The influence of sampling strategies and spatial variation on the detected soil bacterial communities under three different land-use types.
To determine the influence of pooling strategies on detected soil bacterial communities, we sampled 45 soil cores each from a eucalypt woodland, a sown pasture and a revegetated site in an Australian landscape. We assessed the spatial variation within each land-use plot, including the influence of sampling distance, soil chemical characteristics and, where appropriate, proximity to trees on the soil bacterial community, by generating terminal restriction fragment length polymorphism profiles of the bacterial 16S rRNA genes. The soil bacterial community under the revegetated site was more similar to the original woodland than the pasture, and this result was found regardless of the soil- or the DNA-pooling strategy used. Analyzing as few as eight cores per plot was sufficient to detect significant differences between the bacterial communities under the different plots to be distinguished. Soil pH was found to be most strongly associated with soil bacterial community composition within the plots and there was no association found with proximity to trees. This study has investigated sampling strategies for further research into the transitions of soil microbial communities with land-use change across broader temporal and spatial scales.


Genomic analysis distinguishes phases of early development of the mouse atrio-ventricular canal.
Valve formation during embryonic heart development involves a complex interplay of regional specification, cell transformations, and remodeling events. While many studies have addressed the role of specific genes during this process, a global understanding of the genetic basis for the regional specification and development of the heart valves is incomplete. We have undertaken genome-wide transcriptional profiling of the developing heart valves in the mouse. Four Serial Analysis of Gene Expression libraries were generated and analyzed from the mouse atrio-ventricular canal (AVC) at embryonic days 9.5-12.5, covering the stages from initiation of endothelial to mesenchymal transition (EMT) through to the beginning of endocardial cushion remodeling. We identified 14 distinct temporal patterns of gene expression during AVC development. These were associated with specific functions and signaling pathway members. We defined the temporal distribution of mesenchyme genes during the EMT process and of specific Notch and transforming growth factor-beta targets. This work provides the first comprehensive temporal dataset during the formation of heart valves. These results identify molecular signatures that distinguish different phases of early heart valve formation allowing gene expression and function to be further investigated.


Gene of the month: cancer testis antigen gene 1b (NY-ESO-1).
Cancer testis antigen gene 1B (CTAG1B) and its associated gene product; New York oesophageal squamous carcinoma 1 (NY-ESO-1), represent a unique and promising target for cancer immunotherapy. As a member of the cancer testis antigen family (CTA), the protein's restricted expression pattern and ability to elicit spontaneous humoural and cellular immune responses has resulted in a plethora of novel modalities and approaches attempting to harness its immunotherapeutic anti-cancer potential. Here, we discuss the structure and function of CTAG1B/NY-ESO-1 in both health and disease, immunohistochemical detection, as well as the most promising advances in the development of associated anti-cancer therapies. From cancer vaccines to engineered cellular therapy approaches, a multitude of immunotherapies targeting CTA's are coming to the forefront of oncology. Although the efficacy of such approaches have yet to provide convincing evidence of durable response, early phase clinical trial data has resulted in some exciting findings which will have significant potential to act as a platform for future practice changing technologies.


Peptidyl-CCA deacylation on the ribosome promoted by induced fit and the O3'-hydroxyl group of A76 of the unacylated A-site tRNA.
The last step in ribosome-catalyzed protein synthesis is the hydrolytic release of the newly formed polypeptide from the P-site bound tRNA. Hydrolysis of the ester link of the peptidyl-tRNA is stimulated normally by the binding of release factors (RFs). However, an unacylated tRNA or just CCA binding to the ribosomal A site can also stimulate deacylation under some nonphysiological conditions. Although the sequence of events is well described by biochemical studies, the structural basis of the mechanism underlying this process is not well understood. Two new structures of the large ribosomal subunit of Haloarcula marismortui complexed with a peptidyl-tRNA analog in the P site and two oligonucleotide mimics of unacylated tRNA, CCA and CA, in the A site show that the binding of either CA or CCA induces a very similar conformational change in the peptidyl-transferase center as induced by aminoacyl-CCA. However, only CCA positions a water molecule appropriately to attack the carbonyl carbon of the peptidyl-tRNA and stabilizes the proper orientation of the ester link for hydrolysis. We, thus, conclude that both the ability of the O3'-hydroxyl group of the A-site A76 to position the water and the A-site CCA induced conformational change of the PTC are critical for the catalysis of the deacylation of the peptidyl-tRNA by CCA, and perhaps, an analogous mechanism is used by RFs.


Genome-wide analyses based on a novel donkey 40K liquid chip reveal the gene responsible for coat color diversity in Chinese Dezhou donkey.
Dezhou donkey is one of the representative local breeds in China, which is mainly divided into two strains: Sanfen and Wutou. There are obvious differences in coat color between the two strains. The former shows light points around the eyes, around the muzzle and under the belly, while the latter is completely solid black. In this study, genome-wide association analysis was performed for the differences in coat color traits between the Sanfen (n = 97) and Wutou (n = 108) strains using a novel donkey 40K liquid chip developed based on GenoBaits technology, to identify genomic regions and causal genes that could explain this variation. We also used FST and The cross-population composite likelihood ratio test (XPCLR) analyses to explore selected regions related to coat color differences. We identified one significant region on chromosome 15, with the most significant SNP located within the agouti signaling protein (ASIP) gene. At the same time, both FST and XPCLR methods detected the same selected region on chromosome 15, and ASIP was the gene with the strongest signal. ASIP and melanocortin 1 receptor (MC1R) control the ratio of eumelanin to pheomelanin through their protein activity. They are deeply involved in the process of melanosome organation and melanogenesis, thus affecting mammals' coat color variation. We used a range of genome-wide approach to identify the genetic basis of coat color variation in Dezhou donkeys. The results provide a supplement to the color variation study in Chinese donkeys at the genome-wide level, and preliminarily verified the reliability of the Molbreeding Donkey No. 1 40K liquid chip.


Cost-Effectiveness of Pneumococcal Vaccination and Uptake Improvement Programs in Underserved and General Population Adults Aged < 65 Years.
In US adults aged < 65 years, pneumococcal vaccination is recommended when high-risk conditions are present, but vaccine uptake is low. Additionally, there are race-based differences in illness risk and vaccination rates. The cost-effectiveness of programs to improve vaccine uptake or of alternative vaccination policies to increase protection is unclear. A decision analysis compared, in US black and general population cohorts aged 50 years, the public health impact and cost-effectiveness of pneumococcal vaccination recommendations, without and with a vaccine uptake improvement program, and alternative population vaccine policies. Program-based uptake improvement (base case: 12.3% absolute increase, costing $1.78/eligible patient) was based on clinical trial data. US data informed population-specific pneumococcal risk. Vaccine effectiveness was estimated using Delphi panel and trial data. In both black and general population cohorts, an uptake improvement program for current vaccination recommendations was favored, costing $48,621 per QALY gained in black populations ($54,929/QALY in the general population) compared to current recommendations without a program. Alternative vaccination policies largely prevented less illness and were economically unfavorable. In sensitivity analyses, uptake programs were favored, at a $100,000/QALY threshold, unless they improved absolute vaccine uptake < 2.1% in blacks or < 2.6% in the general population. Results were robust in sensitivity analyses. Programs to increase adult pneumococcal vaccination uptake are economically reasonable compared to changes in vaccination recommendations, and more favorable in underserved minorities than in the general population. If addressing race-based health disparities is a priority, evidence-based programs to increase vaccination should be considered.


Don't bring me your tired, your poor: the crowded state of America's emergency departments.
If the time comes, people expect that the emergency department (ED) will have the resources necessary to treat them in a timely, high-quality manner. Increasingly, however, EDs may not be able to meet that expectation. Hospitals in urban areas with large populations, high population growth, and higher-than-average numbers of uninsured are particularly crowded: ambulances are often diverted to other hospitals and patients are frequently forced to "board" in the hallways (while they wait to be transferred to another facility or part of the hospital). This issue brief places EDs in the context of the U.S. health care system and its economics, discusses existing ED capacity and utilization, where crowding is happening and ways of measuring it, what is causing crowding in EDs, and the consequences of crowding. It highlights a number of potential ways to alleviate crowding at both the health system and the individual hospital level.


