Pneumothorax as an adverse drug event: an exploratory aggregate analysis of the US FDA AERS database including a confounding by indication analysis inspired by Cornfield's condition.
Pneumothorax is either primary or secondary. Secondary pneumothorax is usually due to trauma, including various non-pharmacologic iatrogenic triggers. Although not normally thought of as an adverse drug event (ADE) secondary pneumothorax is associated with numerous drugs, though it is often difficult to determine whether this association is causal in nature, or reflects an epiphenomenon of efficacy or inefficacy, or confounding by indication (CBI). Herein we explore this association in a large health authority drug safety surveillance database. A quantitative pharmacovigilance (PhV) methodology known as disproportionality analysis was applied to the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (AERS) database to explore the quantitative reporting dependencies between drugs and the adverse event pneumothorax as well the corresponding reporting dependencies between drugs and reported indications that may be risk factors for pneumothorax themselves in order to explore the potential contribution of CBI. We found 1. Multiple drugs are associated with pneumothorax; 2. Surfactants and oncology drugs account for most statistically distinctive associations with pneumothorax; 3. Pulmonary surfactants, pentamidine and nitric oxide have the largest statistical reporting associations 4. CBI may play a prominent role in reports of drug-associated pneumothorax. Disproportionality analysis (DA) can provide insights into the spontaneous reporting dependencies between drugs and pneumothorax. CBI assessment based on DA and Cornfield's inequality presents an additional novel option for the initial exploration of potential safety signals in PhV.


Genome Sequence and Analysis of Peptoclostridium difficile Strain ZJCDC-S82.
Peptoclostridium difficile (Clostridium difficile) is the major pathogen associated with infectious diarrhea in humans. Concomitant with the increased incidence of C. difficile infection worldwide, there is an increasing concern regarding this infection type. This study reports a draft assembly and detailed sequence analysis of C. difficile strain ZJCDC-S82. The de novo assembled genome was 4.19 Mb in size, which includes 4,013 protein-coding genes, 41 rRNA genes, and 84 tRNA genes. Along with the nuclear genome, we also assembled sequencing information for a single plasmid consisting of 11,930 nucleotides. Comparative genomic analysis of C. difficile ZJCDC-S82 and two other previously published strains, such as M120 and CD630, showed extensive similarity. Phylogenetic analysis revealed that genetic diversity among C. difficile strains was not influenced by geographic location. Evolutionary analysis suggested that four genes encoding surface proteins exhibited positive selection in C. difficile ZJCDC-S82. Codon usage analysis indicated that C. difficile ZJCDC-S82 had high codon usage bias toward A/U-ended codons. Furthermore, codon usage patterns in C. difficile ZJCDC-S82 were predominantly affected by mutation pressure. Our results provide detailed information pertaining to the C. difficile genome associated with a strain from mainland China. This analysis will facilitate the understanding of genomic diversity and evolution of C. difficile strains in this region.


Unraveling the Molecular Mechanism of pH-Induced Misfolding and Oligomerization of the Prion Protein.
The misfolding of the prion protein (PrP) to aggregated forms is linked to several neurodegenerative diseases. Misfolded oligomeric forms of PrP are associated with neurotoxicity and/or infectivity, but the molecular mechanism by which they form is still poorly understood. A reduction in pH is known to be a key factor that triggers misfolded oligomer formation by PrP, but the residues whose protonation is linked with misfolding remain unidentified. The structural consequences of the protonation of these residues also remain to be determined. In the current study, amino acid residues whose protonation is critical for PrP misfolding and oligomerization have been identified using site-directed mutagenesis and misfolding/oligomerization assays. It is shown that the protonation of either H186 or D201, which mimics the effects of pathogenic mutations (H186R and D201N) at both residue sites, is critically linked to the stability, misfolding and oligomerization of PrP. Hydrogen-deuterium exchange studies coupled with mass spectrometry show that the protonation of either H186 or D201 leads to the same common structural change: increased structural dynamics in helix 1 and that in the loop between helix 1 and β-strand 2. It is shown that the protonation of either of these residues is sufficient for accelerating misfolded oligomer formation, most likely because the protonation of either residue causes the same structural perturbation. Hence, the increased structural dynamics in helix 1 and that in the loop between helix 1 and β-strand 2 appear to play an early critical role in acid-induced misfolding of PrP.


Differential gene expression in the pathogenic dermatophyte Arthroderma benhamiae in vitro versus during infection.
Although dermatophytes are the most common agents of superficial mycoses in humans and animals, the molecular basis of the pathogenicity of these fungi is largely unknown. In vitro digestion of keratin by dermatophytes is associated with the secretion of multiple proteases, which are assumed to be responsible for their particular specialization to colonize and degrade keratinized host structures during infection. To investigate the role of individual secreted proteases in dermatophytosis, a guinea pig infection model was established for the zoophilic dermatophyte Arthroderma benhamiae, which causes highly inflammatory cutaneous infections in humans and rodents. By use of a cDNA microarray covering approximately 20-25 % of the A. benhamiae genome and containing sequences of at least 23 protease genes, we revealed a distinct in vivo protease gene expression profile in the fungal cells, which was surprisingly different from the pattern elicited during in vitro growth on keratin. Instead of the major in vitro -expressed proteases, others were activated specifically during infection. These enzymes are therefore suggested to fulfil important functions that are not exclusively associated with the degradation of keratin. Most notably, the gene encoding the serine protease subtilisin 6, which is a known major allergen in the related dermatophyte Trichophyton rubrum and putatively linked to host inflammation, was found to be the most strongly upregulated gene during infection. In addition, our approach identified other candidate pathogenicity-related factors in A. benhamiae, such as genes encoding key enzymes of the glyoxylate cycle and an opsin-related protein. Our work provides what we believe to be the first broad-scale gene expression profile in human pathogenic dermatophytes during infection, and points to putative virulence-associated mechanisms that make these micro-organisms the most successful aetiological agents of superficial mycoses.


Implantable Cardiac Alert System for Early Recognition of ST-Segment Elevation Myocardial Infarction.
Symptoms remain a poor prompt for acute coronary syndromes (ACS). Timely restoration of perfusion in ST-segment elevation myocardial infarction is associated with improved left ventricular function and survival. This report details the results of ALERTS (AngelMed for Early Recognition and Treatment of STEMI), a multicenter, randomized trial of an implantable cardiac monitor that alerts patients with rapidly progressive ST-segment deviation. High-risk ACS subjects (N = 907) were randomized to a control (alarms deactivated) or treatment group for 6 months, after which alarms were activated in all subjects. The primary safety endpoint was absence of system-related complications (>90%). The composite primary efficacy endpoint was cardiac/unexplained death, new Q-wave myocardial infarction, or detection to presentation time >2 h. Safety was met with 96.7% freedom from system-related complications (n = 30). The efficacy endpoint for a confirmed occlusive event within 7 days was not significantly reduced in the treatment compared with control group (16 of 423 [3.8%] vs. 21 of 428 [4.9%], posterior probability = 0.786). Within a 90-day window, alarms significantly decreased detection to arrival time at a medical facility (51 min vs. 30.6 h; Pr [pt < pc] >0.999). In an expanded analysis using data after the randomized period, positive predictive value was higher (25.8% vs. 18.2%) and false positive rate significantly lower in the ALARMS ON group (0.164 vs. 0.678 false positives per patient-year; p < 0.001). The implantable cardiac system detects early ST-segment deviation and alerts patients of a potential occlusive event. Although the trial did not meet its pre-specified primary efficacy endpoint, results suggest that the device may be beneficial among high-risk subjects in potentially identifying asymptomatic events. (AngelMed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).


Changes in the balance between formal and informal care supply in England between 2001 and 2011: evidence from census data.
Informal care plays a crucial role in the social care system in England and is increasingly recognised as a cornerstone of future sustainability of the long-term care (LTC) system. This paper explores the variation in informal care provision over time, and in particular, whether the considerable reduction in publicly-funded formal LTC after 2008 had an impact on the provision of informal care. We used small area data from the 2001 and 2011 English censuses to measure the prevalence and intensity (i.e. the number of hours of informal care provided) of informal care in the population. We controlled for changes in age structure, health, deprivation, income, employment and education. The effects of the change in formal social care provision on informal care were analysed through instrumental variable models to account for the well-known endogeneity. We found that informal care provision had increased over the period, particularly among high-intensity carers (20+ hours per week). We also found that the reduction in publicly-funded formal care provision was associated with significant increases in high-intensity (20+ hours per week) informal care provision, suggesting a substitutive relationship between formal and informal care of that intensity in the English system.


Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins.
Stress or heat shock proteins (Hsps) Hsp90, Hsp70 and Hsp27 are chaperones that assist the proteins in their folding, stability, assembly into multi-protein complexes and transport across cellular membranes. The expression of some of them is highly induced in response to a wide variety of physiological and environmental insults. Hsps have a dual function depending on their intracellular or extracellular location. Intracellular Hsps have a protective function. They allow the cells to survive to lethal conditions. The cytoprotective functions of Hsps can largely explain by their anti-apoptotic properties. Hsp90, Hsp70 and Hsp27 can directly interact with different proteins of the tightly regulated programmed cell death machinery and thereby block the apoptotic process at distinct key points. In cancer cells, where the expression of Hsp27, Hsp70 and/or Hsp90 is frequently abnormally high, they participate in oncogenesis and in resistance to chemotherapy. Therefore, the inhibition of Hsps has become an interesting strategy in cancer therapy. In contrast to intracellular Hsps, extracellular located or membrane-bound Hsps mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. In cancer, most immunotherapeutical approaches based on extracellular Hsps exploit their carrier function for immunogenic peptides. This review will discuss this different and often paradoxical approaches in cancer therapy based on the dual role of Hsps, protective/tumorigenic versus immunogenic.


