Renal functional reserve and microalbuminuria in offspring of hypertensive parents.
Renal functional reserve, microalbuminuria, and plasma atrial natriuretic factor were measured in 21 offspring (9.5 +/- 0.5 years of age, mean +/- SEM) of hypertensive parents and in eight children (10 +/- 0.5 years of age) with no family history of hypertension who were used as a control group. Renal functional reserve was evaluated by measurement of the changes in creatinine clearance after an oral protein load of 45 g/m2. Atrial natriuretic factor levels were determined before and 60 minutes after the protein load, and microalbuminuria in fractional urine before and 120 minutes after the same stimulus as well as in a 24-hour urine collection. All children in the control group significantly increased their creatinine clearance after the protein load (preload, 122 +/- 12; 60 minutes, 144 +/- 9; 120 minutes, 154 +/- 11; 180 minutes, 144 +/- 9 ml/min/1.73 m2; all values were significant vs. preload, p less than 0.005). In contrast, only 13 of 21 offspring of hypertensive parents increased their creatinine clearance to values within 2 SD of the increase shown by the control group (preload, 144 +/- 11; 60 minutes, 153 +/- 7; 120 minutes, 202 +/- 13 ml/min/1.73 m2; p less than 0.001 vs. preload; 180 minutes, 214 +/- 19 ml/min/1.73 m2, p less than 0.001 vs. preload). The remaining eight offspring of hypertensive parents showed no detectable changes (nonresponders) (preload, 189 +/- 18; 60 minutes, 146 +/- 11; 120 minutes, 170 +/- 14; 180 minutes, 168 +/- 13 ml/min/1.73 m2; all values p = NS). No changes in atrial natriuretic factor after the protein load were observed in any group. Offspring of hypertensive parents presented higher microalbuminuria levels in 24-hour urine specimens (3.1 micrograms/min, tolerance factor [TF]2.2) than controls (2.1 micrograms/min, TF 1.5) (p less than 0.05). Although microalbuminuria increased significantly after the water load in the control group (p less than 0.05) and in the offspring of hypertensive parents (p less than 0.01), it returned to baseline at 120 minutes in the former but not in the latter (p less than 0.05 vs. baseline). The lack of renal functional reserve in nonresponders was significantly related (p less than 0.05) to the presence of higher levels of microalbuminuria. We conclude that the absence of renal functional reserve and increased microalbuminuria in some normotensive children who are offspring of essential hypertensive parents can indicate that subtle alterations in renal function may precede the onset of clinical hypertension.


Presynaptic inhibition rapidly stabilises recurrent excitation in the face of plasticity.
Hebbian plasticity, a mechanism believed to be the substrate of learning and memory, detects and further enhances correlated neural activity. Because this constitutes an unstable positive feedback loop, it requires additional homeostatic control. Computational work suggests that in recurrent networks, the homeostatic mechanisms observed in experiments are too slow to compensate instabilities arising from Hebbian plasticity and need to be complemented by rapid compensatory processes. We suggest presynaptic inhibition as a candidate that rapidly provides stability by compensating recurrent excitation induced by Hebbian changes. Presynaptic inhibition is mediated by presynaptic GABA receptors that effectively and reversibly attenuate transmitter release. Activation of these receptors can be triggered by excess network activity, hence providing a stabilising negative feedback loop that weakens recurrent interactions on sub-second timescales. We study the stabilising effect of presynaptic inhibition in recurrent networks, in which presynaptic inhibition is implemented as a multiplicative reduction of recurrent synaptic weights in response to increasing inhibitory activity. We show that networks with presynaptic inhibition display a gradual increase of firing rates with growing excitatory weights, in contrast to traditional excitatory-inhibitory networks. This alleviates the positive feedback loop between Hebbian plasticity and network activity and thereby allows homeostasis to act on timescales similar to those observed in experiments. Our results generalise to spiking networks with a biophysically more detailed implementation of the presynaptic inhibition mechanism. In conclusion, presynaptic inhibition provides a powerful compensatory mechanism that rapidly reduces effective recurrent interactions and thereby stabilises Hebbian learning.


Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue.
Because the influenza A virus has an RNA genome, its RNA-dependent RNA polymerase, comprising the PA, PB1, and PB2 subunits, is essential for viral transcription and replication. The binding of RNA primers/promoters to the polymerases is an initiation step in viral transcription. In our current study, we reveal the 2.7 A tertiary structure of the C-terminal RNA-binding domain of PB2 by x-ray crystallography. This domain incorporates lysine 627 of PB2, and this residue is associated with the high pathogenicity and host range restriction of influenza A virus. We found from our current analyses that this lysine is located in a unique "phi"-shaped structure consisting of a helix and an encircled loop within the PB2 domain. By electrostatic analysis, we identified a highly basic groove along with this phi loop and found that lysine 627 is located in the phi loop. A PB2 domain mutant in which glutamic acid is substituted at position 627 shows significantly lower RNA binding activity. This is the first report to show a relationship between RNA binding activity and the pathogenicity-determinant lysine 627. Using the Matras program for protein three-dimensional structural comparisons, we further found that the helix bundles in the PB2 domain are similar to that of activator 1, the 40-kDa subunit of DNA replication clamp loader (replication factor C), which is also an RNA-binding protein. This suggests a functional and structural relationship between the RNA-binding mechanisms underlying both influenza A viral transcription and cellular DNA replication. Our present results thus provide important new information for developing novel drugs that target the primer/promoter RNA binding of viral RNA polymerases.


Elephants know when they need a helping trunk in a cooperative task.
Elephants are widely assumed to be among the most cognitively advanced animals, even though systematic evidence is lacking. This void in knowledge is mainly due to the danger and difficulty of submitting the largest land animal to behavioral experiments. In an attempt to change this situation, a classical 1930s cooperation paradigm commonly tested on monkeys and apes was modified by using a procedure originally designed for chimpanzees (Pan troglodytes) to measure the reactions of Asian elephants (Elephas maximus). This paradigm explores the cognition underlying coordination toward a shared goal. What do animals know or learn about the benefits of cooperation? Can they learn critical elements of a partner's role in cooperation? Whereas observations in nature suggest such understanding in nonhuman primates, experimental results have been mixed, and little evidence exists with regards to nonprimates. Here, we show that elephants can learn to coordinate with a partner in a task requiring two individuals to simultaneously pull two ends of the same rope to obtain a reward. Not only did the elephants act together, they inhibited the pulling response for up to 45 s if the arrival of a partner was delayed. They also grasped that there was no point to pulling if the partner lacked access to the rope. Such results have been interpreted as demonstrating an understanding of cooperation. Through convergent evolution, elephants may have reached a cooperative skill level on a par with that of chimpanzees.


Results of Simultaneous Liver and Kidney Transplantation: A Single-Center Review.
The decision for a simultaneous liver and kidney transplantation (SLKT) is fraught with controversy. The aim of this study was to compare SLKT with liver transplantation alone (LTA) in patients with pretransplantation renal failure. A retrospective review comparing patients undergoing SLKT and LTA (with renal failure) between January 2000 and December 2014 was performed. Of 1,129 liver transplantations, 132 had renal failure pretransplantation; 52 had SLKT and 80 recipients had LTA. Model for End-Stage Liver Disease score and BMI were lower in the SLKT group (p = 0.001). Simultaneous liver and kidney transplantation patients had better overall survival rates at 1 and 5 years compared with LTA (92.3% and 81.6% vs 73.3% and 64.3% respectively; p < 0.01). Graft survival was also superior in patients undergoing SLKT vs LTA. Six of 52 (11.5%) SLKT patients had final positive cross match, but only 1 of 52 (1.9%) kidney grafts was lost to rejection. In the SLKT group, 9 of 52 (17.3%) patients required dialysis post transplantation, but only 2 remained on dialysis beyond 30 days. All patients in the LTA group were on dialysis pretransplantation and significantly more patients (52 of 80 [65%]) required dialysis post LTA (p ≤ 0.0001); 31 of 80 (38.8%) were dialysis dependent for more than 30 days or died on dialysis within 30 days. Two LTA recipients were subsequently listed for kidney transplant. Patients with end-stage liver disease on dialysis who undergo liver transplantation have significantly better survival when SLKT is performed. In selected patients, SLKT is an appropriate use of a scarce resource, but better prognostic indicators for selection of patients are still needed.


Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes.
Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders.


Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips.
Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.