Hemolytic-uremic syndrome in a dog.
A 3-year-old, spayed, female Boxer was presented because of acute onset of anorexia, vomiting, and hemorrhagic diarrhea. Microangiopathic hemolytic anemia with intravascular hemolysis, thrombocytopenia, and acute renal failure were detected. The dog was treated with fluids, antiemetics, antibiotics, and diuretics. Despite supportive therapy, the dog's condition worsened, and the owners elected euthanasia. Necropsy revealed disseminated petechiae on the parietal peritoneum and serosal surfaces of the intestinal tract. The histologic lesions were consistent with severe arteritis and microvascular thrombosis involving only the renal and intestinal arterioles. The final diagnosis was hemolytic-uremic syndrome (HUS), a rarely described disorder in dogs. The clinical presentation of primarily gastrointestinal clinical signs was similar to that of typical or diarrhea-associated HUS (D+ HUS) in humans (mainly children), which is caused by gastrointestinal proliferation of verocytotoxin-producing Escherichia coli. Bacterial toxins can be adsorbed and cause endothelial injury, activation of hemostasis, and thrombosis, with lesions confined primarily to the kidneys. Although rare, HUS should be considered in the differential diagnosis of dogs with microangiopathic hemolytic anemia.


Unlocking the secrets of galectins: a challenge at the frontier of glyco-immunology.
Over the last decade, we have witnessed an explosion of information regarding the function of glycoconjugates, carbohydrate-binding proteins, and the elucidation of the sugar code. This progress has yielded not only important insights into fundamental areas of glycobiology but has also influenced other fields such as immunology and molecular medicine. A family of galactoside-binding proteins, called galectins, has emerged recently as a novel kind of bioactive molecules with powerful, immunoregulatory functions. Different members of this family have been shown to modulate positively or negatively multiple steps of the inflammatory response, such as cell-matrix interactions, cell trafficking, cell survival, cell-growth regulation, chemotaxis, and proinflammatory cytokine secretion. To introduce a comprehensive overview of these new advances, here we will explore the molecular mechanisms and biochemical pathways involved in these functions. We will also examine the role of these proteins in the modulation of different pathological processes, such as chronic inflammation, autoimmunity, infection, allergic reactions, and tumor spreading. Understanding the intimate mechanisms involved in galectin functions will help to delineate selective and novel strategies for disease intervention and diagnosis.


Arthropathy in acromegaly: a questionnaire-based estimation of motor disability and its relation with quality of life and work productivity.
Arthropathy is a common and disabling complication of acromegaly. Since in this condition radiological findings rarely correspond to functional impairment, we elected to quantify in a large cohort of acromegalic patients: the degree of motor disability compared with data from general population, the impact of joint involvement on quality of life and work productivity, and to look for associated factors. In 211 acromegalic patients, 131 with controlled disease and 80 with active disease, eight validated scales were used to evaluate the (i) prevalence and distribution of arthropathy, (ii) degree of motor disability and joint symptoms (VAS, AIMS symptoms and WOMAC), (iii) quality of life (AcroQoL and PASQ) and work capability (WPAI:GH) as consequences of joint complications. Using the WOMAC questionnaire, for which population based normative values are available, a significantly higher prevalence and severity of motor disability was detected in acromegalics compared to the general population from literature. The results provided by the different questionnaires turned out to be highly concordant. All measures of motor disability correlated both with impaired quality of life and motor disability and were worse in females and in patients with higher BMI. The questionnaires VAS, AIMS symptoms, and WOMAC (this latter both as a whole and with its functionality subscale), with their scores, proved to be the most adequate tools to evaluate motor disability and its consequences on both quality of life and work productivity in acromegaly. Female gender and higher BMI are associated with worse articular symptoms.


Circadian Metabolism: From Mechanisms to Metabolomics and Medicine.
The circadian clock directs nearly all aspects of diurnal physiology, including metabolism. Current research identifies several major axes by which it exerts these effects, including systemic signals as well as direct control of cellular processes by local clocks. This redundant network can transmit metabolic and timing information bidirectionally for optimal synchrony of metabolic processes. Recent advances in cellular profiling and metabolomics technologies have yielded unprecedented insights into the mechanisms behind this control. They have also helped to illuminate individual variation in these mechanisms that could prove important in personalized therapy for metabolic disease. Finally, these technologies have provided platforms with which to screen for the first potential drugs affecting clock-modulated metabolic function.


Impact of Graft Steatosis on Postoperative Complications after Liver Transplantation.
Background Steatotic grafts are more susceptible to ischemia-reperfusion injury than are normal grafts. Therefore, using steatotic grafts for liver transplantation (LT) is associated with high primary dysfunction and decreased survival rates. The aim of this study is to evaluate the impact of graft steatosis on post LT outcomes. Methods A retrospective cohort analysis of 271 LT recipients from 2005 to 2016 was performed and patients were classified based on two types of steatosis, macrosteatosis (MaS), and microsteatosis (MiS). Each category was subdivided into three groups according to the degree of steatosis: no (< 5%), mild (≥5 to < 30%), and moderate (≥30 to ≤60%). The primary hospital stays and 6-month postoperative complications were analyzed by the Clavien-Dindo classification system. Additionally, patient and graft survivals were studied. Results Significant differences were observed in grade III MaS ( p -value = 0.019) and grade V MiS ( p -value = 0.020). A high trend of early graft dysfunction was found in the moderate MaS and MiS groups; however, they were not statistically significant ( p -value = 0.199 and 0.282, respectively). Interestingly, the acute cellular rejection (ACR) rate was found to be inversely proportional to the degree of steatosis in both categories but it did not reach a significant level ( p -value = 0.161 and 0.111, respectively). Conclusion Excellent post LT long-term outcomes using grafts with mild and moderate steatosis were determined. Further studies are needed to evaluate the newly proposed relationship between ACR and steatosis.


Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors.
The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m(2)/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m(2)/day (n = 6) or 15 mg/m(2)/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m(2)/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing's sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O(6)-methylguanine-DNA methyltransferase expression in tumor tissue. The MTD using this schedule was temozolomide (100 mg/m(2)/day) and irinotecan (10 mg/m(2)/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.


An unusual case of vaginal myiasis.
Myiasis, a term used to describe the infestation of a live animal by fly larvae, is rarely reported in human subjects. The adult fly lays its eggs on living tissue that progresses to become larvae that feed on living tissue having gone through three developmental stages known as the first, second and third instar. The larvae become pupae before finally developing into adults. We describe an unusual case of a 79-year-old female who collapsed in her garden and lay there for several days before presenting to her local hospital Accident and Emergency department with an infestation of larvae in her vagina labia, identified as those from the Protophormia species northern blowfly. After complete removal of the larvae using tweezers followed by cleansing of the affected area and a course of antibiotics, the patient's condition improved. A follow-up review by the local gynaecology team revealed no evidence of further infestation. It is our understanding that this is the first highly unusual case of a blowfly larvae infestation to be reported in a human within the UK.


Mechanical forces alter endothelin-1 signaling: comparative ovine models of congenital heart disease.
The risk and progression of pulmonary vascular disease in patients with congenital heart disease is dependent on the hemodynamics associated with different lesions. However, the underlying mechanisms are not understood. Endothelin-1 is a potent vasoconstrictor that plays a key role in the pathology of pulmonary vascular disease. We utilized two ovine models of congenital heart disease: (1) fetal aortopulmonary graft placement (shunt), resulting in increased flow and pressure; and (2) fetal ligation of the left pulmonary artery resulting in increased flow and normal pressure to the right lung, to investigate the hypothesis that high pressure and flow, but not flow alone, upregulates endothelin-1 signaling. Lung tissue and pulmonary arterial endothelial cells were harvested from control, shunt, and the right lung of left pulmonary artery lambs at 3-7 weeks of age. We found that lung preproendothelin-1 mRNA and protein expression were increased in shunt lambs compared to controls. Preproendothelin-1 mRNA expression was modestly increased, and protein was unchanged in left pulmonary artery lambs. These changes resulted in increased lung endothelin-1 levels in shunt lambs, while left pulmonary artery levels were similar to controls. Pulmonary arterial endothelial cells exposed to increased shear stress decreased endothelin-1 levels by five-fold, while cyclic stretch increased levels by 1.5-fold. These data suggest that pressure or an additive effect of pressure and flow, rather than increased flow alone, is the principal driver of increased endothelin signaling in congenital heart disease. Defining the molecular drivers of the pathobiology of pulmonary vascular disease due to differing mechanical forces will allow for a more targeted therapeutic approach.


CUUCGG hairpins: extraordinarily stable RNA secondary structures associated with various biochemical processes.
The mRNA of bacteriophage T4 contains a strikingly abundant intercistronic hairpin. Within the 55 kilobases of known T4 sequence, the hexanucleotide sequence CTTCGG is found 13 times in the DNA strand equivalent to mRNA sequences. In 12 of those occurrences, the sequence is flanked by inverted repeats predictive of RNA hairpins with UUCG in the loop. Avian myeloblastosis virus reverse transcriptase, which can traverse hairpins of larger calculated stability, terminates efficiently at these CUUCGG hairpins. Thermal denaturation studies of model hairpins show that the loop sequence UUCG dramatically stabilizes RNA hairpins when compared to a control sequence. These data, when combined with previously described parameters of helix stability, suggest that T4 has utilized this loop sequence to optimize the stability of intercistronic hairpins. The stability of CUUCGG hairpins is also utilized in the RNAs of many organisms besides T4.


