Large-Scale Sparse Learning From Noisy Tags for Semantic Segmentation.
In this paper, we present a large-scale sparse learning (LSSL) approach to solve the challenging task of semantic segmentation of images with noisy tags. Different from the traditional strongly supervised methods that exploit pixel-level labels for semantic segmentation, we make use of much weaker supervision (i.e., noisy tags of images) and then formulate the task of semantic segmentation as a weakly supervised learning (WSL) problem from the view point of noise reduction of superpixel labels. By learning the data manifolds, we transform the WSL problem into an LSSL problem. Based on nonlinear approximation and dimension reduction techniques, a linear-time-complexity algorithm is developed to solve the LSSL problem efficiently. We further extend the LSSL approach to visual feature refinement for semantic segmentation. The experiments demonstrate that the proposed LSSL approach can achieve promising results in semantic segmentation of images with noisy tags.


The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro ).
With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The Mpro enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug-like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure-based virtual screening. After extensive filtering, docking, and post-docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a Mpro non-competitive reversible inhibitor with a Ki of 115 μM and an IC50 of 101.9 μM. Throughout the 200 ns-long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure-activity relationship. To sum up, drug-like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses-caused diseases.


Plants as biomarkers for monitoring heavy metal contaminants on landfill sites using sequential extraction and inductively coupled plasma atomic emission spectrophotometry (ICP-AES).
There have been a number of studies investigating metal uptake in plants on contaminated landfill sites, but little on their role as biomarkers to identify metal mobility for continuous monitoring purposes. Vegetation can be used as a biomonitor of site pollution, by identifying the mobilisation of heavy metals and by providing an understanding of their bioavailability. Plants selected were the common nettle (Uritica Dioica), bramble (Rubus Fruticosa) and sycamore (Acer Pseudoplatanus). A study of the soil fractionation was made to investigate the soil properties that are likely to influence metal mobility and a correlation exercise was undertaken to investigate if variations in concentration of metals in vegetation can reflect variations in concentration of the metals in soil. The soil was digested using aqua regia in a microwave closed vessel. The vegetation was digested using both microwave and a hydrogen peroxide-nitric acid mixture, refluxed on a heating block and a comparison made. The certified reference materials (CRMs) used were Standard Reference Material (SRM) 1547, peach leaves for vegetation (NIST) and for soil CRM 143R, sewage sludge-amended soil (BCR). The relative standard deviations (RSDs) were 2-6% for the analyses. Our findings show evidence of phytoextraction by some plants, (especially bramble and nettle), with certain plants, (sycamore) exhibiting signs of phytostabilisation. The evidence suggests that there is a degree of selectivity in metal uptake and partitioning within the plant compartments. It was also possible to correlate mobility phases of certain metals (Pb, Cu and Zn) using the soil and plant record. Zn and Cu exhibited the greatest potential to migrate from the roots to the leaves, with Pb found principally in the roots of ground vegetation. Our results suggest that analysis of bramble leaves, nettle leaves and roots can be used to monitor the mobility of Pb in the soil with nettle, bramble and sycamore leaves to monitor Cu and Zn.


Tiered co-payments, pricing, and demand in reference price markets for pharmaceuticals.
Health insurance companies curb price-insensitive behavior and the moral hazard of insureds by means of cost-sharing, such as tiered co-payments or reference pricing in drug markets. This paper evaluates the effect of price limits - below which drugs are exempt from co-payments - on prices and on demand. First, using a difference-in-differences estimation strategy, we find that the new policy decreases prices by 5 percent for generics and increases prices by 4 percent for brand-name drugs in the German reference price market. Second, estimating a nested-logit demand model, we show that consumers appreciate co-payment exempt drugs and calculate lower price elasticities for brand-name drugs than for generics. This explains the different price responses of brand-name and generic drugs and shows that price-related co-payment tiers are an effective tool to steer demand to low-priced drugs.


Stroke location, characterization, severity, and outcome in mitral vs aortic valve endocarditis.
To characterize the incidence and clinical features of patients with infective endocarditis (IE) and stroke. The authors reviewed the records of 707 patients diagnosed with definite or possible IE between January 1984 and November 1999. Stroke was confirmed by application of strict definitions and classified by type, pathophysiology, vascular territory, and severity. The authors determined mortality rates for the initial hospitalization and 12 months after admission. Strokes occurred in 68 (9.6%) of 707 patients with IE, 38 (17%) of 218 patients with mitral valve endocarditis (MVE), 14 (9%) of 149 patients with aortic valve endocarditis (AVE), and 16 (5%) of 340 patients with other forms of IE (OR for MVE vs AVE = 2.0, 95% CI 1.1 to 3.9). Among the patients with MVE or AVE and stroke, there were no significant relationships between site of vegetation and length of hospitalization, stroke severity, mortality during the initial hospitalization, or 12-month mortality. Fifty-two percent of patients with stroke and IE died within 1 year of admission. The overall incidence of stroke in patients with IE (9.6%) is lower than previous reports (21 to 39%). Patients with MVE had a greater risk of stroke than patients with AVE. Fifty-two percent of patients died within 1 year of admission for IE.


Human dental pulp cells: a new source of cell therapy in a mouse model of compressive spinal cord injury.
Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists and neuroscientists throughout the world. Many cell-based therapies have been tested, with limited success in terms of functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mouse model of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of the extraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal and mesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 and compression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days after the lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. We performed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, and ultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better white-matter preservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissue organization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, in addition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. We also demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functional analysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans.


A diagnostic tool for population models using non-compartmental analysis: The ncappc package for R.
Non-compartmental analysis (NCA) calculates pharmacokinetic (PK) metrics related to the systemic exposure to a drug following administration, e.g. area under the concentration-time curve and peak concentration. We developed a new package in R, called ncappc, to perform (i) a NCA and (ii) simulation-based posterior predictive checks (ppc) for a population PK (PopPK) model using NCA metrics. The nca feature of ncappc package estimates the NCA metrics by NCA. The ppc feature of ncappc estimates the NCA metrics from multiple sets of simulated concentration-time data and compares them with those estimated from the observed data. The diagnostic analysis is performed at the population as well as the individual level. The distribution of the simulated population means of each NCA metric is compared with the corresponding observed population mean. The individual level comparison is performed based on the deviation of the mean of any NCA metric based on simulations for an individual from the corresponding NCA metric obtained from the observed data. The ncappc package also reports the normalized prediction distribution error (NPDE) of the simulated NCA metrics for each individual and their distribution within a population. The ncappc produces two default outputs depending on the type of analysis performed, i.e., NCA and PopPK diagnosis. The PopPK diagnosis feature of ncappc produces 8 sets of graphical outputs to assess the ability of a population model to simulate the concentration-time profile of a drug and thereby evaluate model adequacy. In addition, tabular outputs are generated showing the values of the NCA metrics estimated from the observed and the simulated data, along with the deviation, NPDE, regression parameters used to estimate the elimination rate constant and the related population statistics. The ncappc package is a versatile and flexible tool-set written in R that successfully estimates NCA metrics from concentration-time data and produces a comprehensive set of graphical and tabular output to summarize the diagnostic results including the model specific outliers. The output is easy to interpret and to use in evaluation of a population PK model. ncappc is freely available on CRAN (http://cran.r-project.org/web/packages/ncappc/index.html/) and GitHub (https://github.com/cacha0227/ncappc/).


