Mitochondrial-derived N-formyl peptides: novel links between trauma, vascular collapse and sepsis.
Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses.


Stokes and anti-Stokes differential pulse pair based distributed Brillouin fiber sensor with double-sideband probe wave.
We propose and demonstrate a distributed Brillouin fiber sensor using Stokes and anti-Stokes differential pulse pair based on double- sideband probe wave, in which the two sidebands of probe wave are used to balance the power of two pump pulses. The spatial resolution is determined by the slightly width difference of the two balanced pulses, without Brillouin gain spectrum broadening. The pulses perform gain-loss process in optical field before the probe signal being detected, without any post-processing or extra measurement time. The proposed technique can achieve high spatial resolution, natural Brillouin gain spectrum linewidth, normal measurement time and long sensing range simultaneously.


Where Are the Disease-Associated eQTLs?
Most disease-associated variants, although located in putatively regulatory regions, do not have detectable effects on gene expression. One explanation could be that we have not examined gene expression in the cell types or conditions that are most relevant for disease. Even large-scale efforts to study gene expression across tissues are limited to human samples obtained opportunistically or postmortem, mostly from adults. In this review we evaluate recent findings and suggest an alternative strategy, drawing on the dynamic and highly context-specific nature of gene regulation. We discuss new technologies that can extend the standard regulatory mapping framework to more diverse, disease-relevant cell types and states.


Type 1 sodium-dependent phosphate transporter acts as a membrane potential-driven urate exporter.
SLC17A1 protein (NPT1) was the first identified member of the SLC17 phosphate transporter family, and is known to mediate Na(+)/inorganic phosphate (Pi) co-transport when expressed in Xenopus oocytes. Although this protein was suggested to be a renal polyspecific anion exporter, its transport properties were not well characterized. The clean biochemical approach revealed that proteoliposomes comprising purified NPT1 as the only protein source transport various organic anions such as urate, p-aminohippuric acid (PAH), and acetylsalicylic acid (aspirin) in a membrane potential (Δψ)-driven and Cl(-) -dependent manner. Human NPT1 carrying an SNP mutation, Thr269Ile, known to increase the risk of gout, exhibited 32% lower urate transport activity compared to the wild type protein, leading to the conclusion that NPT1 is the long searched for transporter responsible for renal urate excretion. In the present article, we summarized the history of identification of the urate exporter and its possible involvement in the dynamism of urate under physiological and pathological conditions.


Developmentally regulated expression of mouse HtrA3 and its role as an inhibitor of TGF-beta signaling.
The expression of mouse HtrA1 is developmentally regulated and restricted in embryo tissues which depend largely on TGF-beta signaling for their differentiation. We examined whether mouse HtrA3, another HtrA family member very close to HtrA1, shows similar expression patterns. HtrA3 and -1 were expressed mostly in the same embryonic organs but exhibited complementary patterns in various tissues; the lens epithelial cells in day 12.5 embryo expressed HtrA3 whereas the ciliary body and pigment retina expressed HtrA1. In the vertebrae of day 14.5 embryo, HtrA3 was expressed in the tail region, but HtrA1 was predominantly expressed in the thoracic and lumbar regions. Similar to HtrA1, HtrA3 bound to various TGF-beta proteins and inhibited the signaling of BMP-4, -2 and TGF-beta 1. HtrA3 did not inhibit signaling originated from a constitutively active BMP receptor, indicating that the inhibition occurred upstream of the cell surface receptor. HtrA3 also showed proteolytic activities indistinguishable from those of HtrA1 toward beta-casein and some extracellular matrix (ECM) proteoglycans. The protease activity was absolutely required for the TGF-beta signal inhibition activity. All these data suggest that HtrA3 and -1 have the overlapping biological activities but can function in complementary fashion in certain types of tissues.


Towards the prevention of behavioural and psychiatric disorders in people with intellectual disabilities.
Intervention for behavioural and psychiatric disorders in people with intellectual disabilities often only takes place once these conditions are well established and more resistant to change. As an alternative, this paper promotes a public health prevention model and maps out opportunities for intervention at primary, secondary and tertiary levels. The resulting model is partly derived from generic research into these issues and partly on specific evidence on interventions for people with intellectual disabilities; it also contains more theoretical considerations. The additional research that is necessary to demonstrate the efficacy of the interventions identified is also considered. Central to this proposal is a greater integration of issues for people with intellectual disabilities within much broader policy and research agendas.


Effects of Early Retirement Policy Changes on Working until Retirement: Natural Experiment.
Many European countries have implemented pension reforms to increase the statutory retirement age with the aim of increasing labor supply. However, not all older workers may be able or want to work to a very high age. Using a nation-wide register data of labor market transitions, we investigated in this natural experiment the effect of an unexpected change in the Dutch pension system on labor market behaviors of older workers. Specifically, we analyzed transitions in labor market positions over a 5-year period in two nation-wide Dutch cohorts of employees aged 60 years until they reached the retirement age (n = 23,703). We compared transitions between the group that was still entitled to receive early retirement benefits to a group that was no longer entitled to receive early retirement benefits. Results showed that the pension reform was effective in prolonging work participation until the statutory retirement age (82% vs. 61% at age 64), but also to a larger proportion of unemployment benefits in the 1950 cohort (2.0%-4.2%) compared to the 1949 cohort (1.4%-3.2%). Thus, while ambitious pension reforms can benefit labor supply, the adverse effects should be considered, especially because other studies have shown a link between unemployment and poor health.


The Phenomenon of Family Suicides: An Explorative Study into Consecutive 32 Incidents in Kerala.
Suicides rank high as the cause of human deaths. But research on whole family ending life is scanty. This study explored the family suicides in Kerala. All the family suicides reported from four central districts of Kerala State during the year 2000 were included. Cases were prospectively located from different sources. A research associate systematically gathered information, from survivors, family and key persons in the locality. 84 lives lost in 32 incidents involving 99 persons. No report from Muslim dominated district. Largest age group was 19 and below, others progressively decreased. Poisoning formed most frequent method; drowning, burns, hanging and wrist slashing followed. Suicide notes were left in half. Mental illness and physical illness were noted in five and eight incidents respectively. Financial crisis reported as the main reason. The SES of the deceased and their parents were same but half of the families were leading a life at a higher level than could be afforded. Warning signals noted in 12 incidents. Decision was taken by father and mother (17), mother (10) or father alone (5). The incidents came to the attention of others without long delay. Firm stand of the religion against suicides on individual reasons could explain absence of family suicides from Muslim dominated district. Selection of sure method and flawless execution explains high lethality. Presence of victims explains more loss of young lives and profile difference from reported suicide attempts. Opening up of avenues for higher dreaming due to globalisation and wider visual media could be a reason for living unaffordable standard of life and resulting financial difficulty. The warning signals were recognised, but not responded by others. Social support was strong within the family but was non-existing with outside. Strong social support could be pathological if it is narrow.


Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus.
Chronic, infected wounds typically contain multiple genera of bacteria, including Staphylococcus aureus, many of which are strong biofilm formers. Bacterial biofilms are thought to be a direct impediment to wound healing. New therapies that focus on a biofilm approach may improve the recovery and healing rate for infected wounds. In this study, cathelicidins and related short, synthetic peptides were tested for their anti-microbial effectiveness as well as their ability to inhibit the ability of S. aureus to form biofilms. The helical human cathelicidin LL-37 was tested against S. aureus, and was found to exhibit effective anti-microbial, anti-attachment as well as anti-biofilm activity at concentrations in the low μg/ml range. The effect of peptide chirality and associated protease-resistance was explored through the use of an all-D amino acid peptide, D-LL-37, and in turn compared to scrambled LL-37. Helical cathelicidins have been identified in other animals such as the Chinese cobra, Naja atra (NA-CATH). We previously identified an 11-residue imperfectly repeated pattern (ATRA motif) within the sequence of NA-CATH. A series of short peptides (ATRA-1, -2, -1A), as well as a synthetic peptide, NA-CATH:ATRA1-ATRA1, were designed to explore the significance of the conserved residues within the ATRA motif for anti-microbial activity. The CD spectrum of NA-CATH and NA-CATH:ATRA1-ATRA1 revealed the structural properties of these peptides and suggested that helicity may factor into their anti-microbial and anti-biofilm activities. The NA-CATH:ATRA1-ATRA1 peptide inhibits the production of biofilm by S. aureus in the presence of salt, exhibiting anti-biofilm activity at lower peptide concentrations than NA-CATH, LL-37 and D-LL-37; and demonstrates low cytoxicity against host cells but does not affect bacterial attachment. The peptides utilized in this anti-biofilm approach may provide templates for a new group of anti-microbials and potential future topical therapeutics for treating chronic wound infections.