[Clinical manifestation and diagnosis of ocular borreliosis].
To present severe involvements of Borrelia burgdorferi in the etiology of uveitis, optic neuritis and other ocular inflammatory conditions. IgM and IgG antibodies for Borrelia burgdorferi were detected by ELISA. Since May 1995 we have examined 78 patients for borreliosis. Borreliosis was diagnosed in 11 patients (4 males, 7 females; aged 7 to 48). 7 persons remembered being bitten by a tick, 3 months to 3 years before the onset of ocular symptoms. All patients had systemic symptoms and signs. Ocular manifestations were as follows: nonspecific chronic conjunctivitis in 4 patients, keratitis in 2, diminished corneal sensation in 1, iritis in 1, intermediate uveitis and perivasculitis in 1, posterior uveitis in 3, retinal haemorrhage in 1, optic neuritis in 1, optic disc oedema in 2, sixth nerve paresis in 1 patient. We emphasize the importance of performing serological tests for borreliosis in patients with uveitis, inflammatory diseases of unknown etiology, optic neuritis and other neuro-ophthalmic conditions.


Use of TSAR, Thermal Shift Analysis in R, to identify Folic Acid as a Molecule that Interacts with HIV-1 Capsid.
Thermal shift assay (TSA) is a versatile biophysical technique for studying protein interactions. Here, we report a free, open-source software tool TSAR (Thermal Shift Analysis in R) to expedite and automate the analysis of thermal shift data derived either from individual experiments or large screens of chemical libraries. The TSAR package incorporates multiple, dynamic workflows to facilitate the analysis of TSA data and returns publication-ready graphics or processed results. Further, the package includes a graphic user interface (GUI) that enables easy use by non-programmers, aiming to simplify TSA analysis while diversifying visualization. To exemplify the utility of TSAR we screened a chemical library of vitamins to identify molecules that interact with the capsid protein (CA) of human immunodeficiency virus type 1 (HIV-1). Our data show that hexameric CA interacts with folic acid in vitro .


SPICODYN: A Toolbox for the Analysis of Neuronal Network Dynamics and Connectivity from Multi-Site Spike Signal Recordings.
We implemented an automated and efficient open-source software for the analysis of multi-site neuronal spike signals. The software package, named SPICODYN, has been developed as a standalone windows GUI application, using C# programming language with Microsoft Visual Studio based on .NET framework 4.5 development environment. Accepted input data formats are HDF5, level 5 MAT and text files, containing recorded or generated time series spike signals data. SPICODYN processes such electrophysiological signals focusing on: spiking and bursting dynamics and functional-effective connectivity analysis. In particular, for inferring network connectivity, a new implementation of the transfer entropy method is presented dealing with multiple time delays (temporal extension) and with multiple binary patterns (high order extension). SPICODYN is specifically tailored to process data coming from different Multi-Electrode Arrays setups, guarantying, in those specific cases, automated processing. The optimized implementation of the Delayed Transfer Entropy and the High-Order Transfer Entropy algorithms, allows performing accurate and rapid analysis on multiple spike trains from thousands of electrodes.


Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis.
Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.


Tuberculosis and diabetes in southern Mexico.
To determine the impact of diabetes on the rates of tuberculosis in a region where both diseases are prevalent. Data from a population-based cohort of patients with pulmonary tuberculosis undergoing clinical and mycobacteriologic evaluation (isolation, identification, drug-susceptibility testing, and IS6110-based genotyping and spoligotyping) were linked to the 2000 National Health Survey (ENSA2000), a national probabilistic, polystage, stratified, cluster household survey of the civilian, noninstitutionalized population of Mexico. From March 1995 to March 2003, 581 patients with Mycobacterium tuberculosis culture and fingerprint were diagnosed, 29.6% of whom had been diagnosed previously with diabetes by a physician. According to the ENSA2000, the estimated prevalence of diabetes in the study area was 5.3% (95% CI 4.1-6.5). The estimated rates of tuberculosis for the study area were greater for patients with diabetes than for nondiabetic individuals (209.5 vs. 30.7 per 100000 person-years, P < 0.0001). In this setting, the rate of tuberculosis was increased 6.8-fold (95% CI 5.7-8.2, P < 0.0001) in patients with diabetes due to increases in both reactivated and recently transmitted infection. Comorbidity with diabetes may increase tuberculosis rates as much as coinfection with human immunodeficiency virus (HIV), with important implications for the allocation of health care resources.


Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.
Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).


Mouse leukemia: therapy with monoclonal antibodies against a thymus differentiation antigen.
Monoclonal antibodies against a thymus cell differentiation antigen (Thy-1.1) were effective in the therapy of a transplanted mouse leukemia. Passive immunization resulted in high titers of cytotoxic antibody in the serum of treated mice and the suppression of metastatic tumor cells. The tumor-suppressive effects of the monoclonal antibodies were amplified by the administration of exogenous complement. This combined antibody and complement therapy resulted in the cure of leukemia in a significant proportion of the treated animals.


Local sequence alignments statistics: deviations from Gumbel statistics in the rare-event tail.
The optimal score for ungapped local alignments of infinitely long random sequences is known to follow a Gumbel extreme value distribution. Less is known about the important case, where gaps are allowed. For this case, the distribution is only known empirically in the high-probability region, which is biologically less relevant. We provide a method to obtain numerically the biologically relevant rare-event tail of the distribution. The method, which has been outlined in an earlier work, is based on generating the sequences with a parametrized probability distribution, which is biased with respect to the original biological one, in the framework of Metropolis Coupled Markov Chain Monte Carlo. Here, we first present the approach in detail and evaluate the convergence of the algorithm by considering a simple test case. In the earlier work, the method was just applied to one single example case. Therefore, we consider here a large set of parameters: We study the distributions for protein alignment with different substitution matrices (BLOSUM62 and PAM250) and affine gap costs with different parameter values. In the logarithmic phase (large gap costs) it was previously assumed that the Gumbel form still holds, hence the Gumbel distribution is usually used when evaluating p-values in databases. Here we show that for all cases, provided that the sequences are not too long (L > 400), a "modified" Gumbel distribution, i.e. a Gumbel distribution with an additional Gaussian factor is suitable to describe the data. We also provide a "scaling analysis" of the parameters used in the modified Gumbel distribution. Furthermore, via a comparison with BLAST parameters, we show that significance estimations change considerably when using the true distributions as presented here. Finally, we study also the distribution of the sum statistics of the k best alignments. Our results show that the statistics of gapped and ungapped local alignments deviates significantly from Gumbel in the rare-event tail. We provide a Gaussian correction to the distribution and an analysis of its scaling behavior for several different scoring parameter sets, which are commonly used to search protein data bases. The case of sum statistics of k best alignments is included.


Recent advances in Japanese encephalitis.
Japanese encephalitis is a flaviviral disease that is endemic to the South, Southeast Asia, and Asia Oceania regions. Given that about 60% of the world's population (about 7.4 billion) resides in this region (about 4.4 billion), this disease poses a significant threat to global health. Active vaccination campaigns conducted in endemic countries have led to a decrease in the number of reported cases over the years. In this article, we strive to briefly highlight recent advances in understanding the role of microRNAs in disease pathology, focus on providing brief summaries of recent clinical trials in the field of Japanese encephalitis therapeutics, and review the current prophylactic strategies.


Heterogeneity in the recognition of Ostertagia circumcincta antigens by serum antibody from mature, infected sheep.
The recognition of parasite molecules from third-stage and adult Ostertagia circumcincta by serum antibody was studied in a group of matched, mature Scottish Blackface sheep that had been naturally and then deliberately infected. A total of 20 molecules was recognized in somatic extracts from third-stage larvae and 31 molecules in somatic extracts from adult parasites. However, no sheep recognized all immunogenic molecules and no molecule was recognized by all sheep. There was no obvious relationship between recognition of any parasite antigen and polymorphism at class I loci or at the DRBI class II locus of the major histocompatibility complex in these outbred animals. Only 15 molecules from third-stage larvae were present at a frequency suitable for statistical analysis and recognition of three of these 15 molecules was associated with differences in worm burdens. Recognition of two of five molecules from adult parasites was associated with differences in worm length. These results indicate that variation in the recognition of specific, identifiable parasite molecules may be partly responsible for variation among sheep in resistance to O. circumcincta.