Optimizing Rhizobium-legume symbioses by simultaneous measurement of rhizobial competitiveness and N2 fixation in nodules.
Legumes tend to be nodulated by competitive rhizobia that do not maximize nitrogen (N2) fixation, resulting in suboptimal yields. Rhizobial nodulation competitiveness and effectiveness at N2 fixation are independent traits, making their measurement extremely time-consuming with low experimental throughput. To transform the experimental assessment of rhizobial competitiveness and effectiveness, we have used synthetic biology to develop reporter plasmids that allow simultaneous high-throughput measurement of N2 fixation in individual nodules using green fluorescent protein (GFP) and barcode strain identification (Plasmid ID) through next generation sequencing (NGS). In a proof-of-concept experiment using this technology in an agricultural soil, we simultaneously monitored 84 different Rhizobium leguminosarum strains, identifying a supercompetitive and highly effective rhizobial symbiont for peas. We also observed a remarkable frequency of nodule coinfection by rhizobia, with mixed occupancy identified in ∼20% of nodules, containing up to six different strains. Critically, this process can be adapted to multiple Rhizobium-legume symbioses, soil types, and environmental conditions to permit easy identification of optimal rhizobial inoculants for field testing to maximize agricultural yield.


Two consecutive microtubule-based epithelial seaming events mediate dorsal closure in the scuttle fly Megaselia abdita.
Evolution of morphogenesis is generally associated with changes in genetic regulation. Here, we report evidence indicating that dorsal closure, a conserved morphogenetic process in dipterans, evolved as the consequence of rearrangements in epithelial organization rather than signaling regulation. In Drosophila melanogaster, dorsal closure consists of a two-tissue system where the contraction of extraembryonic amnioserosa and a JNK/Dpp-dependent epidermal actomyosin cable result in microtubule-dependent seaming of the epidermis. We find that dorsal closure in Megaselia abdita, a three-tissue system comprising serosa, amnion and epidermis, differs in morphogenetic rearrangements despite conservation of JNK/Dpp signaling. In addition to an actomyosin cable, M. abdita dorsal closure is driven by the rupture and contraction of the serosa and the consecutive microtubule-dependent seaming of amnion and epidermis. Our study indicates that the evolutionary transition to a reduced system of dorsal closure involves simplification of the seaming process without changing the signaling pathways of closure progression.


Pulsing dynamics in Ytterbium based chirped-pulse oscillators.
The properties of passively mode-locked laser oscillators based on Ytterbium doped gain media are studied theoretically along with experimental data. Based on the chirped-pulse approach limitations due to excessive non-linearities are avoided, opening up new routes for energy scaling of mode-locked solid-state oscillators. Predictions about potential future pulse energies are made and possible experimental problems are discussed.


Lack of regression of anal squamous intraepithelial lesions despite immune restoration under cART.
A high prevalence of anal squamous intraepithelial lesions (ASIL) and human papillomavirus (HPV) infections were observed in HIV-infected men who have sex with men (MSM) in the precART (combined antiretroviral therapy) era. The impact of cART on the natural history of HPV infection and ASIL is poorly documented. Ninety-four HIV-infected MSM naive of cART were enrolled in a longitudinal study before starting cART. Patients were evaluated for anal cytology, histology and anal HPV DNA at baseline, month 12 and month 24 of cART. HPV DNA genotyping was performed by Linear Array assay. Anal cytologic samples were processed by the Thin Prep method. Analyses included 76 patients with at least two visits with available cytology. The median age was 39.4 years. The median (interquartile range) CD4 cell count was 301 cells/μl (242-339) at baseline and 545 cells/μl at month 24, when 93% of patients had plasma HIV-RNA 50 copies/ml or less. An abnormal result was observed in 45 of 76 patients at baseline (59%) with prevalent low-grade squamous intraepithelial lesion (LSIL) in 27 patients (36%) and high-grade squamous intraepithelial lesion (HSIL) in seven patients (9%) and in 36 of 69 patients assessed at month 24 (52%) with LSIL in 23 patients (33%) and HSIL in six patients (9%). At month 24, regression of the severity of lesions was observed in 44% of patients, whereas a lesion occurred in 37% of patients. Our results show a high prevalence and incidence of ASIL in HIV-infected MSM despite immune restoration under cART. These data emphasize that HIV-positive MSM although receiving effective cART remain at high risk of anal squamous intra-epithelial lesions.


Proceedings of a Sickle Cell Disease Ontology workshop - Towards the first comprehensive ontology for Sickle Cell Disease.
Sickle cell disease (SCD) is a debilitating single gene disorder caused by a single point mutation that results in physical deformation (i.e. sickling) of erythrocytes at reduced oxygen tensions. Up to 75% of SCD in newborns world-wide occurs in sub-Saharan Africa, where neonatal and childhood mortality from sickle cell related complications is high. While SCD research across the globe is tackling the disease on multiple fronts, advances have yet to significantly impact on the health and quality of life of SCD patients, due to lack of coordination of these disparate efforts. Ensuring data across studies is directly comparable through standardization is a necessary step towards realizing this goal. Such a standardization requires the development and implementation of a disease-specific ontology for SCD that is applicable globally. Ontology development is best achieved by bringing together experts in the domain to contribute their knowledge. The SCD community and H3ABioNet members joined forces at a recent SCD Ontology workshop to develop an ontology covering aspects of SCD under the classes: phenotype, diagnostics, therapeutics, quality of life, disease modifiers and disease stage. The aim of the workshop was for participants to contribute their expertise to development of the structure and contents of the SCD ontology. Here we describe the proceedings of the Sickle Cell Disease Ontology Workshop held in Cape Town South Africa in February 2016 and its outcomes. The objective of the workshop was to bring together experts in SCD from around the world to contribute their expertise to the development of various aspects of the SCD ontology.


Ground-based detection of an extended helium atmosphere in the Saturn-mass exoplanet WASP-69b.
Hot gas giant exoplanets can lose part of their atmosphere due to strong stellar irradiation, and these losses can affect their physical and chemical evolution. Studies of atmospheric escape from exoplanets have mostly relied on space-based observations of the hydrogen Lyman-α line in the far ultraviolet region, which is strongly affected by interstellar absorption. Using ground-based high-resolution spectroscopy, we detected excess absorption in the helium triplet at 1083 nanometers during the transit of the Saturn-mass exoplanet WASP-69b, at a signal-to-noise ratio of 18. We measured line blueshifts of several kilometers per second and posttransit absorption, which we interpret as the escape of part of the atmosphere trailing behind the planet in comet-like form.


Enhanced visible-light photocatalytic H2-generation activity of carbon/g-C3N4 nanocomposites prepared by two-step thermal treatment.
Photocatalytic hydrogen (H2) production from water by using solar energy and a photocatalyst is a green and sustainable route to tackle the energy issues. Herein, carbon/g-C3N4 nanocomposites were successfully synthesized via a two-step thermal treatment of urea and glucose with different ratios. As confirmed by X-ray photoelectron spectroscopy, a C-O-C bond was formed between carbon and g-C3N4, which leads to a strong interaction between carbon and g-C3N4. The prepared samples were evaluated for photocatalytic H2 generation under visible light irradiation. The experimental results indicate that the carbon/g-C3N4 nanocomposites show great photocatalytic H2 evolution activity, as high as 410.1 μmol g-1 h-1, which is 13.6-fold of pure g-C3N4. The enhanced photocatalytic performance not only originates from the enlarged surface area and extended visible light response range, but also from the effectively separated photo-generated charge carriers. This spatial charge separation greatly suppresses the recombination of photo-generated hole-electron pairs and facilitates efficient H2 production. This work provides a facile way to design highly efficient carbon nitride-based photocatalysts for potential application in photocatalytic reaction by using solar energy.


ECM remodeling in hypertensive heart disease.
Hypertensive heart disease (HHD) occurs in patients that clinically have both diastolic and systolic heart failure and will soon become the most common cause of heart failure. Two key aspects of heart failure secondary to HHD are the relatively highly prevalent LV hypertrophy and cardiac fibrosis, caused by changes in the local and systemic neurohormonal environment. The fibrotic state is marked by changes in the balance between MMPs and their inhibitors, which alter the composition of the ECM. Importantly, the fibrotic ECM impairs cardiomyocyte function. Recent research suggests that therapies targeting the expression, synthesis, or activation of the enzymes responsible for ECM homeostasis might represent novel opportunities to modify the natural progression of HHD.


Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation.
UV radiation (UVR) is a complete carcinogen that elicits a constellation of pathological events, including direct DNA damage, generation of reactive oxidants that peroxidize lipids and damage other cellular components, initiation of inflammation, and suppression of the immune response. Recent dramatic increases in the incidence of nonmelanoma skin cancers are largely attributable to higher exposure of an aging population to UVR. Therefore, the development of cellular strategies for intrinsic protection of the skin against the deleterious effects of UVR is imperative. Here we show that erythema resulting from UVR is a comprehensive and noninvasive biomarker for assessing UVR damage and can be precisely and easily quantified in human skin. Topical application of sulforaphane-rich extracts of 3-day-old broccoli sprouts up-regulated phase 2 enzymes in the mouse and human skin, protected against UVR-induced inflammation and edema in mice, and reduced susceptibility to erythema arising from narrow-band 311-nm UVR in humans. In six human subjects (three males and three females, 28-53 years of age), the mean reduction in erythema across six doses of UVR (300-800 mJ/cm(2) in 100 mJ/cm(2) increments) was 37.7% (range 8.37-78.1%; P = 0.025). This protection against a carcinogen in humans is catalytic and long lasting.