Performance of formulae based estimates of glomerular filtration rate for carboplatin dosing in stage 1 seminoma.
Single cycle carboplatin, dosed by glomerular filtration rate (GFR), is standard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essential for correct dosing. Isotopic methods remain the gold standard for the determination of GFR. Formulae to estimate GFR have improved the assessment of renal function in non-oncological settings. We assessed the utility of these formulae for carboplatin dosing. We studied consecutive subjects receiving adjuvant carboplatin for stage 1 seminoma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diamine tetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using the Calvert formula. Theoretical carboplatin doses were calculated from estimated GFR using Chronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) formulae with additional correction for actual body surface area (BSA). Carboplatin doses calculated by formulae were compared with dose calculated by isotopic GFR; a difference <10% was considered acceptable. 115 patients were identified. Mean isotopic GFR was 96.9 ml/min/1.73 m(2). CG and CKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. The CKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA, performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patients predicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p=0.013); there were no predictors of the 40.5% receiving an excess dose. Our data support further evaluation of the CKD-EPI formula in this patient population but clinically significant variances in carboplatin dosing occur using non-isotopic methods of GFR estimation. Isotopic determination of GFR should remain the recommended standard for carboplatin dosing when accuracy is essential.


Muscle dysmorphia: a critical review of the proposed criteria.
While body-image related disorders such as anorexia nervosa have focused on thinness, only recently have clinical criteria for a disorder that centers around muscularity--muscle dysmorphia--been proposed. An individual affected by muscle dysmorphia is overly concerned with his or her degree of muscularity. This preoccupation is manifested in the individual's behavior (excessive weight lifting, excessive attention to diet, social impairment). This article examines the historical aspects and proposed criteria for muscle dysmorphia and contrasts them with those of anorexia nervosa. While the authors of the proposed criteria have suggested that muscle dysmorphia be classified as a subcategory of body dysmorphic disorder, both the historical and clinical aspects of this syndrome are more consistent with its classification as an obsessive-compulsive disorder.


Induction of Alzheimer-specific Tau epitope AT100 in apoptotic human fetal astrocytes.
In Alzheimer's and other neurodegenerative diseases, hyperphosphorylated tau accumulates in affected neuronal and glial cells in the form of paired helical filaments (PHFs). This tau binds antibody AT100, which recognizes the double phosphorylation site (Thr212/Ser214) that is not present in normal biopsy tau. In primary cultures, highly enriched (>98%) in astrocytes of human fetal brain, three polypeptides of 52, 64, and 70 kD showed immunoreactivity with tau antibodies against non-phosphorylated epitopes, accounting for 88, 12, and <1%, respectively, of the total reactivity. All three polypeptides were phosphorylated at the PHF-1 epitope but not at the epitopes Tau-1, 12E8, AT8, and AT100. Treatment of cultures with okadaic acid resulted in apoptosis characterized by the blebbing of the plasma membrane, condensation of nuclear chromatin, and fragmentation of the nucleus. This treatment also resulted in a 3- to 5-fold increase in the content of both tau protein and phosphorylation. The increases were observed in all phosphorylation sites examined, and included the AT100 site. The AT100 site has been proposed to be generated by protein kinase B/Akt and Cdc2. Since okadaic acid can induce an AD-like hyperphosphorylated state of normal tau in primary cultures of human brain cells, a simple cellular model is available permitting study of self-aggregation of tau and phosphorylation events characteristic of neurodegeneration.


Expectations of postgraduate nursing students: an inquiry.
Postgraduate supervision in South Africa currently takes place in the context of university transformation with a notable increase in concern for quality. The latter is determined by the extent to which students' expectations within a supervisory practice are met. This study investigated students' expectations regarding their research supervision in a postgraduate nursing programme. A 48-item questionnaire was mailed to 24 postgraduate students, of which 22 (92%) responded, to determine their expectations within a supervisory relationship. Items in the questionnaire included students' perceptions of the responsibilities of the institution, the department, the supervisor and students' responsibilities regarding their supervised postgraduate studies in the School of Nursing Science. Descriptive statistics, namely frequencies and percentages for categorical data and means and standard deviations or medians and percentiles for continuous data, were calculated. Findings indicate that more than 80% of the postgraduate students in the study expected the university and the department to provide them with structures that would enable them to succeed in their studies. They also believed that the student had a major role to play in ensuring that studies were completed. Recommendations included making a code of practice for postgraduate supervision available to students and the use of a learning contract to clarify roles and expectations in the supervisory process. It was also recommended that supervisors should be trained to supervise students.


Antibody response to Plasmodium vivax antigens in Fy-negative individuals from the Colombian Pacific coast.
The Duffy antigen (Fy) is necessary for Plasmodium vivax invasion of human erythrocytes. Some populations have a highly prevalent Fy-negative phenotype; such persons are naturally protected from P. vivax blood infection but are expected to completely support the P. vivax pre-erythrocytic cycle, representing a valuable model for studying the immune response during these parasitic stages. We typed 214 individuals, mostly Afro-Colombians, from a P. vivax-endemic area for Fy expression and determined the antibody response to P. vivax pre-erythrocytic (sporozoites and CS) and blood-stage antigens (blood forms, P. vivax merozoite surface protein 1, and P. vivax Duffy binding protein [PvDBP]). Antibody titers to P. vivax circumsporozoite protein, P11, and N-terminal peptides and the number of responders were similar in Fy-negative and Fy-positive individuals. The number of responders to sporozoites, blood forms, and PvDBP were different between these groups. Thus, Fy-negative individuals from malaria-endemic areas can be used to study the immune response to the P. vivax liver phase without interference of the erythrocytic cycle.


Stress-induced surface instabilities and defects in thin films sputter deposited on compliant substrates.
Existing analyses predict that thin metal films deposited on compliant substrates are subject to a variety of surface instabilities, such as wrinkles, folds, creases, etc., that become more prominent with increased compressive residual stress. Under compressive stress, cracks have been assumed to form only when the interfacial strength is weak, allowing the film to detach from the substrate. In this work, we demonstrate that cracks also form on surfaces under compressive mismatch strain when the interface is strong. In particular, we consider metal alloy films sputter deposited under bias on elastomers with different thicknesses, curing temperatures or surface treatments. The deposition parameters created residual compressive strains and strong adhesion in the bilayers. Samples without surface treatment formed wrinkles and through-thickness cracks at 0.25-0.4% mismatch strains. Only through-thickness cracks were observed in UV treated samples. The crack spacing was found to decrease by a factor of 4 when the surface was UV treated and by a factor of 3 as the elastomer thickness decreased from 30 to 6 μm. Cracks penetrated through the elastomer, 15-30 times deeper than the film thickness, and formed in all samples with a brittle coating. A numerical model was developed to explain the formation of through-thickness cracks and wrinkles under applied compressive mismatch strains. The model suggests that cracks can initiate from the peak of wrinkles when the critical fracture strength of the coating is exceeded. For the UV treated samples, through-thickness cracks are possibly impacted by the formation of an embrittled near surface PDMS layer.


A semi-combinatorial approach for investigating polycatenar ligand-controlled synthesis of rare-earth fluoride nanocrystals.
Rare-earth nanocrystals (RE NCs) are a valuable class of nanomaterials due to their ability to bring the attractive properties of rare earth bulk crystals to biomedical applications and solution-processable engineering. Of the bottom-up synthesis approaches, solvothermal methods yield highly crystalline and monodisperse RE NCs. Herein, we report a polycatenar ligand controlled synthesis of RE NCs using a semi-combinatorial approach with a microreactor setup that enables the investigation of the influences of several reaction parameters on the growth of the RE NCs. This approach enabled the discovery of conditions that yield highly monodisperse elongated plates with neutral, positive, and negative curvatures, as well as provide evidence of the formation of chiral morphologies.


Two potato proteins, including a novel RING finger protein (HIP1), interact with the potyviral multifunctional protein HCpro.
Potyviral helper-component proteinase (HCpro) is a multifunctional protein exerting its cellular functions in interaction with putative host proteins. In this study, cellular protein partners of the HCpro encoded by Potato virus A (PVA) (genus Potyvirus) were screened in a potato leaf cDNA library using a yeast two-hybrid system. Two cellular proteins were obtained that interact specifically with PVA HCpro in yeast and in the two in vitro binding assays used. Both proteins are encoded by single-copy genes in the potato genome. Analysis of the deduced amino acid sequences revealed that one (HIP1) of the two HCpro interactors is a novel RING finger protein. The sequence of the other protein (HIP2) showed no resemblance to the protein sequences available from databanks and has known biological functions.


Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia.
Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged <5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a 2-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10; interquartile range [IQR]: 0.03-0.19) than those with CM (0.24; IQR: 0.14-0.69; P=0.006) or asymptomatic malaria (0.19; IQR: 0.09-0.46; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL; IQR: 4.7-49.8) and hepcidin/ferritin ratios (0.03; IQR: 0.01-0.22) than those with NTS alone (105.8 ng/mL; IQR: 17.3-233.3; P=0.02 and 0.31; IQR: 0.06-0.66; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole, we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.