Factors of susceptibility of human myiasis caused by the New World screw-worm, Cochliomyia hominivorax in São Gonçalo, Rio de Janeiro, Brazil.
This study was carried out between July 2007 and June 2008 and reports on the occurrence of human myiasis caused by the New World screwworm, Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae) in São Gonçalo in the state of Rio de Janeiro, Brazil. Liquid or solid vaseline was used to suffocate the larvae, which were then preserved in 70% ethanol and sent to the Instituto Oswaldo Cruz for identification. C. hominivorax were identified in all 22 cases of myiasis. There were 12 male and 10 female patients with ages ranging from 03 to 71. Ethnically the highest incidence was among black people, with 17 cases. Open wounds were the main cause of the parasitosis, whereas poor personal hygiene, the low educational level, alcoholism, bedridden patients, and physical or mental disability were possibly secondary factors; in addition to all these factors the income of the patients was very low.


Louis Pasteur-The life of a controversial scientist with a prepared mind, driven by curiosity, motivation, and competition.
Louis Pasteur, born December 27, 1822 in Dole, France, showed in his childhood and youth great abilities as an artistic painter; however by an age of 19, his interest changed toward science, and he moved to Paris to study chemistry and physics at École Normale Supérieure. During graduation, he initiated research on chiral crystallography and stereochemistry and got his doctorates in 1847 in both chemistry and physics. In 1848, he started as high school teacher in Dijon, but shortly after he became a deputy professor at the University of Strasbourg in chemistry and got married to the rector's daughter Marie Laurent. They had five children, of which only two survived. The family moved to Lille in 1854, where he worked as professor in chemistry and became the dean at the new Faculty of Science at the University of Lille. He initiated his famous research on fermentation in 1855. Louis Pasteur moved back to École Normale Supérieure in 1857, where a major part of his innovative research on fermentation took place ending up with the development of pasteurization in 1864. Through genius experiments, he disputed the spontaneous genesis theory and founded the basis for the germ theory, later confirmed by his enemy Robert Koch and several other research teams, which he for lifetime competed with on the cure and prevention against infectious disease causes by both bacteria such as cholera, anthrax, and virus-induced infections as yellow fever and rabies. However, most of his experiments were done on animals since Pasteur and his colleagues at École Normale Superiére were not physicians but scientists. The first successful attenuated vaccine used in humans against rabies was, when the 9-year-old Joseph Meister was cured or prevented from rabies in 1885 after 13 vaccine injections done by the young pediatrician Joseph Grancher. This worldwide known intervention is both world famous and ethically criticized and disputed. The Pasteur Institute was inaugurated in 1888-now an international prestigious research institute-which has been expanded since in a network of affiliated Pasteur institutes over the whole world. There were multiple links to Danish scientists of the 19th century and to the Danish brewery industry. Most well known is the strong friendship between Louis Pasteur and the Carlsberg brewery and especially to its founder Jacob Christian Jacobsen, who was a great believer on a scientific approach to a cleaner fermentation process and better beer quality. Louis Pasteur stands as a milestone example of the fruitful outcome of scientific competition and collaboration and should therefore be remembered as an inspiration for present and future scientists.


Carcinoma of the head of the pancreas. Morbidity and mortality of surgical procedures.
This retrospective study analyses the peri-operative morbidity and mortality of 165 patients presenting with carcinoma of the head of the pancreas over a 5-year period. Patients clinically fit for surgery (84%) were subdivided into three main groups, namely: group I (6%) underwent pancreaticoduodenal resection; group II (42%) had locoregionally advanced disease; and group III (36%) with metastatic disease. The latter group was subdivided into groups IIIa (22%) without ascites and IIIb (14%) with ascites. In the palliative groups (II and III), 61% underwent operative biliary drainage procedures, 33% a combined biliary drainage and a duodenal bypass procedure and 5% a duodenal bypass only. Obstructive jaundice recurred in 3% of cases after operative biliary drainage. Only 7% of patients required a duodenal bypass during follow-up. The mortality rates after surgery were 22% following pancreaticoduodenectomy (group I), 1.5% for the palliative procedures in group II, but 17% in group IIIa patients with metastatic disease without ascites and 83% when ascites was present (group IIIb). This study demonstrates that patients with ascites, although clinically fit for surgery, had a prohibitively high operative mortality rate and represented a subgroup of patients better treated by non-operative methods. Surgical drainage of the biliary system in all other cases had acceptably low morbidity and mortality rates. A prophylactic duodenal bypass is not mandatory.


Multilevel Modeling of Cognitive Diagnostic Assessment: The Multilevel DINA Example.
Many multilevel linear and item response theory models have been developed to account for multilevel data structures. However, most existing cognitive diagnostic models (CDMs) are unilevel in nature and become inapplicable when data have a multilevel structure. In this study, using the log-linear CDM as the item-level model, multilevel CDMs were developed based on the latent continuous variable approach and the multivariate Bernoulli distribution approach. In a series of simulations, the newly developed multilevel deterministic input, noisy, and gate (DINA) model was used as an example to evaluate the parameter recovery and consequences of ignoring the multilevel structures. The results indicated that all parameters in the new multilevel DINA were recovered fairly well by using the freeware Just Another Gibbs Sampler (JAGS) and that ignoring multilevel structures by fitting the standard unilevel DINA model resulted in poor estimates for the student-level covariates and underestimated standard errors, as well as led to poor recovery for the latent attribute profiles for individuals. An empirical example using the 2003 Trends in International Mathematics and Science Study eighth-grade mathematical test was provided.


Recent advances in laccase activity assays: A crucial challenge for applications on complex substrates.
Despite being one of the first enzymes discovered in 1883, the determination of laccase activity remains a scientific challenge, and a barrier to the full use of laccase as a biocatalyst. Indeed, laccase, an oxidase of the blue multi-copper oxidases family, has a wide range of substrates including substituted phenols, aromatic amines and lignin-related compounds. Its one-electron mechanism requires only oxygen and releases water as a reaction product. These characteristics make laccase a biocatalyst of interest in many fields of applications including pulp and paper industry, biorefineries, food, textile, and pharmaceutical industries. But to fully envisage the use of laccase at an industrial scale, its activity must be reliably quantifiable on complex substrates and in complex matrices. This review aims to describe current and emerging methods for laccase activity assays and place them in the context of a potential industrial use of the enzyme.


Junctional ectopic tachycardia in infancy: report of two cases.
Junctional ectopic tachycardia (JET) in infancy is one of the serious arrhythmias which can be fatal. Typical features of JET include rapid and irregular heart beats with atrioventricular dissociation. Two cases of JET are reported: Case 1 was a 35-week-gestational age newborn who was found to have hydropsy and fetal tachycardia at the 21st week of gestational age. Antiarrhythmic agents including digoxin, propranolol and verapamil were administered to his mother to treat the fetal arrhythmia without success. JET was recognized at birth which was spontaneously converted into a sinus rhythm at 1 month of age. The maternal history revealed that two previous pregnancies ended in hydrops fetalis, and one of these was documented to have fetal tachycardia. Case 2 was a 6-month-old male infant with JET and congestive heart failure. After failure of various antiarrhythmic agents, amiodarone finally slowed down his heart rate and controlled his congestive heart failure.


Evaluation of State-Mandated Reporting of Neonatal Abstinence Syndrome - Six States, 2013-2017.
From 2004 to 2014, the incidence of neonatal abstinence syndrome (NAS) in the United States increased 433%, from 1.5 to 8.0 per 1,000 hospital births. The latest national data from 2014 indicate that one baby was born with signs of NAS every 15 minutes in the United States (1). NAS is a drug withdrawal syndrome that most commonly occurs among infants after in utero exposure to opioids, although other substances have also been associated with NAS. Prenatal opioid exposure has also been associated with poor fetal growth, preterm birth, stillbirth, and possible specific birth defects (2-5). NAS surveillance has often depended on hospital discharge data, which historically underestimate the incidence of NAS and are not available in real time, thus limiting states' ability to quickly direct public health resources (6,7). This evaluation focused on six states with state laws implementing required NAS case reporting for public health surveillance during 2013-2017 and reviews implementation of the laws, state officials' reports of data quality before and after laws were passed, and advantages and challenges of legally mandating NAS reporting for public health surveillance in the absence of a national case definition. Using standardized search terms in an online legal research database, laws in six states mandating reporting of NAS from medical facilities to state health departments (SHDs) or from SHDs to a state legislative body were identified. SHD officials in these six states completed a questionnaire followed by a semistructured telephone interview to clarify open-text responses from the questionnaire. Variability was found in the type and number of surveillance data elements reported and in how states used NAS surveillance data. Following implementation, five states with identified laws reported receiving NAS case reports within 30 days of diagnosis. Mandated NAS case reporting allowed SHDs to quantify the incidence of NAS in their states and to inform programs and services. This information might be useful to states considering implementing mandatory NAS surveillance.


