Validation of a new antiserum directed towards the synthetic c-terminus of the FOS protein in avian species: immunological, physiological and behavioral evidence.
In the past 10 years, the study of the expression of immediate early genes, such as c-fos, in the brain has become a common method for the identification of brain areas involved in the regulation of specific physiological and behavioral functions. The use of this method in avian species has been limited by the paucity of suitable antibodies that cross-react with the FOS protein in birds. We describe in this paper the preparation of an antibody directed against a synthetic fragment of the protein product of the c-fos gene in chickens (Gallus domesticus). We demonstrate that this new antibody can be used in several avian species to study FOS expression induced by a variety of pharmacological, physiological and behavioral stimuli. Western blot studies indicated that this antibody recognizes a protein of the expected size (47 kDa) but also cross reacts to some extent with proteins of lower molecular weight that share sequence homology with FOS (Fos-related antigens). FOS immunocytochemistry was performed with this antibody in four species of birds in three different laboratories utilizing diverse variants of the immunocytochemical procedure. In all cases the antibody provided a reliable identification of the FOS antigen. The new antibody described here appears to be suitable for the study of FOS expression in several different avian species and situations. It is available in substantial amounts and will therefore make it possible to use FOS expression as a tool to map brain activity in birds as has now been done for several years in mammalian species.


Pneumocystis Pneumonia Secondary to Idiopathic CD4+ T-lymphocytopenia: A Comparison of AIDS and Non-AIDS Patients.
A 67-year-old man was admitted to our hospital complaining of dry cough. Chest computed tomography showed diffuse infiltrates and ground-glass opacities in the bilateral lung fields. Transbronchial lung biopsy specimens showed alveoli filled with yeast-like fungi. With a diagnosis of pneumocystis pneumonia (PCP), he was given oral sulfamethoxazole/trimethoprim, to which he responded well. However, seven months later, PCP relapsed. Analyses revealed a low bronchoalveolar lavage fluid CD4/CD8 ratio of 0.04 and CD4+ lymphocytopenia (250/μL). Despite intensive work-up, we were unable to detect the underlying cause of CD4+ lymphocytopenia; therefore, a final diagnosis of idiopathic CD4+ T-lymphocytopenia was made.


Parenchyma Sparing ALPPS Ultrasound Guided Partition Through Segment 4 to Maximize Resectability (with video).
Associating liver partition and portal vein ligation (ALPPS) has evolved as a treatment strategy for patients with liver tumors who are not amenable for upfront hepatectomy because of an insufficient future liver remnant (FLR). Aim of this study was to test the applicability of ultrasound guided parenchyma sparing surgery to ALPPS concept, by non-anatomically shifting the plane of transection in favor of FLR, resulting in a new technical variant of ALPPS, entitled parenchyma sparing ALPPS (psALPPS). Patients who could not safely undergo right trisectionectomy ALPPS because of insufficient FLR were considered eligible for psALPPS, consisting in liver partition through segment 4 using ultrasound guidance. Between April 2017 and April 2021, five patients with median age of 68 years (range: 66-78), four male and one female, underwent psALPPS for colorectal liver metastases (N=2), intrahepatic cholangiocarcinoma (N=2), and hepatocellular carcinoma (N=1). Standardized FLR (sFLR) for segments 2-3 before stage 1 surgery would have been a median of 11.6%. PsALPPS could double the sFLR at stage 1 resulting in an increase of ps-sFLR from a median of 22.7% (at stage 1) to 34.0% (at stage 2) after a median interstage interval of 15 days. All patients tolerated surgery well and no major complications were recorded. Applying the principles of parenchyma sparing surgery to ALPPS offers the advantage to maximize FLR and simultaneously reduce ischemic injury of segment 4 compared to conventional ALPPS. In this way, psALPPS may markedly increase resectability while reducing morbidity. https://www.revistachirurgia.ro/pdfs/?EntryID=922974&art=2021-parenchyma-sparing-ALPPS-ultrasound-guided-partition.pdf


Predicting COVID-19 disease progression and patient outcomes based on temporal deep learning.
The coronavirus disease 2019 (COVID-19) pandemic has caused health concerns worldwide since December 2019. From the beginning of infection, patients will progress through different symptom stages, such as fever, dyspnea or even death. Identifying disease progression and predicting patient outcome at an early stage helps target treatment and resource allocation. However, there is no clear COVID-19 stage definition, and few studies have addressed characterizing COVID-19 progression, making the need for this study evident. We proposed a temporal deep learning method, based on a time-aware long short-term memory (T-LSTM) neural network and used an online open dataset, including blood samples of 485 patients from Wuhan, China, to train the model. Our method can grasp the dynamic relations in irregularly sampled time series, which is ignored by existing works. Specifically, our method predicted the outcome of COVID-19 patients by considering both the biomarkers and the irregular time intervals. Then, we used the patient representations, extracted from T-LSTM units, to subtype the patient stages and describe the disease progression of COVID-19. Using our method, the accuracy of the outcome of prediction results was more than 90% at 12 days and 98, 95 and 93% at 3, 6, and 9 days, respectively. Most importantly, we found 4 stages of COVID-19 progression with different patient statuses and mortality risks. We ranked 40 biomarkers related to disease and gave the reference values of them for each stage. Top 5 is Lymph, LDH, hs-CRP, Indirect Bilirubin, Creatinine. Besides, we have found 3 complications - myocardial injury, liver function injury and renal function injury. Predicting which of the 4 stages the patient is currently in can help doctors better assess and cure the patient. To combat the COVID-19 epidemic, this paper aims to help clinicians better assess and treat infected patients, provide relevant researchers with potential disease progression patterns, and enable more effective use of medical resources. Our method predicted patient outcomes with high accuracy and identified a four-stage disease progression. We hope that the obtained results and patterns will aid in fighting the disease.


Diagnostic Value of Mid-esophageal Biopsies in Pediatric Patients With Eosinophilic Esophagitis.
Eosinophilic esophagitis (EoE) is histologically defined as the presence of 15 or more intraepithelial eosinophils per high-power fields. Limited consensus exists on where to sample the esophagus in pediatrics. This study aimed to identify whether endoscopic and histologic examination of the mid esophagus offers diagnostic value compared to proximal/distal esophageal biopsies. A retrospective chart review of pediatric patients with EoE was performed. Endoscopic and histologic parameters were assessed at the initial and follow-up visits, and concordance between proximal/distal biopsy and mid biopsy was determined. A total of 100 patients with a mean age of 9.6 ± 4.07 years were included. Endoscopic parameters between proximal/distal and mid esophagus were concordant in 84% to 97% of patients (initial assessment) and in 80% to 97% of patients (at follow-up). Mid esophagus showed endoscopic abnormalities, which were absent at the proximal/distal esophagus in 1% to 5% of patients, as well as histologic abnormalities in 2% to 8% of patients overall at initial and follow-up examinations. We recommend continued endoscopic and histologic assessment of the proximal/distal biopsy; however, examination of the mid esophagus does offer small diagnostic value in our subset of patients. Future studies need to be conducted before conclusive recommendations supporting the use of mid-esophageal biopsies can be made.


[Dietotherapy children with liver diseases].
In children with liver diseases disorders of the nutritional status appear more quickly and delay normal growth and development. Administration of the nutritional support based on nosological and syndromal approaches lets provide optimal conditions for normalization of the liver functions, improves efficiency of therapy and prognosis of the disease. The article contents modern recommendations on the organization of nutrition in children with different liver diseases, correction of metabolic disorders during complications of liver pathology.


Venus' Atmospheric Chemistry and Cloud Characteristics Are Compatible with Venusian Life.
Venus is Earth's sister planet, with similar mass and density but an uninhabitably hot surface, an atmosphere with a water activity 50-100 times lower than anywhere on Earths' surface, and clouds believed to be made of concentrated sulfuric acid. These features have been taken to imply that the chances of finding life on Venus are vanishingly small, with several authors describing Venus' clouds as "uninhabitable," and that apparent signs of life there must therefore be abiotic, or artefactual. In this article, we argue that although many features of Venus can rule out the possibility that Earth life could live there, none rule out the possibility of all life based on what we know of the physical principle of life on Earth. Specifically, there is abundant energy, the energy requirements for retaining water and capturing hydrogen atoms to build biomass are not excessive, defenses against sulfuric acid are conceivable and have terrestrial precedent, and the speculative possibility that life uses concentrated sulfuric acid as a solvent instead of water remains. Metals are likely to be available in limited supply, and the radiation environment is benign. The clouds can support a biomass that could readily be detectable by future astrobiology-focused space missions from its impact on the atmosphere. Although we consider the prospects for finding life on Venus to be speculative, they are not absent. The scientific reward from finding life in such an un-Earthlike environment justifies considering how observations and missions should be designed to be capable of detecting life if it is there.


Challenges associated with missing data in electronic health records: A case study of a risk prediction model for diabetes using data from Slovenian primary care.
The increasing availability of data stored in electronic health records brings substantial opportunities for advancing patient care and population health. This is, however, fundamentally dependant on the completeness and quality of data in these electronic health records. We sought to use electronic health record data to populate a risk prediction model for identifying patients with undiagnosed type 2 diabetes mellitus. We, however, found substantial (up to 90%) amounts of missing data in some healthcare centres. Attempts at imputing for these missing data or using reduced dataset by removing incomplete records resulted in a major deterioration in the performance of the prediction model. This case study illustrates the substantial wasted opportunities resulting from incomplete records by simulation of missing and incomplete records in predictive modelling process. Government and professional bodies need to prioritise efforts to address these data shortcomings in order to ensure that electronic health record data are maximally exploited for patient and population benefit.