Fresnel and Fraunhofer diffraction of a Gaussian laser beam by fork-shaped gratings.
Expressions describing the vortex beams that are generated by the process of Fresnel diffraction of a Gaussian beam incident out of waist on fork-shaped gratings of arbitrary integer charge p, and vortex spots in the case of Fraunhofer diffraction by these gratings, are deduced. The common general transmission function of the gratings is defined and specialized for the cases of amplitude holograms, binary amplitude gratings, and their phase versions. Optical vortex beams, or carriers of phase singularity with charges mp and -mp, are the higher negative and positive diffraction-order beams. The radial part of their wave amplitudes is described by the product of the mpth-order Gauss-doughnut function and a Kummer function, or by the first-order Gauss-doughnut function and the difference of two modified Bessel functions whose orders do not match the singularity charge value. The wave amplitude and the intensity distributions are discussed for the near and far fields in the focal plane of a convergent lens, as well as the specialization of the results when the grating charge p=0; i.e., the grating turns from forked into rectilinear. The analytical expressions for the vortex radii are also discussed.


Potassium and sodium ion complexes with a partial peptide of the selectivity filter in K+ channels studied by cold ion trap infrared spectroscopy: the effect of hydration.
Potassium channels allow K+ to rapidly diffuse, while the selectivity filter (SF) actively blocks Na+. The presence of water in the SF during ion translocation remains under debate due to the experimental and computational challenges in characterizing the interactions between water, ions, and the SF. Our bottom-up approach has been applied to a system composed of a partial peptide of the SF (Ac-tyrosine-NHMe) with a metal ion and a single water molecule to probe these interactions. The IR photodissociation spectra of M+Ac-tyrosine-NHMe(H2O) (M = Na, K) combined with quantum chemical calculations revealed that the water molecule binding sites are ion-dependent. In addition, the ion-peptide distances are elongated significantly for the K+ complex in comparison to the Na+ complex by the addition of a single water molecule. This striking structural difference with the water molecule is discussed in relation to ion selectivity and translocation within the K+ channel.


Dentate gyrus formation requires Emx2.
Emx 1 and 2 are the murine homologues of the Drosophila empty spiracles gene and based on their expression pattern may be involved in the regional specification of the mammalian forebrain. During early embryogenesis, Emx2 is expressed in the presumptive cerebral cortex and olfactory bulbs and later, in the hippocampus proper and dentate gyrus. The latter are involved in memory processes. To understand the role of Emx2 in vivo, we have mutated the gene in mice. Homozygous embryos die postnatally because of severe urogenital alterations. These mice present cerebral hemispheres with a reduced size and exhibit specific morphological alterations in allocortical structures of the medial wall of the brain. The dentate gyrus is missing and the hippocampus proper is reduced. The medial limbic cortex is also severely shortened. The development of the dentate gyrus is affected at the onset of its formation with defects in the neuroepithelium from which it originates. These findings demonstrate that Emx2 is required for the development of several forebrain structures.


Pencil beam scanning proton therapy for pediatric intracranial ependymoma.
To assess the clinical outcome and late side effect profile of pencil beam scanning proton therapy (PT) delivered to children with intracranial ependymoma. Between July-2004 and March-2013, 50 patients with intracranial ependymoma (n = 46, grade 3) received involved-field PT at Paul Scherrer Institute (PSI). Median age at time of PT was 2.6 years (range 1.1-15.2). Thirty-six patients had infratentorial and 14 supratentorial ependymomas. Seventeen patients presented with macroscopic residual disease after subtotal resection before starting PT (8 with ≤1.5 cc and 9 with >1.5 cc residual tumor respectively). Forty-three (86 %) patients received post-operative chemotherapy before PT according to protocols; 44 (88 %) patients younger than 5 years required general anesthesia. Median prescribed dose was 59.4 Gy (RBE) (range 54-60) delivered in 1.8-2 Gy (RBE) per fraction. Late toxicity was assessed according to CTCAE v4.0. With a mean follow-up time of 43.4 months (range 8.5-113.7) seven patients experienced local failure (6 with infratentorial tumors and 1 with supratentorial tumor); four of the local failures were in patients with residual disease ≥1.5 cc at the time of PT and 3 without residual macroscopic disease. Five patients died from tumor progression. Actuarial 5-year Local Control rates were 78 ± 7.5 % and 5-year OS rates were 84 ± 6.8 %. Three patients developed grade ≥3 toxicity: 2 developed unilateral deafness (infratentorial tumors infiltrating into the internal acoustic canal), one patient developed a fatal brainstem necrosis. Repeated general anesthesia in children younger than 5 years was delivered without complications. Our data indicate the safety and the effectiveness of PT for pediatric ependymomas. Local control and survival rates are encouraging considering the high grade histology in 92 % of the patients and the number of patients with residual tumor ≥1.5 cc. The rates of late effects compare favorably with published photon-treated cohorts.


XPS experimental and DFT investigations on solid solutions of Mo1-xRexS2 (0 < x < 0.20).
The synthesis, characterization, experimental X-ray photoelectron spectra (XPS) and density-functional theory (DFT) investigations on solid solutions of Mo1-xRexS2 (x = 0.05, 0.10, 0.15 and 0.20) are reported herein. It is shown that even at a low concentration of dopant Re atoms, clustering occurs. At an Re concentration of 5% the formation of dimer-like impregnations is observed. An increase in the dopant concentration leads to an increase in the amount of clustered rhenium atoms and to the formation of rhombic clusters. The absence of magnetism within the studied Mo1-xRexS2 solid solutions allowed us to suggest a mechanism for the distribution of rhenium inside molybdenum disulphide through the initial formation of rhenium disulphide and its subsequent spreading.


Current Approaches in Implementing Citizen Science in the Classroom.
Citizen science involves a partnership between inexperienced volunteers and trained scientists engaging in research. In addition to its obvious benefit of accelerating data collection, citizen science has an unexplored role in the classroom, from K-12 schools to higher education. With recent studies showing a weakening in scientific competency of American students, incorporating citizen science initiatives in the curriculum provides a means to address deficiencies in a fragmented educational system. The integration of traditional and innovative pedagogical methods to reform our educational system is therefore imperative in order to provide practical experiences in scientific inquiry, critical thinking, and problem solving for school-age individuals. Citizen science can be used to emphasize the recognition and use of systematic approaches to solve problems affecting the community.


Utilization of an intra-oral diamagnetic passive shim in functional MRI of the inferior frontal cortex.
Due to the presence of gross magnetic susceptibility artifacts, functional MRI (fMRI) has proved problematic in studies of the human inferior frontal cortex (IFC). There is a strong desire, therefore, to employ techniques that mitigate susceptibility artifacts in the IFC while preserving the imaging parameters of an fMRI study. It has been shown that the use of a single, strongly diamagnetic, intra-oral passive shim significantly improves the homogeneity of the static magnetic field (B(0)) and, as a result, alleviates the susceptibility artifacts within the IFC. In this study, practical issues regarding the use of an intra-oral passive shim are examined. We investigated B(0) instabilities within the IFC resulting from subject head motion in order to calculate the effects of an intra-oral passive shim on the temporal variance of an EPI time series. These studies show that the addition of an intra-oral passive shim improves both B(0) homogeneity and signal stability, and increases sensitivity to functional activation.


Sleep disturbances during pregnancy and adverse maternal and fetal outcomes: A systematic review and meta-analysis.
Sleep disturbances are highly prevalent in pregnancy and are frequently overlooked as a potential cause of significant morbidity. The association between sleep disturbances and pregnancy outcomes remains largely controversial and needs to be clarified to guide management. To evaluate the association between sleep disturbances and maternal complications and adverse fetal outcomes, we performed a systematic search of PubMed, Embase and Web of Science for English-language articles published from inception to March 6, 2020, including observational studies of pregnant women with and without sleep disturbances assessing the risk of obstetric complications in the antenatal, intrapartum or postnatal period, and neonatal complications. Data extraction was completed independently by two reviewers. We utilized the Newcastle-Ottawa Scales to assess the methodological quality of included studies and random-effect models to pool the associations. A total of 120 studies with 58,123,250 pregnant women were included. Sleep disturbances were assessed, including poor sleep quality, extreme sleep duration, insomnia symptoms, restless legs syndrome, subjective sleep-disordered breathing and diagnosed obstructive sleep apnea. Significant associations were found between sleep disturbances in pregnancy and a variety of maternal complications and adverse fetal outcomes. Overall sleep disturbances were significantly associated with pre-eclampsia (odds ratio = 2.80, 95% confidence interval: 2.38-3.30), gestational hypertension (1.74, 1.54-1.97), gestational diabetes mellitus (1.59, 1.45-1.76), cesarean section (1.47, 1.31-1.64), preterm birth (1.38, 1.26-1.51), large for gestational age (1.40, 1.11-1.77), and stillbirth (1.25, 1.08-1.45), but not small for gestational age (1.03, 0.92-1.16), or low birth weight (1.27, 0.98-1.64). Sleep disturbances were related to higher morbidities in pregnant women who are 30 y or older and overweight before pregnancy. The findings indicate that sleep disturbances, which are easily ignored and treatable for both pregnant women and clinical services, deserve more attention from health care providers during prenatal counseling and health care services.


Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings.
To evaluate a new 2-step technique for obtaining adequate but short-term parenchymal hypertrophy in oncologic patients requiring extended right hepatic resection with limited functional reserve. Patients presenting with primary or metastatic liver tumors often face the dilemma that the remaining liver tissue may not be sufficient. Preoperative portal vein embolization has thus far been established as the standard procedure for achieving resectability. Two-staged hepatectomy was performed in patients who preoperatively appeared to be marginally resectable but had a tumor-free left lateral lobe. Marginal respectability was defined as a left lateral lobe to body weight ratio of less than 0.5. In the first step, surgical exploration, right portal vein ligation (PVL), and in situ splitting (ISS) of the liver parenchyma along the falciform ligament were performed. Computed tomographic volumetry was performed before ISS and before completion surgery. The study included 25 patients with primary liver tumors (hepatocellular carcinoma: n = 3, intrahepatic cholangiocarcinoma: n = 2, extrahepatic cholangiocarcinoma: n = 2, malignant epithelioid hemangioendothelioma: n = 1, gallbladder cancer: n = 1 or metastatic disease [colorectal liver metastasis]: n = 14, ovarian cancer: n = 1, gastric cancer: n = 1). Preoperative CT volumetry of the left lateral lobe showed 310 mL in median (range = 197-444 mL). After a median waiting period of 9 days (range = 5-28 days), the volume of the left lateral lobe had increased to 536 mL (range = 273-881 mL), representing a median volume increase of 74% (range = 21%-192%) (P < 0.001). The median left lateral liver lobe to body weight ratio was increased from 0.38% (range = 0.25%-0.49%) to 0.61% (range = 0.35-0.95). Ten of 25 patients (40%) required biliary reconstruction with hepaticojejunostomy. Rapid perioperative recovery was reflected by normalization of International normalized ratio (INR) (80% of patients), creatinine (84% of patients), nearly normal bilirubin (56% of patients), and albumin (64% of patients) values by day 14 after completion surgery. Perioperative morbidity was classified according to the Dindo-Clavien classification of surgical complications: grade I (12 events), grade II (13 events), grade III (14 events, III a: 6 events, III b: 8 events), grade IV (8 events, IV a: 3 events, IV b: 5 events), and grade V (3 events). Sixteen patients (68%) experienced perioperative complications. Follow-up was 180 days in median (range: 60-776 days) with an estimated overall survival of 86% at 6 months after resection. Two-step hepatic resection performing surgical exploration, PVL, and ISS results in a marked and rapid hypertrophy of functional liver tissue and enables curative resection of marginally resectable liver tumors or metastases in patients that might otherwise be regarded as palliative.


Tuning oxide activity through modification of the crystal and electronic structure: from strain to potential polymorphs.
Discovering new materials with tailored chemical properties is vital for advancing key technologies in catalysis and energy conversion. One strategy is the modification of a material's crystal structure, and new methods allow for the synthesis and stabilization of potential materials in a range of crystal polymorph structures. We assess the potential reactivity of four metastable oxide polymorphs of MO2 (M = Ru, Rh, Pt, Ir) transition metal oxides. In spite of the similar local geometry and coordination between atoms in the metastable polymorphic and stable rutile structure, we find that polymorph reactivities cannot be explained by strain alone and offer tunable reactivity and increased stability. Atom-projected density of states reveals that the unique reactivity of polymorphs are caused by a redistribution of energy levels of the t2g-states. This structure-activity relationship is induced by slight distortions to the M-O bonds in polymorphic structures and is unattainable by strain. We predict columbite IrO2 to be more active than rutile IrO2 for oxygen evolution.


The potential of cell sheet technique on the development of hepatocellular carcinoma in rat models.
Hepatocellular carcinoma (HCC) is considered the 3rd leading cause of death by cancer worldwide with the majority of patients were diagnosed in the late stages. Currently, there is no effective therapy. The selection of an animal model that mimics human cancer is essential for the identification of prognostic/predictive markers, candidate genes underlying cancer induction and the examination of factors that may influence the response of cancers to therapeutic agents and regimens. In this study, we developed a HCC nude rat models using cell sheet and examined the effect of human stromal cells (SCs) on the development of the HCC model and on different liver parameters such as albumin and urea. Transplanted cell sheet for HCC rat models was fabricated using thermo-responsive culture dishes. The effect of human umbilical cord mesenchymal stromal cells (UC-MSCs) and human bone marrow mesenchymal stromal cells (BM-MSCs) on the developed tumour was tested. Furthermore, development of tumour and detection of the liver parameter was studied. Additionally, angiogenesis assay was performed using Matrigel. HepG2 cells requires five days to form a complete cell sheet while HepG2 co-cultured with UC-MSCs or BM-MSCs took only three days. The tumour developed within 4 weeks after transplantation of the HCC sheet on the liver of nude rats. Both UC-MSCs and BM-MSCs improved the secretion of liver parameters by increasing the secretion of albumin and urea. Comparatively, the UC-MSCs were more effective than BM-MSCs, but unlike BM-MSCs, UC-MSCs prevented liver tumour formation and the tube formation of HCC. Since this is a novel study to induce liver tumour in rats using hepatocellular carcinoma sheet and stromal cells, the data obtained suggest that cell sheet is a fast and easy technique to develop HCC models as well as UC-MSCs have therapeutic potential for liver diseases. Additionally, the data procured indicates that stromal cells enhanced the fabrication of HepG2 cell sheets. This provides the foundation for future research using stromal cells in preclinical and clinical investigations.


Combining epidemiological and genetic networks signifies the importance of early treatment in HIV-1 transmission.
Inferring disease transmission networks is important in epidemiology in order to understand and prevent the spread of infectious diseases. Reconstruction of the infection transmission networks requires insight into viral genome data as well as social interactions. For the HIV-1 epidemic, current research either uses genetic information of patients' virus to infer the past infection events or uses statistics of sexual interactions to model the network structure of viral spreading. Methods for a reliable reconstruction of HIV-1 transmission dynamics, taking into account both molecular and societal data are still lacking. The aim of this study is to combine information from both genetic and epidemiological scales to characterize and analyse a transmission network of the HIV-1 epidemic in central Italy.We introduce a novel filter-reduction method to build a network of HIV infected patients based on their social and treatment information. The network is then combined with a genetic network, to infer a hypothetical infection transmission network. We apply this method to a cohort study of HIV-1 infected patients in central Italy and find that patients who are highly connected in the network have longer untreated infection periods. We also find that the network structures for homosexual males and heterosexual populations are heterogeneous, consisting of a majority of 'peripheral nodes' that have only a few sexual interactions and a minority of 'hub nodes' that have many sexual interactions. Inferring HIV-1 transmission networks using this novel combined approach reveals remarkable correlations between high out-degree individuals and longer untreated infection periods. These findings signify the importance of early treatment and support the potential benefit of wide population screening, management of early diagnoses and anticipated antiretroviral treatment to prevent viral transmission and spread. The approach presented here for reconstructing HIV-1 transmission networks can have important repercussions in the design of intervention strategies for disease control.


The association of psychosocial factors with the resolution of abdominal pain.
Although abdominal pain is a common presenting complaint in the family practice setting, its natural history and psychosocial associations have not been clearly described. A prospective study was conducted of 92 patients who presented with abdominal pain to the University of Iowa and Cedar Rapids Family Practice Centers between September 1982 and March 1983. Patients were given a self-administered questionnaire for measuring stress, family functioning, and psychological symptoms. All patients were followed for at least six weeks. Resolution of the pain was documented by chart audit, telephone, or mail follow-up. Two-thirds of the patients experienced resolution of their pain within six to eight weeks. The scores on the Hopkins Psychological Symptom Checklist, Family APGAR, and the Daily Hassles Stress Scale did not predict resolution of pain. Age, sex, education, occupation, and final diagnosis also did not predict resolution of pain. Marital status was not associated with pain resolution, though widowed and separated individuals more often had pain at follow-up.


Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage.
Frizzled receptors are the mediators of the wnt canonical and non-canonical pathways, which play fundamental roles in cell differentiation and organism development. A large body of work indicates that dysregulation of wnt signalling is a feature of oncogenic transformation, but most of the studies published so far focus on the assessment of the consequences of aberrations of the canonical pathway in human cancer. In this review, we discuss the emerging role of the wnt non-canonical pathway regulated by frizzled receptor 6 (Fzd6) in the pathogenesis of different types of human malignancies. The function played by Fzd6 in the physiology of normal and cancer cells has been highlighted in the view that an increased knowledge of the signalling pathways upstream and downstream of this receptor could ultimately result in the identification of new targets for cancer therapy.


Women's views on chemoprevention of breast cancer: qualitative study.
To determine, in a family practice setting, women's views on incentives for and barriers to taking chemopreventive therapy for breast cancer. Descriptive, qualitative study using in-depth semistructured interviews. Women's College Family Practice Health Centre, an academic centre in Toronto, Ont. THREE GROUPS OF WOMEN WERE RECRUITED: women who might in future be candidates for chemoprevention, women who were then candidates for chemoprevention, and then-current participants in the Study of Tamoxifen and Raloxifene (STAR) chemoprevention trial. Women were asked about their views on taking a pill to prevent breast cancer, their hopes and expectations regarding chemoprevention, incentives for and barriers to accepting chemopreventive therapy, and their preferred sources of information. Visual analogue scales were used to estimate perceived risk of breast cancer and personal interest in chemoprevention. Participants' Gail scores, perceptions of risk of breast cancer, perceptions of likelihood of accepting chemopreventive treatment, attitudes, views, and experiences were recorded. The 27 women interviewed (median age 61 years, range 38 to 77) had a mean Gail score of 3.3 (indicating a 3.3% estimated risk of breast cancer within the next 5 years), range 1.4 to 6.8. Women were very interested in chemoprevention (62% to 67% likelihood of their taking it in the next 5 years). Perceived risk of breast cancer was not correlated with actual risk or with likelihood of taking chemopreventive therapy. To accept chemoprevention, women needed to know it would lead to an acceptable decrease in risk of breast cancer and needed more information about the medication. Incentives for acceptance included clear evidence of efficacy, prevention of cancer, altruism (contributing to an important area of research), secondary gain, and the feeling of being proactive and in control. Barriers included fear of side effects, lack of information, denial, aversion to medication, the term "chemoprevention," and the effect of the "HRT fiasco." Women's most trusted information source was their family physicians. Women overestimated their risk of breast cancer. Women were interested in chemoprevention, but required more information, preferably from their family physicians. Our data suggest that at least 4 conditions must be met for women to accept chemopreventive therapy. They must believe in its effectiveness, be proactive about their health care, believe side effects will be tolerable, and be able to overcome the fear of ingesting a pill. To make the therapy more acceptable, the term "chemoprevention" should be discontinued.