Molecular dynamics investigation on the interaction of human angiotensin-converting enzyme with tetrapeptide inhibitors.
Angiotensin-converting enzyme (ACE) is a well-known zinc metalloenzyme whose physiological functions are vital to blood pressure regulation and management of hypertension. The development of more efficient peptide inhibitors is of great significance for the prevention and treatment of hypertension. In this research, molecular dynamics (MD) simulations were implemented to study the specific binding mechanism and interaction between human ACE (hACE) and tetrapeptides, YIHP, YKHP, YLVR, and YRHP. The calculation of relative binding free energy on the one hand verified that YLVR, an experimentally identified inhibitor, has a stronger inhibitory effect and, on the other hand, indicated that YRHP is the "best" inhibitor with the strongest binding affinity. Inspection of atomic interactions discriminated the specific binding mode of each tetrapeptide inhibitor with hACE and explained the difference of their affinity. Moreover, in-depth analysis of the MD production trajectories, including clustering, principal component analysis, and dynamic network analysis, determined the dynamic correlation between tetrapeptides and hACE and obtained the communities' distribution of a protein-ligand complex. The present study provides essential insights into the binding mode and interaction mechanism of the hACE-peptide complex, which paves a path for designing effective anti-hypertensive peptides.


The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells.
The structurally related immunosuppressive macrolides FK-506 and rapamycin (RAP) were previously shown to inhibit T cell stimulation through different mechanisms. FK-506 acts similarly to cyclosporin A (CsA) and prevents IL-2 production and IL-2R expression. RAP has little or no effect on these events but markedly impedes the response to IL-2. The present study was initiated to examine the possibility of a complementation between the immunosuppressive actions of RAP and FK-506 or CsA on various murine T cell responses. RAP potentiated the effect of CsA on proliferation and IL-2R expression in T cells stimulated with ionomycin + PMA. However, in the same system, RAP acted as a potent antagonist of FK-506 suppression. RAP also blocked FK-506- but not CsA-mediated inhibition of IL-2 mRNA induction. By using model systems sensitive to inhibition by RAP but not FK-506 we further demonstrated that FK-506 reciprocally behaves as an antagonist of RAP. In one such model, the stimulation of splenic T cells with IL-2 + PMA, FK-506, but not CsA, reversed the suppressive effect of RAP on proliferation. FK-506 also antagonized RAP-mediated inhibition with respect to the induction of Ly-6E Ag expression by IFN in YAC cells. To explore further the competition between the two macrolides at the cellular level, we performed binding experiments with a radiolabeled derivative of FK-506. Both FK-506 and RAP, but not CsA, inhibited the binding of this probe in YAC cells. Taken together, these data demonstrate that FK-506 and RAP antagonize each other's biologic activity and physically interact with a common receptor site(s) in T cells. Moreover, CsA acts at a site distinct from the cellular target(s) of FK-506 or RAP.


Colorectal polyps and the risk of subsequent carcinoma.
Of 323 patients with colorectal polyps that either were larger than 1 cm in diameter or were 1 cm or smaller but had been subjected to biopsy or excision, 20 (6%) had subsequent development of a colorectal carcinoma, an incidence rate of 4.6 per 1,000 person-years of follow-up. These 20 cases of cancer compared with 7.38 cases expected; thus, the risk of colorectal carcinoma in these patients was 2.7 times that in the general population (P less than 0.001). Although risks were greater for certain subgroups of patients, the differences detected were usually modest. We conclude that patients with large colorectal polyps (more than 1 cm in diameter) should be closely followed up after treatment of the initial polyp, regardless of the size, site, or histologic type of the polyp, the age or sex of the patient, or the type of initial treatment (excision or fulguration). Those patients with more than one polyp, especially if more than one segment of the colon is involved, need special attention. Examination of the entire colon is important because the site of development of carcinoma may be distant from the site of the initial polyp.


Clinical range and MRI in Creutzfeldt-Jakob disease with heterozygosity at codon 129 and prion protein type 2.
A 68 year old woman with sporadic Creutzfeldt-Jakob disease is described, who neither showed characteristic EEG abnormalities nor a positive test of the neuronal protein 14-3-3 or neuron specific enolase (NSE) in CSF, despite a clinical presentation with ataxia of cerebellar type, rapidly progressive dementia, myoclonus, and marked hyperintense signal abnormalities in the deep cortical layers and the basal ganglia on T2 and diffusion weighted MRI. Moreover she showed atypical clinical features with a syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and a peripheral sensorimotor polyneuropathy. Whether these disturbances are independent of Creutzfeldt-Jakob disease or a feature of it is discussed. It has recently been shown that in Creutzfeldt-Jakob disease different clinical and pathological phenotypes correlate with the polymorphism at codon 129 of the prion protein gene (PRNP) and the type of the protease resistant fragment that accumulates in the brain. According to the new classification at least six sporadic variants of Creutzfeldt-Jakob disease exist. The molecular genetic analysis showed heterozygosity of PRNP at codon 129 for methionine and valine and the presence of PrP(CJD) type 2 in the brain of this patient. As a new feature of changes on MRI, striking cortical changes of hyperintense signals are described in diffusion weighted as well as T2 weighted MRI that directly correlate with the histomorphological spongy degeneration of the brain in this region. In cases of rapidly progressive dementia, Creutzfeldt-Jakob disease always needs to be considered even if unusual features are present and current diagnostic criteria are not in favour of this disease.


Transoral robotic surgery experience in 44 cases.
To report a single institution's experience with transoral robotic surgery (TORS) and its clinical outcomes. This was a retrospective study carried out at a university-affiliated teaching hospital. Forty-four consecutive TORS patients with benign and malignant diseases were reviewed. Data on demographics, clinical parameters, and diet were collected. Surgical margins, local and regional recurrence, distant metastasis, 2-year disease-free survival rate, and 2-year survival data were reviewed for the malignant cases. Nine benign and 35 proven squamous cell carcinoma (SCCA) cases underwent TORS. The set-up time was 17.12 minutes (range, 10-40 minutes), and operative time was 53 minutes (range, 10-300 minutes). Average length of stay was 2.5 days. There were seven (6.8%) grade 3 surgical complications. Surgical infection rate was 2.3%. Benign cases were on a regular diet after TORS. Of the malignant cases, 94% were taking peroral diet immediately after the TORS procedure. There were no intraoperative complications and no 30-day postoperative mortalities. The mean follow-up time was 25.2 months (range, 16-38 months) for malignant disease. The SCCA sites were in the oropharynx (30/35), larynx (2/35), and unknown primary with neck metastasis (3/35). Unknown primary patients were excluded in the surgical margin analyses. Negative margins were achieved in 91% of cases. The local and regional recurrence rates were 6.3% (2/32) and 3.1% (1/32), respectively. Two patients (6.3%) developed distant metastasis. Oropharyngeal SCCA cases were reviewed, of which 23 were human papillomavirus (HPV)/p16 positive and 7 were HPV/p16 negative. The 2-year actual survival for HPV-positive and -negative patients was 96% (22/23) and 86% (6/7), respectively. The 2-year disease-free survival for HPV-positive and -negative cases was 91% (21/23) and 71.4% (5/7), respectively. All malignant cases that underwent TORS received postoperative adjuvant therapy. TORS is a safe procedure with minimal complications and acceptable clinical and functional outcomes.