Digital photography as a novel technique of measuring ocular surface dimensions.
To introduce a novel technique for measuring ocular surface dimensions using digital photography and computerized image analysis in the context of ptosis repair surgery. Digital photographs and patient questionnaires on dry eye symptoms were obtained from 31 patients before and after ptosis repair. Patients were examined preoperatively and at 1 and 6 weeks postoperatively. Adobe Photoshop 7.0 (Adobe Systems Incorporated, 345 Parkl Avenue, San Jose, CA 95110-2704, USA) was used to digitally measure palpebral fissure height, fissure width, and ocular surface area (OSA). Similar digital measurements were obtained on 30 control subjects as well. Digital calculations of OSA for control, preoperative, and postoperative groups were compared with other published techniques. Graphical comparison between our method of measuring OSA and the mathematical estimations proposed by previous studies suggests that our method is more precise in measuring OSA, and that it is also better able to identify individual variations of OSA from general population trends. Digital ocular photography combined with computerized image analysis is a fast, easy to use, and reliable method of measuring ocular surface dimensions. In addition to ptosis surgery, this method can be used in other ocular surface studies.


Longitudinal study of leukocyte DNA methylation and biomarkers for cancer risk in older adults.
Changes in DNA methylation over the course of life may provide an indicator of risk for cancer. We explored longitudinal changes in CpG methylation from blood leukocytes, and likelihood of future cancer diagnosis. Peripheral blood samples were obtained at baseline and at follow-up visit from 20 participants in the Health, Aging and Body Composition prospective cohort study. Genome-wide CpG methylation was assayed using the Illumina Infinium Human MethylationEPIC (HM850K) microarray. Global patterns in DNA methylation from CpG-based analyses showed extensive changes in cell composition over time in participants who developed cancer. By visit year 6, the proportion of CD8+ T-cells decreased (p-value = 0.02), while granulocytes cell levels increased (p-value = 0.04) among participants diagnosed with cancer compared to those who remained cancer-free (cancer-free vs. cancer-present: 0.03 ± 0.02 vs. 0.003 ± 0.005 for CD8+ T-cells; 0.52 ± 0.14 vs. 0.66 ± 0.09 for granulocytes). Epigenome-wide analysis identified three CpGs with suggestive p-values ≤10- 5 for differential methylation between cancer-free and cancer-present groups, including a CpG located in MTA3, a gene linked with metastasis. At a lenient statistical threshold (p-value ≤3 × 10- 5), the top 10 cancer-associated CpGs included a site near RPTOR that is involved in the mTOR pathway, and the candidate tumor suppressor genes REC8, KCNQ1, and ZSWIM5. However, only the CpG in RPTOR (cg08129331) was replicated in an independent data set. Analysis of within-individual change from baseline to Year 6 found significant correlations between the rates of change in methylation in RPTOR, REC8 and ZSWIM5, and time to cancer diagnosis. The results show that changes in cellular composition explains much of the cross-sectional and longitudinal variation in CpG methylation. Additionally, differential methylation and longitudinal dynamics at specific CpGs could provide powerful indicators of cancer development and/or progression. In particular, we highlight CpG methylation in the RPTOR gene as a potential biomarker of cancer that awaits further validation.


Type IIB human skeletal muscle fibers positively correlate with bone mineral density irrespective to age.
Age-associated decrease in type IIA/B human skeletal muscle fibers was detected in human biopsies in our previous study. The relationship between change in muscle fiber typing and bone mineral density (BMD) is, however, unknown either cross-sectionally or longitudinally. We therefore conducted a cross-sectional study to investigate their correlation using human muscle biopsies. Forty human subjects aged (53.4 ± 20.2) years were recruited. Histomorphometric parameters of their muscle biopsies were measured by ATPase staining and image analysis, including average area percentage, fiber number percentage, mean fiber area, and area percentage of connective tissues. Hip and spine BMD was measured by dual-energy X-ray absorptiometry. Partial correlation with adjusting age was performed. Type IIB muscle fiber was found positively correlated with hip BMD irrespective to age and demonstrated significantly stronger relationship with BMD among all fiber types, in terms of its cross-sectional area (r = 0.380, P = 0.029) and size (r = 0.389, P = 0.025). Type IIA muscle fibers associated with hip BMD in mean fiber area only (r = 0.420, P = 0.015). Type IIB muscle fiber may play an important role in maintaining bone quality. This may also be a relatively more sensitive fiber type of sarcopenia and osteoporosis. These findings further consolidate the muscle-bone relationship.


Breast cancer in men in the United States: a population-based study of diagnosis, treatment, and survival.
Breast cancer in men is rare, so clinical trials are not practical. Recommendations suggest treating men who are diagnosed with breast cancer using the guidelines for postmenopausal women; however, to date, no population-based studies have evaluated patterns of care. To examine characteristics, treatment, and survival among men with newly diagnosed breast cancer, in 2003 and 2004, 512 men were identified from the Surveillance, Epidemiology and End Results Program. Data were reabstracted and therapy was verified through the patients' treating physicians. The majority of men (79%) were diagnosed through discovery of a breast lump or other signs/symptoms. Among men who had invasive disease, 86% underwent mastectomy, 37% received chemotherapy, and 58% received hormone therapy. In multivariate analysis, tumor size (P=.01) and positive lymph node status (P<.0001) were associated positively with the use of chemotherapy, whereas age group (P<.0001) and current unmarried status (P=.01) had negative associations. Among men who had invasive, estrogen receptor (ER)-positive/borderline tumors, the use of tamoxifen or aromatase inhibitors (AIs) was associated with age group (P=.05). Among men who had invasive disease, cancer mortality was associated with tumor size (P<.0001). Among men with ER-positive/borderline disease, increased cancer mortality was associated with tumor size (P<.0001), current unmarried status (P=.04), and decreased mortality with tamoxifen (P=.04). Tumor characteristics and marital status were the primary predictors of therapy and cancer mortality among men with breast cancer. Although AIs are not currently recommended, they are commonly prescribed. However, their use did not result in a decrease in cancer mortality. Research must examine the efficacy of AIs with and without gonadotropin-releasing hormone analogues.


On the method of logarithmic cumulants for parametric probability density function estimation.
Parameter estimation of probability density functions is one of the major steps in the area of statistical image and signal processing. In this paper we explore several properties and limitations of the recently proposed method of logarithmic cumulants (MoLC) parameter estimation approach which is an alternative to the classical maximum likelihood (ML) and method of moments (MoM) approaches. We derive the general sufficient condition for a strong consistency of the MoLC estimates which represents an important asymptotic property of any statistical estimator. This result enables the demonstration of the strong consistency of MoLC estimates for a selection of widely used distribution families originating from (but not restricted to) synthetic aperture radar image processing. We then derive the analytical conditions of applicability of MoLC to samples for the distribution families in our selection. Finally, we conduct various synthetic and real data experiments to assess the comparative properties, applicability and small sample performance of MoLC notably for the generalized gamma and K families of distributions. Supervised image classification experiments are considered for medical ultrasound and remote-sensing SAR imagery. The obtained results suggest that MoLC is a feasible and computationally fast yet not universally applicable alternative to MoM. MoLC becomes especially useful when the direct ML approach turns out to be unfeasible.


Tobamovirus cross protection using a potexvirus vector.
Cross protection is the ability of one virus to prevent or delay infection by a related challenge virus. To examine this phenomena, a potato X potexvirus (PVX) vector (Chapman et al., 1992, Plant J. 2, 549) was used to systemically express the tobacco mosaic tobamovirus (TMV) coat protein (CP) open reading frame in Nicotiana benthamiana. PVX constructs induce mild mosaic symptoms in N. benthamiana, whereas TMV infection results in rapid systemic necrosis and plant death. Healthy plants or plants preinfected with the unmodified PVX vector succumbed to necrosis within 1 week of TMV challenge inoculation. However, plants preinfected with PVX vectors expressing the TMV CP or RNA coding sequence displayed a 1- to 2-week delay in the appearance of TMV-induced necrosis along with reduced accumulations of TMV. Symptom delay and reductions in the accumulation of TMV were more pronounced in plants protected with the vector expressing the TMV CP than with the vector expressing a nontranslatable CP sequence. Protection was overcome more quickly using a 10-fold higher concentration of challenge inoculum and was ineffective against TMV RNA or a TMV construct expressing a distantly related tobamovirus CP. These findings demonstrate that both RNA and protein are involved in this cross protection phenomenon, but that CP is the main contributor to protection. Taken together, these studies indicate that virus vectors can be used to simulate both cross protection and transgene-derived coat protein-mediated protection, thus providing a new method to further investigate the mechanisms behind each.