Developmental impacts of the COVID-19 pandemic on young children: a conceptual model for research with integrated administrative data systems.
The COVID-19 pandemic made its mark on the entire world, upending economies, shifting work and education, and exposing deeply rooted inequities. A particularly vulnerable, yet less studied population includes our youngest children, ages zero to five, whose proximal and distal contexts have been exponentially affected with unknown impacts on health, education, and social-emotional well-being. Integrated administrative data systems could be important tools for understanding these impacts. This article has three aims to guide research on the impacts of COVID-19 for this critical population using integrated data systems (IDS). First, it presents a conceptual data model informed by developmental-ecological theory and epidemiological frameworks to study young children. This data model presents five developmental resilience pathways (i.e. early learning, safe and nurturing families, health, housing, and financial/employment) that include direct and indirect influencers related to COVID-19 impacts and the contexts and community supports that can affect outcomes. Second, the article outlines administrative datasets with relevant indicators that are commonly collected, could be integrated at the individual level, and include relevant linkages between children and families to facilitate research using the conceptual data model. Third, this paper provides specific considerations for research using the conceptual data model that acknowledge the highly-localised political response to COVID-19 in the US. It concludes with a call to action for the population data science community to use and expand IDS capacities to better understand the intermediate and long-term impacts of this pandemic on young children.


Improved fibre dispersion estimation using b-tensor encoding.
Measuring fibre dispersion in white matter with diffusion magnetic resonance imaging (MRI) is limited by an inherent degeneracy between fibre dispersion and microscopic diffusion anisotropy (i.e., the diffusion anisotropy expected for a single fibre orientation). This means that estimates of fibre dispersion rely on strong assumptions, such as constant microscopic anisotropy throughout the white matter or specific biophysical models. Here we present a simple approach for resolving this degeneracy using measurements that combine linear (conventional) and spherical tensor diffusion encoding. To test the accuracy of the fibre dispersion when our microstructural model is only an approximation of the true tissue structure, we simulate multi-compartment data and fit this with a single-compartment model. For such overly simplistic tissue assumptions, we show that the bias in fibre dispersion is greatly reduced (~5x) for single-shell linear and spherical tensor encoding data compared with single-shell or multi-shell conventional data. In in-vivo data we find a consistent estimate of fibre dispersion as we reduce the b-value from 3 to 1.5 ms/μm2, increase the repetition time, increase the echo time, or increase the diffusion time. We conclude that the addition of spherical tensor encoded data to conventional linear tensor encoding data greatly reduces the sensitivity of the estimated fibre dispersion to the model assumptions of the tissue microstructure.


Biological warfare warriors, secrecy and pure science in the Cold War: how to understand dialogue and the classifications of science.
This paper uses a case study from the Cold War to reflect on the meaning at the time of the term 'Pure Science'. In 1961, four senior scientists from Britain's biological warfare centre at Porton Down visited Moscow both attending an International Congress and visiting Russian microbiological and biochemical laboratories. The reports of the British scientists in talking about a limited range of topics encountered in the Soviet Union expressed qualities of openness, sociologists of the time associated with pure science. The paper reflects on the discourses of "Pure Science", secrecy and security in the Cold War. Using Bakhtin's approach, I suggest the cordial communication between scientists from opposing sides can be seen in terms of the performance, or speaking, of one language among several at their disposal. Pure science was the language they were allowed to share outside their institutions, and indeed political blocs.


The effect of vagus nerve stimulation upon vulnerability of the canine ventricle: role of sympathetic-parasympathetic interactions.
The effect of vagus nerve stimulation (VNS) upon ventricular vulnerability was studied in 30 mongrel dogs subjected to varying levels of adrenergic stimulation. Vulnerability was assessed both by determining the minimum current required to produce ventricular fibrillation (VF threshold) and by plotting VF threshold throughout the vulnerable period (VF zone). Chloralose-anesthetized animals were studied by means of sequential pulses applied to the apex of the right ventricular endocardium. Testing was carried out in closed-chest dogs, in open-chest dogs with and without left stellate ganglion stimulation (LSGS), and in open- and closed-chest dogs pretreated with propranolol. In the absence of adrenergic stimulation. VNS was without significant effect on either the VF threshold or the VF zone under closed- or open-chest conditions. During LSGS, however, VNS was associated with a 93 +/- 22% (mean +/- SE) increase in VF threshold (P less than 0.01) and constriction of the VF zone. Vagus nerve stimulation combined with LSGS raised VF threshold to the control value, but not beyond. After beta-adrenergic blockade with propranolol, VNS was without effect on VF threshold in either open- or closed-chest animals. It is concluded that augmented sympathetic tone is a precondition for a VNS-induced elevation in VF threshold. The vagal effect is indirect and is expressed by opposing the effects of heightened adrenergic tone on ventricular vulnerability.


Insulin degradation: progress and potential.
Insulin degradation is a regulated process that plays a role in controlling insulin action by removing and inactivating the hormone. Abnormalities in insulin clearance and degradation are present in various pathological conditions including type 2 diabetes and obesity and may be important in producing clinical problems. The uptake, processing, and degradation of insulin by cells is a complex process with multiple intracellular pathways. Most evidence supports IDE as the primary degradative mechanism, but other systems (PDI, lysosomes, and other enzymes) undoubtedly contribute to insulin metabolism. Recent studies support a multifunctional role for IDE, as an intracellular binding, regulatory, and degradative protein. IDE increases proteasome and steroid hormone receptor activity, and this activation is reversed by insulin. This raises the possibility of a direct intracellular interaction of insulin with IDE that could modulate protein and fat metabolism. The recent findings would place intracellular insulin-IDE interaction into the insulin signal transduction pathway for mediating the intermediate effects of insulin on fat and protein turnover.


Modeling, Measuring, and Compensating Color Weak Vision.
We use methods from Riemann geometry to investigate transformations between the color spaces of color-normal and color-weak observers. The two main applications are the simulation of the perception of a color weak observer for a color-normal observer, and the compensation of color images in a way that a color-weak observer has approximately the same perception as a color-normal observer. The metrics in the color spaces of interest are characterized with the help of ellipsoids defined by the just-noticeable-differences between the colors which are measured with the help of color-matching experiments. The constructed mappings are the isometries of Riemann spaces that preserve the perceived color differences for both observers. Among the two approaches to build such an isometry, we introduce normal coordinates in Riemann spaces as a tool to construct a global color-weak compensation map. Compared with the previously used methods, this method is free from approximation errors due to local linearizations, and it avoids the problem of shifting locations of the origin of the local coordinate system. We analyze the variations of the Riemann metrics for different observers obtained from new color-matching experiments and describe three variations of the basic method. The performance of the methods is evaluated with the help of semantic differential tests.


Study of the excess noise associated with demodulation of ultra-short infrared pulses.
The demodulation of ultra-short light pulses with photodetectors is accompanied by excess phase noise at the pulse repetition rate and harmonics in the spectrum of the photocurrent. The major contribution to this noise is power fluctuations of the detected pulse train that, if not compensated for, can seriously limit the stability of frequency transfer from optical to microwave domain. By making use of an infrared femtosecond laser, we measured the spectral density of the excess phase noise, as well as power-to-phase conversion for different types of InGaAs photodetectors. Noise measurements were performed with a novel type of dual-channel readout system using a fiber coupled beam splitter. Strong suppression of the excess phase noise was observed in both channels of the measurement system when the average power of the femtosecond pulse train was stabilized. The results of this study are important for the development of low-noise microwave sources derived from optical "clocks" and optical frequency synthesis.


CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein.
Obesity-induced adipose tissue (AT) dysfunction results in a chronic low-grade inflammation that predisposes to the development of insulin resistance and type 2 diabetes. During the development of obesity, the AT-resident immune cell profile alters to create a pro-inflammatory state. Very recently, CD1d-restricted invariant (i) natural killer T (NKT) cells, a unique subset of lymphocytes that are reactive to so called lipid antigens, were implicated in AT homeostasis. Interestingly, recent data also suggest that human and mouse adipocytes can present such lipid antigens to iNKT cells in a CD1d-dependent fashion, but little is known about the lipid antigen presentation machinery in adipocytes. Here we show that CD1d, as well as the lipid antigen loading machinery genes pro-saposin (Psap), Niemann Pick type C2 (Npc2), α-galactosidase (Gla), are up-regulated in early adipogenesis, and are transcriptionally controlled by CCAAT/enhancer-binding protein (C/EBP)-β and -δ. Moreover, adipocyte-induced Th1 and Th2 cytokine release by iNKT cells also occurred in the absence of exogenous ligands, suggesting the display of endogenous lipid antigen-D1d complexes by 3T3-L1 adipocytes. Furthermore, we identified microsomal triglyceride transfer protein, which we show is also under the transcriptional regulation of C/EBPβ and -δ, as a novel player in the presentation of endogenous lipid antigens by adipocytes. Overall, our findings indicate that adipocytes can function as non-professional lipid antigen presenting cells, which may present an important aspect of adipocyte-immune cell communication in the regulation of whole body energy metabolism and immune homeostasis.