Anti-proliferative efficacy of icariin on HepG2 hepatoma and its possible mechanism of action.
The aim of the present work was to explore the anti-hepatoma effects of icariin both in vitro and in vivo and to elucidate its potential mechanism of action. The MTT assay was applied to test the anti-proliferative effects of icariin in vitro. HepG2 bearing NMRI nu/nu mice were used to test the anticancer effects of icariin in vivo. Immunohistochemical assay and flow cytometry assay (FACS) were applied to detect the possible mechanisms of action of icariin. MTT assay illustrated that icariin inhibited the proliferation of HepG2 cells in a concentration dependent manner; meanwhile, icariin inhibited the tumor growth in HepG2 bearing NMRI nu/nu mice. The tumor weight was inhibited by 55.6% and tumor volume was inhibited by 47.2%. Icariin did not influence the spleen and body weights or blood parameters. Immunohistochemical analysis indicated that the expressions of both CD31 and Ki67 in the icariin treated group were significantly lower than those in the control group (p < 0.01). FACS assay showed that icariin dramatically decreased the percentage of CD4+ and CD8+ cells in bone marrow and CD19+ cells in blood on day 8. On day 17, the percentage of CD8+ cells in blood was lower than those in the control group. CD4/CD8 ratio in icariin group was significantly elevated in bone marrow on day 17. Icariin showed anticancer efficacy both in vitro and in vivo. The possible mechanism of action could be related to its anti-angiogenesis and anti-proliferative effects in tumors.


Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.
Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.


Addiction and Engagement: An Explorative Study Toward Classification Criteria for Internet Gaming Disorder.
The DSM-5 introduced Internet gaming disorder (IGD) as a condition needing more research. Proposed criteria include tolerance, preoccupation, deceiving, or continued excess despite psychosocial problems. However, studies suggest differences between addicted and engaged players. Therefore, this study investigated differences between engagement and addiction in a German-speaking sample of expert World of Warcraft players. Using an online-based questionnaire, 682 participants were surveyed (Mage=23.26 years; 84.9% male) from German-speaking areas. An adapted version of the "Asheron's call" questionnaire (which covers six addiction criteria, including salience, euphoria, and tolerance), the WHOQOL-BREF, the Gaming Motivation Scale, the BDI, the SPIN, and a brief version of the personality questionnaire BFI-10 were used. The average gamer in the sample played on level 87.93 and had been playing for 5.42 years. Addicted players had higher scores on the BDI and SPIN and significantly lower scores in all dimensions of quality of life. Addicted gamers played for 39.25 hours per week (engaged players: 11.93 hours per week) with significantly higher scores in items tapping achievement and immersion. There were differences regarding the BFI-10 in terms of "agreeableness," "conscientiousness," and "neuroticism." The results suggest that factors such as achievement and immersion set engaged and addicted users apart. Addiction seems to be significantly more connected to other psychopathologies such as depression and social anxiety. The results suggest that euphoria, tolerance, and cognitive salience should be handled with caution when it comes to a classification of IGD similar to (behavioral) addiction.


[Smoked sausages and food additives: evaluation of total mutagenic activity].
The paper deals with the evaluation of the total mutagenic activity of samples of the inorganic and organic fractions of three technology smoked sausages (boiled-smoked, semi-smoked, and raw-smoked) and some food additives used to manufacture the above sausages. Their mild and moderate mutagenic effects were recorded in a Salmonella typhimurium bacterial test system with a metabolic activation system. Physicochemical analysis of the fractions of the smoked sausages has shown that their study samples are substantially contaminated with heavy metals and representatives of polycyclic aromatic hydrocarbons, partially causing the mutagenic effects observed.


Assessing nursing student intent for PHD study.
Nursing faculty shortages threaten a country's ability to produce the amount of nurses necessary to sustain the delivery of healthcare services. Programs that "fast track" graduate education options for registered nurses are one solution to the problem. To (1) evaluate admission criteria into PhD programs for direct entry from a bachelor's degree; (2) ascertain bachelors and masters degree nursing students' perspectives on pursuing a BSN to PhD course of study; (3) clarify factors that influence students' decision-making processes behind pursuing a PhD and identify characteristics of those who would be likely recruits for PhD study; 4) to test the survey questions to develop an instrument for future use. A cross-sectional pilot study. A nursing program at a large urban university in the United States of America with an enrollment of over 1400 students. Currently enrolled bachelor's, master's, and doctor of nursing practice students. Students were sampled via a 10-question (including one open-ended question) electronic mail survey that included 1385 eligible subjects. Among the 606 respondents (57% response rate), 63% were between ages 18 and 30 and 87% indicated that full tuition funding with a living stipend would make them more interested in pursuing a PhD. Current program track was a significant predictor of course of study and area of interest (p=.029). Analysis of the 427 respondents to the open-ended question revealed themes around "time" and "money" as the main barriers to study. The desire to gain clinical experience prior to PhD study was the third theme and an unanticipated finding. The questionnaire offered some predictive ability for gauging intent to study for a PhD among bachelor's and graduate degree prepared nurses. The results do offer some suggestions for nursing workforce development to help address faculty shortages.


Secretion of a bacterial protein by mammalian cells.
The MalE protein is a periplasmic maltooligosaccharide binding protein from Escherichia coli. This protein is widely used as a model for protein export in bacteria and as a vector for the export and one-step affinity purification of foreign polypeptides. Expression of MalE was studied in various animal cell lines. The protein was exported into the culture medium, following the classical pathway of eukaryotic protein secretion. This was shown by a combination of approaches including the use of inhibitors of the Golgi complex and immunocytological methods. The signal sequence of MalE is required for secretion and a specific signal can be added to MalE that targets it to the endoplasmic reticulum. This work opens the way to the study of the secretion of a bacterial protein and to its use as a vector for protein secretion and purification from mammalian cells.