Cost-effectiveness of HIV monitoring strategies in resource-limited settings: a southern African analysis.
Although the number of infected persons receiving highly active antiretroviral therapy (HAART) in low- and middle-income countries has increased dramatically, optimal disease management is not well defined. We developed a model to compare the costs and benefits of 3 types of human immunodeficiency virus monitoring strategies: symptom-based strategies, CD4-based strategies, and CD4 counts plus viral load strategies for starting, switching, and stopping HAART. We used clinical and cost data from southern Africa and performed a cost-effectiveness analysis. All assumptions were tested in sensitivity analyses. Compared with the symptom-based approaches, monitoring CD4 counts every 6 months and starting treatment at a threshold of 200/muL was associated with a gain in life expectancy of 6.5 months (61.9 months vs 68.4 months) and a discounted lifetime cost savings of US $464 per person (US $4069 vs US $3605, discounted 2007 dollars). The CD4-based strategies in which treatment was started at the higher threshold of 350/microL provided an additional gain in life expectancy of 5.3 months at a cost-effectiveness of US $107 per life-year gained compared with a threshold of 200/microL. Monitoring viral load with CD4 was more expensive than monitoring CD4 counts alone, added 2.0 months of life, and had an incremental cost-effectiveness ratio of US $5414 per life-year gained relative to monitoring of CD4 counts. In sensitivity analyses, the cost savings from CD4 count monitoring compared with the symptom-based approaches was sensitive to cost of inpatient care, and the cost-effectiveness of viral load monitoring was influenced by the per test costs and rates of virologic failure. Use of CD4 monitoring and early initiation of HAART in southern Africa provides large health benefits relative to symptom-based approaches for HAART management. In southern African countries with relatively high costs of hospitalization, CD4 monitoring would likely reduce total health care expenditures. The cost-effectiveness of viral load monitoring depends on test prices and rates of virologic failure.


Characterization of T cell receptor repertoire and anti-Ro/SSA autoantibodies in relation to sialadenitis of NOD mice.
Non-obese diabetic (NOD) mice develop sialadenitis which morphologically resembles the exocrinopathy in human Sjögren's syndrome (SS). The sialadenitis is characterized by focal infiltrates of inflammatory cells. Immunoenzyme staining (ABC-technique) and monoclonal antibodies defining CD4, CD8, CD11b, TCR alpha/beta, gamma/delta, V beta 2, V beta 4, V beta 6, V beta 7, V beta 8.1, 2, V beta 10b and V beta 11 were used to examine the infiltrating mononuclear cells (MNC) in salivary glands of NOD mice. TCR alpha beta + cells dominated clearly over TCR gamma delta + cells in the salivary glands. A predominance of CD4+ T-cells was identified, while a small population of CD8+ cells was found in the salivary gland infiltrates. CD11b+ mononuclear cells were sporadically seen within the salivary gland lesions. All different TCR V beta:s which were analysed appeared to be utilized at the site of MNC infiltration in salivary glands; although with various frequencies. The frequency pattern of V beta gene expression in salivary glands was V beta 8.1,2 (15%) > V beta 6 (12%) > V beta 4 (11%) > V beta 10b (5%) > V beta 11 (5%) = V beta 2 (5%) > V beta 7 (3%). Analysis of the TCR V beta utilization in corresponding lymph nodes revealed a quite similar frequency pattern as found in the salivary glands. Serum samples were also tested for anti-Ro52, Ro60 and anti-La antibodies with Western blot. Autoantibody production was limited to anti-Ro/SSA and 3/37 (8%) of the mice were found to produce anti-Ro52 kD antibodies. The degree of sialadenitis (focus score) appeared not to influence reactivity to the Ro52 kD protein.


Region-specific changes in gene expression are associated with cognitive deficits in the alpha-synuclein-induced model of Parkinson's disease: A transcriptomic profiling study.
Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an α-synuclein (αSyn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with H-αSynOs developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-αSynOs treated samples, which showed N = 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-αSynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages. Altogether results show that H-αSynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD.


Pancreatic cancer: current factors and options to determine future research.
There are many factors to consider when reviewing the fact that the prognosis for patients diagnosed with pancreatic carcinoma is "dismal." For this reason, we reviewed various articles regarding the diagnostic factors, treatment and prognostic factors including resection and laparoscopy, along with modalities of treatment to establish the objectives for future developments. We believe that as our population ages, we will see fundamental changes in the factors, options and modalities of treatment for this lethal disease. Public health efforts which are moving for the screening for early cancer detection, a better understanding of the tumor biology and efforts to reduce the gap between the clinical practice and the scientific understanding may ultimately reduce the burden of cancer in society.


Recruitment of unique neural systems to support visual memory in normal aging.
The performance of many cognitive tasks changes in normal aging [1] [2] [3]. Recent behavioral work has identified some tasks that seem to be performed in an age-invariant manner [4]. To understand the brain mechanisms responsible for this, we combined psychophysical measurements of visual short-term memory with positron emission tomography (PET) in young and old individuals. Participants judged the differences between two visual stimuli, and the memory load was manipulated by interposing a delay between the two stimuli. Both age groups performed the task equally well, but the neural systems supporting performance differed between young and old individuals. Although there was some overlap in the brain regions supporting performance (for example, occipital, temporal and inferior prefrontal cortices, and caudate), the functional interconnections between these common regions were much weaker in old participants. This suggests that the regions were not operating effectively as a network in old individuals. Old participants recruited unique areas, however, including medial temporal and dorsolateral prefrontal cortices. These unique areas were strongly interactive and their activity was related to performance only in old participants. Therefore, these areas may have acted to compensate for reduced interactions between the other brain areas.


Recurrent miscarriage: psychological and relational consequences for couples.
Recurrent miscarriage is a rare condition that has been described as a traumatic event for couples. Although symptoms of depression, anxiety and lowered self-esteem have been related after recurrent miscarriage, little is known about its impact on couple sexuality and on gender differences in attitude and the grief that follow. The objectives of this study are to describe the consequences of recurrent pregnancy loss for the couple's relationship, and explore gender differences in attitudes and grief intensity toward this kind of reproductive failure. Each member of 30 couples with at least 3 recurrent miscarriages answered a set of questionnaires, including the Impact of Events Scale (Horowitz, Wilnwe, & Alvarez, 1979), the Perinatal Grief Scale (Toedter, Lasker, & Qlhadeff, 1988), the Partnership Questionnaire (Hahlweg, 1979) and the Intimate Relationship Scale (Hetherington & Soeken, 1990). Results showed that men do grieve, but less intensely than their partners. Although the couple's relationship seemed to not be adversely affected by recurrent miscarriage, couples described sexual changes after those events. Grief was related to the quality of communication in the couple for women, and to the quality of sex life for men.


Epidermal Growth Factor Receptor Gene Amplification in Patients with Advanced-stage NSCLC.
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) represent novel, effective tools in the management of advanced-stage non-small cell lung cancer (NSCLC). We aimed to evaluate the incidence and predictive role of EGFR gene amplification in patients with advanced-stage NSCLC treated with EGFR-TKIs. The study included 290 patients with advanced-stage (IIIB or IV) NSCLC. Multiplex ligation-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) were used for detection of EGFR gene amplification and EGFR mutations, respectively. EGFR amplification was detected in 26 (9.0%) patients. EGFR amplification was found more frequently in patients harboring the EGFR mutation (p<0.001). No significant corelation between EGFR gene amplification and survival was observed. EGFR gene amplification is associated with EGFR gene mutation. EGFR gene amplification is not a feasible predictive biomarker for treatment with EGFR-TKIs in patients with advanced-stage NSCLC.


[Parathyroid carcinoma: diagnosis by a femur fracture].
Carcinoma of the parathyroid gland (PC) described by De Quervain since 1909, it represents the least common neoplasm, with an incidence of 1,25/10,000,000 peoples. It has been reported approximately 1,000 cases of CP in world literature. There are two series in Mexico, one of eight patients and other with four cases. Because CP is functionally active, its early clinical behavior is similar to that of parathyroid benign neoplasms. A 66-year-old female with history of thighbone pain and spontaneous femoral fracture, osteolytic lesions, hypercalcemia, elevated levels of alkaline phosphatase and parathyroid hormone detected; the scintigraphy showed a functioning tumor located in upper mediastinum. By hemithyroidectomy in block, the tumor was resected. Histopathological study reported parathyroid carcinoma. PC is the least common neoplasia, in patients with parathyroid hormone levels greater than 1,000 pg/ml and hypercalcemia upper of 14 mg/dl this disease should be suspected.


Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes.
Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allows for the generation of three-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation had markedly increased myofibril ultrastructural organization, elevated conduction velocity and improved both electrophysiological and Ca(2+) handling properties compared to nonstimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.


Retrospective evaluation of 377 patients with penetrating foreign body injuries: a university hospital experience (a present case of missed sponge foreign body injury)
This study aimed to retrospectively analyse patients with foreign body (FB) injuries in our hospital and to present a patient with missed penetrating sponge FB injury. This study lasted 12 years (2008–2020) and reviewed all patients with FB injuries who were admitted to the emergency department (ED) of our hospital. Along with our overall results, we present a case with missed penetrating sponge FB injury in detail. Approximately 377 patients were included in the study (age: 28.3 ± 18.3 years, m/f: 229/148). The foot (n = 148, 39.3%) and the hand (n = 143, 37.9%) were the most frequently injured body parts. Regarding FB types, sewing needles (n = 140, 37.1%), metal pieces (n = 91, 24.1%), and glass (n = 80, 21.2%) were the most frequently observed objects. Most of the patients were injured at home, often by needles or glass. The injury-admission mean time was 7.38 ± 2.5 days. FBs were frequently removed in the ED (n = 176, 46.7%). Plain radiography is the first line in identifying FBs. Soft tissue infection was the most common complication. MRIs were much useful than USGs in detecting the missed penetrating sponge injury of the single patient in the study. For diagnosis of FBs, besides recording the patient's history, obtaining a two-sided radiogram is of great importance. For nonradiolucent or deeply located FBs, further clinical or radiological investigation must be considered to avoid complications. Although most of the FBs can be removed in the ED, patients may require hospitalisation and operation for FB removal, depending upon FB location and age.