Informed prognosis [corrected] after abdominal aortic aneurysm repair using predictive modeling techniques [corrected].
To identify the best method for the prediction of postoperative mortality in individual abdominal aortic aneurysm surgery (AAA) patients by comparing statistical modelling with artificial neural networks' (ANN) and clinicians' estimates. An observational multicenter study was conducted of prospectively collected postoperative Acute Physiology and Chronic Health Evaluation II data for a 9-year period from 24 intensive care units (ICU) in the Thames region of the United Kingdom. The study cohort consisted of 1205 elective and 546 emergency AAA patients. Four independent physiologic variables-age, acute physiology score, emergency operation, and chronic health evaluation-were used to develop multiple regression and ANN models to predict in-hospital mortality. The models were developed on 75% of the patient population and their validity tested on the remaining 25%. The results from these two models were compared with the observed outcome and clinicians' estimates by using measures of calibration, discrimination, and subgroup analysis. Observed in-hospital mortality for elective surgery was 9.3% (95% confidence interval [CI], 7.7% to 11.1%) and for emergency surgery, 46.7% (95% CI, 42.5 to 51.0%). The ANN and the statistical models were both more accurate than the clinicians' predictions. Only the statistical model was internally valid, however, when applied to the validation set of observations, as evidenced by calibration (Hosmer-Lemeshow C statistic, 14.97; P = .060), discrimination properties (area under receiver operating characteristic curve, 0.869; 95% CI, 0.824 to 0.913), and subgroup analysis. The prediction of in-hospital mortality in AAA patients by multiple regression is more accurate than clinicians' estimates or ANN modelling. Clinicians can use this statistical model as an objective adjunct to generate informed prognosis.


Tissue Augmentation with Allograft Adipose Matrix For the Diabetic Foot in Remission.
Repetitive stress on the neuropathic plantar foot is the primary cause of diabetic foot ulcers. After healing, recurrence is common. Modulating plantar pressure has been associated with extension of ulcer free days. Therefore, the goal of this study was to determine the effects of an injectable allograft adipose matrix in providing a protective padding and reducing the pressure in the plantar foot. After healing his recurrent ulcer using total contact casting, a 71-year-old man with a 9-year history of recurrent diabetic foot ulcers was treated with injection of allograft adipose matrix, procured from donated human tissue. This was delivered under postulcerative callus on the weight-bearing surface of the distal end of the first ray resection. As is standard in our clinic for tissue augmentation procedures, our patient underwent serial plantar pressure mapping using an in-shoe pressure monitoring system. There was a 76.8% decrease in the mean peak pressure due to the fat matrix injected into the second metatarsal region and a 70.1% decrease in mean peak pressure for the first ray resection at the site of the postulcerative callus. By 2 months postoperatively, there was no evidence of residual callus. This extended out to the end of clinical follow-up at 4 months. The results from this preliminary experience suggest that allograft adipose matrix delivered to the high risk diabetic foot may have promise in reducing tissue stress over pre- and postulcerative lesions. This may ultimately assist the clinician in extending ulcer-free days for patients in diabetic foot remission.


BMI1 represses Ink4a/Arf and Hox genes to regulate stem cells in the rodent incisor.
The polycomb group gene Bmi1 is required for maintenance of adult stem cells in many organs. Inactivation of Bmi1 leads to impaired stem cell self-renewal due to deregulated gene expression. One critical target of BMI1 is Ink4a/Arf, which encodes the cell-cycle inhibitors p16(Ink4a) and p19(Arf). However, deletion of Ink4a/Arf only partially rescues Bmi1-null phenotypes, indicating that other important targets of BMI1 exist. Here, using the continuously growing mouse incisor as a model system, we report that Bmi1 is expressed by incisor stem cells and that deletion of Bmi1 resulted in fewer stem cells, perturbed gene expression and defective enamel production. Transcriptional profiling revealed that Hox expression is normally repressed by BMI1 in the adult, and functional assays demonstrated that BMI1-mediated repression of Hox genes preserves the undifferentiated state of stem cells. As Hox gene upregulation has also been reported in other systems when Bmi1 is inactivated, our findings point to a general mechanism whereby BMI1-mediated repression of Hox genes is required for the maintenance of adult stem cells and for prevention of inappropriate differentiation.


[Effect and Mechanism of Litchi Semen Effective Constituents on Insulin Resistance in Rats with Type 2 Diabetes Mellitus].
To observe the effect of Litchi Semen Effective Constituents (LSEC) on insulin resistance (IR) in rats with Type 2 Diabetes Mellitus(T2DM), and to explore its mechanism. T2DM models in rats with IR were induced by high-fat feeding combined with streptozocin, then the rats were randomly divided into four groups: model group, LSEC high-dose group (1. 87 g/kg), LSEC low-dose group(0. 47 g/kg) and rosiglitazone group(3. 87 x 10(-3) g/kg), blank group was established as control. After medication for four weeks, effects of LSEC on glucose or lipid metabolism and insulin resistance were investigated, histopathology and ultrastructure changes of pancreatic tissues were observed,Stem-loop Real-time fluorescence quantitative RT-PCR was used for evaluation of GRP78 mRNA and CHOP mRNA levels in pancreatic tissue of rats. LSEC of high-dose group obviously improved fasting blood glucose, serum TG level and glucose tolerance in T2DM rats (P <0. 05 or P <0. 01). ISI was increased, HOMA-IR index was decreased, histopathology change of pancreatic tissue were alleviated, damaged organelle, such as endoplasmic reticulum and mitochondria were repaired in both groups of LSEC. Expression levels of GRP78 mRNA of both groups of LSEC and CHOP mRNA of high-dose group in pancreatic tissue were obviously lower than those of model group (P <0. 01). LSEC can improve glycolipid metabolism and IR, increase insulin sensitivity to cure T2DM, its effects may be attributed, at least in part, to inhibit the expression of GRP78 mRNA and CHOP mRNA.


Spinal direct current stimulation with locomotor training in chronic spinal cord injury.
Transcutaneous spinal direct current stimulation (tsDCS) is a non-invasive method of stimulating spinal circuits that can modulate and induce changes in corticospinal excitability (CE) in incomplete spinal cord injury (SCI). A double-blinded sham controlled study of 2 male patients (A and B) with SCI was carried out. Patient A received sham and cathodal tsDCS, while Patient B received sham and anodal tsDCS. Four baselines were recorded prior to each arm of stimulation. Outcomes were then measured post each arm of stimulation; 10-meter walk test, modified ashworth scale, berg balance scale, manual muscle testing, and spinal cord independence measure-III. Transcranial magnetic stimulation, assessed motor evoked potentials. Cathodal tsDCS increased the scores in few of the outcome measures and decreased others. Anodal stimulation increased scores in all measures. Motor evoked potentials increased in post-cathode and deteriorated in post-anode. In conclusion, tsDCS modulated gait parameters, spasticity, and CE in incomplete SCI.


General practice: professional preparation for a pandemic.
General practice will play a key role in both prevention and management of an influenza pandemic. Australian pandemic plans acknowledge a role for general practice, but there are few published data addressing the issues that general practitioners and their practices will face in dealing with such a crisis. The outcome will revolve around preparation in three key areas: Definition of the role of general practice within a broad primary care pandemic response, and adequate preparation within general practices so they can play that role well. Planning exercises and forums must include GPs, and rehearsals must include practical experience for general practices and their staff. Local Divisions of General Practice and GP practices can advocate for this, can define their role, and can prepare by using pandemic preparedness checklists; Definition and enactment of communication strategies to facilitate transfer of useful clinical and administrative data from practices and rapid dissemination of information into the community via general practice; Resource provision, which should be centrally funded but locally distributed, with personal protective equipment, vaccines and antivirals readily available for distribution. Resources must include support for human resource management to ensure appropriate health care professionals reach areas of workforce demand. Administrative, clinical and financial resources must be available to train GPs and practices in pandemic awareness and response.


Ultrafast pump-probe microscopy with high temporal dynamic range.
Ultrafast pump-probe microscopy is a common method for time and space resolved imaging of short and ultra-short pulse laser ablation. The temporal delay between the ablating pump pulse and the illuminating probe pulse is tuned either by an optical delay, resulting in several hundred femtoseconds temporal resolution for delay times up to a few ns, or by an electronic delay, resulting in several nanoseconds resolution for longer delay times. In this work we combine both delay types for temporally high resolved observations of complete ablation processes ranging from femtoseconds to microseconds, while ablation is initiated by an ultrafast 660 fs laser pump pulse. For this purpose, we also demonstrate the calibration of the delay time zero point, the synchronization of both probe sources, as well as a method for image quality enhancing. In addition, we present for the first time to our knowledge pump-probe microscopy investigations of the complete substrate side selective ablation process of molybdenum films on glass. The initiation of mechanical film deformation is observed at about 400 ps, continues until approximately 15 ns, whereupon a Mo disk is sheared off free from thermal effects due to a directly induced laser lift-off ablation process.


Cognitive Dysfunction Among Adults With Type 2 Diabetes Mellitus in Karnataka, India.
Background: Type 2 diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia that affects various body systems. Elevated blood glucose levels cause brain malfunction, sorbitol-induced blood vessel damage, and degeneration of the nerves that can lead to dementia or cognitive impairment. Cognitive impairment can result in nonadherence of patients to diabetes treatment, such as diet, medication, and exercise. Methods: We used a cross-sectional design to individually interview 194 patients with type 2 diabetes in a rural field practice area in India. A questionnaire was used to collect sociodemographic and diabetes disease characteristics; anthropometric measurements were also collected. Cognitive dysfunction was assessed with the Kannada version (local language) of the Montreal Cognitive Assessment (MoCA) tool. Blood pressure was measured for all subjects using a standardized sphygmomanometer on the right arm with the patient in a sitting position. Results: Among the 194 diabetic subjects interviewed, 98 (50.5%) were cognitively impaired. More than half of the subjects (56.2%) were ≥65 years, and female participants (53.6%) outnumbered males (46.4%). The majority of patients (62.4%) had had diabetes for <10 years. The sociodemographic characteristics age, sex, education, occupation, and socioeconomic status and the anthropometric measurement of waist-to-hip ratio were significantly associated (P<0.05) with cognitive impairment. Disease characteristics, religion, and blood pressure showed no significant association with cognitive impairment. Conclusion: One in two individuals with type 2 diabetes mellitus in our study population had mild cognitive impairment. Older individuals in the low socioeconomic strata and with low levels of education were identified to be at high risk of cognitive impairment. Hence, screening and appropriate care need to be provided.