Dynorphin-(1-13). I. Structure-function relationships of Ala-containing analogs.
Dynorphin-(1-13) (Dyn-(1-13] and its analogs substituted by single introduction of Ala in positions 1-11 were synthesized by the solid-phase method and purified by high pressure liquid chromatography. Relative potencies of the synthetic compounds were determined by their ability to inhibit electrically-evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with [3H]-etorphine for opiate receptors in rat brain homogenates. Introduction of Ala in positions 1 and 4 of Dyn-(1-13) provoked most important decreases in the activity of the molecule in the three assays (relative potency of 0.2% or less). Substitution of Ala in positions 2 or 5, but not 3, also severely decreased the potency of the peptide in the smooth muscle preparations (0.6-5.0% activity). However, the opiate receptor binding assay was less sensitive to the replacement of residue in position 2 (20% activity) than that in positions 3 or 5 (12% and 6% relative potencies, respectively). In the GPI assay and the opiate binding test, the other substitutions which greatly lowered the potency of the molecule were seen in positions 6, 7, 9 and 11, four basic residues. Among these, Arg6 and Arg7 were demonstrated to be the most important in the three biological tests. Finally, the replacement of Ile8 by Ala increased the relative potency of Dyn-(1-13) up to 191% and 900% in the MVD and the opiate binding tests, respectively.


Lesser Investigated Natural Ingredients for the Management of Obesity.
Obesity, an epidemiological disorder, is related to various complications in both the developed and developing world. It epitomizes a crucial risk factor for health, decreasing productivity and life expectancy while increasing health care costs worldwide. Conventional therapies with synthetic drugs or bariatric surgery, associated with numerous side effects, recurrence, and surgical complexity, have been restricted in their use. Lifestyle changes and dietary restrictions are the proven methods for successful weight loss, although maintaining a strict lifestyle is a challenge. Multiple natural products have been explored for weight management with varied efficacy. The current review explores less explored natural herbs, their active constituents, and their mechanisms of action against obesity.


Essential Elements of Home-based Palliative Care Model: A Rapid Review.
The need for palliative care is increasing due to the rising burden of non-communicable diseases and some communicable diseases. Chronic illnesses demand patient-centred care that focuses on the patient's individual healthcare needs. Palliative care improves the patients' and caregivers' quality of life by providing pain and symptom relief through a holistic approach after the disease is diagnosed. Though there are various models followed in different countries, home-based palliative care is preferred by patients who wish to stay close to their loved ones at their end of life. For providing home-based care, there are certainly important elements that have to be taken care of before planning the implementation because every country has its own healthcare needs, system, and context. India is a developing country where isolated Palliative Care is practiced, hence the situation demands the need of addressing the essential elements that can be included in the protocol of home-based palliative care to enhance the quality of care. Therefore, this study aims to identify a few elements needed to provide home-based palliative care in the Indian context. A rapid review was conducted where seven studies were included that mentioned the elements of home-based palliative care. The electronic databases searched were MedLine, PubMed, and Cochrane databases of systematic reviews. The review was carried out over a period of 8 weeks in June and July 2022. Seven common essential themes were identified; (i) inter-sectoral and inter-professional cooperation, (ii) trust and safety, (iii) holistic management, (iv) non-academic palliative care, (v) spiritual care, (vi) support to caregivers, and (vii) funding and financial support. Our review of effective palliative care models explicates the essential elements for quality home-based care for patients with a terminal illness. The application of the elements must be relevant to the local context due to the huge diversity of the country.


[Comparative study of the effect of drug therapy and its combination with hyperbaric oxygenation and hemosorption on stable angina pectoris].
Seventy seven males aged under 60 years with Functional Classes II-IV stable angina were examined. The patients were randomly divided into 3 groups: 1) 24 patients receiving drug therapy alone; 2) 27 patients taking drug therapy in combination with hyperbaric oxygenation; and 3) 26 patients having drug therapy in combination with hemosorption. In all the patient groups, there was a reduction in the frequency of resting and exercise anginal attacks, in Group 3, exercise tolerance was increased due to drug therapy. In a re-examination, there was a significant fall in total cholesterol and high-density lipoprotein cholesterol levels only in Group 3. A comparison of daily drug doses indicated that the functional class improved only due to the adequate antianginal therapy. Thus, hyperbaric oxygenation and hemosorption have no significant action on the degree of stable angina.


Management of cognitive impairment in bipolar disorder: a systematic review of randomized controlled trials.
Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.


Echocardiography: conotruncal anomaly: a case of common arterial trunk with intact ventricular septum and hypoplastic left heart complex with unbalanced pulmonary stenoses.
We describe the echocardiographic findings of a common arterial trunk with intact ventricular septum, mitral and left ventricular hypoplasia, atretic left ventricular outlet and bilateral, and unbalanced pulmonary artery stenoses.


Effect of vehicle front end profiles leading to pedestrian secondary head impact to ground.
Most studies of pedestrian injuries focus on reducing traumatic injuries due to the primary impact between the vehicle and the pedestrian. However, based on the Pedestrian Crash Data Study (PCDS), some researchers concluded that one of the leading causes of head injury for pedestrian crashes can be attributed to the secondary impact, defined as the impact of the pedestrian with the ground after the primary impact of the pedestrian with the vehicle. The purpose of this study is to understand if different vehicle front-end profiles can affect the risk of pedestrian secondary head impact with the ground and thus help in reducing the risk of head injury during secondary head impact with ground. Pedestrian responses were studied using several front-end profiles based off a mid-size vehicle and a SUV that have been validated previously along with several MADYMO pedestrian models. Mesh morphing is used to explore changes to the bumper height, bonnet leading-edge height, and bonnet rear reference-line height. Simulations leading up to pedestrian secondary impact with ground are conducted at impact speeds of 40 and 30 km/h. In addition, three pedestrian sizes (50th, 5th and 6yr old child) are used to enable us to search for a front-end profile that performs well for multiple sizes of pedestrians, not just one particular size. In most of the simulations, secondary ground impact with pedestrian head/neck/shoulder region occurred. However, there were some front-end profiles that promoted secondary ground impact with pedestrian lower extremities, thus avoiding pedestrian secondary head impact with ground. Previous pedestrian safety research work has suggested the use of active safety methods, such as 'pop up hood', to reduce pedestrian head injury during primary impact. Accordingly, we also conducted simulations using a model with the hood raised to capture the effect of a pop-up hood. These simulations indicated that even though pop-up hood helped reducing the head injury criterion during primary impact, it changed the overall pedestrian kinematics in some cases. The specific design with pop up hood evaluated in this study did not prevent pedestrian head secondary impact with the ground or actually led to more severe pedestrian secondary head impact with the ground.


New insights into the epidemiology of childhood atopic dermatitis.
There is a growing desire to explain the worldwide rise in the prevalence of atopic dermatitis (AD). Trend data on the burden of AD suggest that the picture in the developing world may soon resemble that of wealthier nations, where AD affects over 20% of children. This, combined with significant variations in prevalence within countries, emphasizes the importance of environmental factors. Many hypotheses have been explored, from the modulation of immune priming by hygiene, gut microbiota diversity, and exposure to endotoxins through farm animals to the effects of pollution, climate, and diet. The discovery of the filaggrin skin barrier gene and its importance in AD development and severity has brought the focus on gene-environment interactions and the identification of environmental factors that impact on skin barrier function. This article reviews our current understanding of the epidemiology of AD, with an emphasis on the findings reported in the international literature over the last 5 years.