Coexistence of intracranial and spinal cavernous malformations: a study of prevalence and natural history.
The purpose of this study was to examine the prevalence of intracranial cavernous malformations (CMs) in a large series of predominantly Caucasian patients with spinal cord CMs. The authors also studied the natural history of spinal CMs in patients who were treated nonoperatively. The medical records of 67 consecutive patients (32 female and 35 male patients) in whom a spinal CM was diagnosed between 1994 and 2002 were reviewed. The patients' mean age at presentation was 50 years (range 13-82 years). Twenty-five patients underwent resection of the lesion. Forty-two patients in whom the spinal CM was diagnosed using magnetic resonance (MR) imaging were followed expectantly. Thirty-three (49%) of 67 patients underwent both spinal and intracranial MR imaging. All available imaging studies were reviewed to determine the coexistence of an intracranial CM. Fourteen (42%) of the 33 patients with spinal CMs who underwent intracranial MR imaging harbored at least one cerebral CM in addition to the spinal lesion. Six (43%) of these 14 patients did not have a known family history of CM. Data obtained during the long-term follow-up period (mean 9.7 years, total of 319 patient-years) were available for 33 of the 42 patients with a spinal CM who did not undergo surgery. Five symptomatic lesional hemorrhages (neurological events), four of which were documented on neuroimaging studies, occurred during the follow-up period, for an overall event rate of 1.6% per patient per year. No patient experienced clinically significant neurological deficits due to recurrent hemorrhage. As many as 40% of patients with a spinal CM may harbor a similar intracranial lesion, and approximately 40% of patients with coexisting spinal and intracranial CMs may have the nonfamilial (sporadic) form of the disease. Patients with symptomatic spinal CMs who are treated nonoperatively may have a small risk of clinically significant recurrent hemorrhage. The findings will aid in evaluation of surveillance images and in counseling of patients with spinal CMs, irrespective of family history.


The contribution of semantic memory to the recognition of basic emotions and emotional valence: Evidence from the semantic variant of primary progressive aphasia.
There is compelling evidence that semantic memory is involved in emotion recognition. However, its contribution to the recognition of emotional valence and basic emotions remains unclear. We compared the performance of 10 participants with the semantic variant of primary progressive aphasia (svPPA), a clinical model of semantic memory impairment, to that of 33 healthy participants using three experimental tasks assessing the recognition of: 1) emotional valence conveyed by photographic scenes, 2) basic emotions conveyed by facial expressions, and 3) basic emotions conveyed by prosody sounds. Individuals with svPPA showed significant deficits in the recognition of emotional valence and basic emotions (except happiness and surprise conveyed by facial expressions). However, the performance of the two groups was comparable when the performance on tests assessing semantic memory was added as a covariate in the analyses. Altogether, these results suggest that semantic memory contributes to the recognition of emotional valence and basic emotions. By examining the recognition of emotional valence and basic emotions in individuals with selective semantic memory loss, our results contribute to the refinement of current theories on the role of semantic memory in emotion recognition.


Snake Venom Gland Organoids.
Wnt dependency and Lgr5 expression define multiple mammalian epithelial stem cell types. Under defined growth factor conditions, such adult stem cells (ASCs) grow as 3D organoids that recapitulate essential features of the pertinent epithelium. Here, we establish long-term expanding venom gland organoids from several snake species. The newly assembled transcriptome of the Cape coral snake reveals that organoids express high levels of toxin transcripts. Single-cell RNA sequencing of both organoids and primary tissue identifies distinct venom-expressing cell types as well as proliferative cells expressing homologs of known mammalian stem cell markers. A hard-wired regional heterogeneity in the expression of individual venom components is maintained in organoid cultures. Harvested venom peptides reflect crude venom composition and display biological activity. This study extends organoid technology to reptilian tissues and describes an experimentally tractable model system representing the snake venom gland.


Immediate Single-Stage Cranioplasty Following Calvarial Resection for Benign and Malignant Skull Neoplasms Using Customized Craniofacial Implants.
Craniectomy defects following resection of calvarial lesions are most often reconstructed using on-table manufacturing. With the advent of computer-aided design/manufacturing and customized craniofacial implants (CCIs), there seems to be more suited alternatives. In this study, the authors report their institutional experience and outcome using immediate, single-stage, CCI-based reconstruction for benign and malignant skull neoplasm defects. A retrospective review of a prospectively maintained database of all implant cranioplasties performed between 2011 and 2014, by a single craniofacial surgeon at a tertiary academic medical institution was performed. Preoperative and postoperative computed tomography scans with 3D reconstruction were performed for the purpose of assessing adequate resection and reconstructive outcomes. Primary endpoints included length of surgery, predicted defect versus postoperative implant surface area, contour irregularities, and complications. Of the 108 patients with cranioplasty identified, 7 patients were found to undergo immediate CCI-based reconstruction for calvarial neoplasms; 4 patients (4/7, 57%) presented with malignant pathology. All defects were >5 cm2. As compared with their original size, all implants were modified intraoperatively between 0.2% and 40.8%, with a mean of 13.8%. With follow-up ranging between 1 and 16 months, there were no implant-related complications identified. The immediate and long-term aesthetic results, as well as patient satisfaction, were ideal. With this preliminary experience, the authors have successfully demonstrated that immediate customized implant reconstructive techniques, by way of intraoperative modification, are both safe and feasible for benign and malignant skull neoplasms. The authors believe that with wider acceptance of this multidisciplinary approach and increased surgeon familiarity, this technique will soon become the reconstructive standard of care.


New Hepatitis C Drugs Are Very Costly And Unavailable To Many State Prisoners.
Prisoners bear much of the burden of the hepatitis C epidemic in the United States. Yet little is known about the scope and cost of treating hepatitis C in state prisons-particularly since the release of direct-acting antiviral medications. In the forty-one states whose departments of corrections reported data, 106,266 inmates (10 percent of their prisoners) were known to have hepatitis C on or about January 1, 2015. Only 949 (0.89 percent) of those inmates were being treated. Prices for a twelve-week course of direct-acting antivirals such as sofosbuvir and the combination drug ledipasvir/sofosbuvir varied widely as of September 30, 2015 ($43,418-$84,000 and $44,421-$94,500, respectively). Numerous corrections departments received smaller discounts than other government agencies did. To reduce the hepatitis C epidemic, state governments should increase funding for treating infected inmates. State departments of corrections should consider collaborating with other government agencies to negotiate discounts with pharmaceutical companies and with qualified health care facilities to provide medications through the federal 340B Drug Discount Program. Helping inmates transition to providers in the community upon release can enhance the gains achieved by treating hepatitis C in prison.


Multimodal Imaging-Guided Antitumor Photothermal Therapy and Drug Delivery Using Bismuth Selenide Spherical Sponge.
Elaborately designed biocompatible nanoplatforms simultaneously having diverse therapeutic and imaging functions are highly desired for biomedical applications. Herein, a Bi2Se3 nanoagent with a special morphology as a nanoscale spherical sponge (NSS) has been fabricated and investigated in vitro and in vivo. The highly porous NSS exhibits strong, steady, and broad-band absorbance in the near-infrared range as well as high efficiency and stability of photothermal conversion, resulting in high antitumor efficacy for photothermal therapy (PTT). Together with a high X-ray attenuation coefficient (218% that of the clinically used iopromide), the NSS shows excellent performance on triple-modal high-contrast imaging, including X-ray-computed tomography, multispectral optoacoustic tomography, and infrared thermal imaging. Furthermore, the high surface area and porous structure impart the NSS a competent drug loading capability as high as 600% of that on Bi2Se3 nanoplates, showing a bimodal pH/photothermal sensitive drug release and pronounced synergetic effects of thermo-chemotherapy with a tumor inhibition ratio even higher than that of PTT alone (∼94.4% vs ∼66.0%). Meanwhile, the NSS is highly biocompatible with rather low in vitro/in vivo toxicity and high stability, at variance with easily oxidized Bi2Se3 nanoagents reported previously. Such biocompatible single-component theranostic nanoagents produced by a facile synthesis and highly integrated multimodal imaging and multiple therapeutic functions may have substantial potentials for clinical antitumor applications. This highly porous nanostructure with a large fraction of void space may allow versatile use of the NSS, for example, in catalysis, gas sensing, and energy storage, in addition to accommodating drugs and other biomolecules.


Spatial and temporal distribution of soil-transmitted helminth infection in sub-Saharan Africa: a systematic review and geostatistical meta-analysis.
Interest is growing in predictive risk mapping for neglected tropical diseases (NTDs), particularly to scale up preventive chemotherapy, surveillance, and elimination efforts. Soil-transmitted helminths (hookworm, Ascaris lumbricoides, and Trichuris trichiura) are the most widespread NTDs, but broad geographical analyses are scarce. We aimed to predict the spatial and temporal distribution of soil-transmitted helminth infections, including the number of infected people and treatment needs, across sub-Saharan Africa. We systematically searched PubMed, Web of Knowledge, and African Journal Online from inception to Dec 31, 2013, without language restrictions, to identify georeferenced surveys. We extracted data from household surveys on sources of drinking water, sanitation, and women's level of education. Bayesian geostatistical models were used to align the data in space and estimate risk of with hookworm, A lumbricoides, and T trichiura over a grid of roughly 1 million pixels at a spatial resolution of 5 × 5 km. We calculated anthelmintic treatment needs on the basis of WHO guidelines (treatment of all school-aged children once per year where prevalence in this population is 20-50% or twice per year if prevalence is greater than 50%). We identified 459 relevant survey reports that referenced 6040 unique locations. We estimate that the prevalence of hookworm, A lumbricoides, and T trichiura among school-aged children from 2000 onwards was 16·5%, 6·6%, and 4·4%. These estimates are between 52% and 74% lower than those in surveys done before 2000, and have become similar to values for the entire communities. We estimated that 126 million doses of anthelmintic treatments are required per year. Patterns of soil-transmitted helminth infection in sub-Saharan Africa have changed and the prevalence of infection has declined substantially in this millennium, probably due to socioeconomic development and large-scale deworming programmes. The global control strategy should be reassessed, with emphasis given also to adults to progress towards local elimination. Swiss National Science Foundation and European Research Council.