Mechanisms Involved in the Therapeutic Effect of Cannabinoid Compounds on Gliomas: A Review with Experimental Approach.
Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several thera-peutic approaches are used; however, they are associated with side effects that affect pa-tients'quality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives. This study aimed to review the key enzymatic targets involved in glioma pathophysi-ology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations. Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology. Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3-kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase. The evaluated compounds exhibited favorable interactions with the analyzed enzy-matic targets, thus representing potential candidates for further in vitro and in vivo studies.


Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability.
Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.


Urinary lead concentration and composition of the adult gut microbiota in a cross-sectional population-based sample.
Lead (Pb) is a ubiquitous environmental contaminant with an array of detrimental health effects in children and adults, including neurological and immune dysfunction. Emerging evidence suggests that Pb exposure may alter the composition of the gut microbiota, however few studies have examined this association in human populations. The purpose of this study was to examine the association between urinary Pb concentration and the composition of the adult gut microbiota in a population-based sample of adults. Data used in this study were collected as part of the Survey of the Health of Wisconsin (SHOW) and its ancillary microbiome study. The SHOW is a household-based health examination survey of Wisconsin residents, collecting a variety of survey data on health determinants and outcomes, as well as objective measurements of body habitus, and biological specimens including urine. The ancillary microbiome study added additional questions and biological specimen collection, including stool, from participants age 18+. Pb concentration was analyzed in urine samples, and gut microbiota composition was assessed using DNA sequencing of the 16S rRNA V4 region, extracted from stool samples. Data processing and statistical analyses were performed in mothur, Python, R, and SAS. Of 696 participants, urinary Pb concentration was highest in those age 70+, females, those with a high school diploma or lower, current and former smokers, and those without indoor pets. In adjusted models, increasing urinary Pb levels were associated with increases in microbial α-diversity (p = 0.071) and richness (p = 0.005). Differences in microbial β-diversity were significantly associated (p = 0.003) with differences in urinary Pb level. Presence of Proteobacteria, including members of the Burkholderiales, was significantly associated with increased urinary Pb. These results suggest that Pb exposure is associated with differences in the composition of the adult gut microbiota in a population-based human sample. Further investigation of this association is warranted.


A pioneer of psy: The first Ugandan psychiatric nurse and her (different) tale of psychiatry in Uganda.
In Africa, the emergence of a "modern" mental health regime centered on psychiatry is often portrayed as a unidirectional intervention by "the West." Analyses ranging from medical histories of colonial psychiatry to more recent studies of Global Mental Health focus mostly on the role of external actors and the ways their actions impact(ed) on local populations. Uncritical studies simply reduce the complexity of African therapeutic landscapes to a "treatment gap" and see the introduction of "science-based" mental health approaches as necessary "civilizing" missions. Critical studies emphasize the harms of psychiatric interventions and celebrate local healing practices instead. Both approaches are problematic: they ignore the many interconnections between highly dynamic treatment regimes that cannot be neatly designated as African or western, portray local populations as largely passive, and neglect the multiple ways in which psychiatry has been embraced, adapted, and disrupted by Africans themselves. This article challenges simplistic depictions of "western" psychiatry in Africa by providing a portrait of Rwashana Selina, the first Ugandan psychiatric nurse who-after being sent to the UK in the 1950s for training-became a central figure in Ugandan psychiatry. Based on interview material, I recount her life story and discuss her formative role in the development of psychiatric care in the colonial and postcolonial era. Rwashana's tale of Ugandan psychiatry emphasizes co-operation, mutual acknowledgments and pluralistic leadership and thus breaks with typical images of and dichotomies between white doctors and supposedly inferior African medical staff.


AcrB, AcrD, and MdtABC multidrug efflux systems are involved in enterobactin export in Escherichia coli.
Escherichia coli produces the iron-chelating compound enterobactin to enable growth under iron-limiting conditions. After biosynthesis, enterobactin is released from the cell. However, the enterobactin export system is not fully understood. Previous studies have suggested that the outer membrane channel TolC is involved in enterobactin export. There are several multidrug efflux transporters belonging to resistance-nodulation-cell division (RND) family that require interaction with TolC to function. Therefore, several RND transporters may be responsible for enterobactin export. In this study, we investigated whether RND transporters are involved in enterobactin export using deletion mutants of multidrug transporters in E. coli. Single deletions of acrB, acrD, mdtABC, acrEF, or mdtEF did not affect the ability of E. coli to excrete enterobactin, whereas deletion of tolC did affect enterobactin export. We found that multiple deletion of acrB, acrD, and mdtABC resulted in a significant decrease in enterobactin export and that plasmids carrying the acrAB, acrD, or mdtABC genes restored the decrease in enterobactin export exhibited by the ΔacrB acrD mdtABC mutant. These results indicate that AcrB, AcrD, and MdtABC are required for the secretion of enterobactin.


Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons.
Adenosine receptors were made visible on light microscopy by autoradiography with tritiated cyclohexyladenosine. In the cerebellum, adenosine receptors were absent in Weaver mice, which lack granule cells, and were displaced in Reeler mice, which have displacements of granule cells. Thus, adenosine receptors appear to be located on the axon terminals of excitatory granule cells in the cerebellum. Removal of one eye of a rat depleted adenosine receptors in the contralateral superior colliculus, suggesting that the receptors occur on axon terminals of excitatory projections from retinal ganglion cells. The presence of adenosine receptors on excitatory axon terminals may explain synaptic inhibition by adenosine and the behavioral effects of xanthines.


Evaluation of early cardiac dysfunction in patients with systemic lupus erythematosus with or without anticardiolipin antibodies.
The aim of this study was to use transthoracic Doppler echocardiographic (TTE) imaging methods to identify cardiac dysfunction, an indicator of subclinical atherosclerosis in asymptomatic systemic lupus erythematosus (SLE) patients in terms of cardiac effects. This study involved 80 patients: a study group (n = 50) and control group (n = 30). They were categorized into four subgroups: anticardiolipin antibodies (aCL) (+) (n = 14) and aCL (-) (n = 36); systemic lupus erythematosus disease activity index (SLEDAI) ≥ 6 (n = 15) and SLEDAI < 6 (n = 35); disease period ≥ 5 years (n = 21) and disease period < 5 years (n = 29); major organ involvement (+) (n = 19), major organ involvement (-) (n = 31). The ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/E') for the study group was found to be higher than the control (p < 0.01). Systolic septal motion velocity (Ssm) was lower in the study group compared with the control (p < 0.01). Left atrium (LA) dimension was greater in the study group than the control (p < 0.01). Ssm was found to be lower in the aCL (+) patients compared with the control and aCL (-) groups (p < 0.01, p < 0.05, respectively). LA dimension was greater in the aCL (+) and (-) groups compared with the control, (p < 0.01, p < 0.05, respectively) and aCL groups compared with each other (p < 0.05). The E/E' ratio for the aCL (+) and (-) groups was found to be greater than the control (p < 0.05). In the study, both the Ssm and the late diastolic septal velocity (sA') was found to be lower in the SLEDAI ≥ 6 group compared with SLEDAI<6 group, (p < 0.001, p < 0.05, respectively). LA dimension was statistically greater in the SLEDAI ≥ 6 group compared with the SLEDAI <6 group (p < 0.001). E' and early diastolic septal velocity (sE') were statistically lower in the disease period >5 years group compared with the disease period <5 years group (p < 0.01, p < 0.05, respectively). Carrying out regular scans with TTE image of SLE patients is important in order to identify early cardiac involvement during monitoring and treatment. Identifying early cardiac involvement in SLE may lead to a reduction in mortality and morbidity rates.


Implementing clinical guidelines to prevent catheter-associated urinary tract infections and improve catheter care in nursing homes: Systematic review.
Catheter-associated urinary tract infection is the most common health care-associated infection, is considered avoidable, and has cost implications for health services. Prevalence is high in nursing homes, but little research has been undertaken to establish whether implementing clinical guidelines can reduce infection rates in long-term care or improve quality of urinary catheter care. Systematic search and critical appraisal of the literature. Three studies evaluated the impact of implementing a complete clinical guideline. Five additional studies evaluated the impact of implementing individual elements of a clinical guideline. Prevention of catheter-associated urinary tract infection in nursing homes has received little clinical or research attention. Studies concerned with whole guideline implementation emerged as methodologically poor using recognized criteria for critically appraising epidemiologic studies concerned with infection prevention. Research evaluating the impact of single elements of clinical guidelines is more robust, and their findings could be implemented to prevent urinary infections in nursing homes.