Clinical applications of spleen ultrasound elastography - a review.
In the last few years, notable technical progress has taken place in ultrasound elastography. Qualitative methods have been replaced by quantitative ones, such as: transient elastography, acoustic radiation force impulse and shear wave elastography. Owing to the fact that the spleen is superficially located, it is possible to obtain reliable measuring accuracy of its hardness using sonoelastography. Lately, many researchers have been investigating how spleen elasticity changes in patients infected with hepatitis B virus or hepatitis C virus and in patients suffering from liver fibrosis, portal hypertension, esophageal varices or myelofibrosis. In this article, we review the role and current status of accessible qualitative ultrasound elastography methods, including recent advances in the evaluation of spleen stiffness and its clinical utility. As study results demonstrate, spleen stiffness correlates with liver fibrosis and is helpful in determining the level of fibrosis in the METAVIR scoring system. In patients infected with hepatitis B virus or hepatitis C virus, spleen stiffness increases even when liver elasticity remains unaltered. Furthermore, it is useful in diagnosing portal hypertension or predicting existence of esophageal varices. Moreover, in patients suffering from biliary atresia after Kasai portoenterostomy, spleen sonoelastography may be helpful in selecting patients for liver transplantation as well as for choosing the best strategy for portal vein reconstruction before liver transplantation. In myelofibrosis, spleen stiffness correlates with bone marrow fibrosis and may be used to assess the response to treatment. Spleen sonoelastography is also useful in the monitoring of transjugular intrahepatic portosystemic shunt function.


Cellular adaptive response to chronic radiation exposure in interventional cardiologists.
Aims Invasive cardiologists are the most exposed to ionizing radiation among health professionals and show an increased rate of somatic DNA damage. To evaluate the effects of chronic low-dose exposure to ionizing radiation on redox state and apoptotic activation. Methods and results We enrolled 10 healthy exposed professionals (all interventional cardiologists, Group II, exposed: age = 38 ± 5 years) and 10 age- and gender-matched unexposed controls (Group I, non-exposed). Exposed subjects had a median exposure of 4 mSv/year (range 1-8) by film badge dosimetry (below lead apron). We measured reduced glutathione (GSH, a marker of antioxidant response) in erythrocytes and plasma generation of hydrogen peroxide (a marker of oxyradical stress) by ferrous oxidation-xylenol orange assay in plasma. In both groups, lymphocytes were isolated and caspase-3 activity (a marker of apoptotic response) measured at baseline and following 2 Gy in vitro irradiation. Exposed subjects showed a three-fold increase in hydrogen peroxide (Group I = 2.21 ± 1.03 vs. II = 6.51 ± 1.55 μM H(2)O(2) equivalents) and a 1.7-fold increase in GSH (I = 12.37 ± 1.22 vs. II = 20.61 ± 2.16 mM). Exposed subjects also showed higher values of caspase-3 activity, both at baseline and-more strikingly-following high-dose radiation challenge. Conclusion In interventional cardiologists, chronic exposure to low-dose radiation is associated with an altered redox balance mirrored by an increase in hydrogen peroxide and with two possibly adaptive cellular responses: (i) an enhanced antioxidant defence (increase in GSH, counteracting increased oxyradical stress) and (ii) an increased susceptibility to apoptotic induction which might efficiently remove genetically damaged cells.


Health survey of former workers in a Norwegian coke plant: Part. 1. Estimation of historical exposures.
To estimate historical exposure levels at a coke plant for all agents considered to be of importance for epidemiological studies of mortality and cancer incidence. Time weighted average exposure (8 h TWA) was estimated based on personal measurements for polycyclic aromatic hydrocarbons (PAHs) and carbonaceous particulates. Exposure to quartz was estimated relative to the concentration of carbonaceous particulates. These estimates were adjusted for the use of airstream helmets. Exposure to other agents were estimated qualitatively (asbestos, benzene, and arsenic) or semi-quantitatively (carbon monoxide (CO) and heat) based on measurements and other indicators of exposure. Exposure to PAHs was highest for those who worked at the top of the ovens (300 micrograms/m3) in the period from 1970-6. The estimated PAH exposure was reduced to an average of 65 micrograms/m3 after the introduction of exposure control measures in 1976. The estimates for carbonaceous particulates ranged from 1 to 16 mg/m3, with the highest exposure for workers at the top of the ovens and at the coke screening station. The exposure of greatest concern in this study is to PAHs, but exposures to carbonaceous particulates and CO may also be of importance. The major limitations of this study are the lack of personal measurements before 1975 and the total lack of measurements for some of the exposed categories of workers. Despite these limitations, we think that this assessment reflects the actual exposures for most of the former employees. The assessment thus provides a reasonable tool for the subsequent epidemiological study and for future epidemiological follow up studies at the coke plant.


Intrabronchial instillation of paraquat in rats: lung morphology and retention study.
Various amounts of paraquat (10(-5) to 10(-12) g) in 0.1 ml saline were instilled directly into the left bronchus of male adult rats. Gravimetric, macroscopic, and microscopic studies on the left lobe of the lung showed that 10(-5) g of paraquat produced lung oedema and macroscopic lesions two and 14 days after doing. The pathology of the lung was similar to that seen after systemic poisoning. When 10(-6) g of paraquat was instilled, some animals developed lung oedema and macroscopic lesions. Microscopic examination showed subtle changes in the parenchyma of the lung. With amounts of paraquat equal to or less than 10(-7) g (doses as little as 10(-12) g were used), no changes in the lung were seen. This is contrary to published accounts in which amounts as low as 10(-12) g (1 Pg) were reported to cause acute damage to the rabbit lung. When 3H paraquat was instilled into the left lobe (doses of 10(-5) to 10(-10) g were used), the loss of paraquat from the lung was biphasic. The initial half-life was less than one hour. The secondary phase obeyed first-order kinetics, and the half-life was dependent on the dose of paraquat instilled. This half-life was as short as 11 hours when 10(-5) g paraquat was instilled and was 76 hours after the instillation of 10(-10) g paraquat. The decrease in the half-life of the secondary phase with increasing doses of paraquat is possibly associated with the production of oedema or lung cell damage, or both. After the instillation of 10(-8) g 3H paraquat, the initial half-life was less than 15 minutes, and paraquat was detected in the urine and plasma at that time. This suggests that 50% of the instilled paraquat was rapidly absorbed from the lung into the plasma.


Molecular detection of inflammation in cell models using hyperpolarized 13C-pyruvate.
The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.