The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region.
Acute lung injury (ALI) is a life-threatening condition in critically ill patients. Injury to the alveolar epithelium is a critical event in ALI, and accumulating evidence suggests that it is linked to proapoptotic Fas/FasL signals. Active soluble FasL (sFasL) is detectable in the bronchoalveolar lavage (BAL) fluid of patients with ALI, but the mechanisms controlling its bioactivity are unclear. We therefore investigated how the structure of sFasL influences cellular activation in human and mouse lungs and the role of oxidants and proteases in modifying sFasL activity. The sFasL in BAL fluid from patients with ALI was bioactive and present in high molecular weight multimers and aggregates. Oxidants generated from neutrophil myeloperoxidase in BAL fluid promoted aggregation of sFasL in vitro and in vivo. Oxidation increased the biological activity of sFasL at low concentrations but degraded sFasL at high concentrations. The amino-terminal extracellular stalk region of human sFasL was required to induce lung injury in mice, and proteolytic cleavage of the stalk region by MMP-7 reduced the bioactivity of sFasL in human cells in vitro. The sFasL recovered from the lungs of patients with ALI contained both oxidized methionine residues and the stalk region. These data provide what we believe to be new insights into the structural determinants of sFasL bioactivity in the lungs of patients with ALI.


Blood Count of Eosinophil Polymorphonuclear Leucocytes and Bronchial Hyperreactivity in Chronic Obstructive Pulmonary Disease.
Polymorphonuclear eosinophil leucocytes (eosinophils) are found in increased numbers in the circulation and sputum in asthma patients, usually in relation to the severity of asthma but it is the question whether they have a significant role in the development and level of bronchial hyperreactivity in patients with chronic obstructive pulmonary disease (COPD). to show the role of the eosinophils in the development and level of BHR in patients with COPD and so in the severity of illness. We observed 240 patients with COPD treated in Clinic for Pulmonary Diseases and TB «Podhrastovi» Sarajevo during five years: from 2012 to 2016. They were divided into groups and subgroups according to the first registration of BHR in the course of illness and to the number of exacerbations of the disease in one year. The number of blood eosinophils was measured at the onset of exacerbation of the disease before switching on any therapy, at the beginning and at the end of the research. we did not find any significant difference in the eosinophil blood count between the COPD patients with and without BHR, nor according to the time of the first registration of BHR in the course of illness nor according to the number of exacerbations of illness per one year. There was not statistically significant difference in eosinophil count (increase-drop) within any of the groups or subgroups, or between the groups and subgroups between the first and last test. There is not significant correlation between the eosinophil blood count and the level of BHR, number of exacerbations and the severity of COPD.


Prevalence of Drug Prescriptions and Potential Safety in Patients with Cirrhosis: A Retrospective Real-World Study.
Patients with cirrhosis are at risk for adverse drug reactions (ADRs) due to altered pharmacokinetics and pharmacodynamics. We aimed to determine the prevalence of drug prescriptions and the potential safety of these prescriptions in a real-world cohort of patients with cirrhosis. This was a retrospective cohort study based on linked real-world data from the Out-patient Pharmacy Database and the Hospitalisation Database of the PHARMO Database Network. Patients with a diagnosis of cirrhosis between January 1998 and December 2015 were included. Follow-up ended when the patient underwent a liver transplant, died, transferred out of the database, or on 31 December 2015. Prescription data were derived from a community pharmacy database and were compared with our previously developed safety recommendations for 209 drugs. In total, 5618 patients were included and followed for a median of 3 years (interquartile range [IQR] 1-7). In the first year after the diagnosis, patients used a median of nine drugs (IQR 5-14), with proton pump inhibitors (prevalence 53.9%), aldosterone antagonists (43.6%), and sulfonamide diuretics (41.3%) being the most commonly used drug groups. Almost half (48.3%) of 102,927 prescriptions consisted of drugs with a safety recommendation. The prevalence of potentially unsafe drug use was 60.0% during the total follow-up. Three nonsteroidal anti-inflammatory drugs (NSAIDs) were among the five most commonly used potentially unsafe drugs. Patients with cirrhosis use a large number of drugs. Almost two-thirds of patients in our cohort used potentially unsafe drugs. To prevent ADRs in these frail patients, personalised pharmacotherapy is necessary.


Voice-related complaints and vocal and nonvocal habits of Hindustani classical singers: a questionnaire-based study.
This study aimed to profile voice-related complaints, as well as vocal and nonvocal habits among Hindustani classical singers. Cross-sectional study design was used to profile voice-related complaints and vocal and nonvocal habits among Hindustani classical singers. Phase I involved developing a questionnaire for exploring vocal and nonvocal habits. Phase II involved the administration of the survey to 61 Hindustani classical singers. Based on the overall findings, 41% of singers reported of at least three vocal symptoms. The most common vocal symptoms included out of breath while singing, felling tired after singing and experiencing tension or tightness in neck/shoulder. The commonly reported vocal habits included excessive phone use, loud coughing/sneezing, throat clearing and excessive speaking. A high consumption of caffeinated beverages and spicy food were also reported. This study helps to highlight the voice-related complaints and vocal and nonvocal habits of Hindustani classical singers. Further studies, need to explore the prevalence of voice problems incorporating other dimensions of voice evaluation such as acoustic, auditory perceptual, self-reported and laryngeal examination.


A comparison of the sensitivity and fecal egg counts of the McMaster egg counting and Kato-Katz thick smear methods for soil-transmitted helminths.
The Kato-Katz thick smear (Kato-Katz) is the diagnostic method recommended for monitoring large-scale treatment programs implemented for the control of soil-transmitted helminths (STH) in public health, yet it is difficult to standardize. A promising alternative is the McMaster egg counting method (McMaster), commonly used in veterinary parasitology, but rarely so for the detection of STH in human stool. The Kato-Katz and McMaster methods were compared for the detection of STH in 1,543 subjects resident in five countries across Africa, Asia and South America. The consistency of the performance of both methods in different trials, the validity of the fixed multiplication factor employed in the Kato-Katz method and the accuracy of these methods for estimating 'true' drug efficacies were assessed. The Kato-Katz method detected significantly more Ascaris lumbricoides infections (88.1% vs. 75.6%, p<0.001), whereas the difference in sensitivity between the two methods was non-significant for hookworm (78.3% vs. 72.4%) and Trichuris trichiura (82.6% vs. 80.3%). The sensitivity of the methods varied significantly across trials and magnitude of fecal egg counts (FEC). Quantitative comparison revealed a significant correlation (Rs >0.32) in FEC between both methods, and indicated no significant difference in FEC, except for A. lumbricoides, where the Kato-Katz resulted in significantly higher FEC (14,197 eggs per gram of stool (EPG) vs. 5,982 EPG). For the Kato-Katz, the fixed multiplication factor resulted in significantly higher FEC than the multiplication factor adjusted for mass of feces examined for A. lumbricoides (16,538 EPG vs. 15,396 EPG) and T. trichiura (1,490 EPG vs. 1,363 EPG), but not for hookworm. The McMaster provided more accurate efficacy results (absolute difference to 'true' drug efficacy: 1.7% vs. 4.5%). The McMaster is an alternative method for monitoring large-scale treatment programs. It is a robust (accurate multiplication factor) and accurate (reliable efficacy results) method, which can be easily standardized.


A shortened course of parenteral antibiotic therapy in the management of acute septic arthritis of the hip.
We reviewed 20 consecutive patients with a culture-proven acute septic arthritis of the hip who were treated with a shortened course of parenteral antibiotic therapy after a surgical drainage. Patients were switched over to an oral antibiotic when they showed clinical improvement. Sixteen of the 20 patients had parenteral antibiotic therapy of <10 days, whereas nine of these patients received <7 days of parenteral therapy (mean, 8.2 days). No recurrence of infection, readmission, or osteomyelitis was observed after the discharge. At the follow-up interview (mean, 32 months), 18 patients were completely asymptomatic, and two patients had occasional hip pain with activity but no physical limitations. All 20 patients had normal hip range of motion and gait. Their latest radiographs (mean, 26 months) revealed 11 patients with normal findings, six patients with mild coxa magna, and three patients with a smaller ossific nucleus compared with the unaffected side. We conclude that a community-acquired, acute gram-positive septic arthritis of the hip can be managed safely with a surgical drainage and a shortened course of parenteral antibiotic therapy, which can be switched over to an oral therapy based on the patient's response to the therapy.


Exome sequencing in one family with gastric- and rectal cancer.
Heritable factors are well known to increase the risk of cancer in families. Known susceptibility genes account for a small proportion of all colorectal cancer cases. The aim of this study was to identify the genetic background in a family suggested to segregate a dominant cancer syndrome with a high risk of rectal- and gastric cancer. We performed whole exome sequencing in three family members, 2 with rectal cancer and 1 with gastric cancer and followed it up in additional family members, other patients and controls. We identified 12 novel non-synonymous single nucleotide variants, which were shared among 5 affected members of this family. The mutations were found in 12 different genes; DZIP1L, PCOLCE2, IGSF10, SUCNR1, OR13C8, EPB41L4B, SEC16A, NOTCH1, TAS2R7, SF3A1, GAL3ST1, and TRIOBP. None of the mutations was suggested as a high penetrant mutation. It was not possible to completely rule out any of the mutations as contributing to disease, although seven were more unlikely than the others. Neither did we rule out the effect of all thousands of intronic, intergenic and synonymous variants shared between the three persons used for exome sequencing. We propose this family, suggested to segregate dominant disease, could be an example of complex inheritance.