[Effect of duration of the intervals between immunization with DPT vaccine on the serological indices in children].
The influence of the interval between injections of adsorbed DPT vaccine on the effectiveness of immunization has been studied. The intensity of antibody formation to the pertussis component has been found to decrease 2.7-3.7 times if the interval between the injections constituting the course of primary immunization is prolonged for more than 6 months. The interval between the course of primary immunization and the first booster injection, which lasts 1.5-2 years in accordance with the currently accepted immunization schedule, is unreasonably long. Immunological characteristics in respect to pertussis have been found to decrease 8-45 times as early as 16 months after the first booster injection. Most of the vaccines catching pertussis at that time had the moderately severe form of this infection.


Electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis of the lipid molecular species composition of yeast subcellular membranes reveals acyl chain-based sorting/remodeling of distinct molecular species en route to the plasma membrane.
Nano-electrospray ionization tandem mass spectrometry (nano-ESI-MS/MS) was employed to determine qualitative differences in the lipid molecular species composition of a comprehensive set of organellar membranes, isolated from a single culture of Saccharomyces cerevisiae cells. Remarkable differences in the acyl chain composition of biosynthetically related phospholipid classes were observed. Acyl chain saturation was lowest in phosphatidylcholine (15.4%) and phosphatidylethanolamine (PE; 16.2%), followed by phosphatidylserine (PS; 29.4%), and highest in phosphatidylinositol (53.1%). The lipid molecular species profiles of the various membranes were generally similar, with a deviation from a calculated average profile of approximately +/- 20%. Nevertheless, clear distinctions between the molecular species profiles of different membranes were observed, suggesting that lipid sorting mechanisms are operating at the level of individual molecular species to maintain the specific lipid composition of a given membrane. Most notably, the plasma membrane is enriched in saturated species of PS and PE. The nature of the sorting mechanism that determines the lipid composition of the plasma membrane was investigated further. The accumulation of monounsaturated species of PS at the expense of diunsaturated species in the plasma membrane of wild-type cells was reversed in elo3Delta mutant cells, which synthesize C24 fatty acid-substituted sphingolipids instead of the normal C26 fatty acid-substituted species. This observation suggests that acyl chain-based sorting and/or remodeling mechanisms are operating to maintain the specific lipid molecular species composition of the yeast plasma membrane.


PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells.
AbstractToll-like receptor 5 (TLR5), a sensor for bacterial flagellin, mounts innate and adaptive immune responses, and has been implicated in infectious diseases, colitis and metabolic syndromes. Although TLR5 is believed to belong to cell surface TLRs, cell surface expression has never been verified. Moreover, it has remained unclear which types of immune cells express TLR5 and contribute to flagellin-dependent responses. In this study we established an anti-mouse TLR5 monoclonal antibody and studied the cell surface expression of TLR5 on immune cells. The macrophage cell line J774 expressed endogenous TLR5 on the cell surface and produced IL-6 and G-CSF in response to flagellin. Cell surface expression of TLR5 and flagellin-induced responses were completely abolished by silencing a TLR-specific chaperone protein associated with TLR4 A (PRAT4A), demonstrating that TLR5 is another client of PRAT4A. In the in vivo immune cells, cell surface TLR5 was mainly found on neutrophils and CD11b (hi) Ly6C (hi) classical monocytes in the bone marrow, circulation, spleen and inflammatory lesions. Ly6C (hi) classical monocytes, but not neutrophils, produced cytokines in response to flagellin. Splenic CD8 (-) CD4 (+) conventional dendritic cells and CD11c (hi) CD11b (hi) lamina propria DCs, also clearly expressed cell surface TLR5. Collectively, cell surface expression of TLR5 is dependent on PRAT4A and restricted to neutrophils, classical monocytes and specific DC subsets.


Patterns of myeloarchitecture in lower limb amputees: an MRI study.
Functional studies of cortical plasticity in humans suggest that the motor cortex reorganizes when the descending motor output pathway is disrupted as a result of limb amputation. The question thus arises if the underlying anatomical organization of the motor cortex is also altered in limb amputation. Owing to challenges involved in imaging the thin cerebral cortex in vivo, there is limited data available on the anatomical or morphological plasticity of the motor cortex in amputation. In this paper, we study the morphology of the primary motor cortex in four lower limb amputees with 37 or more years of amputation and four age and gender-matched controls using 0.7 mm isotropic, T1-weighted MRI optimized to produce enhanced intracortical contrast based on myelin content. We segment the cortex into myelinated and unmyelinated gray matter. We determine the myelinated thickness which is the thickness of the well-myelinated tissue in the deeper layers of the cortex. We compare the bilateral differences in the myelinated thickness between amputees and controls. We also compare bilateral differences in cortical thickness between the two groups. Our measurements show no statistically significant difference between the amputees and controls in the myelinated thickness and in cortical thickness, in the region of the primary motor cortex representing the lower leg.


Arcanobacterium pluranimalium sp. nov., isolated from porpoise and deer.
Two strains of a previously undescribed Arcanobacterium-like bacterium were isolated from a dead harbour porpoise and a dead sallow deer. Biochemical testing and PAGE analysis of whole-cell proteins indicated that the strains were phenotypically closely related to each other and distinct from previously described Actinomyces and Arcanobacterium species. Comparative 16S rRNA gene sequencing studies showed the bacterium to be a hitherto unknown subline within the genus Arcanobacterium. Based on phylogenetic and phenotypic evidence, it is proposed that the unknown bacterium be classified as Arcanobacterium pluranimalium sp. nov. The type strain of Arcanobacterium pluranimalium is CCUG 42575T (= CIP 106442T).


Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study.
Ninety-six assessable patients with advanced or recurrent uterine sarcomas, who were no longer controllable with surgery and radiotherapy, and who had not received prior chemotherapy were treated with cisplatin 50 mg/m2 intravenously every 3 weeks. Of 63 cases with mixed mesodermal tumors, five complete responses (CRs; 8%) and seven partial responses (PRs; 11%) were observed (95% confidence interval [CI], 10.3% to 30.9%). Of 33 patients with leiomyosarcoma, one PR (3%) was observed (95% CI, .1% to 15.8%). Adverse effects included leukopenia (23%), nausea and vomiting (73%), and mild azotemia (42%). No patients experienced life-threatening toxicity. Cisplatin has definite activity when given at the dose and schedule that we tested for patients with mixed mesodermal sarcomas who have not received prior chemotherapy, but has little activity in patients with leiomyosarcoma.


Morphology and morphometric relationships of the sagitta of Diapterus auratus (Perciformes: Gerreidae) from Veracruz, Mexico.
Sagittae otoliths are the most studied because of their morphological variability and size; the sagittae may also have valuable taxonomic use and for D. auratus has not yet been described. In the present study we present a morphological description of the sagitta otolith and an analysis of its correlation with various morphometric parameters. The biological material was captured with a beach seine in the coasts of Alvarado and Port of Veracruz, from November 2009 to June 2010. Sagittae were extracted, cleaned, photographed (SEM and optical), and measured. The analysis included the correlations between sagitta's length and width, versus the fish standard length, height and weight, for a total of 449 fishes. The comparison between left and right sagitta showed no significant difference in both otolith length and width (t-tests, p<0.05) for each sex. The right otolith was used for the correlations for both males and females and the Fisher test (d.f. 161 and 143, p<0.001) showed no significant differences in the slopes and intersections between them. The otolith length vs. fish weight correlation showed a positive allometric growth in males (b=3.9754, p<0.05) and females (b=4.3168, p<0.05).


Expression of integrin subunits alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 in different histological types of ameloblastoma compared with dental germ, dental lamina and adult lining epithelium.
To analyze integrin expression and distribution in different histological types of ameloblastoma, compared with dental germ, dental lamina and adult lining epithelium. Three-micrometer sections from paraffin-embedded specimens were evaluated employing a streptavidin-biotin immunohistochemical method and anti-integrin alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 antibodies. All integrins were present in all specimens, exhibiting different patterns. In follicular ameloblastoma, the integrin staining was stronger in the periphery while integrin alpha2 was not present in the central cells. Acanthomatous ameloblastoma showed a similar pattern, with positive staining for integrins alpha3, alpha5, alphav, beta1 and beta4 in the metaplastic cells. In the unicystic, integrin staining was uniform except for integrins alpha5 and beta3 which showed weaker staining in the upper layers. In the plexiform ameloblastoma, dental germ and lamina integrin staining was uniform. In the adult lining epithelium, staining for integrins alpha2, alpha5 and beta4 was confined to the basal layer, while integrins alphav and beta3 were present in the basal and parabasal, with integrins alpha3 and beta1 in the upper layers. Acanthomatous, follicular and unicystic ameloblastomas showed integrin staining patterns similar to the adult lining epithelium while the plexiform ameloblastoma was similar to the dental germ and lamina.


Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines.
Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.


Three classes of newtonian three-body planar periodic orbits.
We present the results of a numerical search for periodic orbits of three equal masses moving in a plane under the influence of Newtonian gravity, with zero angular momentum. A topological method is used to classify periodic three-body orbits into families, which fall into four classes, with all three previously known families belonging to one class. The classes are defined by the orbits' geometric and algebraic symmetries. In each class we present a few orbits' initial conditions, 15 in all; 13 of these correspond to distinct orbits.


Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit?
A growing body of evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to be a powerful option to improve the cardiovascular (CV) prognosis in high CV-risk patients with type 2 diabetes. Despite a significant reduction in major adverse CV events with SGLT2 inhibitor treatment, however, an unexpected increased risk of amputation was observed in the CANVAS program and the subsequent pharmacovigilance analysis. Although the underlying mechanisms are currently unknown, because amputation has a large negative impact on patient clinical course, clinicians want to know the exact reason for the increased amputation in the canagliflozin treatment. We herein discuss a need to elucidate the actual reasons with more appropriate statistical consideration, taking into account individual clinical course potentially involved in the diabetes-related amputation. Decreases in the hardendpoints by canagliflozin might result in an alternate increase in the other diabetes-related complications, including amputation. In addition, if amputation occurred after stopping canagliflozin, the incidence might be caused by worsened glycemic control and a decrease in hematocrit, accompanied by a subsequent worsening of diabetic foot disease. More detailed approach considering individual clinical course potentially involved in the amputation, would help to further unravel the cause for suspected risk of amputation with canagliflozin.


Trust, sense of community, and civic engagement: Lessons from Australia.
This article examines the association between trust, sense of community, and civic engagement, with a particular focus on the socioeconomic characteristics of individuals, using data from the Household, Income, and Labor Dynamics in Australia Survey. Through the use of panel logit and binary panel data models, we draw three core observations. First, there is evidence that trust is associated with civic engagement in Australia, particularly in the case of volunteering. Trust is a prerequisite for women to participate in volunteering but not for men, where a sense of community matters more. Second, a high sense of community matters for both types of participation, political and volunteering. Third, the relationships between trust, sense of community, and civic engagement are present among the Baby Boomer and Generation X generations but not the Generation Y generation, which participates differently. The study makes an important contribution to the literature by unmasking the gender and generation stories and debunking popular myths about the unwillingness of new Australians to engage in associative behavior.


The Use of Inorganic Compounds in Photodynamic Therapy: Improvements in Methods and Photosensitizer Design
Nanotechnology has provided significant benefits to photodynamic therapy (PDT), which has revolutionized treatments of several diseases. The success of this versatile technique is governed by the sequential in situ generation of reactive oxygen species, after a suitable photosensitizer has been irradiated by a defined wavelength of light. While PDT provides a minimally-invasive and convenient method for the treatment of several afflictions, the efficiency of this therapeutic strategy still has potential for improvements. Several bodies of works within this realm have highlighted the use of inorganic compounds, which is pivotal for the development of photosensitizers (PSs), nanoparticles (NPs) and irradiation sources. The past decade of online patented reports based on PDT were reviewed. The patented reports analyzed showcased the integration of nanomaterials and inorganic compounds into PDT. The patents were grouped according to the following categories, viz., "Nanoparticles in Photodynamic Therapy", "Photosensitizers Incorporating Various Metal Centers", and "Modifications to Light Delivery". PDT is a suitable treatment option for several diseases however there are several challenges and limitations. The incorporation of NPs in the field of PDT is an extremely promising avenue which can be utilized to improve the execution of PDT. Furthermore, the use of inorganic compounds was noted to be frequented in the development of PSs and NP conjugates. The patents presented addressed the associated problems with PDT but there still remains an opportunity for continued research efforts so that more clinical applications are possible.


Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation.
A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and alpha,beta-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.


The catalytic mechanism of human parainfluenza virus type 3 haemagglutinin-neuraminidase revealed.
Human parainfluenza virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human parainfluenza virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this virus. Herein, we used (1) H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.


Leishmanicidal activity of Yucatecan medicinal plants on Leishmania species responsible for cutaneous leishmaniasis.
The leishmanicidal activity of 15 extracts and 4 pure metabolites obtained from Urechites andrieuxii, Colubrina greggii, Dorstenia contrajerva, and Tridax procumbens was evaluated using the newly developed MTS ({3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay, optimized for promastigotes of Leishmania major, Leishmania tropica, and Leishmania aethiopica, as well as for L. aethiopica axenic amastigotes. The assay was then used for calculating the percentage of viable stationary phase parasites after a 24-hr treatment with each plant extract or pure metabolite. The 3 most active samples, 2 from C. greggii (NCG-5C and DCG-3A) and 1 from T. procumbens (TPZ-2A), showed LD50 values of 62.4, 7.2, and 18.5 microg/ml, respectively, on stationary promastigotes, and of 94.2, 27.1, and 95.2 microg/ml, on amastigotes of L. aethiopica. Moreover, TPZ-2A and DCG-3A significantly reduced the percentage of infected monocyte-derived macrophages (THP-I). The percentage of infected cells decreased from 69.9% +/- 2.5% to 20.8% +/- 2% when the cells were treated with the DCG-3A fraction and to 14.9% +/- 0.5% when treated with TPZ-2A, without significantly decreasing the number of human cells. These findings indicate the presence of potentially bioactive metabolites in the roots of C. greggii and in T. procumbens and reflect the importance of pursuing the bioassay-guided purification of these metabolites.


RNAi-mediated silencing of vitellogenin gene function turns honeybee (Apis mellifera) workers into extremely precocious foragers.
The switch from within-hive activities to foraging behavior is a major transition in the life cycle of a honeybee (Apis mellifera) worker. A prominent regulatory role in this switch has long been attributed to juvenile hormone (JH), but recent evidence also points to the yolk precursor protein vitellogenin as a major player in behavioral development. In the present study, we injected vitellogenin double-stranded RNA (dsVg) into newly emerged worker bees of Africanized genetic origin and introduced them together with controls into observation hives to record flight behavior. RNA interference-mediated silencing of vitellogenin gene function shifted the onset of long-duration flights (>10 min) to earlier in life (by 3-4 days) when compared with sham and untreated control bees. In fact, dsVg bees were observed conducting such flights extremely precociously, when only 3 days old. Short-duration flights (<10 min), which bees usually perform for orientation and cleaning, were not affected. Additionally, we found that the JH titer in dsVg bees collected after 7 days was not significantly different from the controls. The finding that depletion of the vitellogenin titer can drive young bees to become extremely precocious foragers could imply that vitellogenin is the primary switch signal. At this young age, downregulation of vitellogenin gene activity apparently had little effect on the JH titer. As this unexpected finding stands in contrast with previous results on the vitellogenin/JH interaction at a later age, when bees normally become foragers, we propose a three-step sequence in the constellation of physiological parameters underlying behavioral development.


Developmental differences in masked form priming are not driven by vocabulary growth.
As children develop into skilled readers, they are able to more quickly and accurately distinguish between words with similar visual forms (i.e., they develop precise lexical representations). The masked form priming lexical decision task is used to test the precision of lexical representations. In this paradigm, a prime (which differs by one letter from the target) is briefly flashed before the target is presented. Participants make a lexical decision to the target. Primes can facilitate reaction time by partially activating the lexical entry for the target. If a prime is unable to facilitate reaction time, it is assumed that participants have a precise orthographic representation of the target and thus the prime is not a close enough match to activate its lexical entry. Previous developmental work has shown that children and adults' lexical decision times are facilitated by form primes preceding words from small neighborhoods (i.e., very few words can be formed by changing one letter in the original word; low N words), but only children are facilitated by form primes preceding words from large neighborhoods (high N words). It has been hypothesized that written vocabulary growth drives the increase in the precision of the orthographic representations; children may not know all of the neighbors of the high N words, making the words effectively low N for them. We tested this hypothesis by (1) equating the effective orthographic neighborhood size of the targets for children and adults and (2) testing whether age or vocabulary size was a better predictor of the extent of form priming. We found priming differences even when controlling for effective neighborhood size. Furthermore, age was a better predictor of form priming effects than was vocabulary size. Our findings provide no support for the hypothesis that growth in written vocabulary size gives rise to more precise lexical representations. We propose that the development of spelling ability may be a more important factor.