The genomics of selection in dogs and the parallel evolution between dogs and humans.
The genetic bases of demographic changes and artificial selection underlying domestication are of great interest in evolutionary biology. Here we perform whole-genome sequencing of multiple grey wolves, Chinese indigenous dogs and dogs of diverse breeds. Demographic analysis show that the split between wolves and Chinese indigenous dogs occurred 32,000 years ago and that the subsequent bottlenecks were mild. Therefore, dogs may have been under human selection over a much longer time than previously concluded, based on molecular data, perhaps by initially scavenging with humans. Population genetic analysis identifies a list of genes under positive selection during domestication, which overlaps extensively with the corresponding list of positively selected genes in humans. Parallel evolution is most apparent in genes for digestion and metabolism, neurological process and cancer. Our study, for the first time, draws together humans and dogs in their recent genomic evolution.


A prospective case-control study to compare the sensitivity and specificity of the grind and traction-shift (subluxation-relocation) clinical tests in osteoarthritis of the thumb carpometacarpal joint.
The diagnosis of osteoarthritis of the thumb carpometacarpal joint is made predominantly by correlating examination findings with patients' symptoms and radiographs. The importance of clinical examination is enhanced due to the poor correlation between radiological severity of osteoarthritis of this joint and symptoms. Despite the importance of clinical examination findings, no previous studies have analyzed the traction-shift test nor compared clinical tests for this diagnosis. In this prospective case-control study the relative performance of the commonly used grind and traction-shift (subluxation-relocation) tests were compared in 30 patients and 30 unaffected controls. The traction-shift test had greater sensitivity (66.7%) and specificity (100%) than the grind test (30% and 96.7%, respectively), whilst also demonstrating superior positive (100%) and negative (75%) predictive value than the grind test (90% and 58%, respectively). Therefore, we believe this to be the superior clinical test for osteoarthritis of the carpometacarpal joint of the thumb.


Inferences on population history of a seed chalcid wasp: invasion success despite a severe founder effect from an unexpected source population.
Most invasive species established in Europe originate from either Asia or North America, but little is currently known about the potential of the Anatolian Peninsula (Asia Minor) and/or the Near East to constitute invasion sources. Mediterranean forests are generally fragile ecosystems that can be threatened by invasive organisms coming from different regions of the Mediterranean Basin, but for which historical data are difficult to gather and the phylogeographic patterns are still poorly understood for most terrestrial organisms. In this study, we characterized the genetic structure of Megastigmus schimitscheki, an invasive seed-feeding insect species originating from the Near East, and elucidated its invasion route in South-eastern France in the mid 1990s. To disentangle the evolutionary history of this introduction, we gathered samples from the main native regions (Taurus Mountains in Turkey, Lebanon and Cyprus) and from the invaded region that we genotyped using five microsatellite markers and for which we sequenced the mitochondrial Cytochrome Oxidase I gene. We applied a set of population genetic statistics and methods, including approximate Bayesian computation. We proposed a detailed phylogeographic pattern for the Near East populations, and we unambiguously showed that the French invasive populations originated from Cyprus, although the available historical data strongly suggested that Turkey could be the most plausible source area. Interestingly, we could show that the introduced populations were founded from an extremely restricted number of individuals that realized a host switch from Cedrus brevifolia to C. atlantica. Evolutionary hypotheses are discussed to account for this unlikely scenario.


Effect of lipopolysaccharides on adipogenic potential and premature senescence of adipocyte progenitors.
The elevation of circulating LPS has been associated with obesity and aging. However, whether and how LPS contributes to adipose tissue dysfunction is unclear. In this study, we investigated the effect of LPS on the adipogenic capacity and cellular senescence of adipocyte progenitors. Stromal-vascular cells were isolated from inguinal adipose tissue of C57BL/6 mice and treated with LPS during the different time periods of adipocyte differentiation. We found that LPS treatment for 24 h prior to the induction of differentiation led to the most profound effect on the inhibition of adipogenesis, as evidenced by the morphological changes and the decreased mRNA expression of adipocyte marker genes. In addition, LPS induced features of premature senescence of SV cells, including the activation of p53, the elevation of SA-β-gal activity, and increased hydrogen peroxide production, but not telomere length. Upon LPS treatment, SV cells also developed senescence-associated secretory phenotype (SASP), as demonstrated by the increased expression of TNFα, IL-1β, IL-6, MCP-1, and VEGFα. Blocking LPS-induced NF-κB activation and cytokine production by Bay 11-7082 failed to rescue the impaired adipogenesis and the reduction in PPARγ and Zfp423 expression. On the contrary, rosiglitazone had little effect on cytokine production but corrected the defective adipogenic potential. In conclusion, we demonstrate that LPS inhibits adipogenesis by disrupting the differentiation of adipocyte progenitors in a NF-κB-independent manner; LPS also induces premature senescence of adipocyte progenitors. Our data suggest that LPS could be a potential contributor to the defective adipogenesis and the development of cellular senescence in adipose tissue during obesity and aging.


Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia.
Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform NaV1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain after local inflammation of the rat lumbar sensory ganglia. In normal dorsal root ganglion (DRG), quantitative polymerase chain reaction showed that cells capable of firing repetitively had significantly higher relative expression of NaV1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of NaV1.6 immunoreactivity. In vivo knockdown of NaV1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on NaV1.8 because it is present primarily in unmyelinated C fiber nociceptors, or on NaV1.7 because lack of this channel causes congenital indifference to pain. However, the results suggest that NaV1.6 may be a useful therapeutic target for chronic pain and that some pain conditions may be mediated primarily by myelinated A fiber sensory neurons.


Social Engagement and Elderly Health in China: Evidence from the China Health and Retirement Longitudinal Survey (CHARLS).
This study examines the impact of social engagement on elderly health in China. A two-stage residual inclusion (2SRI) regression approach was used to examine the causal relationship. Our dataset comprises 9253 people aged 60 or above from the China Health and Retirement Longitudinal Survey (CHARLS) conducted in 2011 and 2013. Social engagement significantly improved the self-rated health of the elderly and reduced mental distress, but had no effect on chronic disease status. Compared with the rural areas, social engagement played a more important role in promoting the elderly health status in urban areas. Social engagement could affect the health status of the elderly through health behavior change and access to health resources. To improve the health of the elderly in China and promote healthy aging, the government should not only improve access to effective medical care but also encourage greater social engagement of the elderly.


Cost-effectiveness of pertussis booster vaccination in the Netherlands.
The aim of the current study is to estimate the epidemiological and economical consequences of several extended pertussis booster vaccination strategies and to explore the impact of parameters surrounded by large uncertainty on the cost-effectiveness. We developed an age structured transmission dynamic model to evaluate the impact of programs targeting (i) adolescents or adults using a single booster dose, (ii) a combination of adolescent and adult vaccination, and (iii) an every 10 years booster dose. The base case analysis, that is a single adolescent booster administered at the age of 12 years, resulted in a reduction of pertussis infections. However, due to an increase in the number of symptomatic infections in adults, the benefits in terms of QALYs gained and costs saved in children were partly offset. Despite these negative indirect effects in the adult population, administering an additional booster dose could still be considered cost effective with an ICER of €4200 per QALY gained. Combining an adolescent booster dose at the age of 10 (most cost-effective age for a single adolescent booster dose) with an adult (18-30 years) booster dose always resulted in favorable ICERs (<€10,000/QALY). Finally the every 10 year booster dose resulted in an ICER of €16,900 per QALY. The impact of different assumptions regarding the disease epidemiology, disease-related parameters, and vaccination program-related issues was limited. To conclude, we show that extended pertussis booster vaccination strategies are likely to be considered as cost-effective.


Inosine and N1-methylinosine within a synthetic oligomer mimicking the anticodon loop of human tRNA(Ala) are major epitopes for anti-PL-12 myositis autoantibodies.
Sera of some patients afflicted with the inflammatory disease myositis contain antibodies of the anti-PL-12 type. A fraction of these polyclonal autoantibodies specifically precipitates the fully matured human tRNA(Ala) bearing the anticodon IGC (PL-12 antigen). Earlier work (Bunn & Mathews, 1987, Science 238:116-119) had shown that the epitopes are located entirely within the anticodon stem-loop of the tRNA(Ala). Here we demonstrate that human anti-tRNA(Ala) autoantibodies immunoprecipitate a synthetic polyribonucleotide containing inosine (I) and N1-methylinosine (m1I) separated by 2 nt as in the anticodon stem-loop of human tRNA(Ala). The shortest polyribonucleotide that can be immunoprecipitated corresponds to the pentanucleotide IpGpCpm1IpUp, which corresponds to part of the anticodon loop of human tRNA(Ala) and lacks the stem-loop structure. The efficiency of immunoprecipitation was about four times greater with longer polyribonucleotides capable of forming a stem-loop structure, and was abolished by altering the relative positions of I and m1I within the synthetic polynucleotide. Synthetic oligodeoxyribonucleotide analogs of the tRNA(Ala) stem-loop, containing the sequence dIpdGdCdm1Ip, are not antigenic. Our results show that human anti-tRNA(Ala) autoantibodies selectively recognize chemical details of modified nucleotides (the 6-keto group of inosine-34 and the 6-keto group and the N1-methyl groups of N1-methylinosine-37) within an anticodon loop structure of a tRNA molecule. We also describe the chemical synthesis of the phosphoramidite derivatives corresponding to N1-methylinosine and N1-methyl-2'-deoxyinosine for use in the automatic chemical synthesis of oligonucleotides containing N1-methylinosine and N1-methyl-2'-deoxyinosine.