Dynamics of Change and Change in Dynamics.
A framework is presented for building and testing models of dynamic regulation by categorizing sources of differences between theories of dynamics. A distinction is made between the dynamics of change, i.e., how a system self-regulates on a short time scale, and change in dynamics, i.e., how those dynamics may themselves change over a longer time scale. In order to clarify the categories, models are first built to estimate individual differences in equilibrium value and equilibrium change. Next, models are presented in which there are individual differences in parameters of dynamics such as frequency of fluctuations, damping of fluctuations, and amplitude of fluctuations. Finally, models for within-person change in dynamics over time are proposed. Simulations demonstrating feasibility of these models are presented and OpenMx scripts for fitting these models have been made available in a downloadable archive along with scripts to simulate data so that a researcher may test a selected models' feasibility within a chosen experimental design.


Graft-Versus-Host Disease-Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology.
As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed. We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen-activated T cells from a patient with post-hematopoietic cell transplantation relapse was performed. The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses. Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.


[Depression: Low-threshold Cardinal Measures as a Complement or Alternative to Pharmacological or Psychotherapeutic Interventions].
The third edition of the German National Clinical Practice Guideline for Depression emphasizes the significance of cardinal measures much more strongly than before. Low-threshold cardinal measures are an indispensable component of every depression treatment, regardless of severity and setting. They are suitable as a standalone treatment for mild and moderate depression. If inadequate improvement is observed, additional therapies should be supplemented. They should be implemented immediately after diagnosis to enhance the success rate.Regarding cardinal measures, among other things, comprehensive patient education in understandable language is essential. Patients with depressive disorders require guidance on structuring their day and building healthy activities. Patients with depression-related sleep disturbances benefit from sleep hygiene rules. Wake therapy constitutes an excellent and low-risk treatment method with immediate effect, which is a standard component of adequate depression treatment. Patients with a seasonal pattern of depression should be advised on light therapy. All patients should be encouraged to engage in regular physical activity with moderate intensity.


Evaluation of Kluyveromyces marxianus endo-polygalacturonase activity through ATR-FTIR.
The endo-polygalacturonase enzyme (endoPG: EC 22.214.171.124) plays an important role in the fruit juice and wine industries, so the development of new tools for the quantitative and qualitative analysis of its enzymatic action is necessary. In this work, we report the development of a simple, fast and practical method that did not use any chemical reagent to identify and evaluate the action of the endoPG enzyme, produced by the yeast Kluyveromyces marxianus CCT3172, using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy combined with principal component analysis-linear discriminant analysis (PCA-LDA). This method evaluated the action of the endoPG enzyme on the polygalacturonic acid (PGA) substrate at 5 different times (0, 10, 15, 20 and 30 minutes), and at each time interval the samples were analyzed by ATR-FTIR. It was demonstrated that there was clear segregation between the samples that were and that were not subjected to the action of the endoPG enzyme, and it was also possible to distinguish the samples that were subjected to different incubation times with the enzyme. Through PCA-LDA it was possible to obtain wavelengths that are biomarkers for this enzymatic reaction and the observed changes as a function of hydrolysis duration were found to be in agreement with the breakdown of the glycosidic chain (1011 cm-1-CH-O- CH stretching) of PGA and release of oligosaccharides (1078 cm-1 C-OH elongation). The activity of the endoPG enzyme and the release of galacturonic acid were verified by the dinitrosalicylic acid (DNS) method in all samples. The efficacy of an automatic classifier using a principal component analysis-linear discriminant classifier (PCA-LDC) was evaluated to diagnose the action of the endoPG enzyme. The results showed an accuracy of 100% for the identification of the endoPG enzyme action and from 91.67% to 100% for classification according to the hydrolysis duration in which PGA was exposed to endoPG. The present study indicates that this methodology may be a new approach for the qualitative evaluation of the endoPG enzyme with the potential to be used in laboratories and industries.


An encounter between a pelagic shark and giant cephalopod.
An oceanic whitetip shark (Carcharhinus longimanus) was observed off the coast of Kona, Hawaii, with scars caused by the tentacles of a large cephalopod. While the exact species could not be confirmed, candidate species include the giant squid (Architeuthis dux) or species from the genera Thysanoteuthis (flying squids) and Megalocranchia (glass squids). Telemetry shows C. longimanus will dive within the mesopelagic zone and may interact with or even forage for large cephalopods.


Characterization of the VPg-dsRNA linkage of infectious pancreatic necrosis virus.
By the use of strong denaturing agents, a genome-linked protein (VPg)-RNA complex was purified from infectious pancreatic necrosis virus. Ribonuclease treatment of 125I-labelled VPg-RNA released a 90K polypeptide identical to the minor structural polypeptide VP1 (the putative RNA polymerase), as determined by peptide mapping. The polypeptide is linked to the RNA by a serine-5' GMP phosphodiester bond. The results identify birnaviruses as the only dsRNA viruses with a VPg, the size of which is the largest of the VPgs of RNA viruses.


Effects of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity.
Alcohol intake has been shown to worsen obstructive sleep apnea and increase nocturnal hypoxemia. The mechanisms of this action are unclear. Animal studies suggest that a reduction in chemoreflex sensitivity may be implicated. Using a double-blind, randomized, vehicle-controlled design, we tested the hypothesis that oral alcohol intake depresses chemoreflex sensitivity in humans. We examined the effects of oral alcohol intake (1.0 g/kg body wt) on blood pressure, heart rate, heart rate variability, muscle sympathetic nerve activity, forearm vascular resistance, and minute ventilation in 16 normal male subjects. Peripheral and central chemoreflex sensitivity were measured in response to hypoxia (n = 10) and hypercapnia (n = 6), respectively. Plasma alcohol increased from 0 to 23.2 +/- 1.5 mmol/L (107 +/- 7 mg/dL) at 60 minutes and 20.2 +/- 1 mmol/L (93 +/- 4 mg/dL) at 85 minutes after alcohol intake (P < .0001). Alcohol induced an increase in heart rate from 59 +/- 2 to 66 +/- 2 beats per minute (P < .01) and increased the ratio of low- to high-frequency variability of heart rate (P < .05). Although alcohol increased sympathetic nerve activity by up to 239 +/- 22% of baseline values (P < .01), forearm vascular resistance after alcohol was lower than that after vehicle (P < .05). Blood pressure did not increase compared with the vehicle session. Oxygen saturation during hypoxia after alcohol was 4 +/- 1% lower than it was during hypoxia after vehicle (P < .05) although arterial blood PO2 was unchanged. Alcohol did not affect the cardiovascular, sympathetic, or ventilatory responses to either hypoxia or hypercapnia. Acute increases in plasma alcohol increase heart rate and sympathetic nerve activity; blood pressure is not increased, probably because of vasodilator effects of alcohol. Alcohol does not alter chemoreflex responses to hypoxia or hypercapnia; thus, alterations in chemoreflex sensitivity are unlikely to explain the effects of alcohol on sleep apnea. Alcohol may reduce the affinity of hemoglobin for oxygen.


A Comparative Study of EEG and aEEG in Seizure Diagnosis in Infants Admitted to the NICU.
Seizure is a common sign in neonates hospitalized in the neonatal intensive care units (NICU) that may lead to morbidity and mortality. Most neonatal seizures are subclinical. Conventional EEG (cEEG) is the gold standard for detecting and monitoring seizures but is not widely available. Amplitude-integrated electroencephalography (aEEG) has been used for over a decade to evaluate infants with seizures. In this study, we tried to determine the efficacy of aEEG as a widely available diagnostic tool in diagnosing seizures. All cases with seizures or suspicious seizures were admitted to the NICU of the Children's Medical Center for one year. cEEG and aEEG were performed for these infants. aEEG was recorded for at least six hours with a description of the tracing. Clinical information, outcomes, and questionnaires (patient information) were recorded in detail. The obtained data were analyzed with the SPSS version 24 software. Eleven out of twenty-five aEEG recordings were abnormal; other patients showed normal aEEGs. The most common clinical and neurological manifestations were seizure (68%) and hypotonia (28%); the mortality rate was 12%. No significant correlation was observed between aEEG findings and gender, age, familial relation, outcome, ultrasound result, type of seizure, and underlying disease. Studies showed variable sensitivity and specificity values for aEEG. aEEG cannot be recommended as the only way to diagnose and manage seizures in neonates. However, Good accessibility and ease of working with aEEG promote a tendency to use this procedure as a screening tool.