Costs of Transmission Assessment Surveys to Provide Evidence for the Elimination of Lymphatic Filariasis.
To reach the global goal of elimination of lymphatic filariasis as a public health problem by 2020, national programs will have to implement a series of transmission assessment surveys (TAS) to determine prevalence of the disease by evaluation unit. It is expected that 4,671 surveys will be required by 2020. Planning in advance for the costs associated with these surveys is essential to ensure that the required resources are available for this essential program activity. Retrospective cost data was collected from reports from 13 countries which implemented a total of 105 TAS surveys following a standardized World Health Organization (WHO) protocol between 2012 and 2014. The median cost per survey was $21,170 (including the costs for rapid diagnostic tests [RDTs]) and $9,540 excluding those costs. Median cost per cluster sampled (without RDT costs) was $101. Analysis of costs (excluding RDTs) by category showed that the main cost drivers were personnel and travel. Transmission assessment surveys are critical to collect evidence to validate elimination of LF as a public health problem. National programs and donors can use the costing results to adequately plan and forecast the resources required to undertake the necessary activities to conduct high-quality transmission assessment surveys.


Does the practice of blood film microscopy for detection and quantification of malaria parasites in northwest Ethiopia fit the standard?
The diagnosis of malaria in clinical laboratories mainly depends on blood smear microscopy and this technique remains the most widely used in Ethiopia. Despite the importance of blood smear microscopy for patient's diagnosis and treatment, little effort has been made to precisely determine and identify sources of error in malaria smear microscopic diagnosis and quantification of parasitaemia. The main objective of the present study was to assess the laboratory practices of health care laboratories carrying out blood films microscopy. A cross sectional study was conducted in northwestern Ethiopia involving 29 health care institutes. A structured and pretested questionnaire were used to collect relevant information on the physical conditions, laboratory logistics and laboratory practices carrying out blood smear microscopy. There was inadequacy of laboratory reagents, guidelines and materials. Most of the health institutes have been practicing re-utilization of microscope slides for malaria microscopy. The technical procedure (preparing of reagents, making of blood films and staining of the slides) were found to be below the standard in 50% of the health institutes. Refresher training and quality assessment has been done only in two and six of the health institutes in the past five years, respectively. In most of the health care laboratories studied, availability of laboratory logistics and technical practices for malaria microscopy were found to be below the standard set by World Health Organization. Improving logistics access for malaria microscopy at all level of health care is important to increase accuracy of diagnosis and quantification of malaria parasites. Moreover, continued training and regular supervision of the staff and implementation of quality control program in the area is also crucial.


Facile synthesis of Koser's reagent and derivatives from iodine or aryl iodides.
The first one-pot synthesis of neutral and electron-rich [hydroxy(tosyloxy)iodo]arenes (HTIBs) from iodine and arenes is presented, thereby avoiding the need for expensive iodine(III) precursors. A large set of HTIBs, including a polyfluorinated analogue, can be obtained from the corresponding aryl iodide under the same conditions. The reaction proceeds under mild conditions, without excess reagents, and is fast and high-yielding. Together, the two presented routes give access to a wide range of HTIBs, which are useful reagents in a variety of synthetic transformations.


Human connectomics.
Recent advances in non-invasive neuroimaging have enabled the measurement of connections between distant regions in the living human brain, thus opening up a new field of research: Human connectomics. Different imaging modalities allow the mapping of structural connections (axonal fibre tracts) as well as functional connections (correlations in time series), and individual variations in these connections may be related to individual variations in behaviour and cognition. Connectivity analysis has already led to a number of new insights about brain organization. For example, segregated brain regions may be identified by their unique patterns of connectivity, structural and functional connectivity may be compared to elucidate how dynamic interactions arise from the anatomical substrate, and the architecture of large-scale networks connecting sets of brain regions may be analysed in detail. The combined analysis of structural and functional networks has begun to reveal components or modules with distinct patterns of connections that become engaged in different cognitive tasks. Collectively, advances in human connectomics open up the possibility of studying how brain connections mediate regional brain function and thence behaviour.


Cannabis: An Overview of its Adverse Acute and Chronic Effects and its Implications.
In many communities, cannabis is perceived as a low-risk drug, leading to political lobbying to decriminalise its use. Acute and chronic cannabis use has been shown to be harmful to several aspects of psychological and physical health, such as mood states, psychiatric outcomes, neurocognition, driving and general health. Furthermore, cannabis is highly addictive, and the adverse effects of withdrawal can lead to regular use. These in turn have adverse implications for public safety and health expenditure. Although the cannabinoid cannabidiol (CBD) has been shown to have positive health outcomes with its antioxidant, anticonvulsant, anti-inflammatory and neuroprotective properties, high-potency cannabis is particularly damaging due to its high tetrahydrocannabinol (THC), low CDB concentration. It is this high-potency substance that is readily available recreationally. While pharmaceutical initiatives continue to investigate the medical benefits of CDB, "medicinal cannabis" still contains damaging levels of THC. Altogether, we argue there is insufficient evidence to support the safety of cannabis and its subsequent legalisation for recreational use. Furthermore, its use for medicinal purposes should be done with care. We argue that the public conversation for the legalisation of cannabis must include scientific evidence for its adverse effects.


Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1.
To test the hypothesis that deficiency in expression of the transcription factor, HIF-1, renders tumours more radioresponsive than HIF-1 proficient tumours. Tumours comprising mouse hepatoma cells lacking HIF-1beta (and thereby HIF-1 function) were grown in nude mice and radiation-induced growth delay compared with that seen for wild-type tumours and tumours derived from HIF-1beta negative cells where HIF-1 function had been restored. The xenografts that lack HIF-1 activity take longer to establish their growth and are more radioresponsive than both parental xenografts and those with restored HIF-1 function. Pre-treatment of the HIF-1 deficient xenografts with the hypoxic radiosensitizer misonidazole, had little effect on radioresponse. In contrast this treatment radiosensitized the parental xenografts. In spite of this, no difference in oxygenation status was found between the tumour types as measured by Eppendorf O(2)-electrodes and by binding of the hypoxic cell marker NITP. Admixing wild type and HIF-1 deficient cells in the same tumour at ratios of 1 in 10 and 1 in 100 restores the growth of the mixed tumours to that of a 100% HIF-1 proficient cell population. However, when comparing the effects of radiation on the mixed tumours, radioresponsiveness is maintained in those tumours containing the high proportion of HIF-1 deficient cells. The differences in radioresponse do not correlate with tumour oxygenation, suggesting that the hypoxic cells within the HIF-1 deficient tumours do not contribute to the outcome of radiotherapy. Thus, hypoxia impacts on tumour radioresponsiveness not simply because of the physio-chemical mechanism of oxygen with radiation-induced radicals causing damage 'fixation', but also because hypoxia/HIF-1 promotes expression of genes that allow tumour cells to survive under these adverse conditions. Further, the results from the cell mixing experiments uncouple the growth promoting effects of HIF-1 and the underlying mechanism by which HIF-1 may increase radiation resistance in solid tumours.


Glutamine metabolism in skeletal muscle of glucocorticoid-treated rats.
1. The effect of dexamethasone (30 micrograms day-1 100 g-1 body weight) on the regulation of glutamine metabolism was studied in skeletal muscles of rats after 9 days of treatment. 2. Dexamethasone resulted in negative nitrogen balance, and produced increases in the plasma concentrations of alanine (23.4%) and insulin (158%) but a decrease in the plasma concentration of glutamine (28.7%). 3. Dexamethasone treatment increased the rate of glutamine production in muscle, skin and adipose tissue preparations, with muscle production accounting for over 90% of total glutamine produced by the hindlimb. 4. Blood flow and arteriovenous concentration difference measurements across the hindlimb showed an increase in the net exchange rates of glutamine (25.3%) and alanine (90.5%) in dexamethasone-treated rats compared with corresponding controls. 5. Dexamethasone treatment produced significant decreases in the concentrations of skeletal muscle glutamine (51.8%) and 2-oxoglutarate (50.8%). The concentrations of alanine (16.2%), pyruvate (45.9%), ammonia (43.3%) and inosine 5'-phosphate (141.8%) were increased. 6. The maximal activity of glutamine synthetase was increased (21-34%), but there was no change in that of glutaminase, in muscles of dexamethasone-treated rats. 7. It is concluded that glucocorticoid administration enhances the rates of release of both glutamine and alanine from skeletal muscle of rats (both in vitro and in vivo). This may be due to changes in efflux and/or increased intracellular formation of glutamine and alanine.