Enhancing Guideline-Based Prescribing and Personalized Medication Scheduling.
Poor communication of medication administration instructions is a preventable cause of medication nonadherence. The Universal Medication Schedule (UMS) framework improves adherence by providing a simplified set of dose timing rules. However, this framework does not readily generalize to individuals with varying daily routines. We propose a point-of-care solution for enhancing guideline-based electronic prescribing and personalizing dose schedules. We describe a JSON-based approach to encode and execute standard treatment guidelines to support electronic prescribing as well as an algorithm for optimizing medication administration schedules based on a patient's daily routine. We evaluated the structure and accuracy of our JavaScript Object Notation (JSON) formalism focusing on Kenya's hypertension treatment guidelines. Our experiments compare the medication schedules generated by our algorithm with those generated by pharmacists. Our findings show that treatment guidelines can be efficiently represented and executed using the JSON formalism, and that different medication administration schedules can be generated automatically and optimized for patients' daily routines.


Ku affects the ataxia and Rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment.
Camptothecin (CPT) that targets DNA topoisomerase I is one of the most promising broad-spectrum anticancer drugs in development today. The cytotoxicity of CPT is S phase (S)-specific because the collision of advancing replication forks with CPT-topoisomerase I-DNA complexes results in DNA damage. After DNA damage, proliferating cells could actively slow down the DNA replication through an S checkpoint to provide time for repair. We report now that there is an activated S checkpoint response in CPT-treated mammalian cells. This response is regulated by Ataxia and Rad3-related (ATR)/CHK1 pathway. Compared with their wild-type counterparts, CPT-treated Ku80-/- cells showed stronger inhibition of DNA replication. This stronger inhibition had no relationship with DNA-dependent protein kinase (DNA-PK) activity but correlated with the higher activities of ATR and the higher activities of CHK1 in such cells. Not only caffeine, the nonspecific inhibitor of ATR, or UCN-01, the nonspecific inhibitor of CHK1, but also the specific CHK1 antisense oligonucleotide abolished the stronger inhibition of DNA replication in CPT-treated Ku80-/- cells. These results in aggregate indicated that the stronger S checkpoint in CPT-treated Ku80-/- cells is regulated through the highly activated ATR/CHK1 pathway.


Grb2-associated binder-1 is required for extrafusal and intrafusal muscle fiber development.
The neuregulin-1 (NRG1) signaling pathway plays an important role in the development of the peripheral neuromuscular system, including in muscle spindle and postnatal myelination. We previously showed that NRG1 on the axonal membrane regulates peripheral nerve myelination through Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling. Here, we determined the role of Gab1 in the development of muscles and the muscle spindle using muscle-specific conditional Gab1 knockout mice. The mutant mice showed general retardation in muscular growth and hypotrophy of extrafusal muscle fibers. In addition, the muscle-specific Gab1 knockout mutant exhibited significant underdevelopment of muscle spindles, which are normally regulated by NRG1, and abnormal proprioceptive behavior. Furthermore, the selective knockdown of Gab1 in C2C12 muscle cells reduced NRG1-induced expression of Egr3, a critical transcription factor for muscle spindle development. However, Gab2 knockout mice did not show any defects in the development of muscles or muscle spindles. Our findings suggest that Gab1 is an essential signaling molecule in mediating axonal NRG1 signaling for the development of both extrafusal and intrafusal muscle fibers.


Ionic Liquid Gating of Suspended MoS2 Field Effect Transistor Devices.
We demonstrate ionic liquid (IL) gating of suspended few-layer MoS2 transistors, where ions can accumulate on both exposed surfaces. Upon application of IL, all free-standing samples consistently display more significant improvement in conductance than substrate-supported devices. The measured IL gate coupling efficiency is up to 4.6 × 10(13) cm(-2) V(-1). Electrical transport data reveal contact-dominated electrical transport properties and the Schottky emission as the underlying mechanism. By modulating IL gate voltage, the suspended MoS2 devices display metal-insulator transition. Our results demonstrate that more efficient charge induction can be achieved in suspended two-dimensional (2D) materials, which with further optimization, may enable extremely high charge density and novel phase transition.


Controlled expression of cholera toxin B subunit from Vibrio cholerae in Escherichia coli.
The ctxB gene, the causative agent of cholera epidemic was successfully cloned from V. cholerae in E. coli. The insertion of the gene was confirmed by PCR as well as restriction digestion analyses. The sequencing results for the gene confirmed that the insert was in the correct orientation and in-frame with the P(BAD) promoter and it showed that the gene was 99% homologous to the published ctxB sequence. The CTB protein was successfully expressed in E. coli using the pBAD/His vector system. The expected protein of approximately 14 kDa was detected by SDS-PAGE and Western blot. The use of pBAD/His vector to express the cholera toxin gene in E. coli would facilitate future study of toxin gene products.


Physical exercise attenuates the cardiac autonomic deficit induced by nitric oxide synthesis blockade.
The nitric oxide (NO) synthesis blockade is characterized by an increase in the cardiac sympathetic activity and the physical training promotes the decrease in the sympathetic activity. We investigated the effect of the NO synthesis blockade on the autonomic cardiovascular control in rats submitted to aerobic exercises during a 10-week period. Male Wistar rats were divided in four groups: control rats, treated with chow food and water ad libitum for 10 weeks (CR); control rats, treated with N G-nitro-L-arginine methyl ester (L-NAME) during the last week (CRL); rats trained during 10 weeks on an electrical treadmill (TR); rats trained for 10 weeks and treated with L-NAME during the last week (TRL). The autonomic cardiovascular control was investigated in all groups with the use of a double blockade with methylatropine and propranolol and analysis of variability. The CRL and TRL groups presented hypertension. The CRL group presented tachycardia and predominance of the sympathetic tonus in heat rate (HR) measurement after the pharmacological autonomic blockade. The TR group presented bradycardia and lower intrinsic HR when compared to the others. The evaluation of the HR variability showed lower absolute and normalized values in the low frequency (LF) band in the CRL group. On the other hand, the TRL presented an increase in the LF band in absolute values. The analysis of variability of the systemic arterial pressure (SAP) showed that the CRL and TRL groups presented higher values in the LF band. The previous physical exercise prevented the deficit in the autonomic cardiac control induced by the treatment with L-NAME, but did not prevent the increase in the SAP variability.


The role of laboratory medicine in psychiatry.
The application of contemporary biological methods in psychiatric practice has encouraged the reintegration of psychiatry into medicine. These investigative techniques assist in the elucidation of factors of aetiological importance, confirmation of diagnosis, regulation of dosage of medication, prediction of response to treatment and assessment of prognostic factors. It is emphasized that there is an urgent need to improve upon available laboratory facilities in mental health institutions in Africa and other third world countries, and also to encourage research in biological psychiatry. This will allow for cross-cultural comparison (between developed and developing countries) on the issue of aetiology, clinical manifestation/nosology, management and prognosis of mental disorders.