Pneumococcus-induced thrombocytopenia in rabbits.
Thrombocytopenia without other hemostatic changes is the most common coagulopathy associated with sepsis. We studied pneumococcus (PNC)-induced hemostatic changes, including thrombocytopenia, in rabbits. Nonviable PNC or saline solution was injected into rabbits preinfused with chromium 51-labeled platelets or iodine 125-fibrinogen. Blood was serially obtained for determination of platelet counts, 51Cr activity or 125I activity, and fibrinogen and fibrin degradation products. Lung, liver, and spleen tissues were counted for 51Cr or 125I activities per gram of wet tissue. PNC-challenged animals displayed profound thrombocytopenia from 0.5 to 48 hours with the mean nadir (-80% relative to the baseline) at 3 hours and a significantly (P less than 0.025) shortened 51Cr-platelet survival of 1.45 +/- 0.71 days vs. 2.72 +/- 1.09 days for saline-injected controls. Circulating fibrinogen level increased, whereas 125I-fibrinogen survival was unchanged (2.6 +/- 0.5 days in PNC-challenged vs. 2.8 +/- 1.0 days in saline-injected). No increased tissue deposition of either 51Cr-labeled platelets or 125I-fibrinogen was found. Rabbits infused with either serum, plasma, or saline solution after each was incubated with PNC all developed significant thrombocytopenia of less than 1 hour duration with maximal mean decreases relative to the baseline of -76% (P less than 0.001), -65% (P less than 0.0005), and -84% (P less than 0.0005), respectively. Inactivation of serum or plasma complement before PNC incubation or heat treatment after PNC incubation in serum or saline solution did not alter the thrombocytopenia. The thrombocytopenia-promoting activity was also trypsin resistant, did not require the presence of serum, plasma, or PNC capsular polysaccharide for its in vitro generation, and had a mol wt of 100,000 to 300,000. Therefore, PNC-induced thrombocytopenia, in the absence of other hemostatic changes, may be explained on the basis of the direct action of a PNC-derived substance(s) on circulating platelets.


Xylella fastidiosa subsp. pauca, Neofusicoccum spp. and the Decline of Olive Trees in Salento (Apulia, Italy): Comparison of Symptoms, Possible Interactions, Certainties and Doubts.
Xylella fastidiosa subsp. pauca (XFP), Neofusicoccum mediterraneum, N. stellenboschiana and other fungi have been found in olive groves of Salento (Apulia, Italy) that show symptoms of severe decline. XFP is well known to be the cause of olive quick decline syndrome (OQDS). It has also been assessed that Neofusicoccum spp. causes a distinct disease syndrome, namely, branch and twig dieback (BTD). All these phytopathogens incite severe symptoms that can compromise the viability of large canopy sectors or the whole tree. However, their specific symptoms are not easily distinguished, especially during the final stages of the disease when branches are definitively desiccated. By contrast, they can be differentiated during the initial phases of the infection when some facets of the diseases are typical, especially wood discoloration, incited solely by fungi. Here, we describe the typical symptomatological features of OQDS and BTD that can be observed in the field and that have been confirmed by Koch postulate experiments. Similar symptoms, caused by some abiotic adverse conditions and even by additional biotic factors, are also described. Thus, this review aims at: (i) raising the awareness that declining olive trees in Salento do not have to be linked a priori to XFP; (ii) defining the guidelines for a correct symptomatic diagnosis to orient proper laboratory analyses, which is crucial for the application of effective control measures. The possibility that bacterium and fungi could act as a polyspecies and in conjunction with predisposing abiotic stresses is also widely discussed.


Accuracy of localization of acute myocardial infarction by 12 lead electrocardiography.
Until recently, ECG accuracy in localizing acute myocardial infarction (AMI) could be assessed only by comparing the ECGs with autopsy findings. This approach, however, preselected patients, including only those who died. It is possible that this postmortem group of patients would be different from the whole population of patients with AMI. Myocardial imaging with 99mTc-pyrophosphate offers the advantage of directly localizing the region of injured myocardium in the acute phase of AMI. In 34 patients with confirmed AMI and focal uptake of 99mTc-pyrophosphate, serial ECGs were obtained and interpreted by two independent observers. The sensitivity and specificity of serial ECGs in determining the location of AMI in the five left ventricular (LV) wall segments were determined: (1) in the anterior wall sensitivity was 86.7% and specificity was 89.5%; (2) in the lateral wall sensitivity was 73.7% and specificity was 80.0%; (3) in the high lateral wall sensitivity was 80.0% and specificity was 87.5%; (4) in the inferior wall sensitivity was 87.5% and specificity was 100%; (5) in the "true" posterior wall sensitivity was 83.3% and specificity was 86.4%. Overall, in the 170 LV wall segments (five per patient) examined, scans localized with a sensitivity of 81.9% and a specificity of 88.8%. After four patients with LBBB were excluded, sensitivity increased to 87.1%. Overall, localization of AMI by serial ECG was accurate in 85.9% of the 34 patients included in the study.


[The impact of endovascular intervention on visual functions in patients with traumatic carotid-cavernous anastomosis].
In 217 patients with traumatic carotid-cavernous anastomosis (TCCA) the visual functions investigation before and after endovascular intervention conduction for the anastomosis exclusion was done. Cessation of the noise in the head synchronous with a pulse, decrease of disappearance of an exophthalmus of an eye or superior optical vein pulsation, of congestional appearance in the orbit, were the signs of the complete anastomosis exclusion. Rehabilitation or increase of visual acuity, improvement of an eye fundus ophthalmological picture, vascular index normalization were noted during deep ophthalmological investigation. Decrease of the blind spot parameters was an objective index of the visual functions rehabilitation, witnessing the disappearance of optical nerve disc (OND) oedema, contrast frequential characteristics normalization, critical frequency of light flashings radiance (CFLFR) rise, decrease of a papillary cycle time (PCT). Studying of the parameters mentioned have special significance for the estimation of postoperative conservative therapy efficiency.


Do bigger bats need more time to forage?
We test the hypothesis is that bats using the same area and at the same time would be using similar preys, but they would have different foraging times due to specific differences in biomass. A total of 730 captures was analyzed 13 species of Vespertilionidae and Molossidae bats netted over a small dam in southeastern Brazil from 1993 and 1999. The relationship between the average time of captures and the biomass of the species of Vespertilinidae and Molossidae most frequent (captures > 4) was positive and significant (r = 0.83, p = 0.022, N = 7). Two lines are discussed to answer the longer foraging time for bigger bats: 1) larger insectivorous bats don't consume proportionally larger preys and 2) larger insects are less available.


An Annealing Mechanism for Adversarial Training Acceleration.
Despite the empirical success in various domains, it has been revealed that deep neural networks are vulnerable to maliciously perturbed input data that can dramatically degrade their performance. These are known as adversarial attacks. To counter adversarial attacks, adversarial training formulated as a form of robust optimization has been demonstrated to be effective. However, conducting adversarial training brings much computational overhead compared with standard training. In order to reduce the computational cost, we propose an annealing mechanism, annealing mechanism for adversarial training acceleration (Amata), to reduce the overhead associated with adversarial training. The proposed Amata is provably convergent, well-motivated from the lens of optimal control theory, and can be combined with existing acceleration methods to further enhance performance. It is demonstrated that, on standard datasets, Amata can achieve similar or better robustness with around 1/3-1/2 the computational time compared with traditional methods. In addition, Amata can be incorporated into other adversarial training acceleration algorithms (e.g., YOPO, Free, Fast, and ATTA), which leads to a further reduction in computational time on large-scale problems.


Transpositional competence and transcription of endogenous Ty elements in Saccharomyces cerevisiae: implications for regulation of transposition.
Transposition of Ty elements in the yeast Saccharomyces cerevisiae occurs through an RNA intermediate. Although Ty RNA accounts for 5 to 10% of the total polyadenylated RNA in a haploid cell, the transposition frequency is only 10(-7) to 10(-8) per gene. To determine whether Ty elements native to the yeast genome are transpositionally competent, two elements were fused to the GAL1 promoter and tested for their ability to transpose. These native elements, Ty1-588 and Ty2-117, transposed at high levels when the GAL1 promoter was induced. Three Ty's identified as spontaneous transpositions in specific target genes were also tested. Of these three, Ty2-917 and the previously characterized element Ty1-H3 were shown to be transpositionally competent. The third element, Ty1-H1, was transposition defective. In addition, we marked the chromosomal copy of Ty1-588 with the NEO gene and demonstrated that Ty1-588NEO was actively transcribed in yeast cells. Ty1-588NEO transcription was regulated by the SPT3 and MAT loci in the same manner as that observed for Ty's collectively. These results indicate that the yeast genome contains functional Ty elements. The presence of a transpositionally competent, actively transcribed element suggests that regulation of Ty transposition occurs at a posttranscriptional level.


Laboratory-based and office-based risk scores and charts to predict 10-year risk of cardiovascular disease in 182 countries: a pooled analysis of prospective cohorts and health surveys.
Worldwide implementation of risk-based cardiovascular disease (CVD) prevention requires risk prediction tools that are contemporarily recalibrated for the target country and can be used where laboratory measurements are unavailable. We present two cardiovascular risk scores, with and without laboratory-based measurements, and the corresponding risk charts for 182 countries to predict 10-year risk of fatal and non-fatal CVD in adults aged 40-74 years. Based on our previous laboratory-based prediction model (Globorisk), we used data from eight prospective studies to estimate coefficients of the risk equations using proportional hazard regressions. The laboratory-based risk score included age, sex, smoking, blood pressure, diabetes, and total cholesterol; in the non-laboratory (office-based) risk score, we replaced diabetes and total cholesterol with BMI. We recalibrated risk scores for each sex and age group in each country using country-specific mean risk factor levels and CVD rates. We used recalibrated risk scores and data from national surveys (using data from adults aged 40-64 years) to estimate the proportion of the population at different levels of CVD risk for ten countries from different world regions as examples of the information the risk scores provide; we applied a risk threshold for high risk of at least 10% for high-income countries (HICs) and at least 20% for low-income and middle-income countries (LMICs) on the basis of national and international guidelines for CVD prevention. We estimated the proportion of men and women who were similarly categorised as high risk or low risk by the two risk scores. Predicted risks for the same risk factor profile were generally lower in HICs than in LMICs, with the highest risks in countries in central and southeast Asia and eastern Europe, including China and Russia. In HICs, the proportion of people aged 40-64 years at high risk of CVD ranged from 1% for South Korean women to 42% for Czech men (using a ≥10% risk threshold), and in low-income countries ranged from 2% in Uganda (men and women) to 13% in Iranian men (using a ≥20% risk threshold). More than 80% of adults were similarly classified as low or high risk by the laboratory-based and office-based risk scores. However, the office-based model substantially underestimated the risk among patients with diabetes. Our risk charts provide risk assessment tools that are recalibrated for each country and make the estimation of CVD risk possible without using laboratory-based measurements. National Institutes of Health.