Student experiences of participating in five collaborative blended learning courses in Africa and Asia: a survey.
As blended learning (BL; a combination of face-to-face and e-learning methods) becomes more commonplace, it is important to assess whether students find it useful for their studies. ARCADE HSSR and ARCADE RSDH (African Regional Capacity Development for Health Systems and Services Research; Asian Regional Capacity Development for Research on Social Determinants of Health) were unique capacity-building projects, focusing on developing BL in Africa and Asia on issues related to global health. We aimed to evaluate the student experience of participating in any of five ARCADE BL courses implemented collaboratively at institutions from Africa, Asia, and Europe. A post-course student survey with 118 students was conducted. The data were collected using email or through an e-learning platform. Data were analysed with SAS, using bivariate and multiple logistic regression. We focused on the associations between various demographic and experience variables and student-reported overall perceptions of the courses. In total, 82 students responded to the survey. In bivariate logistic regression, the course a student took [p=0.0067, odds ratio (OR)=0.192; 95% confidence interval (CI): 0.058-0.633], male gender of student (p=0.0474, OR=0.255; 95% CI: 0.066-0.985), not experiencing technical problems (p<0.001, OR=17.286; 95% CI: 4.629-64.554), and reporting the discussion forum as adequate for student needs (p=0.0036, OR=0.165; 95% CI: 0.049-0.555) were found to be associated with a more positive perception of BL, as measured by student rating of the overall helpfulness of the e-learning component to their studies. In contrast, perceiving the assessment as adequate was associated with a worse perception of overall usefulness. In a multiple regression, the course, experiencing no technical problems, and perceiving the discussion as adequate remained significantly associated with a more positively rated perception of the usefulness of the online component of the blended courses. The results suggest that lack of technical problems and functioning discussion forums are of importance during BL courses focusing on global health-related topics. Through paying attention to these aspects, global health education could be provided using BL approaches to student satisfaction.


A photofuel cell comprising titanium oxide and silver(I/0) photocatalysts for use of acidic water as a fuel.
A photofuel cell comprising two photocatalysts TiO2 and Ag-TiO2 is demonstrated. The open circuit voltage, short circuit current, and maximum electric power of the PFC were 1.59 V, 74 μA, and 14 μW, respectively. The electron flow was rectified due to the Schottky barrier between TiO2 and Ag nanoparticles.


Probing limits on spatial resolution using nonlinear optical effects and nonclassical light.
Using a simple optical setup to detect and characterize transmission gratings in the far field, we demonstrate that going beyond the diffraction limit is not possible using linear interaction of nonclassical illumination with the target grating. We also confirm that nonlinear optical interactions with the target grating, or with the optical medium around it, do allow improvement in resolution.


Encorafenib and Binimetinib Combination Therapy in Metastatic Melanoma.
The treatment landscape for metastatic melanoma has changed dramatically over the past few years as new medications have been developed. Encorafenib, a B-Raf protein kinase inhibitor, and binimetinib, a MEK inhibitor, were approved by the U.S. Food and Drug Administration in 2018 for the treatment of patients with unresectable or metastatic melanoma which harbor a BRAF V600E or V600K mutation. These approvals were based on findings from the COLUMBUS trial, which demonstrated improvement in progression-free survival and overall survival with the combination of encorafenib plus binimetinib compared with vemurafenib alone. Encorafenib plus binimetinib is the third BRAF plus MEK inhibitor combination to be approved, and there are clinical and practical differences between the combination regimens that should be considered when selecting an appropriate treatment regimen for patients.


How do autoimmune diseases cluster in families? A systematic review and meta-analysis.
A primary characteristic of complex genetic diseases is that affected individuals tend to cluster in families (that is, familial aggregation). Aggregation of the same autoimmune condition, also referred to as familial autoimmune disease, has been extensively evaluated. However, aggregation of diverse autoimmune diseases, also known as familial autoimmunity, has been overlooked. Therefore, a systematic review and meta-analysis were performed aimed at gathering evidence about this topic. Familial autoimmunity was investigated in five major autoimmune diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis and type 1 diabetes mellitus. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Articles were searched in Pubmed and Embase databases. Out of a total of 61 articles, 44 were selected for final analysis. Familial autoimmunity was found in all the autoimmune diseases investigated. Aggregation of autoimmune thyroid disease, followed by systemic lupus erythematosus and rheumatoid arthritis, was the most encountered. Familial autoimmunity is a frequently seen condition. Further study of familial autoimmunity will help to decipher the common mechanisms of autoimmunity.


Rapid bacterial detection and antibiotic susceptibility testing in whole blood using one-step, high throughput blood digital PCR.
Sepsis due to antimicrobial resistant pathogens is a major health problem worldwide. The inability to rapidly detect and thus treat bacteria with appropriate agents in the early stages of infections leads to excess morbidity, mortality, and healthcare costs. Here we report a rapid diagnostic platform that integrates a novel one-step blood droplet digital PCR assay and a high throughput 3D particle counter system with potential to perform bacterial identification and antibiotic susceptibility profiling directly from whole blood specimens, without requiring culture and sample processing steps. Using CTX-M-9 family ESBLs as a model system, we demonstrated that our technology can simultaneously achieve unprecedented high sensitivity (10 CFU per ml) and rapid sample-to-answer assay time (one hour). In head-to-head studies, by contrast, real time PCR and BioRad ddPCR only exhibited a limit of detection of 1000 CFU per ml and 50-100 CFU per ml, respectively. In a blinded test inoculating clinical isolates into whole blood, we demonstrated 100% sensitivity and specificity in identifying pathogens carrying a particular resistance gene. We further demonstrated that our technology can be broadly applicable for targeted detection of a wide range of antibiotic resistant genes found in both Gram-positive (vanA, nuc, and mecA) and Gram-negative bacteria, including ESBLs (blaCTX-M-1 and blaCTX-M-2 families) and CREs (blaOXA-48 and blaKPC), as well as bacterial speciation (E. coli and Klebsiella spp.) and pan-bacterial detection, without requiring blood culture or sample processing. Our rapid diagnostic technology holds great potential in directing early, appropriate therapy and improved antibiotic stewardship in combating bloodstream infections and antibiotic resistance.


Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients.
An uncommon histiocytosis primarily involving the lymph nodes, Rosai-Dorfman disease (RDD, originally called sinus histiocytosis with massive lymphadenopathy) involves extranodal sites in 43% of cases; cutaneous RDD (C-RDD) is a rare form of RDD limited to the skin. The clinicopathological diagnosis of C-RDD may sometimes be difficult, with different clinical profiles from those of its nodal counterpart, and occasionally misleading histological pictures. There have been few multipatient studies of C-RDD and documentation of its histological spectrum is rare. To identify the clinical and histopathological profiles, associated features, and the chronological changes of this rare histiocytosis. From 1991 to 2002, patients diagnosed as having C-RDD were collected in four academic hospitals. Clinical presentations, treatments, and courses of each case were documented. In total, 21 biopsy specimens obtained from these patients were re-evaluated and scored microscopically with attention to the uncommon patterns and chronological evolution both clinically and histologically. We examined six patients with C-RDD, three men and three women. The mean age at the first visit was 43.7 years. The clinical presentations were mostly papules, nodules and plaques, varying with the duration and depth of lesions. Although the anatomical distribution was wide, the face was most commonly involved. Evolutional changes were identified clinically, as the lesions typically began with papules or plaques and grew to form nodules with satellite lesions and resolved with fibrotic plaques before complete remission. No patient had lymphadenopathy or extracutaneous lesions during follow-up (mean 50.5 months). At the end of follow-up, the lesions in four patients had completely resolved irrespective of treatment; two patients had persistent lesions. The histopathological pattern of the main infiltrate, the components of cells and the stromal responses showed dynamic changes according to the duration of lesions. The characteristic Rosai-Dorfman cells (RD cells) were found in association with a nodular or diffuse infiltrate in 15 lesions (71%). Four lesions (19%) demonstrated a patchy/interstitial pattern. One lesion (5%) assumed the pattern of a suppurative granuloma. RD cells were less readily found in these atypical patterns. Conspicuous proliferation of histiocytes associated with RD cells was found in three lesions, including xanthoma, localized Langerhans cell histiocytosis and xanthogranuloma. Along with lymphocytes, plasma cells were present in all lesions, often in large numbers with occasional binucleated or trinucleated cells. Variably found in the lesions were neutrophils (nine lesions, 43%) and eosinophils (13 lesions, 62%). The former occasionally formed microabscesses, while the latter were often few in number. Vascular proliferation was a relatively constant feature (90%). Fibrosis was found in 10 lesions (48%). Our study further confirms that C-RDD is a distinct entity with different age and possibly race distributions from RDD. Compared with its nodal counterpart, C-RDD demonstrates a wider histopathological spectrum with different clinicopathological phases depending on duration of the lesions. Awareness of these features is helpful in making a correct diagnosis. The associations of C-RDD with other histiocytoses may have important implications for the pathogenesis of this rare histiocytosis.