Single-clad Tm-Ho:fiber amplifier for high-power sub-100-fs pulses around 1.9 μm.
A Tm-Ho:fiber amplifier based on single-clad geometry is demonstrated for the generation of high-power femtosecond pulses around 1.9 μm. The amplifier is seeded by the low-power Raman soliton generated by an Er:fiber femtosecond laser. Pulse trains at a repetition rate of 250 MHz tunable from 1.84 to 1.92 μm with corresponding powers from 2.6 to 3 W and durations from 80 to 105 fs have been obtained. Beating with a single-frequency Tm laser has shown that the pulse coherence is highly preserved. The overall power fluctuations have been measured to be as low as 0.6%.


Population-based organized cervical cancer screening pilot program in France.
In France, cervical cancer screening is recommended every 3 years for women aged 25-65 years. With the exception of a few local organized programs, screening is mainly opportunistic. In view of setting up a nationwide population-based organized screening program, a pilot intervention was implemented in nine geographic areas using a common protocol. Women aged 25-65 years who had not undergone a cytological screening in the past 3 years were invited for screening during 2010-2012 and reminded up to 1 year after the initial invitation. Cytological results and follow-up data were collected up to the end of 2014 for all women screened irrespective of whether spontaneously or following invitation. Aggregate data were centralized nationally. Among the 2.4 million women from the total target population aged 25-65 years, 1.3 million were invited for screening. The overall screening coverage during 2010-2012 was 62.3%, with wide variations across geographic areas, ranging from 41.6 to 72.5%. Initial invitations and reminders enabled nearly 280 000 women to be screened, corresponding to an estimated increase in coverage of 12% points. Overall, 4.2% of the women screened had an abnormal smear. A total of 5180 high-grade cervical precancers and 323 invasive cervical cancers were reported, corresponding to detection rates of, respectively, 623 and 39 per 100 000 women screened 3-yearly. This study indicates that such organized screening may markedly improve the uptake of cervical cancer screening. On the basis of this pilot program, nationwide organized cervical cancer screening is currently being rolled out in France.


Formation and physical properties of the self-assembled BFO-CFO vertically aligned nanocomposite on a CFO-buffered two-dimensional flexible mica substrate.
Engineering the interfaces between materials of different structures and bonding nature in a well-controlled fashion has been playing a key role in developing new devices with unprecedented functionalities. In particular, direct growth of nanostructures on van der Waals substrates not only is essential for fully exploiting the potential of a wide variety of self-assembled nano-sized heterostructures but also can expand the horizons for electronic and photonic applications that involve nanostructures of specific composition and geometry. In the present work, we demonstrate the epitaxial growth of a self-assembled vertically aligned nanocomposite of magnetoelectric oxides on a flexible substrate via van der Waals epitaxy, which evidently adds an additional dimension of flexibility to similar thin-film heteroepitaxy architectures that have been mostly realized on rigid lattice-matched substrates. It is noted that the utilization of buffer layers is essential for obtaining high-quality flexible thin films with vertically aligned nanocomposite architecture. We believe that this route can provide alternative options for developing flexible thin-film devices with heteroepitaxy architectures of other functional materials.


The Stapes Head Coupler-A Flexible and Safe Option for Vibroplasty.
To investigate the surgical approach and the audiological outcome of a stapes head coupler in active middle ear implant surgery. Retrospective data analysis. Tertiary referral center with a large active middle ear implant program. Twelve patients with active middle ear implant surgery. Therapeutic surgical approach for hearing rehabilitation in human subjects. Auditory brainstem response, sound field thresholds, vibrogram, speech perception in the Freiburger monosyllabic word test. The stapes head was attached safely in different coupling situations. Audiological outcomes were similar to the audiological performance of established vibroplasty couplers presented in the literature. The stapes head coupler is a new and safe tool for vibroplasty with a good audiological outcome.


The similarities between Pseudomonas paucimobilis and allied bacteria derived from analysis of deoxyribonucleic acids and electrophoretic protein patterns.
The chromosomal DNA was isolated and purified from 17 strains of Pseudomonas paucimobilis, and from the type or reference strains of Flavobacterium capsulatum, F. devorans, F. multivorum, 'Chromobacterium lividum', Xanthomonas campestris and seven species of Pseudomonas. The DNA base compositions (mol% G + C) of P. paucimobilis strains were between 62.2 and 68.6%, and typical strains had a mean value of 65.3 +/- 0.4 mol%, determined from thermal denaturation temperature. DNA-DNA molecular hybridization with 3H-labelled probe DNA from NCTC 11030 P. paucimobilis (the type strain) indicated that the species comprised a core of 13 closely related strains (74 to 96%), which included F. devorans NCIB 8195 (= ATCC 10829). Four P. paucimobilis strains displayed lower levels of hybridization (less than or equal to 38%). The hybridization results showed that P. paucimobilis was not closely related to allied yellow-pigmented bacteria or to other reference pseudomonads. The electrophoretic protein patterns of representative strains were analysed by computer-assisted techniques and similarity coefficients were calculated. A high degree of congruence was obtained with the DNA hybridization data, and the protein analyses indicated that the four atypical P. paucimobilis strains were heterogeneous and not a single group within the species. The generic affinities of P. paucimobilis, F. capsulatum, 'P. azotocolligans' and P. echinoides are uncertain, but available chemotaxonomic data indicate these species could provide the basis for a new genus.


Systemic expression of a bacterial gene by a tobacco mosaic virus-based vector.
Tobacco mosaic virus (TMV) produces large quantities of RNA and protein on infection of plant cells. This and other features, attributable to its autonomous replication, make TMV an attractive candidate for expression of foreign sequences in plants. However, previous attempts to construct expression vectors based on plant RNA viruses, such as TMV, have been unsuccessful in obtaining systemic and stable movement of foreign genes to uninoculated leaves in whole plants. A hybrid viral RNA (TB2) was constructed, containing sequences from two tobamoviruses (TMV-U1 and odontoglossum ringspot virus). Two bacterial sequences inserted independently into TB2 moved systemically in Nicotiana benthamiana, although they differed in their stability on serial passage. Systemic expression of the bacterial protein neomycin phosphotransferase was demonstrated. Hybrid RNAs containing both TMV-U1 and the inserted bacterial gene sequences were encapsidated by the odontoglossum ringspot virus coat protein, facilitating their transmission and amplification on passaging to subsequent plants. The vector TB2 provides a rapid means of expressing genes and gene variants in plants.