Neutralisation rate controls the self-assembly of pH-sensitive surfactants.
The degree of ionisation of a weakly acidic surfactant can be continuously modified from nonionic to ionic by adjusting the pH. This property can be used to control the curvature and therefore the morphology of the self-assembled aggregates it forms in solution. Herein, we report the surprising phenomenon, observed in the alkyl ether oligo(ethylene oxide) carboxylate (CH3(CH2)11/13OEO4.5CH2COOH), whereby it is not only the pH but also the neutralisation rate that affects the aggregate morphology. Specifically, when the pH is increased slowly, up to 40 wt% of the surfactant remains in a long-lived vesicle state at high pH. This phenomenon was characterised in detail by small-angle neutron scattering and light scattering techniques. The cause of this phenomenon is thought to be related to a combination of polydispersity and the formation of acid-carboxylate dimers close to the pKa. The transition of these vesicles to the thermodynamically favoured micelles at high pH is inhibited by a high activation energy barrier and therefore only occurs very slowly. Increasing the NaCl concentration eliminates the presence of vesicles at high pH, demonstrating that the activation energy for the vesicle-to-micelle transition depends strongly on electrostatic interactions. These experiments show that the preparation pathway can be used to obtain different self-assembled structures at identical conditions via kinetic control. This phenomenon provides a useful tool for devising formulations where the properties of the system can be altered without changing the composition.


Intravascular laser lithotripsy for calcium fracture in human coronary arteries.
Electrical intravascular lithotripsy (E-IVL) uses shock waves to fracture calcified plaque. We aimed to demonstrate the ability of laser IVL (L-IVL) to fracture calcified plaques in ex vivo human coronary arteries and to identify and evaluate the mechanisms for increased vessel compliance. Shock waves were generated by a Ho:YAG (Holmium: yttrium-aluminium-garnet) laser (2 J, 5 Hz) and recorded by a high-speed camera and pressure sensor. Tests were conducted on phantoms and 19 fresh human coronary arteries. Before and after L-IVL, arterial compliance and optical coherence tomography (OCT) pullbacks were recorded, followed by histology. Additionally, microcomputed tomography (micro-CT) and scanning electron microscopy (SEM) were performed. Finite element models (FEM) were utilised to examine the mechanism of L-IVL. Phantom cracks were obtained using 230 μm and 400 μm fibres with shock-wave pressures of 84±5.0 atm and 62±0.4 atm, respectively. Post-lithotripsy, calcium plaque modifications, including fractures and debonding, were identified by OCT in 78% of the ex vivo calcified arteries (n=19). Histological analysis revealed calcium microfractures (38.7±10.4 μm width) in 57% of the arteries which were not visible by OCT. Calcium microfractures were verified by micro-CT and SEM. The lumen area increased from 2.9±0.4 to 4.3±0.8 mm2 (p<0.01). Arterial compliance increased by 2.3±0.6 atm/ml (p<0.05). FEM simulations suggest that debonding and intimal tears are additional mechanisms for increased arterial compliance. L-IVL has the capability to increase calcified coronary artery compliance by multiple mechanisms.


A Quality Improvement Initiative to Decrease the Rate of Solitary Blood Cultures in the Emergency Department.
Best practice guidelines recommend that at least two sets of blood cultures (BCs) be sent when blood cultures are required. However, high rates of solitary BCs are still common in the emergency department (ED). The aim of this study was to evaluate the efficacy of different quality improvement initiatives aimed at reducing the rate of solitary blood cultures being sent to the laboratory on patients ultimately discharged from our ED. This was a multicenter, multiphase, prospective study evaluating a comprehensive education-based intervention and a second intervention that combined a computerized forcing function (FF) along with a brief education-based intervention. The results were analyzed using segmented regression analysis, as well as statistical process control charts. The baseline rate of solitary sets of BCs was 41.1%. The education intervention reduced this rate to 30.3%. The introduction of a FF with a brief educational intervention further reduced the rate to 11.6%. This represents an absolute reduction of 29.5% from baseline (relative reduction of 71.8%). According to segmental regression analyses, the education intervention alone did not produce a statistically significant change when factoring possible background time-related trends (p = 0.071). However, the FF produced a statistically significant improvement (p < 0.0005), which was maintained for 6 months. The combination of a brief education-based intervention and a computerized FF was more effective than education alone in reducing solitary BC collection in our ED in this time series study. FFs can be a powerful tool in modifying behaviors and processes in the clinical setting.


Printed health information materials: evaluation of readability and suitability.
This study examined readability and suitability of printed health information materials colleted from multiple sources. In phase I, nursing students used Simple Measure of Gobbledygook (SMOG; McLaughlin, 1969) to assess the readability of 21 materials collected from the community. In phases II and III, nursing students and registered nurses used SMOG and the Suitability Assessment of Materials (SAM; Doak, Doak, & Root, 1996) to evaluate 15 prenatal materials from a Healthy Start program. SMOG assigns a reading grade level based on the number of words with 3 or more syllables. SAM has 22 items in 6 evaluation areas: content, literacy demand, graphics, layout and typography, learning stimulation and motivation, and cultural appropriateness. Major findings included that 53% to 86% of the printed materials had a reading level at or higher than 9th grade; materials lacked summary, interaction, and modeled behaviors, and registered nurses rated more materials as not suitable and fewer as superior for suitability qualities than students. Improving printed materials to have lower reading levels and better suitability qualities are indicated.


Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.
Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation.


Have we given up on intra-aortic balloon counterpulsation in post-myocardial infarction cardiogenic shock?
The recently published Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial concluded that intra-aortic counterpulsation (IACP) does not reduce 30-day mortality in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) for whom early revascularization strategy was planned. The study resulted in downgrading IACP in post-AMI CS patients by certain professional organizations like the European Society of Cardiology. Although this is the largest and most important CS study of this decade, it suffers from considerable shortcomings: (1) time intervals from chest-pain onset or AMI recognition to revascularization, enrollment, and IACP initiation are not disclosed; (2) 86.6% of the treatment arm initiated IACP only post-percutaneous coronary intervention (PCI), and 4.3 % did not receive IACP at all; (3) 17.4% of the control arm crossed over to IACP or other mechanical support, mostly due to protocol violations; (4) there is no adjudication of the mortality events; (5) follow-up is limited to 30 days; and (5) both methodology (especially IACP device size) and quality of IACP are not evaluated and documented. Because the study assessed mostly the efficacy and safety of IACP initiated post-PCI, the study conclusions should not be extrapolated to IACP pre-PCI or during PCI in CS. Moreover, IACP had a favorable effect on the mortality of younger patients. Intra-aortic counterpulsation should remain the first line of mechanical circulatory support for the hemodynamically compromised AMI patients with or without CS who are undergoing primary PCI. Early upgrade to more advanced mechanical circulatory support should be considered for selective suitable candidates who remain in refractory CS despite revascularization and IACP.


[Vestibular apparatus study of the toad, Xenopus laevis, and rats under prolonged weightlessness].
Fertilized eggs of the clawed toad Xenopus laevis were placed aboard of orbital laboratory of "Salut-6" spacecraft where they developed for 20 days at temperature 15 degrees C. The larvae were fixed in weightlessness. Light and electronmicroscopic studies revealed undisturbed structure on the saccular and utricular maculae and otolith membranes. Some ultrastructural abnormalities were found in the inner ear of adult rats after 20 days of weightlessness ("Kosmos-936").


A reduced somatosensory gating response in individuals with multiple sclerosis is related to walking impairment.
When identical stimuli are presented in rapid temporal succession, neural responses to the second stimulation are often weaker than those observed for the first. This phenomenon is termed sensory gating and is believed to be an adaptive feature that helps prevent higher-order cortical centers from being flooded with unnecessary information. Recently, sensory gating in the somatosensory system has been linked to deficits in tactile discrimination. Additionally, studies have linked poor tactile discrimination with impaired walking and balance in individuals with multiple sclerosis (MS). In this study, we examine the neural basis of somatosensory gating in patients with MS and healthy controls and assess the relationship between somatosensory gating and walking performance. We used magnetoencephalography to record neural responses to paired-pulse electrical stimulation applied to the right posterior tibial nerve. All participants also walked across a digital mat, which recorded their spatiotemporal gait kinematics. Our results showed the amplitude of the response to the second stimulation was sharply reduced only in controls, resulting in a significantly reduced somatosensory gating in the patients with MS. No group differences were observed in the amplitude of the response to the first stimulation nor the latency of the neural response to either the first or second stimulation. Interestingly, the altered somatosensory gating responses were correlated with aberrant spatiotemporal gait kinematics in the patients with MS. These results suggest that inhibitory GABA circuits may be altered in patients with MS, which impacts somatosensory gating and contributes to the motor performance deficits seen in these patients.NEW & NOTEWORTHY We aimed to determine whether somatosensory gating in patients with multiple sclerosis (MS) differed compared with healthy controls and whether a relationship exists between somatosensory gating and walking performance. We found reduced somatosensory gating responses in patients with MS, and these altered somatosensory gating responses were correlated with the mobility impairments. These novel findings show that somatosensory gating is impaired in patients with MS and is related to the mobility impairments seen in these patients.