Surfactant for bacterial pneumonia in late preterm and term infants.
Pulmonary surfactant is an important part of the host defence against respiratory infections. Bacterial pneumonia in late preterm or term newborn infants often leads to surfactant deficiency or dysfunction, as surfactant is either inactivated or peroxidated. Studies of animal models of pneumonia and clinical case reports suggest that exogenous surfactant might be beneficial to infants with bacterial pneumonia. To assess the effect of exogenous surfactant treatment on mortality and pulmonary complications in infants with bacterial pneumonia. We used standard Cochrane Collaboration methodology to conduct our search of databases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 6); MEDLINE (accessed via Ovid SP June 2011); EMBASE (via Ovid SP 1980 to June 2011); and CINAHL Plus (accessed via EBSCOHost June 2011). We limited our search to randomised and quasi-randomised trials of surfactant replacement therapy in infants > 35 weeks gestation with bacterial pneumonia in the first 28 days of life. The primary outcome measures were death, time to resolution of pneumonia, incidence of chronic lung disease, pneumothoraces and pulmonary haemorrhage. We assessed all studies with predefined criteria as to whether they were eligible for inclusion. We extracted data using RevMan 5 (RevMan 2011). We used the standard Cochrane Collaboration methodology for data collection and analysis to assess risk of bias, heterogeneity, treatment effect, missing data and reporting bias where appropriate. We did not identify any studies that met our inclusion criteria. There is no evidence from randomised controlled trials (RCTs) to support or refute the efficacy of surfactant in near-term and term infants with proven or suspected bacterial pneumonia. RCTs are still required to answer this question.


Schnitzler syndrome: an under-diagnosed clinical entity.
Schnitzler syndrome is considered to be a rare disorder characterized by a monoclonal IgM protein and chronic urticaria that is associated with considerable morbidity. We hypothesized that the syndrome may be under-recognized and patients may be deprived of highly effective therapy in the form of anakinra. We performed a retrospective search of the dysproteinemia database at Mayo Clinic as well as the medical records of all patients with chronic urticaria to determine the true incidence of the disease. We compared patients with the diagnosis of Schnitzler syndrome and those who met the criteria but in whom the syndrome was not recognized. Comparisons between groups were performed and survival curves determined. We identified 16 patients with diagnosed Schnitzler syndrome and an additional 46 patients who met diagnostic criteria. The monoclonal protein was IgMκ in 94% of patients. Therapy with anakinra in 4 patients led to rapid and complete resolution of symptoms. The median overall survival for this syndrome is over 12.8 years. Progression to lymphoma was only observed in 8% of patients; this is lower than previous reports. Schnitzler syndrome may be present in up to 1.5% of patients with a monoclonal IgM in their serum and likely under-recognized as a clinical syndrome.


Two-scale multi-model ensemble: is a hybrid ensemble of opportunity telling us more?
In this study we introduce a hybrid ensemble consisting of air quality models operating at both the global and regional scale. The work is motivated by the fact that these different types of models treat specific portions of the atmospheric spectrum with different levels of detail, and it is hypothesized that their combination can generate an ensemble that performs better than mono-scale ensembles. A detailed analysis of the hybrid ensemble is carried out in the attempt to investigate this hypothesis and determine the real benefit it produces compared to ensembles constructed from only global-scale or only regional-scale models. The study utilizes 13 regional and 7 global models participating in the Hemispheric Transport of Air Pollutants phase 2 (HTAP2)-Air Quality Model Evaluation International Initiative phase 3 (AQMEII3) activity and focuses on surface ozone concentrations over Europe for the year 2010. Observations from 405 monitoring rural stations are used for the evaluation of the ensemble performance. The analysis first compares the modelled and measured power spectra of all models and then assesses the properties of the mono-scale ensembles, particularly their level of redundancy, in order to inform the process of constructing the hybrid ensemble. This study has been conducted in the attempt to identify that the improvements obtained by the hybrid ensemble relative to the mono-scale ensembles can be attributed to its hybrid nature. The improvements are visible in a slight increase of the diversity (4 % for the hourly time series, 10 % for the daily maximum time series) and a smaller improvement of the accuracy compared to diversity. Root mean square error (RMSE) improved by 13-16 % compared to G and by 2-3 % compared to R. Probability of detection (POD) and false-alarm rate (FAR) show a remarkable improvement, with a steep increase in the largest POD values and smallest values of FAR across the concentration ranges. The results show that the optimal set is constructed from an equal number of global and regional models at only 15 % of the stations. This implies that for the majority of the cases the regional-scale set of models governs the ensemble. However given the high degree of redundancy that characterizes the regional-scale models, no further improvement could be expected in the ensemble performance by adding yet more regional models to it. Therefore the improvement obtained with the hybrid set can confidently be attributed to the different nature of the global models. The study strongly reaffirms the importance of an in-depth inspection of any ensemble of opportunity in order to extract the maximum amount of information and to have full control over the data used in the construction of the ensemble.


Impact of successive freezing-thawing cycles on 3-T magnetic resonance images of the digits of isolated equine limbs.
To assess the impact of cycles of freezing and thawing on magnetic resonance (MR) images (obtained by use of a 3-T magnet) of equine feet examined ex vivo. 9 forelimbs from 9 horse cadavers. 9 forefeet underwent MR imaging first at ambient temperature within 12 hours after the horses' death and then after each freezing-thawing cycle. Three digits underwent freezing and thawing (at 4°C for 36 hours) 2 times, 3 digits underwent freezing and thawing (at 4°C for 36 hours) once and rescanning after 24 hours at ambient temperature, and 3 digits underwent freezing and thawing at ambient temperature for 24 hours once. Images of the digits obtained prior to freezing were subjectively compared with images obtained after freezing and thawing. Changes in the signal-to-noise ratio between examinations were assessed. Overall image quality was considered unchanged except for the hoof capsule. Quantitative analysis revealed signal-to-noise ratio changes in bone marrow, soft tissues, and hoof capsule induced with both thawing processes. The signal-to-noise ratio in the synovial recess of the distal interphalangeal joint significantly increased as a result of thawing at 4°C. Although overall image quality was considered unchanged except for the hoof capsule, results suggested that changes induced in cadaver limbs following freezing and thawing, which are probably attributable both to modified and inhomogeneous temperature distribution and direct tissue damage, may alter the reliability of signal intensity in ex vivo MR examinations.


Colossal mid-infrared bulk photovoltaic effect in a type-I Weyl semimetal.
Broadband, efficient and fast conversion of light to electricity is crucial for sensing and clean energy. The bulk photovoltaic effect (BPVE) is a second-order nonlinear optical effect that intrinsically converts light into electrical current. Here, we demonstrate a large mid-infrared BPVE in microscopic devices of the Weyl semimetal TaAs. This discovery results from combining recent developments in Weyl semimetals, focused-ion beam fabrication and theoretical works suggesting a connection between BPVE and topology. We also present a detailed symmetry analysis that allows us to separate the shift current response from photothermal effects. The magnitude and wavelength range of the assigned shift current may impact optical detectors, clean energy and topology, and demonstrate the utility of Weyl semimetals for practical applications.


The significance of blood pressure variability for the development of hemorrhagic transformation in acute ischemic stroke.
Elevated blood pressure (BP) is commonly observed in acute ischemic stroke and is known to be associated with hemorrhagic transformation (HT). However, the effect of BP variability on the development of HT is not known well. A consecutive series of patients with acute ischemic stroke, who were hospitalized within 24 hours of onset and showed no HT on initial gradient echo MRI, were enrolled in this study. BP measurements during the first 72 hours were obtained, and BP variability of each patient was described using various summary parameters: SD, maximum (max), minimum (min), difference between max and min (max-min), average squared difference between successive measurements (sv), and maximum sv (svmax). Of 792 patients meeting the eligibility criteria, 70 (8.8%) developed HT. Among BP variability parameters categorized into quartiles, SBP(max), SBP(min), SBP(max-min), SBP(svmax), DBP(SD), DBP(max), DBP(min), DBP(max-min), and DBP(svmax) were significantly associated with HT independent of mean SBP, age, interval from onset to arrival, initial stroke severity, diabetes mellitus, stroke subtype, thrombolysis, initial glucose, and total cholesterol (P<0.05 on likelihood ratio test of trend). The analyses about the interaction between thrombolysis and variability parameters showed that the effects of BP variability on the development of HT did not differ by whether patients received thrombolysis or not. Our study suggests that we may consider not only the absolute level of BP but also its variability to prevent hemorrhagic transformation.


Pre-Clinical Translation of Second Harmonic Microscopy of Meniscal and Articular Cartilage Using a Prototype Nonlinear Microendoscope.
Previous studies using nonlinear microscopy have demonstrated that osteoarthritis (OA) is characterized by the gradual replacement of Type II collagen with Type I collagen. The objective of this study was to develop a prototype nonlinear laser scanning microendoscope capable of resolving the structural differences of collagen in various orthopaedically relevant cartilaginous surfaces. The current prototype developed a miniaturized femtosecond laser scanning instrument, mounted on an articulated positioning system, capable of both conventional arthroscopy and second-harmonic laser-scanning microscopy. Its optical system includes a multi-resolution optical system using a gradient index objective lens and a customized multi-purpose fiber optic sheath to maximize the collection of backscattered photons or provide joint capsule illumination. The stability and suitability of the prototype arthroscope to approach and image cartilage were evaluated through preliminary testing on fresh, minimally processed, and partially intact porcine knee joints. Image quality was sufficient to distinguish between hyaline cartilage and fibrocartilage through unique Type I and Type II collagen-specific characteristics. Imaging the meniscus revealed that the system was able to visualize differences in the collagen arrangement between the superficial and lamellar layers. Such detailed in vivo imaging of the cartilage surfaces could obviate the need to perform biopsies for ex vivo histological analysis in the future, and provide an alternative to conventional external imaging to characterize and diagnose progressive and degenerative cartilage diseases such as OA. Moreover, this system is readily customizable and may provide a suitable and modular platform for developing additional tools utilizing femtosecond lasers for tissue cutting within the familiar confines of two or three portal arthroscopy techniques.