Age, period and cohort effects on time trends in alcohol consumption in the Swedish adult population 1979-2011.
In Sweden, alcohol abstention has increased over the last 20 years and consumption has recently decreased after a peak in 2004. To understand the dynamics of these trends the present study aims at estimating age, period and cohort (APC) effects on trends in alcohol use prevalence as well as overall and beverage-specific volume of drinking over the last three decades. APC analysis of seven cross-sectional surveys from 1979 to 2011 was conducted using cross-classified random effects models (CCREMs) by gender. The nationally representative samples comprised 77,598 respondents aged 16-80 years. Outcome measures were 30-day prevalence of alcohol use and overall as well as beverage-specific alcohol volume. Trends in prevalence, overall and beverage-specific volume were significantly affected by APC. The period effects of prevalence and overall volume show a small decline after an increase up to the year 2005. Mean beer and wine volume levelled off after a peak in 2005 and volume of spirits drinking decreased constantly. Predicted alcohol prevalence rates in male cohorts (1945-1985) remained generally at the same level, while they declined in post-World War II female generations. Results point to high overall and beverage-specific consumption among cohorts born in the 1940s, 1950s and 1980s. High consuming cohorts of the 1940-1950s were key in rising consumption up to 2005. Progression through the life course of these cohorts, a decrease in prevalence and drinking volume in successive cohorts seem to have contributed to the recent downward trend in alcohol use in Sweden.


Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets.
Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register β sheets, which may constitute one of the toxic species in aggregation related diseases. Here we sought to determine the presence of such a motif in islet amyloid polypeptide (IAPP), whose amyloidogenic properties are associated with type 2 diabetes. We determined four new crystal structures of segments within IAPP, all forming steric zippers. Most interestingly, one of the segments in the fibril core of IAPP forms an out-of-register steric zipper. Analysis of this structure reveals several commonalities with previously solved out-of-register fibrils. Our results provide additional evidence of out-of-register β sheets as a common structural motif in amyloid aggregates.


Can nurses perform manual vacuum aspiration (MVA) as safely and effectively as physicians? Evidence from India.
Although legal, access to safe abortion remains limited in India. Given positive experiences of task-shifting from other developing countries, there is a need to explore the feasibility of expanding the manual vacuum aspiration (MVA) provider base to include nurses in India. A prospective, two-sided equivalence study was undertaken in five facilities of a non-government organisation in Bihar and Jharkhand to explore whether efficacy and safety rates associated with MVA provided by newly trained nurses were equivalent to those provided by physicians. Eight hundred and ninety-seven consenting women with gestation ages of ≤ 10 weeks were recruited. Nurses were as skilled as physicians in assessing gestation age and completed abortion status, performing MVA and obtaining patient compliance. Overall failure and complication rates were low and equivalent between the two provider types, and both provider types were equally acceptable to women who underwent the procedure (98%). Findings of the study make a compelling case for amending existing laws to expand the MVA provider base in order to increase access to safe abortion in India.


Cell surface antigens of human melanocytes and melanoma. Expression of adenosine deaminase binding protein is extinguished with melanocyte transformation.
It has been proposed that the pathogenesis of melanoma proceeds through multiple stages, ranging from benign proliferation of melanocytic cells to acquisition of the capacity to invade tissues and metastasize. During investigations of cell surface antigens expressed by melanocytes and melanoma, we identified an antigen system that was expressed by cultured normal melanocytes but not by melanoma cell lines. mAbs against this antigen detected a 120-kD cell surface glycoprotein on melanocytes. This molecule had been identified previously as the binding protein for adenosine deaminase (ADAbp). ADAbp was expressed by 51 melanocyte cell lines derived from normal fetal, newborn, and adult skin and adult choroid, but not by 102 melanoma cell lines derived from primary and metastatic lesions. Studies with radiolabeled bovine adenosine deaminase, confirmed that melanocytes expressed binding sites for adenosine deaminase, but no binding sites were detected on cultured melanoma cells. Further studies showed that ADAbp+ melanocytes became ADAbp- upon malignant transformation in vitro. Immunohistochemical studies on a panel of frozen tissues demonstrated reactivity of anti-ADAbp mAbs with epidermal melanocytes and benign junctional nevi, but not with potentially premalignant dysplastic nevi or primary/metastatic melanoma lesions. These studies demonstrate that ADAbp expression is lost with malignant transformation of melanocytes, presumably at an early stage in the transformation process.


Longitudinal relationships among visual acuity and tasks of everyday life: the Salisbury Eye Evaluation study.
To study the relationships among visual and physical function trajectories of aging adults. The community-based random sample consists of 2520 adults who were aged 65 to 84 years in 1993 to 1995 and reassessed 2, 6, and 8 years later. Presenting and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity were obtained. Activities of daily living (ADLs) and instrumental ADLs (IADLs) were evaluated through survey instruments. Growth curve models were used to simultaneously estimate health trajectories and obtain associations among the trajectories while controlling for relevant covariates. Best-corrected acuity (logMAR) worsened by an average of 0.013 (∼1 letter) annually. ADL difficulties increased by 0.22 standard deviations (SD) and IADL difficulties increased by 0.28 SD annually. Controlling for demographic and health covariates, visual acuity rates of decline correlated with rates of increase in ADL difficulties (r = 0.15, P = 0.05) and IADL difficulties (r = 0.41, P < 0.001). Acuity loss was significantly related to increases in ADLs for men (b = 0.039, P < 0.01), but not for women (b = 0.001, P > 0.9). The direct effects of acuity loss were strongest for IADLs where a 1-unit decline in acuity (logMAR) was associated with a 0.067 SD increase in IADL difficulties (P < 0.001) at baseline, and a 1-unit acuity decline (logMAR) per year resulted in a 0.10 SD unit increase in the rate of change in IADL difficulties (P < 0.001) per year. Over time, increases in visual acuity loss were related to increased IADL difficulties in men and women and increases in ADL difficulties for men only. The findings support the importance of maintaining vision in older adults.


Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats.
Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135706, (250 mg.kg-1.day-1) and an ARI, WAY-121509, (10 mg.kg-1.day-1) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135706 whereas WAY-121509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135706 and WAY-121509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9%, respectively with diabetes. These deficits were corrected by WAY-121509, but WAY-135706 was completely ineffective. A 48.6% diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121509, but was unaltered by WAY-135706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase.


Face masks to prevent transmission of influenza virus: a systematic review.
Influenza viruses circulate around the world every year. From time to time new strains emerge and cause global pandemics. Many national and international health agencies recommended the use of face masks during the 2009 influenza A (H1N1) pandemic. We reviewed the English-language literature on this subject to inform public health preparedness. There is some evidence to support the wearing of masks or respirators during illness to protect others, and public health emphasis on mask wearing during illness may help to reduce influenza virus transmission. There are fewer data to support the use of masks or respirators to prevent becoming infected. Further studies in controlled settings and studies of natural infections in healthcare and community settings are required to better define the effectiveness of face masks and respirators in preventing influenza virus transmission.


On modeling and state estimation for genetic regulatory networks with polytopic uncertainties.
It is widely believed that gene expression data contains rich information that could discover the higher-order structures of an organism and even interpret its behavior. The modeling problem of gene regulatory networks (GRNs) from the experimental data has recently received increasing research attention. In this paper, we investigate the uncertainty quantification and state estimation issues. The polytopic uncertainty model (PUM) is exploited for describing the GRNs where the parameter uncertainties are constrained in a convex polytope domain. To cope with the high-dimension problem for GRN models, the principal component plane (PCP) algorithm is proposed to construct a pruned polytope in order to use as less vertices as possible to maintain the essential information from original polytope. The so-called system equivalence transformation is developed to transform the original system into a simpler canonical form and therefore facilitate the subsequent state estimation problem. For the state estimation problem, a robust stability condition is incorporated with guaranteed H2 performance via the semi-definite programme method, and then a new sufficient condition is derived for the desired H2 estimators with several free slack matrices. Such a condition is vertex-dependent and therefore possesses less conservatism. It is shown, via simulation from real-world microarray time-series data, that the designed H2 estimators have strong capability of dealing with modeling and estimation problems for short but high-dimensional gene expression time series.


Does applicability domain exist in microarray-based genomic research?
Constructing an accurate predictive model for clinical decision-making on the basis of a relatively small number of tumor samples with high-dimensional microarray data remains a very challenging problem. The validity of such models has been seriously questioned due to their failure in clinical validation using independent samples. Besides the statistical issues such as selection bias, some studies further implied the probable reason was improper sample selection that did not resemble the genomic space defined by the training population. Assuming that predictions would be more reliable for interpolation than extrapolation, we set to investigate the impact of applicability domain (AD) on model performance in microarray-based genomic research by evaluating and comparing model performance for samples with different extrapolation degrees. We found that the issue of applicability domain may not exist in microarray-based genomic research for clinical applications. Therefore, it is not practicable to improve model validity based on applicability domain.