Activation of protein kinase C in the spinal cord produces mechanical hyperalgesia by activating glutamate receptors, but does not mediate chronic muscle-induced hyperalgesia.
Protein kinase C (PKC) in the spinal cord appears to mediate chronic injury-induced pain, but not acute nociceptive pain. Muscle insult results in increased release of glutamate spinally, and hyperalgesia that is reversed by spinal blockade of NMDA and non-NMDA glutamate receptors. Therefore, we hypothesized that spinal activation of PKC 1) mediates the late phase of hyperalgesia 1 week after muscle insult, and 2) produces mechanical hyperalgesia through activation of NMDA and non-NMDA glutamate receptors. Rats were implanted with intrathecal catheters for delivery of drugs directly to the spinal cord. Mechanical withdrawal thresholds of the paw were determined using von Frey filaments. Intrathecal phorbol 12,13 dibutyrate (PDBu) produced a dose-dependent decrease in the mechanical withdrawal threshold of the paw that was prevented by pretreatment with the PKC inhibitor, GF109203X. Pretreatment with an NMDA receptor antagonist (AP5) or a AMPA/kainate receptor antagonist (NBQX) prevented the decrease in mechanical withdrawal threshold by PDBu. Two injections of acidic saline in the gastrocnemius muscle decreased the mechanical withdrawal thresholds of the paw bilaterally 24 h and 1 week after the second injection. However, blockade PKC in the spinal cord had no effect on the decreased withdrawal thresholds of the paw when compared to vehicle controls. Spinal activation of PKC produces mechanical hyperalgesia of the paw that depends on activation of NMDA and non-NMDA receptors. Chronic muscle-induced mechanical hyperalgesia, on the other hand, does not utilize spinal PKC.


Copy number variants and selective sweeps in natural populations of the house mouse (Mus musculus domesticus).
Copy-number variants (CNVs) may play an important role in early adaptations, potentially facilitating rapid divergence of populations. We describe an approach to study this question by investigating CNVs present in natural populations of mice in the early stages of divergence and their involvement in selective sweeps. We have analyzed individuals from two recently diverged natural populations of the house mouse (Mus musculus domesticus) from Germany and France using custom, high-density, comparative genome hybridization arrays (CGH) that covered almost 164 Mb and 2444 genes. One thousand eight hundred and sixty one of those genes we previously identified as differentially expressed between these populations, while the expression of the remaining genes was invariant. In total, we identified 1868 CNVs across all 10 samples, 200 bp to 600 kb in size and affecting 424 genic regions. Roughly two thirds of all CNVs found were deletions. We found no enrichment of CNVs among the differentially expressed genes between the populations compared to the invariant ones, nor any meaningful correlation between CNVs and gene expression changes. Among the CNV genes, we found cellular component gene ontology categories of the synapse overrepresented among all the 2444 genes tested. To investigate potential adaptive significance of the CNV regions, we selected six that showed large differences in frequency of CNVs between the two populations and analyzed variation in at least two microsatellites surrounding the loci in a sample of 46 unrelated animals from the same populations collected in field trappings. We identified two loci with large differences in microsatellite heterozygosity (Sfi1 and Glo1/Dnahc8 regions) and one locus with low variation across the populations (Cmah), thus suggesting that these genomic regions might have recently undergone selective sweeps. Interestingly, the Glo1 CNV has previously been implicated in anxiety-like behavior in mice, suggesting a differential evolution of a behavioral trait.


Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials.
Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.


Pathogenesis of atopic dermatitis (AD) and the role of allergic factors.
In this paper we will demonstrate that the exact pathogenesis of atopic dermatitis (AD) remains enigmatic, however the central defect is genetically determined, and the several dysfunctions we will highlight all point to a vicious cycle of allergen exposure, allergen-specific IgE production, and chronic Th2 cell stimulation. An important role is played by the late phase of IgE-mediated hypersensitivity, and evidence is accumulating that eosinophils actively participate in late phase-allergic reactions also in the skin. AD is the first atopic disease to appear in the absolute sense: dendritic cells (DC) develop firstly in the skin and then in lung, in addition to homing receptors for T lymphocytes that are selective for skin localizations and not for lung. Among the DC, a primary role is reserved to Langerhans cells (LC) that express E-cadherin, a homophilic adhesion molecule that is prominently represented in epithelia. In addition keratinocytes and the interleukins (IL) they express are capable of activating a host of IgE-bearing cells. Although much new information regarding the pathogenesis of AD has evolved over the past several years, the basic underlying etiology of this disorder remains elusive. Preventive measures are the only treatment for AD. We hope that the coming years will witness the development of new strategies for the treatment of AD, aimed at specific targets based on a thorough understanding of its pathogenesis.


Comparing the phenotypic, genotypic, and proteomic identification of Trichosporon species: A globally emerging yeast of medical importance.
Trichosporon spp. are widely distributed in the nature, comprising species that inhabit different ecological niches and can be found in the water, soil, and body surface of animals and humans. Such microorganisms have been classically associated with superficial infections; however, in the last decades, they have also been related to disseminated infections in immunocompromised patients, behaving as opportunistic agents, which demands rapid and accurate species identification for efficient therapy. Concordance level between the traditional phenotypic method and the molecular technique (gold standard) in the identification of all 59 Trichosporon samples was 59.3%. Identification concordance between MALDI-TOF spectrometry and the molecular technique was 71.2%. No isolate of environmental origin was identifiable by MALDI-TOF mass spectrometry (MS), and 100% of such environmental isolates were discordant for IGS region sequencing and phenotypic characterization. Both comparisons evidenced greatest concordance in the identification of T. asahii. The species T. debeurmannianum, T. dermatis, T. venhuisii and T. insectorum were not properly identified by both MALDI-TOF MS and the phenotypic technique. MALDI-TOF MS, in particular, seems to be appropriate to investigate yeasts of the genus Trichosporon; however, database updates are still necessary, especially for species that are not common in the clinical routine. With the aim of helping understand the aspects involved in early and accurate diagnosis of infections caused by this opportunistic agent, the present study compared the phenotypic, molecular (IGS region) and mass-spectrometry (MALDI-TOF) identification of 59 yeasts of the genus Trichosporon which had clinical and environmental origin and were kept in a mycology collection.


Regulation of thrombin-induced mast cell degranulation by zinc and manganese.
This study was undertaken to determine whether zinc, manganese and copper could regulate the thrombin-induced secretion of the granule-associated mediator, beta-hexosaminidase, from mast cells derived from mouse bone marrow. Exposure of thrombin to copper (2-100 microM) does not affect the enzyme-induced release of beta-hexosaminidase from the mast cells. Zinc at 50 microM reduced the degranulation of calcium ionophore A23187 activated cells by 75% and that of immunological challenge or thrombin by 30% each. Exposure of the thrombin to incremental concentrations of manganese (2-100 microM) prevents its degranulation activity in a dose-related fashion. 75% inhibition of the enzyme activity was achieved at 100 microM manganese. However, exposure of IgE sensitized or unsensitized cells to incremental concentrations of manganese (2-400 microM) prior to antigen or calcium ionophore A23187 stimulation, does not significantly affect the exocytosis of beta-hexosaminidase. The binding of purified human FITC-thrombin to E-mast cells was analyzed by fluorescence flow cytometry. All cells bound specifically the labelled thrombin. Pretreatment of the FITC-thrombin with 100 micron zinc or manganese had no effect on the binding of the labelled thrombin to the cells. It was assumed that manganese modulates either directly the thrombin activity or the substrate for the enzyme on the cell surface.


Left-lateralized fMRI activation in the temporal lobe of high repressive women during the identification of sad prosodies.
We investigated with fMRI whether different lateralization types of cortical activation in prosodic tasks are caused by individually different stress-related coping strategies. After healthy women had been classified as high or low repressive they performed four different identification tasks with acoustically presented speech material while being in the MR scanner. The two materials presented in blocks were emotionally irrelevant CV syllables and adjectives with a mix of different prosodic intonations. Sad and happy intonations had to be targeted by two affective identification tasks in the same adjective mixtures. For testing stimulus-material effects the phoneme /a/ had to be identified both in the syllables and the adjectives. This design allowed us to test influences of coping strategies and affective tasks on cortical activation in both hemispheres. Results showed no differences in global cortical lateralization as a function of high or low repressiveness and no global support for either the valence hypothesis or the right-hemisphere hypothesis of emotional processing. However, we observed differences in auditory and speech cortex. In accordance to the construct of repression/sensitization, high repressive women showed larger left, low repressive women larger right hemisphere activation during the identification of sad intonations. Thus, differences in stress-related coping strategies may not lead to general differences in cortical lateralization, but may depend on specific elicitors and task-relevant brain areas. In contrast, the identification of happy intonations led to strong and right-lateralized global cortical activation independent of coping strategies which complies with the right-hemisphere hypothesis of emotional processing. In addition, this may reflect general cognitive and arousal effects of task difficulty as well as auditory cue-specific attentional effects.