Adverse Effects of Direct Acting Antivirals in HIV/HCV Coinfected Patients: A 4-Year Experience in Miami, Florida.
The new direct acting antivirals (DAA) have demonstrated low rates of adverse effects in controlled studies. However, real world-studies have disclosed emerging toxicities and drug-drug interactions in special populations. We conducted a retrospective review of HIV/HCV coinfected patients who were treated with DAA at Jackson Memorial Hospital from 2014 to 2017. Our aim was to determine the adverse effects (AE) and factors that are associated with AE in HIV/HCV individuals who are treated with DAA. There were 78 coinfected patients treated with DAA. AE that were secondary to DAA were reported by 21 (26.9%) patients. The most common AE were fatigue (47.6%), gastrointestinal symptoms (38.1%), anemia (14.3%), and headache (14.3%). In comparison with the rest of the study cohort, the patients who developed AE were more often Caucasian (33.3% vs. 10.5%, p = 0.017) and were more frequently treated with PrOD/Ribavirin (9.5% vs. 0%, p = 0.018). In terms of antiretroviral therapy (ART), there was a trend towards a more frequent use of TDF/FTC + NNRTI (33.3% vs. 14%, p = 0.055). These findings demonstrated good tolerability of DAAs in HIV/HCV coinfected patients. More real-world studies are needed to explore the variables that are associated with AE.


Exposure to Mn/Zn ethylene-bis-dithiocarbamate and glyphosate pesticides leads to neurodegeneration in Caenorhabditis elegans.
Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24h (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC(50)=8.0% (r(2)=0.6890), while the chronic LC(50)=5.7% (r(2)=0.9433). Acute MZ exposure led to an LC(50)=0.22% (r(2)=0.5093), and chronic LC(50)=0.50% (r(2)=0.9733). The combined treatment for TD+MZ yielded an LC(50)=12.5% (r(2)=0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p<0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally relevant concentrations of TD or MZ.


Effects of low-pass filtering on acoustic analysis of voice.
Low-pass filtering is often applied to eliminate effects of environmental noise when preparing voice recordings for acoustic analysis. This study tested the effects of low-pass filter cutoff frequency on the results of acoustic voice analysis, with a particular interest in the effects of low cutoff frequencies on nonlinear dynamic parameters. A crossover randomized controlled trial was performed using voice recordings of sustained vowel phonation obtained from the Disordered Voice Database. A second-order Butterworth filter was applied to the voices at cutoff frequencies ranging from 5000 to 40 Hz. Percent jitter, percent shimmer, fundamental frequency (F(0)), signal-to-noise ratio (SNR), correlation dimension (D(2)), and second-order entropy (K(2)) were calculated for each signal. Traditional acoustic parameters were validly measured at cutoff frequencies as low as 300 Hz. The SNR and percent shimmer were improved by cutoff frequencies of 300 Hz or higher; F(0) and percent jitter were unaffected by filtering at these frequencies. D(2) and K(2) were measured stably for signals filtered at cutoff frequencies as low as 100 Hz. To ensure accuracy in acoustic voice analysis, setting the cutoff frequency of a low-pass filter at least one octave above the F(0) (minimum of 300 Hz) is recommended. Nonlinear dynamic measures of D(2) and K(2) proved more robust and maintained accuracy at lower frequencies.


Burnout in elite rugby: relationships with basic psychological needs fulfilment.
In this study, we examined the utility of self-determination theory (Ryan & Deci, 2002) as a framework for understanding the antecedents of athlete burnout in elite New Zealand rugby union players (n=133). Perceptions of competence, autonomy, and relatedness (i.e. basic psychological needs) were hypothesized to be negatively related to burnout scores, while players classified as "high-burnouts" were predicted to report lower needs fulfilment than players with low burnout. Canonical correlation analysis indicated that relatedness was a low to moderate predictor of burnout, but players' competence and autonomy accounted for substantial portions of variance in two athlete burnout symptoms: reduced accomplishment and sport devaluation. The proportion of variance accounted for in the exhaustion dimension of athlete burnout was not substantive. Multivariate analysis of variance supported these results, as "high-burnout" players had lower competence and autonomy scores than athletes reporting low burnout symptoms. The two groups did not report significantly different relatedness scores. Implications of these results for researchers and practitioners are discussed.


Analysis of p16(CDKN2A) methylation and HPV-16 infection in oral mucosal dysplasia.
The purpose of this study was to investigate the relationship between p16(CDKN2A) methylation and epithelial dysplasia (ED). We also evaluated the expressions of proteins related to methylation (DNMT3B and DNMT1). Finally, we tested whether HPV-16/18 or the dmt3b (C46359T) polymorphism is associated with p16(CDKN2A) methylation status. To test the hypothesis, a case-control study with 72 (control, n = 24; ED, n = 48) tissue samples from subjects was performed. Methylation-specific PCR, RFLP, and immunohistochemical analyses were performed to evaluate p16(CDKN2A) methylation status, dmt3b (C46359T) genotyping, and protein levels, respectively. The methylation of p16(CDKN2A) and HPV-16 was associated with ED gradation (p = 0.001 and 0.002, respectively). In addition, most HPV-16-positive samples (77.8%) exhibited p16(CDKN2A) methylation; however, changes in DNMT3B and DNMT1 protein levels were not observed in HPV-positive samples. Neither HPV-18 nor the dmt3b polymorphism was associated with p16(CDKN2A) methylation. There is an association between the presence of HPV-16 in ED and the occurrence of p16(CDKN2A) methylation. Both variables are also associated with ED development, but further studies are necessary to clarify if they operate independently and if they have any impact on OD malignization.


Carboxylate Ion Pairing with Alkali-Metal Ions for β-Lactoglobulin and Its Role on Aggregation and Interfacial Adsorption.
We report a combined experimental and computational study of the whey protein β-lactoglobulin (BLG) in different electrolyte solutions. Vibrational sum-frequency generation (SFG) and ellipsometry were used to investigate the molecular structure of BLG modified air-water interfaces as a function of LiCl, NaCl, and KCl concentrations. Molecular dynamics (MD) simulations and thermodynamic integration provided details of the ion pairing of protein surface residues with alkali-metal cations. Our results at pH 6.2 indicate that BLG at the air-water interface forms mono- and bilayers preferably at low and high ionic strength, respectively. Results from SFG spectroscopy and ellipsometry are consistent with intimate ion pairing of alkali-metal cations with aspartate and glutamate carboxylates, which is shown to be more effective for smaller cations (Li(+) and Na(+)). MD simulations show not only carboxylate-alkali-metal ion pairs but also ion multiplets with the alkali-metal ion in a bridging position between two or more carboxylates. Consequently, alkali-metal cations can bridge carboxylates not only within a monomer but also between monomers, thus providing an important dimerization mechanism between hydrophilic surface patches.


Pathophysiology of Migraine.
Migraine is a serious health problem which impair quality of life. It is the second most common primary headache that affects approximately more than %10 people in general population. Migraine pathophysiology is still unclear. Increasing results of studies suggest to migraine pathophysiology is related with primary neuronal mechanisms. Migraine pain starts in which region of brain and what brain regions are activated in different stages is unenlightened. There is evidences that growing number of studies which using new imaging techniques as positron emission tomography (PET) and functional magnetic resonans imaging (fMRI) show that migraine and cluster headaches are related with neuronal structures and vasodilatation. There are four phases to a migraine. The prodrome phase, aura, the attack, and the postdrome phase. Some datas obtained from last ten years indicate that cortical excitability has increased in interictal phase too. For many years, studies in rodents show trgimenial nerve is activated and it leads to vasodilatation and neurogenic inflammation in the headache phase. Although the majority of patients encountered in clinical practice are migraine without aura or chronic migraine, experimental studies of the migraine pathophysiology are focusing on the aura model which is used cortical spreading depression.


Caenorhabditis elegans homologue of the human azoospermia factor DAZ is required for oogenesis but not for spermatogenesis.
DAZ (Deleted in Azoospermia), the putative azoospermia factor gene in human, encodes a ribonucleoprotein-type RNA-binding protein required for spermatogenesis. A Drosophila homologue of DAZ, called boule, is also essential for spermatogenesis. A mouse homologue, Dazla, is implicated in both spermatogenesis and oogenesis. Here, we report the identification and characterization of daz-1, the single DAZ homologue in the nematode Caenorhabditis elegans. Loss of daz-1 function caused sterility in hermaphrodites, by blocking oogenesis at the pachytene stage of meiosis I. Epistasis analysis suggested that this gene executes its function succeeding gld-1, which governs the early pachytene stage in the oogenic pathway. Spermatogenesis did not appear to be affected in daz-1 hermaphrodites. Males defective in daz-1 produced sperm fully competent in fertilization. Analysis employing sex-determination mutants indicated that the daz-1 function was required for meiosis of female germline regardless of the sex of the soma. Transcription of daz-1 was restricted to the germline, starting prior to the onset of meiosis and was most conspicuous in cells undergoing oogenesis. Thus, daz-1 in C. elegans is an essential factor for female meiosis but, unlike other DAZ family members so far reported, it is dispensable for male meiosis.