Increased risk of rheumatoid arthritis in women with pregnancy complications and poor self-rated health: a study within the Danish National Birth Cohort.
This study assessed the suggested association between pregnancy-associated hypertensive disorders, hyperemesis and subsequent risk of RA using a cohort with information about pre-pregnancy health. Self-reported information on pre-pregnancy health, pregnancy course, gestational hypertension, pre-eclampsia and hyperemesis was available from 55 752 pregnant women included in the Danish National Birth Cohort. Information about pregnancy-related factors and lifestyle was obtained by interviews twice during pregnancy and at 6 months post-partum. Women were followed for RA hospitalizations identified in the Danish National Patient Register. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards models. Women with RA and non-specific musculoskeletal problems at the time of pregnancy were excluded. On average, women were followed for 11 years after childbirth and 169 cases of RA were identified. The risk of RA was increased in women with pre-eclampsia (n = 11, HR = 1.96, 95% CI 1.06, 3.63), a poor self-rated pregnancy course (n = 32, HR = 1.63, 95% CI 1.11, 2.39) and fair or poor self-rated pre-pregnancy health (fair health: n = 86, HR = 1.52, 95% CI 1.11, 2.09; poor health: n = 14, HR = 3.24, 95% CI 1.82, 5.76). Hyperemesis was not associated with risk of RA. We confirmed the previously suggested increased risk of RA in women with pre-eclampsia and also found an inverse association between self-rated pre-pregnancy health and risk of RA. These results suggest that the clinical onset of RA is preceded by a prolonged subclinical phase that may interfere with women's general well-being and pregnancy course or that some women carry a shared predisposition to pre-eclampsia and RA.


The impact of multiple protein sequence alignment on phylogenetic estimation.
Multiple sequence alignment is typically the first step in estimating phylogenetic trees, with the assumption being that as alignments improve, so will phylogenetic reconstructions. Over the last decade or so, new multiple sequence alignment methods have been developed to improve comparative analyses of protein structure, but these new methods have not been typically used in phylogenetic analyses. In this paper, we report on a simulation study that we performed to evaluate the consequences of using these new multiple sequence alignment methods in terms of the resultant phylogenetic reconstruction. We find that while alignment accuracy is positively correlated with phylogenetic accuracy, the amount of improvement in phylogenetic estimation that results from an improved alignment can range from quite small to substantial. We observe that phylogenetic accuracy is most highly correlated with alignment accuracy when sequences are most difficult to align, and that variation in alignment accuracy can have little impact on phylogenetic accuracy when alignment error rates are generally low. We discuss these observations and implications for future work.


The mechanism of renomedullary antihypertensive action: haemodynamic studies in hydronephrotic rats with one-kidney renal-clip hypertension.
1. The protective action of the renal medulla was studied in one-kidney renal-clip hypertension in rats with unilateral hereditary hydronephrosis and almost complete atrophy of the medulla of the affected kidney. 2. Rats were unilaterally nephrectomized. The first group had a normal kidney remaining, and the animals from the second and third groups were left with a hydronephrotic kidney and received renomedullary and renocortical autotransplants respectively. Two weeks later all rats were made hypertensive by placing a silver clip (0.2 mm) on the renal artery. 3. From the fourth day after clipping until the end of the experiment blood pressure was found to be significantly (P less than 0.01) lower in rats with medullary transplants than in the other groups. No differences in renal excretory function, plasma volume and plasma renin activity were found between the groups either before or during development of hypertension (5 and 21 days after clipping). Early in the course of hypertension (5 days) cardiac output was significantly (P less than 0.05) lower in the rats with medullary transplants than in the other groups, although an increase in plasma volume was noted in all three groups. At that time no difference in total peripheral resistance was found between the groups. 4. The results are consistent with the hypothesis that the renomedullary antihypertensive substance(s) mitigates hypertension by preventing a hypertensive haemodynamic response to sodium/volume overload.


Arterial filter bypass loop: what occurs in this area during cardiopulmonary bypass and are there potential patient implications.
The arterial filter is an integral part of bypass circuitry. When introduced, manufacturers suggested a bypass loop for retrograde priming and de-airing, and for uninterrupted blood flow in case of malfunction. Practice has shown antegrade priming and de-airing is possible. This questions the necessity of the loop and presents the question-what occurs in the loop during bypass? After obtaining Human Research Ethics Board approval, eight consecutive patients (n = 8) were chosen for this study. Exclusive exclusion criterion was receiving any transfusions during cardiopulmonary bypass, as this could possibly influence results. The choice of patient numbers was based simply on proof of concept. Investigation involved isolation and collection of loop contents after cardiopulmonary bypass was completed. Testing included complete blood count, prothrombin time, international normalized ratio, partial thromboplastin time, activated clotting time, plasma free hemoglobin, slide photography with analysis for platelet clumping, and debris detection. One perfusionist collected samples, providing uniform collection and isolation technique. Regular blood samples were collected from the bypass circuitry, and from patients' pre-operative blood work. Analysis of data revealed that platelet counts in the bypass loops were statistically lower than control. Evidence of platelet clumping was present in 3 of 8 bypass loop samples, representing 37.5% of the study population. There was no clumping detected in any of the controls. In patients where platelet clumping was present, a positive correlation was noted between mean bypass time and size of platelet clumps. Prothrombin time and international normalized ratio results were immeasurable. Hemoglobin levels were higher in the loop samples. There was no evidence of debris or fibrin monomer present in any of the samples analyzed. The study results indicate that during "normal" cardiopulmonary bypass with an arterial filter bypass loop, platelet aggregates can accumulate in the loop, therefore opening the arterial bypass loop in any case may subject the patient to micro/macro emboli.


SARS-CoV-2 infection and multi-organ system damage: A review.
The SARS-CoV-2 infection causes COVID-19, which has affected approximately six hundred million people globally as of August 2022. Organs and cells harboring angiotensin-converting enzyme 2 (ACE2) surface receptors are the primary targets of the virus. However, once it enters the body through the respiratory system, the virus can spread hematogenously to infect other body organs. Therefore, COVID-19 affects many organs, causing severe and long-term complications, even after the disease has ended, thus worsening the quality of life. Although it is known that the respiratory system is most affected by the SARS-CoV-2 infection, many organs/systems are affected in the short and long term. Since the COVID-19 disease simultaneously affects many organs, redesigning diagnostic and therapy policies to fit the damaged organs is strongly recommended. Even though the pathophysiology of many problems the infection causes is unknown, the frequency of COVID-19 cases rises with age and the existence of preexisting symptoms. This study aims to update our knowledge of SARS-CoV-2 infection and multi-organ dysfunction interaction based on clinical and theoretical evidence. For this purpose, the study comprehensively elucidates the most recent studies on the effects of SARS-CoV-2 infection on multiple organs and systems, including respiratory, cardiovascular, gastrointestinal, renal, nervous, endocrine, reproductive, immune, and parts of the integumentary system. Understanding the range of atypical COVID-19 symptoms could improve disease surveillance, limit transmission, and avoid additional multi-organ-system problems.


Capsules, toxins and AtxA as virulence factors of emerging Bacillus cereus biovar anthracis.
Emerging B. cereus strains that cause anthrax-like disease have been isolated in Cameroon (CA strain) and Côte d'Ivoire (CI strain). These strains are unusual, because their genomic characterisation shows that they belong to the B. cereus species, although they harbour two plasmids, pBCXO1 and pBCXO2, that are highly similar to the pXO1 and pXO2 plasmids of B. anthracis that encode the toxins and the polyglutamate capsule respectively. The virulence factors implicated in the pathogenicity of these B. cereus bv anthracis strains remain to be characterised. We tested their virulence by cutaneous and intranasal delivery in mice and guinea pigs; they were as virulent as wild-type B. anthracis. Unlike as described for pXO2-cured B. anthracis, the CA strain cured of the pBCXO2 plasmid was still highly virulent, showing the existence of other virulence factors. Indeed, these strains concomitantly expressed a hyaluronic acid (HA) capsule and the B. anthracis polyglutamate (PDGA) capsule. The HA capsule was encoded by the hasACB operon on pBCXO1, and its expression was regulated by the global transcription regulator AtxA, which controls anthrax toxins and PDGA capsule in B. anthracis. Thus, the HA and PDGA capsules and toxins were co-regulated by AtxA. We explored the respective effect of the virulence factors on colonisation and dissemination of CA within its host by constructing bioluminescent mutants. Expression of the HA capsule by itself led to local multiplication and, during intranasal infection, to local dissemination to the adjacent brain tissue. Co-expression of either toxins or PDGA capsule with HA capsule enabled systemic dissemination, thus providing a clear evolutionary advantage. Protection against infection by B. cereus bv anthracis required the same vaccination formulation as that used against B. anthracis. Thus, these strains, at the frontier between B. anthracis and B. cereus, provide insight into how the monomorphic B. anthracis may have emerged.


Moxifloxacin resistance and genotyping of Mycobacterium avium and Mycobacterium intracellulare isolates in Japan.
Although fluoroquinolones are considered as alternative therapies of pulmonary Mycobacterium avium complex (MAC) disease, the association between fluoroquinolone resistance and MAC genotypes in clinical isolates from individuals not previously treated for MAC infection is not fully clear. Totals of 154 M. avium isolates and 35 Mycobacterium intracellulare isolates were obtained from treatment-naïve patients with pulmonary MAC disease at the diagnosis of MAC infection at 8 hospitals in Japan. Their susceptibilities of moxifloxacin were determined by broth microdilution methods. Moxifloxacin-resistant isolates were examined for mutations of gyrA and gyrB. Variable numbers of tandem repeats (VNTR) assay was performed using 15 M. avium VNTR loci and 16 M. intracellulare VNTR loci. Moxifloxacin susceptibility was categorized as resistant and intermediate for 6.5% and 16.9%, respectively, of M. avium isolates and 8.6% and 17.1% of M. intracellulare isolates. Although the isolates of both species had amino acid substitutions of Thr 96 and Thr 522 at the sites corresponding to Ser 95 in the M. tuberculosis GyrA and Gly 520 in the M. tuberculosis GyrB, respectively, these substitutions were observed irrespective of susceptibility and did not confer resistance. The VNTR assays showed revealed three clusters among M. avium isolates and two clusters among M. intracellulare isolates. No significant differences in moxifloxacin resistance were observed among these clusters. Although resistance or intermediate resistance to moxifloxacin was observed in approximately one-fourth of M. avium and M. intracellulare isolates, this resistance was not associated with mutations in gyrA and gyrB or with VNTR genotypes.