Antagonising TLR4-TRIF signalling before or after a low-dose alcohol binge during adolescence prevents alcohol drinking but not seeking behaviour in adulthood.
Adolescents frequently engage in risky behaviours such as binge drinking. Binge drinking, in turn, perturbs neurodevelopment reinforcing reward seeking behaviour in adulthood. Current animal models are limited in their portrayal of this behaviour and the assessment of neuroimmune involvement (specifically the role of Toll-like receptor 4 (TLR4)). Therefore, the aims of this project were to develop a more relevant animal model of adolescent alcohol exposure and to characterise its effects on TLR4 signalling and alcohol-related behaviours later life. Balb/c mice received a short (P22-P25), low dose alcohol binge during in early adolescence, and underwent tests to investigate anxiety (elevated plus maze), alcohol seeking (conditioned place preference) and binge drinking behaviour (drinking in the dark) in adulthood. Four doses of alcohol during adolescence increased alcohol-induced conditioned place preference and alcohol intake in adulthood. However, this model did not affect basal elevated plus maze performance. Subsequent analysis of nucleus accumbal mRNA, revealed increased expression of TLR4-related mRNAs in mice who received alcohol during adolescence. To further elucidate the role of TLR4, (+)-Naltrexone, a biased TLR4 antagonist was administered 30 min before or after the adolescent binge paradigm. When tested in adulthood, (+)-Naltrexone treated mice exhibited reduced alcohol intake however, alcohol seeking and anxiety behaviour was unaltered. This study highlights that even a small amount of alcohol, when given during a critical neurodevelopmental period, can potentiate alcohol-related behaviours and TLR4 activation later in life. Interestingly, attenuation of TLR4 before or after adolescent alcohol exposure reduced only binge alcohol intake in adulthood.


Complications of Endovascular Treatments for Brain Arteriovenous Malformations: A Nationwide Surveillance.
Embolization is widely performed to treat brain arteriovenous malformations, but little has been reported on factors contributing to complications. We retrospectively reviewed a nationwide surveillance to identify risk factors contributing to complications and short-term clinical outcomes in the endovascular treatment of brain arteriovenous malformations. Data for endovascular treatment of brain arteriovenous malformations were extracted from the Japanese nationwide surveillance. Patient characteristics, brain arteriovenous malformation features, procedures, angiographic results, complications, and clinical outcomes at 30 days postprocedure were analyzed. A total of 1042 endovascular procedures (788 patients; mean, 1.43 ± 0.85 procedures per patient) performed in 111 institutions from 2010 to 2014 were reviewed. Liquid materials were used in 976 procedures (93.7%): to perform presurgical embolization in 638 procedures (61.2%), preradiosurgical embolization in 160 (15.4%), and as sole endovascular treatment in 231 (22.2%). Complete or near-complete obliteration of brain arteriovenous malformations was obtained in 386 procedures (37.0%). Procedure-related complications occurred in 136 procedures (13.1%), including hemorrhagic complications in 59 (5.7%) and ischemic complications in 57 (5.5%). Univariate analysis identified deep venous drainage, associated aneurysms, infratentorial location, and preradiosurgical embolization as statistically significant risk factors for complications. Multivariate analysis showed that embolization of brain arteriovenous malformations in the infratentorial location was significantly associated with complications. Patients with complications due to endovascular procedures had worse clinical outcomes 30 days after the procedures than those without complications. Complications arising after endovascular treatment of brain arteriovenous malformations are not negligible even though they may play a role in adjunctive therapy, especially in the management of infratentorial brain arteriovenous malformations.


Reproducible Measurements of Muscle Characteristics Using the MyotonPRO Device: Comparison Between Individuals With and Without Paratonia.
The MyotonPRO is a portable device that measures muscle tone and biomechanical muscle properties objectively. MyotonPRO has already proven to be effective in measuring muscle properties in healthy and diseased populations. However, to the best of our knowledge, it has never been tested in individuals suffering from paratonia, a form of hypertonia frequently accompanying dementia. The aims of the present study were to (1) compare muscle tone, elasticity, and stiffness between 3 different subpopulations of young and old healthy adults and individuals with paratonia, and (2) investigate the intra- and interrater reproducibility of MyotonPRO measurements of the biceps brachii (BB) muscle in each subpopulation. MyotonPRO measurements of muscle tone, elasticity, and dynamic stiffness were carried out by 2 investigators on 2 different days over the BB muscles of 54 participants (18 healthy young adults, 20 healthy older adults, and 16 older individuals with paratonia). Muscle properties were compared between subpopulations using ANOVA/Welch and post hoc tests. Reliability (intraclass correlation coefficient) and agreement parameters (standard error of measurement and the minimal detectable change) were calculated. Statistically significant differences between subpopulations were found in all parameters, except for stiffness between healthy elderly and individuals with paratonia. In the healthy subpopulations, (a) intrarater reliability was very high and intrarater agreement was good between 2 consecutive series, (b) between days intrarater reliability was low to high and intrarater agreement was variable, (c) interrater reliability was high to very high and interrater agreement was good. In individuals with paratonia, (a) intrarater reliability was moderate to high and agreement was variable between series, (b) between days intrarater reliability was poor to moderate and agreement was poor, (c) interrater reliability ranged from low to high with poor agreement. MyotonPRO measurements of the BB muscle showed good reproducibility in both healthy subpopulations, particularly for measurements performed within the same day. In individuals with paratonia, reliability and agreement were substantially lower. MyotonPRO can be used in clinical assessment and research. However, in individuals with paratonia, careful interpretation of results is required. Research in a larger sample of persons with paratonia at different stages of disease severity is recommended.


Genetic and transcriptional variations in NRAMP-2 and OPAQUE1 genes are associated with salt stress response in wheat.
SNP alleles on chromosomes 4BL and 6AL are associated with sensitivity to salt tolerance in wheat and upon validation can be exploited in the development of salt-tolerant wheat varieties. The dissection of the genetic and molecular components of salt stress response offers strong opportunities toward understanding and improving salt tolerance in crops. In this study, GWAS was employed to identify a total of 106 SNP loci (R2 = 0.12-63.44%) linked to salt stress response in wheat using leaf chlorophyll fluorescence, grain quality and shoot ionic (Na+ and K+ ions) attributes. Among them, 14 SNP loci individually conferred pleiotropic effects on multiple independent salinity tolerance traits including loci at 99.04 cM (R2 ≥ 14.7%) and 68.45 cM (R2 ≥ 4.10%) on chromosomes 6AL and 4BL, respectively, that influenced shoot Na+-uptake, shoot K+/Na+ ratio, and specific energy fluxes for absorption (ABS/RC) and dissipation (DIo/RC). Analysis of the open reading frame (ORF) containing the SNP markers revealed that they are orthologous to genes involved in photosynthesis and plant stress (salt) response. Further transcript abundance and qRT-PCR analyses indicated that the genes are mostly up-regulated in salt-tolerant and down-regulated in salt-sensitive wheat genotypes including NRAMP-2 and OPAQUE1 genes on 4BL and 6AL, respectively. Both genes showed highest differential expression between contrasting genotypes when expressions of all the genes within their genetic intervals were analyzed. Possible cis-acting regulatory elements and coding sequence variation that may be involved in salt stress response were also identified in both genes. This study identified genetic and molecular components of salt stress response that are associated with Na+-uptake, shoot Na+/K+ ratio, ABS/RC, DIo/RC, and grain quality traits and upon functional validation would facilitate the development of gene-specific markers that could be deployed to improve salinity tolerance in wheat.


Trends in cancer incidence in Maputo, Mozambique, 1991-2008.
Very limited information is available regarding the incidence of cancer in sub-Saharan Africa. We analyzed changes in cancer patterns from 1991 to 2008 in Maputo (Mozambique). We calculated the rates of incidence of different cancer sites by sex in the 5-year age-group of the population of Maputo city as well as age-standardized rates (ASRs) and average annual percentage changes (AAPC). Over the 18-year study period a total of 12,674 cases of cancer (56.9% females) were registered with an overall increase in the risk of cancer in both sexes. In males, the most common cancers were those of the prostate, Kaposi sarcoma (KS) and the liver. Prostate cancer showed the most dramatic increase over the whole study period (AAPC +11.3%; 95% CI: 9.7-13.0), with an ASR of 61.7 per 105 in 2003-2008. In females, the most frequent cancers were of the uterine cervix, the breast and KS, with the former increasing along the whole study period (AAPC + 4.7%; 95% CI: 3.4-6) with an ASR of 62.0 per 105 in 2003-2008 as well as breast cancer (AAPC +6.5%; 95%CI: 4.3-8.7). Overall, the risk of cancer rose in both sexes during the study period, particularly among cancers associated with westernization of lifestyles (prostate, breast), combined with increasingly rising incidences or limited changes in cancers associated with infection and poverty (uterine cervix, liver). Moreover, the burden of AIDS-associated cancers has shown a marked increase.


Nanocrystal size distribution analysis from transmission electron microscopy images.
We propose a method, with minimal bias caused by user input, to quickly detect and measure the nanocrystal size distribution from transmission electron microscopy (TEM) images using a combination of Laplacian of Gaussian filters and non-maximum suppression. We demonstrate the proposed method on bright-field TEM images of an a-SiC:H sample containing embedded silicon nanocrystals with varying magnifications and we compare the accuracy and speed with size distributions obtained by manual measurements, a thresholding method and PEBBLES. Finally, we analytically consider the error induced by slicing nanocrystals during TEM sample preparation on the measured nanocrystal size distribution and formulate an equation to correct this effect.


New pathophysiological insights and modern treatment of IBD.
Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn's disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today's differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.


Interleukin-2: inception, impact, and implications.
Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.