Correlations between anatomic and MRI sections of human cadaver temporomandibular joints in the coronal and sagittal planes.
Cadaver material was used in this study to correlate sequential sagittal and coronal T1-weighted magnetic resonance images against anatomic detail. Magnetic resonance imaging (MRI) was found to accurately represent soft tissues in normal and deranged joints. In contrast to previous reports, MRI was found to accurately represent the discal-retrodiscal junction and did not appear to give false positive findings for disc displacement. Magnetic resonance imaging provided good images of bony outline, particularly in coronal views. Difficulties in interpretation arose when different adjoining tissues produced the same MR image; the central tendon of the lateral pterygoid muscle can appear as an extension of the disc, imaging as a distorted and displaced disc. In anatomic sections, a medial hernia sac in the lower joint space was seen as a constant indicator of the medial component of disc displacement; however, this was not evident in sagittal and coronal T1-weighted images. Fibrocartilaginous remodeling of the articular surface projecting into a discal perforation presented the same image as normal discal tissue. Because discs are often thinned over the lateral pole, it is difficult to determine whether discal tissue is present between the articular surfaces when MRI is at its present resolution. Subcortical bone spaces may be misinterpreted as areas of avascular necrosis and osteochondritis dissecans. It is recommended that an imaging sequence of the TMJ include a midcondyle image and lateral, central, and medial sagittal images; however, the lateral sagittal image is the most difficult to interpret.


The cholecystokinin receptor antagonist devazepide enhances morphine-induced analgesia but not morphine-induced respiratory depression in the squirrel monkey.
The effects of the cholecystokinin antagonist devazepide on analgesia and respiratory depression induced by morphine in squirrel monkeys were examined. Pain thresholds were determined using the tail withdrawal procedure, in which monkeys restrained in chairs kept their tails in cool (35 degrees C) water for at least 20 sec, but withdrew them from warm (55 degrees C) water in less than 4 sec. Morphine produced a dose-related increase in tail withdrawal latencies from warm water. Devazepide (injected i.p. or p.o.) had no effect on tail withdrawal latencies when given alone but enhanced the analgesic effects of morphine. The devazepide dose-response curve for morphine enhancement was bell-shaped with doses of 3, 10, 30 and 100 micrograms/kg injected i.p. increasing morphine analgesia whereas higher and lower dose did not. In a separate group of monkeys, morphine produced dose-dependent decreases in respiratory rate and oxygen tension and increases in carbon dioxide tension. In contrast to its effects on morphine analgesia, devazepide had no effect on the various indices of morphine-induced respiratory depression. These data suggest that devazepide may have therapeutic utility as an adjuvant to morphine analgesia allowing lower dose of the opiate to be used to relieve pain and reducing the risk of opiate-induced respiratory depression.


A general mechanism for network-dosage compensation in gene circuits.
Coping with variations in network dosage is crucial for maintaining optimal function in gene networks. We explored how network structure facilitates network-level dosage compensation. By using the yeast galactose network as a model, we combinatorially deleted one of the two copies of its four regulatory genes and found that network activity was robust to the change in network dosage. A mathematical analysis revealed that a two-component genetic circuit with elements of opposite regulatory activity (activator and inhibitor) constitutes a minimal requirement for network-dosage invariance. Specific interaction topologies and a one-to-one interaction stoichiometry between the activating and inhibiting agents were additional essential elements facilitating dosage invariance. This mechanism of network-dosage invariance could represent a general design for gene network structure in cells.


Characterization and Complete Genome Analysis of the Carbazomycin B-Producing Strain Streptomyces luteoverticillatus SZJ61.
Members of marine Actinobacteria have been highly regarded as potentially important sources of antimicrobial compounds. Here, we isolated a strain of Actinobacteria, SZJ61, and showed that it inhibits the in vitro growth of fungi pathogenic to plants. This new isolate was identified as Streptomyces luteoverticillatus by morphological, biochemical and genetic analyses. Antifungal compounds were isolated from S. luteoverticillatus strain SZJ61 and characterized as carbazomycin B by nuclear magnetic resonance spectra. We then sequenced the genome of the S. luteoverticillatus SZJ61 strain, which consists of only one 7,367,863 bp linear chromosome that has a G+C content of 72.05%. Thirty-five putative biosynthetic gene clusters for secondary metabolites, including a variety of bioactive products, were found. Mining of the genome sequence information revealed the putative biosynthetic gene cluster of carbazomycin B. This genomic information is valuable for interpreting the biosynthetic mechanisms of diverse bioactive compounds that have potential applications in the pharmaceutical industry.


Brain Computer Interface on Track to Home.
The novel BackHome system offers individuals with disabilities a range of useful services available via brain-computer interfaces (BCIs), to help restore their independence. This is the time such technology is ready to be deployed in the real world, that is, at the target end users' home. This has been achieved by the development of practical electrodes, easy to use software, and delivering telemonitoring and home support capabilities which have been conceived, implemented, and tested within a user-centred design approach. The final BackHome system is the result of a 3-year long process involving extensive user engagement to maximize effectiveness, reliability, robustness, and ease of use of a home based BCI system. The system is comprised of ergonomic and hassle-free BCI equipment; one-click software services for Smart Home control, cognitive stimulation, and web browsing; and remote telemonitoring and home support tools to enable independent home use for nonexpert caregivers and users. BackHome aims to successfully bring BCIs to the home of people with limited mobility to restore their independence and ultimately improve their quality of life.


Recent trends in the intrinsic water-use efficiency of ringless rainforest trees in Borneo.
Stable carbon isotope (δ(13)C) series were developed from analysis of sequential radial wood increments from AD 1850 to AD 2009 for four mature primary rainforest trees from the Danum and Imbak areas of Sabah, Malaysia. The aseasonal equatorial climate meant that conventional dendrochronology was not possible as the tree species investigated do not exhibit clear annual rings or dateable growth bands. Chronology was established using radiocarbon dating to model age-growth relationships and date the carbon isotopic series from which the intrinsic water-use efficiency (IWUE) was calculated. The two Eusideroxylon zwageri trees from Imbak yielded ages of their pith/central wood (±1 sigma) of 670 ± 40 and 759 ± 40 years old; the less dense Shorea johorensis and Shorea superba trees at Danum yielded ages of 240 ± 40 and 330 ± 40 years, respectively. All trees studied exhibit an increase in the IWUE since AD 1960. This reflects, in part, a response of the forest to increasing atmospheric carbon dioxide concentration. Unlike studies of some northern European trees, no clear plateau in this response was observed. A change in the IWUE implies an associated modification of the local carbon and/or hydrological cycles. To resolve these uncertainties, a shift in emphasis away from high-resolution studies towards long, well-replicated time series is proposed to develop the environmental data essential for model evaluation. Identification of old (greater than 700 years) ringless trees demonstrates their potential in assessing the impacts of climatic and atmospheric change. It also shows the scientific and applied value of a conservation policy that ensures the survival of primary forest containing particularly old trees (as in Imbak Canyon and Danum).


Glenohumeral kinematics after soft tissue interposition graft and glenoid reaming: A cadaveric study.
The management of young patients with glenohumeral arthritis is controversial. Resurfacing of the glenoid with biologic interposition and reaming of the glenoid have been suggested as potential treatment options. The goal of this study was to determine the change in glenohumeral contact pressures in interposition arthroplasty, as well as glenoid reaming in an arthritis model. We hypothesized that interposition with meniscal allograft will lead to the best normalization of contact pressure throughout the glenohumeral range of motion. Eight fresh-frozen cadaveric shoulders were tested in static positions of humeral abduction with a compressive load. Glenohumeral contact area, contact pressure, and peak force were determined sequentially for (1) intact glenoid (2) glenoid with cartilage removed (arthritis model) (3) placement of lateral meniscus allograft (4) placement of Achilles allograft (5) arthritis model with reamed glenoid. The arthritis model demonstrated statistically higher peak pressures than intact glenoid and glenoid with interpositional allograft. Meniscal and Achilles allograft lowered mean contact pressure and increased contact area to a level equal to or more favorable than the control state. In contrast, the reamed glenoid did not show any statistical difference from the arthritis model for any of the recorded measures. Glenohumeral contact pressure is significantly improved with interposition of allograft at time zero compared to an arthritic state. Our findings suggest that concentric reaming did not differ from the arthritic model when compared to normal. These findings favor the use of allograft for interposition as a potential treatment option in patients with glenoid wear.