The dangers of using 'negative durations' to estimate pre- and post-migration fertility.
To keep childbearing that occurs before and after migration separate from each other, many analysts apply a technique that uses 'negative durations' to estimate the childbearing risks that migrants have before they migrate. This strategy can lead to incorrect results and should be abandoned. In this research note, we use data for births and internal migration in Sweden to highlight how the two types of behaviour can be kept apart conceptually and analytically without use of 'negative durations'. The procedures used can easily be generalized to any similarly linked pair of behaviours.


Does 'right to work' imperil the right to health? The effect of labour unions on workplace fatalities.
Economic policies can have unintended consequences on population health. In recent years, many states in the USA have passed 'right to work' (RTW) laws which weaken labour unions. The effect of these laws on occupational health remains unexplored. This study fills this gap by analysing the effect of RTW on occupational fatalities through its effect on unionisation. Two-way fixed effects regression models are used to estimate the effect of unionisation on occupational mortality per 100 000 workers, controlling for state policy liberalism and workforce composition over the period 1992-2016. In the final specification, RTW laws are used as an instrument for unionisation to recover causal effects. The Local Average Treatment Effect of a 1% decline in unionisation attributable to RTW is about a 5% increase in the rate of occupational fatalities. In total, RTW laws have led to a 14.2% increase in occupational mortality through decreased unionisation. These findings illustrate and quantify the protective effect of unions on workers' safety. Policymakers should consider the potentially deleterious effects of anti-union legislation on occupational health.


Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device.
Pump thrombosis remains an uncommon but potentially catastrophic complication of durable continuous-flow left ventricular assist devices (LVAD). A perceived increase in the incidence of pump thrombosis in the HeartMate II (HMII) LVAD (Thoratec, Pleasanton, CA) by clinicians prompted this analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. Between 2006 and June 2013, 8,988 United States patients aged older than 18 years received a durable LVAD. Of these, 6,910 adult patients from 132 institutions who received a HMII LVAD were entered in the INTERMACS database and constitute the study group for this analysis. Overall survival (with censoring at transplant or explant for recovery) with the HMII LVAD was 80% at 1 year and 69% at 2 years and was not significantly different when stratified by era of implant. Freedom from device exchange or death due to thrombosis decreased from 99% at 6 months in 2009 to 94% in 2012 (p < 0.0001). Multivariable hazard function analysis showed risk factors for pump thrombosis included later implant year (p < 0.0001), younger age (p < 0.0001), higher creatinine (p = 0.002), larger body mass index (p = 0.004), white race (p = 0.0004), left ventricular ejection fraction above 20% (p = 0.02), and higher lactate dehydrogenase level at 1 month (p < 0.0001). Survival (p < 0.0001) and freedom from infection (p = 0.008) and cerebrovascular accident (p < 0.0001) were lower after pump exchange than after primary implant. Pump exchange or death due to pump thrombosis increased during 2011 and 2012, but the magnitude of the increase remained relatively small. Survival remains high (80% at 1 year) with the HMII LVAD. Risk factor analysis suggests that a number of patient-related factors contribute to the risk of thrombosis. Markedly elevated lactate dehydrogenase in the first month is a predictor of pump thrombosis. This analysis could not examine the potential role of technical factors during implant, such as sub-optimal pump or graft positioning, changes in patient management paradigms with pump speed settings, improved recognition and change in the threshold for pump exchange, or design or production changes with the pump, as contributors to the risk of pump thrombosis.


Ultrasonic field modeling in anisotropic materials by distributed point source method.
DPSM (distributed point source method) is a modeling technique which is based on the concept of Green's function. First, a collection of source and target points are distributed over the solution domain based on the problem description and solution requirements. Then, the effects from all source points are superimposed at the location of every individual target point. Therefore, a successful implementation of DPSM entails an effective evaluation of Green's function between many pairs of source and target points. For homogeneous and isotropic media, the Green's function is available as a closed-form analytical expression. But for anisotropic solids, the evaluation of Green's function is more complicated and needs to be done numerically. Nevertheless, important applications such as defect detection in composite materials require anisotropic analysis. In this paper, the DPSM is used for ultrasonic field modeling in anisotropic materials. Considering the prohibitive computational cost of evaluating Green's function numerically for a large number of points, a technique called "windowing" is suggested which employs the repetitive pattern of points in DPSM in order to considerably reduce the number of evaluations of Green's function. In addition, different resolutions of numerical integration are used for computing Green's function corresponding to different distances in order to achieve a good balance between time and accuracy. The developed anisotropic DPSM model equipped with windowing technique and multi-resolution numerical integration is then applied to the problem of ultrasonic wave modeling in a plate immersed in a fluid. The transducers are placed in the fluid on both sides of the plate. First an isotropic plate is considered for the sake of verification and rough calibration of numerical integration. Then a composite plate is considered to demonstrate applicability and effectiveness of the developed model for simulating ultrasonic wave propagation in anisotropic media.


The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis.
Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease


Pedestrians struck by motor vehicles further worsen race- and insurance-based disparities in trauma outcomes: the case for inner-city pedestrian injury prevention programs.
Pedestrian trauma is the most lethal blunt trauma mechanism, and the rate of mortality in African Americans and Hispanics is twice that compared with whites. Whether insurance status and differential survival contribute to this disparity is unknown. This study is a review of vehicle-struck pedestrians in the National Trauma Data Bank, v7.0. Patients <16 years and > or =65 years, as well as patients with Injury Severity Score (ISS) <9, were excluded. Patients were categorized as white, African American, or Hispanic, and as privately insured, government insured, or uninsured. With white and privately insured patients as reference, logistic regression was used to evaluate mortality by race and insurance status after adjusting for patient and injury characteristics. In all, 26,404 patients met inclusion criteria. On logistic regression, African Americans had 22% greater odds of mortality (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.06-1.41) and Hispanics had 33% greater odds of mortality (OR, 1.33; 95% CI, 1.14-1.54) compared with whites. Uninsured patients had 77% greater odds of mortality (OR, 1.77; 95% CI, 1.52-2.06) compared with privately insured patients. African American and Hispanic race, as well as uninsured status, increase the risk of mortality after pedestrian crashes. Given the greater incidence of pedestrian crashes in minorities, this compounded burden of injury mandates pedestrian trauma prevention efforts in inner cities to decrease health disparities.


Bisphenol A exposure during early pregnancy impairs uterine spiral artery remodeling and provokes intrauterine growth restriction in mice.
Endocrine disrupting chemicals are long suspected to impair reproductive health. Bisphenol A (BPA) has estrogenic activity and therefore the capacity of interfering with endocrine pathways. No studies dissected its short-term effects on pregnancy and possible underlying mechanisms. Here, we studied how BPA exposure around implantation affects pregnancy, particularly concentrating on placentation and uterine remodeling. We exposed pregnant female mice to 50 µg/kg BPA/day or 0.1% ethanol by oral gavage from day 1 to 7 of gestation. High frequency ultrasound was employed to document the presence and size of implantations, placentas and fetuses throughout pregnancy. Blood velocity in the arteria uterina was analyzed by Doppler measurements. The progeny of mothers exposed to BPA was growth-restricted compared to the controls; this was evident in vivo as early as at day 12 as analyzed by ultrasound and confirmed by diminished fetal and placenta weights observed after sacrificing the animals at day 14 of gestation. The remodeling of uterine spiral arteries (SAs) was considerably impaired. We show that short-term exposure to a so-called "safe" BPA dose around implantation has severe consequences. The intrauterine growth restriction observed in more than half of the fetuses from BPA-treated mothers may owe to the direct negative effect of BPA on the remodeling of uterine SAs that limits the blood supply to the fetus. Our work reveals unsuspected short-term effects of BPA on pregnancy and urges to more studies dissecting the mechanisms behind the negative actions of BPA during early pregnancy.


Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties.
Osteogenesis imperfecta (OI or brittle bone disease) is a disorder of connective tissues caused by mutations in the collagen genes. We previously showed that intrauterine transplantation of human blood fetal stem/stromal cells in OI mice (oim) resulted in a significant reduction of bone fracture. This work examines the cellular mechanisms and mechanical bone modifications underlying these therapeutic effects, particularly examining the direct effects of donor collagen expression on bone material properties. In this study, we found an 84% reduction in femoral fractures in transplanted oim mice. Fetal blood stem/stromal cells engrafted in bones, differentiated into mature osteoblasts, expressed osteocalcin, and produced COL1a2 protein, which is absent in oim mice. The presence of normal collagen decreased hydroxyproline content in bones, altered the apatite crystal structure, increased the bone matrix stiffness, and reduced bone brittleness. In conclusion, expression of normal collagen from mature osteoblast of donor origin significantly decreased bone brittleness by improving the mechanical integrity of the bone at the molecular, tissue, and whole bone levels.