engineered stem cell constructs can be of immense importance in relation to various osteochondral defects which are difficult to treat otherwise. Using pMSCs successful treatment of various disorders like Parkinson's disease, cardiac ischemia, hepatic failure, has been reported by many studies. Here, in this review we highlight current research findings in the area of porcine mesenchymal stem cells dealing with their isolation methods, differentiation ability, transplantation applications and their therapeutic potential towards various diseases.