Exploring the Early Organization and Maturation of Linguistic Pathways in the Human Infant Brain.
Linguistic processing is based on a close collaboration between temporal and frontal regions connected by two pathways: the "dorsal" and "ventral pathways" (assumed to support phonological and semantic processing, respectively, in adults). We investigated here the development of these pathways at the onset of language acquisition, during the first post-natal weeks, using cross-sectional diffusion imaging in 21 healthy infants (6-22 weeks of age) and 17 young adults. We compared the bundle organization and microstructure at these two ages using tractography and original clustering analyses of diffusion tensor imaging parameters. We observed structural similarities between both groups, especially concerning the dorsal/ventral pathway segregation and the arcuate fasciculus asymmetry. We further highlighted the developmental tempos of the linguistic bundles: The ventral pathway maturation was more advanced than the dorsal pathway maturation, but the latter catches up during the first post-natal months. Its fast development during this period might relate to the learning of speech cross-modal representations and to the first combinatorial analyses of the speech input.


Surgical treatment of spinal extradural arachnoid cysts in the thoracolumbar spine.
Because an idiopathic spinal extradural arachnoid cyst (SEAC) is rare, its optimal surgical treatment remains controversial. To evaluate the results of surgical treatments for SEACs and to clarify features of the disease associated with poor outcomes. Twelve patients with SEACs who underwent surgery at our hospital between 1988 and 2008 were examined retrospectively. The mean follow-up period was 4.7 years. Total resection of the cyst was performed in 7 patients and closure of the dural defect without cyst resection in 5 patients. Surgical outcomes were evaluated with regard to the duration of symptoms, the size of the cyst, and the surgical procedure used. Neurological recovery was observed in all patients, and there was no recurrence. Poor outcomes were observed in patients with a long duration of symptoms (>1 year, P < .01) and large cyst size (>5 vertebrae, P < .05). The surgical procedure had no significant association with the postoperative neurological recovery. However, there was a significant difference in the degree of the mean postoperative kyphotic angle between the patients treated by total resection of the cyst (9.7 degrees) and those treated by closure of the dural defect without cyst resection through selective laminectomy (2.2 degrees) (P < .01). There was no significant difference in postoperative neurological recovery between the 2 surgical procedures. However, closure of the dural defect without cyst resection was less invasive, preventing postoperative kyphotic deformity of the thoracolumbar spine.


Homoserine and diaminobutyric acid in the mucopeptide-precursor-nucleotides and cell walls of some plant-pathogenic corynebacteria.
The nucleotide precursors of cell-wall mucopeptide were prepared by vancomycin inhibition of Corynebacterium insidiosum and Corynebacterium poinsettiae. The amino acid in the third position in the former peptide was shown by optical rotatory dispersion of the bisdinitrophenyl derivative to be l-diaminobutyric acid. Homoserine in the nucleotide from C. poinsettiae was catalytically oxidized to aspartic acid, which was then shown to be the l-isomer by optical rotatory dispersion of the trinitrophenyl compound. The sequence for C. insidiosum was UDP-N-acetylmuramyl-glycyl-isoglutamyl- (gamma-acetyl)-diaminobutyryl-alanyl-alanine. The cell walls of C. insidiosum and Corynebacterium sepedonicum contained diaminobutyric acid that was optically inactive. It is proposed, therefore, that the primary peptide chain contains the l-isomer with its gamma-amino group blocked by acetylation and that cross-linking is achieved by means of the d-isomer, analogous to d-ornithine in C. poinsettiae.


Curcumin Nanoparticles and Their Cytotoxicity in Docetaxel-Resistant Castration-Resistant Prostate Cancer Cells.
Most prostate cancer patients develop resistance to anti-androgen therapy. This is referred to as castration-resistant prostate cancer (CRPC). Docetaxel (DTX) is the mainstay treatment against CRPC. However, over time patients eventually develop DTX resistance, which is the cause of the cancer-related mortality. Curcumin (CUR) as a natural compound has been shown to have very broad pharmacological activities, e.g., anti-inflammatory and antioxidant properties. However, CUR is very hydrophobic. The objective of this study was to develop CUR nanoparticles (NPs) and evaluate their cytotoxicity in DTX-resistant CRPC cells for the treatment of DTX-resistant CRPC. We tested solubility of CUR in different lipids and surfactants. Finally, Miglyol 812 and D-alpha-tocopheryl poly (ethylene glycol) succinate 1000 (TPGS) were chosen to prepare lipid-based NPs for CUR. We fully characterized CUR NPs that had particle size < 150 nm, high drug loading (7.5%), and entrapment efficiency (90%). Moreover, the CUR NPs were successfully lyophilized without using cryoprotectants. We tested the cytotoxicity of blank NPs, free CUR, and CUR NPs in sensitive DU145 and PC3 cells as well as their matching docetaxel-resistant cells. Cytotoxicity studies showed that blank NPs were very safe for all tested prostate cancer cell lines. Free CUR overcame the resistance in PC3 cells, but not in DU145 cells. In contrast, CUR NPs significantly increased CUR potency in all tested cell lines. Importantly, CUR NPs completely restored CUR potency in both resistant DU145 and PC3 cells. These results demonstrate that the CUR NPs have potential to overcome DTX resistance in CRPC.


Plasma-mediated neutrophil activation during acute myocardial infarction: role of platelet-activating factor.
1. Polymorphonuclear neutrophils are involved in the development of myocardial injury during ischaemia through the release of free oxygen radicals and by adhesion of activated polymorphonuclear neutrophils to endothelium, resulting in plugging of coronary capillaries. Polymorphonuclear neutrophil activation may be a result of contact with ligands expressed by endothelial cells and/or a response to soluble stimuli released from ischaemic tissue to the plasma. 2. To investigate this we studied plasma-mediated polymorphonuclear neutrophil activation in vitro using plasma samples collected from 14 patients with acute myocardial infarction at time of admission and 6 h and 1, 2, 5 and 7 days later. Plasma samples were incubated with washed polymorphonuclear neutrophils isolated from healthy donors. Expression of adhesion molecules CD18/CD11b integrin and L-selectin (Leu-8) were measured by flow cytometry and superoxide anion production in polymorphonuclear neutrophils was measured by chemiluminescence. 3. Plasma samples obtained 6 h and 1 day after admission were capable of inducing CD18/CD11b antigen expression, superoxide anion production and L-selectin shedding in the washed polymorphonuclear neutrophils, and this effect was significant when compared with plasma taken at 5 and 7 days after admission. 4. The plasma-mediated polymorphonuclear neutrophil stimulation was prevented when the PMN were pretreated with platelet-activating factor receptor antagonists BN52021 or BN50739. The platelet-activating factor concentrations detected in the plasma samples were not higher than those detected in plasma from healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Gender role beliefs, work-family conflict, and father involvement after the birth of a second child.
A major task for parents during the transition to second-time parenthood is to help their firstborn adjust to their new roles as siblings. Increased father involvement has been theorized to be protective for firstborn adjustment. Fathers, however, are under increasing pressure to balance both work and family responsibilities. Here we evaluate fathers' relative involvement in two-child families as a function of family structure, gender role beliefs, and work-family conflict in 222 dual- and single-earner families from the Midwestern region of the United States after the birth of a second child. Couples reported on father involvement with firstborns and infants when the infants were 1, 4, 8, and 12 months old. On average, fathers increased their involvement with infants but decreased their involvement with firstborns. Dual-earner fathers were more involved with their children than single-earner fathers. Although mean levels of father involvement were different between dual- and single-earners, multi-group parallel process trajectory latent growth curve models revealed more similarities than differences between dual- and single-earners in processes guiding father involvement. Both dual- and single-earner fathers engaged in juggling childcare between children and both dual- and single-earner fathers' involvement with infants was constrained by work-family conflict. Gender role beliefs predicted child care involvement for dual-earner, but not single-earner fathers: more egalitarian gender roles predicted greater involvement with the firstborn immediately after the birth of the second child. Results underscore the need for greater workplace support for fathers' caregiving roles after the birth of an infant.


Prevalence of musculoskeletal disorders in subjects not exposed to biomechanical overload.
Data on the prevalence of work-related musculoskeletal disorders (WMSDs) in groups of unexposed subjects may serve for comparison in studies on risk/damage in groups of exposed subjects and for the planning of preventive interventions. To assess the musculoskeletal health status in a group of working subjects not exposed to biomechanical overload. Medical histories were collected by occupational health physicians as part of an active health surveillance program. An ad hoc questionnaire was administered to the subjects to detect musculoskeletal disorders. The sample consisted of 1023 subjects (605 females and 418 males) with a mean age of 40 years. The prevalence of acute low back pain and disc hernia was 4% and 5.6% respectively; 4.3% of subjects were affected by at least one disorder of the upper limbs while the prevalence of knee disorders was 1.7%. Standardized data proved to be in line with previous studies with the exception of a greater prevalence of shoulder disorders and disc hernia. WMSDs occur ubiquitously across the general working population unexposed to biomechanical overload. Such findings represent a valid reference for groups of exposed working subjects, in that any excess of such disorders/pathology may be due to specific work conditions.