Development of the immune system and immunological protection in marsupial pouch young.
At birth the tissues of marsupial immune system are underdeveloped. The young animal is not immunocompetent. Histological and immunohistochemical studies of pouch young epithelial tissues provide a clear picture of tissue development but the timing of onset of immunocompetence awaits definition. The survival of the neonatal marsupial in a microbially rich environment is dependent on maternal strategies, including immunoglobulin transfer via milk and, in some species, prenatally via the yolk sac placenta. It is also likely that pouch secretions play a role. This review summarizes our current knowledge of the pathway of immunological development in marsupials and the protection and threats afforded by the pouch environment.


Disulfides as mercapto-precursors in nucleophilic ring opening reaction of polymeric epoxides: establishing equimolar stoichiometric conditions in a thiol-epoxy 'click' reaction.
The base-catalyzed oxirane ring opening reaction with thiol nucleophiles is frequently employed for post-polymerization modification of polymeric glycidyl scaffolds. Due to various beneficial attributes, it is often referred to as a 'click' reaction. However, the tendency of the free thiol molecules to undergo oxidative dimerization through the formation of a disulfide bond under ambient conditions results in partial consumption of the sulfhydryl precursors. Therefore, an excess of the thiol precursors is typically used to counterbalance the side-reaction. This violates the equimolar stoichiometry conditions required for 'click' reactions in the context of polymer synthesis. Here, we show that commercially available disulfides can be used to generate the necessary thiolate nucleophiles in situ through the reduction of the SS-bond with sodium borohydride. Such activation strategy eliminates the sulfhydryl oxidation mechanism to disulfides and ensures that the post-synthesis functionalization of epoxy polymers can be performed under equimolar 'click' conditions.


Adaptation to New Microphones Using Artificial Neural Networks With Trainable Activation Functions.
Model adaptation is a key technique that enables a modern automatic speech recognition (ASR) system to adjust its parameters, using a small amount of enrolment data, to the nuances in the speech spectrum due to microphone mismatch in the training and test data. In this brief, we investigate four different adaptation schemes for connectionist (also known as hybrid) ASR systems that learn microphone-specific hidden unit contributions, given some adaptation material. This solution is made possible adopting one of the following schemes: 1) the use of Hermite activation functions; 2) the introduction of bias and slope parameters in the sigmoid activation functions; 3) the injection of an amplitude parameter specific for each sigmoid unit; or 4) the combination of 2) and 3). Such a simple yet effective solution allows the adapted model to be stored in a small-sized storage space, a highly desirable property of adaptation algorithms for deep neural networks that are suitable for large-scale online deployment. Experimental results indicate that the investigated approaches reduce word error rates on the standard Spoke 6 task of the Wall Street Journal corpus compared with unadapted ASR systems. Moreover, the proposed adaptation schemes all perform better than simple multicondition training and comparable favorably against conventional linear regression-based approaches while using up to 15 orders of magnitude fewer parameters. The proposed adaptation strategies are also effective when a single adaptation sentence is available.


Epigallocatechin gallate prevents mitochondrial impairment and cell apoptosis by regulating miR-30a/p53 axis.
This study was designed to investigate whether EGCG prevents cardiac I/R mitochondrial impairment and cell apoptosis by regulating miR-30a/p53 axis. The H9c2 cardiomyocytes hypoxia/reoxygenation (H/R) model in vitro and myocardial ischemia /reperfusion (I/R) model in vivo were made, with or without EGCG treatment. The levels of I/R-induced creatine kinase-MB (CK-MB) and the release of lactate dehydrogenase (LDH), as well as the adenosine triphosphate (ATP) and cardiac functional impairment were examined. Stablely transfecting miR-30a mimic or inhibitor in H9c2 cardiomyocytes was built. The expression of miR-30a, p53 and related proteins in cells was measured by western blotting and qRT-PCR. Cell viability and apoptosis were examined using CCK-8 assay and flow cytometry. The content of reactive oxygen species (ROS), mitochondrial permeability transition pores (MPTP) opening and mitochondrial transmembrane potential (ΔΨm) in cells was measured by fluorescent probes. The levels of miR-30a and p53, some related proteins expression and apoptosis in the cardiac muscle tissues were determined by quantitative real-time PCR (qRT-PCR), H&E staining, western blotting and TUNEL assays. We found that EGCG preconditioning significantly decreased the levels of CK-MB and LDH, increased the activity of ATP, reduced the apoptotic rate and partially preserved heart function. Furthermore, EGCG decreased ROS levels, MPTP opening and depolarization of ΔΨm, and improved the activity of post-I/R cardiomyocyte. The beneficial effect of EGCG was associated with restored levels of miR-30a expression in the I/R injury that correspond to p53 mRNA downregulation. The regulatory effect of EGCG was greatly enhanced by miR-30a mimic and suppressed by miR-30a inhibitor. More importantly, EGCG pretreatment inhibited the expression of mitochondrial apoptotic related proteins downstream of the miR-30a/p53 pathway. This study demonstrated that EGCG pretreatment may attenuate mitochondrial impairment and myocardial apoptosis by regulation of miR-30a/p53 axis.


Brucella sacroiliitis. A case report.
Brucellosis is an uncommon infectious disease in the United States though it remains endemic in many parts of the world. Signs and symptoms of the disease are highly variable, with musculoskeletal complaints occurring frequently. The combination of an uncommon infection presenting with protean manifestations often results in missed or delayed diagnosis in the Western world.


Isolation of thermophilic mutants of Bacillus subtilis and Bacillus pumilus and transformation of the thermophilic trait to mesophilic strains.
Thermophilic mutants were isolated from mesophilic Bacillus subtilis and Bacillus pumilus by plating large numbers of cells and incubating them for several days at a temperature about 10 degrees C above the upper growth temperature limit for the parent mesophiles. Under these conditions we found thermophilic mutant strains that were able to grow at temperatures between 50 degrees C and 70 degrees C at a frequency of less than 10(-10). The persistence of auxotrophic and antibiotic resistance markers in the thermophilic mutants confirmed their mesophilic origin. Transformation of genetic markers between thermophilic mutants and mesophilic parents was demonstrated at frequencies of 10(-3) to 10(-2) for single markers and about 10(-7) for two unlinked markers. With the same procedure we were able to transfer the thermophilic trait from the mutant strains of Bacillus to the mesophilic parental strains at a frequency of about 10(-7), suggesting that the thermophilic trait is a phenotypic consequence of mutations in two unlinked genes.


Detection of Device-Related Thrombosis Following Left Atrial Appendage Occlusion: A Comparison Between Cardiac Computed Tomography and Transesophageal Echocardiography.
Device-related thrombosis (DRT) following left atrial appendage occlusion is a rare but feared complication. The diagnostic value of cardiac compute tomography (CT) for detection of DRT is unknown. This study sought to evaluate the clinical value of cardiac CT for detection of DRT using transesophageal echocardiography (TEE) as the reference standard and to provide insights into the causes, natural history, and risk of DRT. We reviewed 301 consecutive patients undergoing left atrial appendage occlusion at Aarhus University Hospital, Denmark, between 2010 and 2017. Of these, 248 patients had cardiac CT and TEE imaging available at 8-week follow-up; 139 had complete 12-month imaging. A blinded investigator analyzed all images. On TEE, an echo-dense mass attached to the device was defined as DRT. Cardiac CT was analyzed for presence of hypoattenuated thickening (HAT) on the device, which was subclassified as low grade or high grade. High-grade HAT was considered as definite DRT. At 8 weeks, TEE detected 5 (2%) cases with DRT; and cardiac CT 6 (2.4%) cases with high-grade HAT. At 12 months, both TEE and cardiac CT detected 2 (1.4%) cases with DRT or high-grade HAT, respectively. Cardiac CT demonstrated low-grade HAT in 9 (3.6%) cases at 8 weeks; and 13 cases (9.4%) at 12-months. High-grade HAT/DRT was associated with thromboembolism in 2 cases, whereas low-grade HAT was not related to embolic events. Low-grade HAT resolved spontaneously over time. Cardiac CT seems equally good as TEE for detection of DRT. In addition, cardiac CT demonstrates cases with low-grade HAT, not visualized by TEE. The clinical significance hereof requires further investigation.


Influence of aquatic exercises in physical condition in patients with multiple sclerosis.
Multiple sclerosis (MS) is a disabling chronic disease of the nervous system in which the myelin system of the central nervous system is deteriorated. This study aimed to evaluate the effectiveness of an aquatic exercise program on the physical condition of patients suffering from multiple sclerosis. The study included 26 participants divided into two groups: an experimental group (EG) with 13 individuals and a control group (CG) also with 13 individuals. The EG underwent 12 weeks of aquatic exercise, three times per week and 45-60 minutes per session. The groups were evaluated pre- and post-intervention, and were later compared to check for differences between groups. Data was collected by using functional tests such as the Timed "Up and Go" Test, the Timed 7.62 Meters Walk Test, the Getting up from a Sitting Position Test and the Balance Test. Significant differences were found between the groups in the post-intervention stage. Furthermore, significant differences were also observed in all domains of physical condition of EG patients, in the post-intervention stage. Results obtained from the intention-to-treat analysis were consistent with those found in the literature. Therefore, this study's results suggest that aquatic exercise programs can effectively improve multiple sclerosis patient's physical condition and should be considered when coping with this public health problem.