Genetic stability of equine arteritis virus during horizontal and vertical transmission in an outbreak of equine viral arteritis.
An imported carrier stallion (A) from Europe was implicated in causing an extensive outbreak of equine viral arteritis (EVA) on a Warmblood breeding farm in Pennsylvania, USA. Strains of equine arteritis virus (EAV) present in the semen of two carrier stallions (A and G) on the farm were compared to those in tissues of foals born during the outbreak, as well as viruses present in the semen of two other stallions that became persistently infected carriers of EAV following infection during the outbreak. The 2822 bp segment encompassing ORFs 2-7 (nt 9807-12628; which encode the G(S), GP3, GP4, G(L), M and N proteins, respectively) was directly amplified by RT-PCR from semen samples and foal tissues. Nucleotide and phylogenetic analyses confirmed that virus present in the semen of stallion A initiated the outbreak. The genomes of viruses present in most foal tissues (10/11) and serum from an acutely infected mare collected during the outbreak were identical to that of virus present in the lung of the first foal that died of EVA. Virus in the placenta of one foal differed by one nucleotide (99.9% identity) from the predominant outbreak virus. The relative genetic stability of viruses that circulated during the outbreak contrasts markedly with the heterogeneous virus populations variously present in the semen of persistently infected stallions on the farm. These findings are consistent with the hypothesis that the carrier stallion can be a source of genetic diversity of EAV, and that outbreaks of EVA can be initiated by the horizontal aerosol transmission of specific viral variants that occur in the semen of particular carrier stallions.


[The non-occlusive modality of optical coherence tomography image acquisition: a new concept for wide clinical application].
Optical coherence tomography (OCT) is a novel intravascular imaging modality, based on infrared light emission. This technique enables a high resolution arterial wall imaging but requires a complicated image acquisition process. The aim of this review is to describe a new non-occlusive modality of OCT acquisition, developed by our group, which does not require balloon occlusion of target artery, and to point out its safety and efficacy, describing the required steps to generate good quality images. In the article we referred to previous experimental studies conducted in animals to identify the solution to be used to acquire images of good quality with least adverse effects. Iodixanol 320 was found to have the best image quality/side-effect ratio and enabled the study of long arterial segments. The same solution was then tested in humans, on a large patient population, having either acute coronary syndromes or stable angina. OCT imaging by means of this non-occlusive modality proved to be successful in the vast majority of patients, enabling in over 95% of cases the comparison of the lesion with a reference site. Vessel interrogation was found to be fast and safe. The nonocclusive modality of OCT image acquisition is safe and effective and promises to simplify the complex current occlusive technique, leading to a marked reduction of procedural time.


OpenChrom: a cross-platform open source software for the mass spectrometric analysis of chromatographic data.
Today, data evaluation has become a bottleneck in chromatographic science. Analytical instruments equipped with automated samplers yield large amounts of measurement data, which needs to be verified and analyzed. Since nearly every GC/MS instrument vendor offers its own data format and software tools, the consequences are problems with data exchange and a lack of comparability between the analytical results. To challenge this situation a number of either commercial or non-profit software applications have been developed. These applications provide functionalities to import and analyze several data formats but have shortcomings in terms of the transparency of the implemented analytical algorithms and/or are restricted to a specific computer platform. This work describes a native approach to handle chromatographic data files. The approach can be extended in its functionality such as facilities to detect baselines, to detect, integrate and identify peaks and to compare mass spectra, as well as the ability to internationalize the application. Additionally, filters can be applied on the chromatographic data to enhance its quality, for example to remove background and noise. Extended operations like do, undo and redo are supported. OpenChrom is a software application to edit and analyze mass spectrometric chromatographic data. It is extensible in many different ways, depending on the demands of the users or the analytical procedures and algorithms. It offers a customizable graphical user interface. The software is independent of the operating system, due to the fact that the Rich Client Platform is written in Java. OpenChrom is released under the Eclipse Public License 1.0 (EPL). There are no license constraints regarding extensions. They can be published using open source as well as proprietary licenses. OpenChrom is available free of charge at http://www.openchrom.net.


Inequalities in unintentional injuries between indigenous and non-indigenous children: a systematic review.
Indigenous children suffer a disproportionally high burden of unintentional injuries. A more detailed understanding of the underlying causes, risk factors and gaps in research is required to inform prevention efforts and direct future research. The aim of this review was to systematically assess the evidence regarding differences in rates of unintentional injuries between indigenous and non-indigenous children and to identify leading causes and underlying risk factors contributing to these differences. We systematically searched the literature including 10 electronic databases, institutional websites and reference lists of relevant studies. Due to the substantial heterogeneity between studies, results were summarised in a narrative synthesis and no meta-analysis was carried out. A total of 39 studies were included in this review. Most studies were descriptive and only five adjusted for potential confounding in the analysis. Indigenous to non-indigenous rate ratios for morbidity and mortality for unintentional injury ranged from 1.2 to 2.3 and 1.8 to 8.2, respectively. The difference varied greatly by cause of injury and between studies, ranging from a reduced risk of hospitalisation due to fall injuries to a 17-fold increased risk of mortality due to pedestrian injuries. Burns, poisoning and transport injuries were the major contributors to the increased injury burden in indigenous children. The studies offered only limited insight into the underlying causes of these differences, but socioeconomic status and parents' educational attainment were contributing factors. Indigenous children experience a significantly higher burden of morbidity and mortality from unintentional injuries across different indigenous communities worldwide. Most of these injuries are highly preventable, presenting substantial potential to improve indigenous child health. However, there is limited evidence to illuminate the underlying risk factors for unintentional injuries in indigenous children, and this is a priority for further research.


Interaction of age, cognitive function, and gait performance in 50-80-year-olds.
The variability of walking gait timing increases with age and is strongly related to fall risk. The purpose of the study was to examine the interaction of age, cognitive function, and gait performance during dual-task walking. Forty-two, healthy men and women, 50-80 years old, completed the Mini-Mental State Exam (MMSE) and Trail Making Test (TMT) to assess cognitive performance and were separated into groups by decade of life. They then performed dual-task walking, at a self-selected pace, on an instrumented treadmill during three cognitive loading conditions: (1) no cognitive load, (2) subtraction from 100 by 1s, and (3) subtraction from 100 by 3s. The treadmill recorded spatiotemporal gait parameters that were used to calculate the mean and coefficient of variation for each variable over ten strides. Time to complete the TMT was positively correlated with age, stride time, double-limb support time, and mediolateral instability and was inversely correlated with single-limb support time. Subjects in their 70s increased their stride time and double-limb support time during the most challenging dual-task condition (subtraction by 3s), whereas subjects in their 50s and 60s did not. Across conditions, the variability of stride length, stride time, and single-limb support time was greatest in the 70s. Mediolateral instability increased only for subjects in their 70s in the subtraction by 3s condition. Reduced cognitive function with age makes it difficult for older adults to maintain a normal, rhythmical gait pattern while performing a cognitive task, which may place them at greater risk for falling.


Alcohol and drug use among university students: gender differences.
This study compared the pattern of alcohol, legal and illegal drugs use among students of the Universidade de São Paulo (Brazil) in 1996 and 2001. Samples of 2.564 (1996) and 2.837 (2001) students answered a questionnaire proposed by the World Health Organization, which characterizes the consumption of alcohol, legal and illegal drugs in lifetime, in the last 12 months and in the last 30 days. Men showed a significant increase in lifetime use of tobacco (44.8% to 50.9%), marijuana (33.7% to 39.5%) and hallucinogens (6.6% to 14.1%) between 1996 and 2001. No significant change was observed among women between 1996 and 2001 in tranquilizer use. Concerning the consumption reported in the last 12 months, both genders displayed significant increases in the consumption of marijuana (22.3% to 27.1% for men and 12.9% to 16.9% for women), amphetamines (1.9% to 5.0% for men and 3.4% to 5.6% for women), and inhalants (9.8% to 15.7% for men and 5.4% to 10.6% for women). The greatest gender difference was observed in consumption reported in the last 30 days with significant increases in male use of tobacco (19.6% to 23.5%), marijuana (15.8% to 20.5%), amphetamines (1.1% to 3.2%), and inhalants (4.0% to 7.9%). Substance use reported in the last 30 days remained stable among women between the 2 surveys. Rates of substance use among university students increased. These gender differences in substance consumption should be taken into account in the development of preventive and treatment strategies for undergraduate university students.