Safety and Efficacy of C-reactive Protein-guided Antibiotic Use to Treat Acute Respiratory Infections in Tanzanian Children: A Planned Subgroup Analysis of a Randomized Controlled Noninferiority Trial Evaluating a Novel Electronic Clinical Decision Algorithm (ePOCT).
The safety and efficacy of using C-reactive protein (CRP) to decide on antibiotic prescription among febrile children at risk of pneumonia has not been tested. This was a randomized (1:1) controlled noninferiority trial in 9 primary care centers in Tanzania (substudy of the ePOCT trial evaluating a novel electronic decision algorithm). Children aged 2-59 months with fever and cough and without life-threatening conditions received an antibiotic based on a CRP-informed strategy (combination of CRP ≥80 mg/L plus age/temperature-corrected tachypnea and/or chest indrawing) or current World Health Organization standard (respiratory rate ≥50 breaths/minute). The primary outcome was clinical failure by day (D) 7; the secondary outcomes were antibiotic prescription at D0, secondary hospitalization, or death by D30. A total of 1726 children were included (intervention: 868, control: 858; 0.7% lost to follow-up). The proportion of clinical failure by D7 was 2.9% (25/865) in the intervention arm vs 4.8% (41/854) in the control arm (risk difference, -1.9% [95% confidence interval {CI}, -3.7% to -.1%]; risk ratio [RR], 0.60 [95% CI, .37-.98]). Twenty of 865 (2.3%) children in the intervention arm vs 345 of 854 (40.4%) in the control arm received antibiotics at D0 (RR, 0.06 [95% CI, .04-.09]). There were fewer secondary hospitalizations and deaths in the CRP arm: 0.5% (4/865) vs 1.5% (13/854) (RR, 0.30 [95% CI, .10-.93]). CRP testing using a cutoff of ≥80 mg/L, integrated into an electronic decision algorithm, was able to improve clinical outcome in children with respiratory infections while substantially reducing antibiotic prescription. NCT02225769.


Lifetime prevalence of DSM-IV mental disorders among new soldiers in the U.S. Army: results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).
The prevalence of 30-day mental disorders with retrospectively reported early onsets is significantly higher in the U.S. Army than among socio-demographically matched civilians. This difference could reflect high prevalence of preenlistment disorders and/or high persistence of these disorders in the context of the stresses associated with military service. These alternatives can to some extent be distinguished by estimating lifetime disorder prevalence among new Army recruits. The New Soldier Study (NSS) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) used fully structured measures to estimate lifetime prevalence of 10 DSM-IV disorders in new soldiers reporting for Basic Combat Training in 2011-2012 (n = 38,507). Prevalence was compared to estimates from a matched civilian sample. Multivariate regression models examined socio-demographic correlates of disorder prevalence and persistence among new soldiers. Lifetime prevalence of having at least one internalizing, externalizing, or either type of disorder did not differ significantly between new soldiers and civilians, although three specific disorders (generalized anxiety, posttraumatic stress, and conduct disorders) and multimorbidity were significantly more common among new soldiers than civilians. Although several socio-demographic characteristics were significantly associated with disorder prevalence and persistence, these associations were uniformly weak. New soldiers differ somewhat, but not consistently, from civilians in lifetime preenlistment mental disorders. This suggests that prior findings of higher prevalence of current disorders with preenlistment onsets among soldiers than civilians are likely due primarily to a more persistent course of early-onset disorders in the context of the special stresses experienced by Army personnel.


Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers.
Alzheimer's disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer's disease-associated synaptotoxicity and reduce Alzheimer's disease-like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood-brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer's disease and related disorders.


[Effect of Hymenolepis nana infection on immunological responses of mice to sRBC].
In an attempt to investigate the effect of Hymenolepis nana infection on immunological responses to sRBC in ICR strain of mice, cellular and humoral immune responses were chronologically monitored after sensitization with sRBC. Mice weighing about 20 g were allocated into artificial and natural infection groups. The shell-free eggs of H. nana were inoculated into mice on the day 0 (initial) and day 10 in the former group, and praziquantel (25 mg/kg/day) was administered for 3 days to the one half of the mice at the 15th day after the first inoculation and to all of the mice in natural infection group. In artificial infection group, the delayed-type hypersensitivity (DTH) to sRBC was considerably decreased on the day 10 after the first inoculation, and then elevated gradually to normal. Eosinophils in the peripheral blood increased slightly. The hemagglutinin (HA) and hemolysin (HE) titers during the early stage were shown to be more or less higher than those of control. Thereafter, the titers were returned to normal, followed by a transient decrease on the day 15 post-infection. The sRBC rosette and antibody-treated rosette-forming capacities on the day 15 post-infection were temporarily lowered but became higher thereafter. The mucosal mast cells (MMC) in the small intestine were gradually increased to make a peak on the day 10 post-infection and then maintained more or less at lower level. After praziquantel treatment, the DTH and the number of eosinophils were decreased slightly and the MMC number and sRBC rosette-forming capacity were considerably decreased. The titers of HA and HE and antibody-treated rosette-forming capacity, however, were elevated in general. In natural infection group, the DTH, the number of eosinophils, and MMC which were elevated due to H. nana infection were gradually returned to normal after praziquantel treatment. The titers of HA and HE which were decreased by parasite infection were increased to normal after the treatment. However, the capacities of sRBC rosette or antibody-treated rosette formation were maintained at low levels in spite of the treatment. These results revealed that the immune responses to sRBC were significantly activated during H. nana infection, although they were transiently decreased during the days 10-15 post-infection.


Deep learning-enabled assessment of cardiac allograft rejection from endomyocardial biopsies.
Endomyocardial biopsy (EMB) screening represents the standard of care for detecting allograft rejections after heart transplant. Manual interpretation of EMBs is affected by substantial interobserver and intraobserver variability, which often leads to inappropriate treatment with immunosuppressive drugs, unnecessary follow-up biopsies and poor transplant outcomes. Here we present a deep learning-based artificial intelligence (AI) system for automated assessment of gigapixel whole-slide images obtained from EMBs, which simultaneously addresses detection, subtyping and grading of allograft rejection. To assess model performance, we curated a large dataset from the United States, as well as independent test cohorts from Turkey and Switzerland, which includes large-scale variability across populations, sample preparations and slide scanning instrumentation. The model detects allograft rejection with an area under the receiver operating characteristic curve (AUC) of 0.962; assesses the cellular and antibody-mediated rejection type with AUCs of 0.958 and 0.874, respectively; detects Quilty B lesions, benign mimics of rejection, with an AUC of 0.939; and differentiates between low-grade and high-grade rejections with an AUC of 0.833. In a human reader study, the AI system showed non-inferior performance to conventional assessment and reduced interobserver variability and assessment time. This robust evaluation of cardiac allograft rejection paves the way for clinical trials to establish the efficacy of AI-assisted EMB assessment and its potential for improving heart transplant outcomes.


MAIT Cells in Health and Disease.
Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor-mediated signals-substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.


Identification of biological/biochemical marker(s) for preterm delivery.
Fetal and neonatal mortality and morbidity rates are strongly associated with gestational age for delivery: the risk for poor outcome increases as gestational age decreases. Attempts to predict preterm delivery (PTD, spontaneous delivery before 37 weeks' gestation) have been largely unsuccessful, and rates of PTD have not improved in recent decades. More recently, the reported associations between infections in pregnancy and PTD suggest preventive initiatives that could be taken. The overall objective of the current study is to assess whether specific markers of infection (primarily interleukin (IL) 1beta, tumour necrosis factor (TNF) alpha, IL-6, and IL-10) obtained from maternal blood during pregnancy, alone or in combination with other risk factors for PTD, permit identification of women at risk for spontaneous PTD. To achieve this objective, data are obtained from two Danish prospective cohort studies involving serial collection of maternal blood samples, newborn cord blood samples, and relevant confounders and other risk factors for PTD. The first study consists of a completed Danish regional cohort of 3000 pregnant women enrolled in a study of microbiological causes of PTD, upon which a nested case-control study of PTD in 84 cases and 400 controls has been performed. The second study is a nested case-control study of 675 PTD cases (equally divided into three gestational age categories of 24-29 weeks' gestation, 30-33 weeks' gestation, and 34-36 weeks' gestation) and 675 controls drawn from the ongoing Danish National Birth Cohort study of 100 000 pregnant women enrolled during 1997-2001. The second study will provide the opportunity to refine and retest hypotheses from the first study, as well as to explore new hypotheses. Our preliminary work suggests that a single predictive marker effectively accounting for a large proportion of PTD is unlikely to be found. Rather, a search for multiple markers indicative of the multifactorial aetiology of PTD is likely to be more successful. Knowledge gained from the proposed studies will be implemented in a third, clinical intervention study against PTD. The first phase of the clinical intervention study will be to establish a risk-assessment model based on the "best" combination of biological/biochemical measures and other factors associated with PTD in order to identify pregnant women at very high risk of PTD. The second phase will be to apply an intervention model of tailored obstetric care to the very high-risk pregnant women for PTD identified in phase one. The intervention will be carried out against each specific risk factor associated with PTD identified for the individual. The aim is to reduce the risk for PTD attributed to the combination of risk factors included in the clinical intervention study.


ICRP Publication 114. Environmental protection: transfer parameters for reference animals and plants.
In Publication 103 (ICRP, 2007), the Commission included a section on the protection of the environment, and indicated that it would be further developing its approach to this difficult subject by way of a set of Reference Animals and Plants (RAPs) as the basis for relating exposure to dose, and dose to radiation effects, for different types of animals and plants. Subsequently, a set of 12 RAPs has been described in some detail (ICRP, 2008), particularly with regard to estimation of the doses received by them, at a whole-body level, in relation to internal and external radionuclide concentrations; and what is known about the effects of radiation on such types of animals and plants. A set of dose conversion factors for all of the RAPs has been derived, and the resultant dose rates can be compared with evaluations of the effects of dose rates using derived consideration reference levels (DCRLs). Each DCRL constitutes a band of dose rates for each RAP within which there is likely to be some chance of the occurrence of deleterious effects. Site-specific data on Representative Organisms (i.e. organisms of specific interest for an assessment) can then be compared with such values and used as a basis for decision making. It is intended that the Commission's approach to protection of the environment be applied to all exposure situations. In some situations, the relevant radionuclide concentrations can be measured directly, but this is not always possible or feasible. In such cases, modelling techniques are used to estimate the radionuclide concentrations. This report is an initial step in addressing the needs of such modelling techniques. After briefly reviewing the basic factors relating to the accumulation of radionuclides by different types of biota, in different habitats, and at different stages in the life cycle, this report focuses on the approaches used to model the transfer of radionuclides through the environment. It concludes that equilibrium concentration ratios (CRs) are most commonly used to model such transfers, and that they currently offer the most comprehensive data coverage. The report also reviews the methods used to derive CRs, and describes a means of summarising statistical information from empirical data sets. Emphasis has been placed on using data from field studies, although some data from laboratory experiments have been included for some RAPs. There are, inevitably, many data gaps for each RAP, and other data have been used to help fill these gaps. CRs specific to each RAP were extracted from a larger database, structured in terms of generic wildlife groups. In cases where data were lacking, values from taxonomically-related organisms were used to derive suitable surrogate values. The full set of rules which have been applied for filling gaps in RAP-specific CRs is described. Statistical summaries of the data sets are provided, and CR values for 39 elements and 12 RAP combinations are given. The data coverage, reliance on derived values, and applicability of the CR approach for each of the RAPs is discussed. Finally, some consideration is given to approaches where RAPs and their life stages could be measured for the elements of interest under more rigorously controlled conditions to help fill the current data gaps.


Analysis of four-wave mixing between pulses in high-data-rate quasi-linear subchannel-multiplexed systems.
We study four-wave mixing between pulses in two subchannels of a quasi-linear 40-Gbit/s subchannel-multiplexed system. For a pseudorandom bit string there are resonances in the mean of the ghost pulse energy and in the jitter of the energy in the marks as functions of the subchannel frequency spacing. However, away from these resonances the effect of four-wave mixing decreases as the subchannel spacing increases, permitting propagation over longer distances.


IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.
In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.


1D-3D hybrid modeling-from multi-compartment models to full resolution models in space and time.
Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator-which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.


DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.
Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.


Improving bariatric patient transport and care with simulation.
Obesity is prevalent in the United States. Obese patients have physiologic differences from non-obese individuals. Not only does transport and maintenance of these patients require use of specialized equipment, but it also requires a distinct skill set and knowledge base. To date, there is no literature investigating simulation as a model for educating pre-hospital providers in the care of bariatric patients. The purpose of this study was to determine if a 3-hour educational course with simulation could improve paramedics' knowledge and confidence of bariatric procedures and transport. This study also examined if prior experience with bariatric transport affected training outcomes. Our study took place in August 2012 during paramedic training sessions. Paramedics completed a pre- and post-test that assessed confidence and knowledge and provided information on previous experience. They had a 30-minute didactic and participated in 2 20-minute hands-on skills portions that reviewed procedural issues in bariatric patients, including airway procedures, peripheral venous and intraosseous access, and cardiopulmonary resuscitation. Study participants took part in one of two simulated patient encounters. Paramedics were challenged with treating emergent traumatic and/or medical conditions, as well as extricating and transporting bariatric patients. Each group underwent a debriefing of the scenario immediately following their case. We measured confidence using a 5-point Likert-type response scale ranging from 1 (strongly disagree) to 5 (strongly agree) on a 7-item questionnaire. We assessed knowledge with 12 multiple choice questions. Paired-sample t-tests were used to compare pre- and post-simulation confidence and knowledge with a significance level of p≤0.05. We used analysis of covariance to examine the effect of previous experiences on pre-and post-educational activity confidence and knowledge with a significance level of p ≤0.05. Proportions and 95% confidence intervals are presented as appropriate. We determined the magnitude of significant pre-post differences with Cohen's d. We assessed scale reliability using Cronbach's alpha and was found to be reliable with scores of 0.83 and 0.88 across pre- and post-test responses, respectively. Participants exhibited a significant increase in confidence in performing procedures (p<0.01) and knowledge of bariatric patient management (p<0.001) after the simulation. The current study also found an increase in knowledge of transport, vascular access/circulation and airway management (p<0.001). Participant background showed no effects on these changes. This study suggests that simulation paired with a didactic is an effective method of education for paramedics caring for and transporting bariatric patients. The data show a significant increase in knowledge and confidence with a 3-hour training session, irrespective of previous training or experience with bariatric patients. This is the first study of its kind to apply simulation training for the pre-hospital care of bariatric patients.


DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.
Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.


Use and utility of Web-based residency program information: a survey of residency applicants.
The Internet has become essential to the residency application process. In recent years, applicants and residency programs have used the Internet-based tools of the National Residency Matching Program (NRMP, the Match) and the Electronic Residency Application Service (ERAS) to process and manage application and Match information. In addition, many residency programs have moved their recruitment information from printed brochures to Web sites. Despite this change, little is known about how applicants use residency program Web sites and what constitutes optimal residency Web site content, information that is critical to developing and maintaining such sites. To study the use and perceived utility of Web-based residency program information by surveying applicants to an internal medicine program. Our sample population was the applicants to the Oregon Health & Science University Internal Medicine Residency Program who were invited for an interview. We solicited participation using the group e-mail feature available through the Electronic Residency Application Service Post-Office application. To minimize the possibility for biased responses, the study was confined to the period between submission of National Residency Matching Program rank-order lists and release of Match results. Applicants could respond using an anonymous Web-based form or by reply to the e-mail solicitation. We tabulated responses, calculated percentages for each, and performed a qualitative analysis of comments. Of the 431 potential participants, 218 responded (51%) during the study period. Ninety-nine percent reported comfort browsing the Web; 52% accessed the Web primarily from home. Sixty-nine percent learned about residency Web sites primarily from residency-specific directories while 19% relied on general directories. Eighty percent found these sites helpful when deciding where to apply, 69% when deciding where to interview, and 36% when deciding how to rank order programs for the Match. Forty-nine percent found sites most useful in deciding where to apply, while 40% found them most useful while preparing for their interviews. Seventy-two percent felt that a "complete" Web site could substitute for a mailed printed brochure. Qualitative analysis identified additional important information needs. Applicants are turning to residency Web sites for information during critical phases of the application process. Though usually helpful, many of these sites are felt to be incomplete and may not be meeting important applicant information needs. These findings should be useful to those involved in residency recruitment efforts and in counseling applicants.


Use of creative activities in occupational therapy practice in Sweden.
The aim of this study was to describe the prevalence of creative activities in occupational therapy in Sweden and how often Swedish occupational therapists use creative activities as a means of intervention. A web-mail survey was sent to 2975 Swedish occupational therapists working in health care at regional, county council or primary health care level, and those working in vocational rehabilitation. A total of 1867 (63%) answered the questionnaire and showed that 44% did use creative activities as a means of intervention and most often by practitioners working in psychiatric health care. The most commonly used form of creative activity was arts and crafts followed by gardening. This web-mail survey was based on a limited amount of items regarding creative activities. Further research should focus on in-depth inquiries about how occupational therapists and their patients perceive the use of creative activities as a means of treatment in occupational therapy.