MicroRNAs as a Tool for Differential Diagnosis of Neuromuscular Disorders.
Neuromuscular disorders (NMD) are a class of progressive disorders that are characterized by wasting of the muscles. Some of the disorders like Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophies (LGMD), and mild spinal muscular atrophy (SMA) type III share several presenting clinical features, and hence, diagnosis is usually a challenging task. In this study, the diagnostic potential of some species of microRNAs (miRNAs) that are known to play roles in normal and pathological contexts of myocytes (myomiRs) were evaluated to assess their potential in differential diagnosis of NMDs. In this study, seventy-four patients with different neuromuscular disorders along with thirty age-matched healthy control subjects were enrolled. Peripheral blood samples were collected from enrolled subjects followed by miRNA extraction and reverse transcription followed by quantification of the circulating levels of the studied miRNAs (miR-499, miR-206, miR-208a, miR-223, miR-191, miR-103a-3p, miR-103a-5p), by real-time PCR and statistical analysis. The data indicated that miR-499 level showed high circulating levels in DMD patients as well as in patients with other related disorders such as BMD. However, the levels of miR-499 were much higher in DMD patients and it can be used to diagnose DMD. In addition, miR-206 can selectively differentiate between DMD and all other disorders. The results also revealed that miR-208a and miR-223 were significantly dysregulated in SMA patients, and miR-103a-3p could distinguish DMD from BMD. The expression levels of some miRNA species can be utilized in the process of differential diagnosis of NMDs and can serve as a diagnostic biomarker, and such findings will pave the way towards generating targeted therapies.


Mesenteric lymph flow in adult and aged rats.
The objective of study was to evaluate the aging-associated changes, contractile characteristics of mesenteric lymphatic vessels (MLV), and lymph flow in vivo in male 9- and 24-mo-old Fischer-344 rats. Lymphatic diameter, contraction amplitude, contraction frequency, and fractional pump flow, lymph flow velocity, wall shear stress, and minute active wall shear stress load were determined in MLV in vivo before and after N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) application at 100 μM. The active pumping of the aged rat MLV in vivo was found to be severely depleted, predominantly through the aging-associated decrease in lymphatic contractile frequency. Such changes correlate with enlargement of aged MLV, which experienced much lower minute active shear stress load than adult vessels. At the same time, pumping in aged MLV in vivo may be rapidly increased back to levels of adult vessels predominantly through the increase in contraction frequency induced by nitric oxide (NO) elimination. Findings support the idea that in aged tissues surrounding the aged MLV, the additional source of some yet unlinked lymphatic contraction-stimulatory metabolites is counterbalanced or blocked by NO release. The comparative analysis of the control data obtained from experiments with both adult and aged MLV in vivo and from isolated vessel-based studies clearly demonstrated that ex vivo isolated lymphatic vessels exhibit identical contractile characteristics to lymphatic vessels in vivo.


Improving neuromuscular performance in young basketball players: plyometric vs. technique training.
The aim of this study was to compare the effects of plyometric training versus basketball technique training on improving neuro-muscular performance. Thirty-six (age 14.9±0.9 years, body height 164.0±7.6 cm, body weight 54.0±8.7 kg, BMI 20.1±2.4 kg·m-2) basketball players girls were randomly allocated to 2 groups: Basketball Plyometric Training (BPT, N.=18) and Basketball Technique Training (BTT, N.=18). The players were tested by two specific tests: counter movement jump (CMJ) and squat jump (SJ) before and after 6 training weeks. The jump height, as dependent variable, showed a different trend as an effect of the different training protocols, in contrast with the current knowledge. Manova did not show significant interactions between the two groups for the height of jumps, while significant differences were found for interaction time × training (P<0.05) and for main effect × time (P<0.001). After training, the BPT group increased significantly CMJ performance by 11.3% (P<0.05), whereas the BTT group increased by 4.6%. Likewise, the BPT group demonstrated a significant greater improvement of jump height than BTT group (an increase of 15.4% vs. 7.5%, P<0.01; respectively). These results suggest that both training protocols proposed in this study improved vertical jump performance. However, a combination of the two protocols, plyometric training and sport-specific-exercises, could be useful to optimize performance by an easy transition from controlled a-specific to sport-specific performance requirements. In conclusion, BPT is a safe and effective method of achieving a favourable neuro-muscular performance than BTT in female basketball players.


Direct Determination rather than Oscillometric Estimation of Systolic Blood Pressure in Patients with Severe Chronic Kidney Disease.
Although arterial hypertension is a major concern in patients with chronic kidney disease (CKD), obtaining accurate systolic blood pressure (SBP) measurement is challenging in this population for whom automatic oscillometric devices may yield erroneous results. This cross-sectional study was conducted in 89 patients with stages 4, 5, and 5D CKD, for whom we compared SBP values obtained by the recently described systolic foot-to-apex time interval (SFATI) technique which provides direct SBP determination, the standard technique (Korotkoff sounds), and oscillometry. We investigated the effects of age, sex, diabetes, CKD stage, and pulse pressure to explain measurement errors defined as biases or misclassification relative to the SBP thresholds of 110-130-mm Hg. All 3 techniques showed satisfactory reproducibility for SBP measurement (CCC > 0.84 and >0.91, respectively, in dialyzed and nondialyzed patients). The mean ± SD from SBP as determined via Korotkoff sounds was 1.7 ± 4.6 mm Hg for SFATI (CCC = 0.98) and 5.9 ± 9.3 mm Hg for oscillometry (CCC = 0.88). Referring to the 110-130-mm Hg SBP range outside which treatment prescription or adaptation is recommended for CKD patients, SFATI underestimated SBP in 3 patients and overestimated it in 1, whereas oscillometry underestimated SBP in 12 patients and overestimated it in 3. Higher pulse pressure was the main explanatory factor for measurement and classification errors. SFATI provides accurate SBP measurements in patients with severe CKD and paves the way for the standardization of automated noninvasive blood pressure measurement devices. Before prescribing or adjusting antihypertensive therapy, physicians should be aware of the risk of misclassification when using oscillometry.


Efficient reduction of CO2 to CO with high current density using in situ or ex situ prepared Bi-based materials.
The development of inexpensive electrocatalysts that can promote the reduction of CO2 to CO with high selectivity, efficiency, and large current densities is an important step on the path to renewable production of liquid carbon-based fuels. While precious metals such as gold and silver have historically been the most active cathode materials for CO2 reduction, the price of these materials precludes their use on the scale required for fuel production. Bismuth, by comparison, is an affordable and environmentally benign metal that shows promise for CO2 conversion applications. In this work, we show that a bismuth-carbon monoxide evolving catalyst (Bi-CMEC) can be formed under either aqueous or nonaqueous conditions using versatile electrodeposition methods. In situ formation of this thin-film catalyst on an inexpensive carbon electrode using an organic soluble Bi(3+) precursor streamlines preparation of this material and generates a robust catalyst for CO2 reduction. In the presence of appropriate imidazolium based ionic liquid promoters, the Bi-CMEC platform can selectively catalyze conversion of CO2 to CO without the need for a costly supporting electrolyte. This inexpensive system can catalyze evolution of CO with current densities as high as jCO = 25-30 mA/cm(2) and attendant energy efficiencies of ΦCO ≈ 80% for the cathodic half reaction. These metrics highlight the efficiency of Bi-CMEC, since only noble metals have been previously shown to promote this fuel forming half reaction with such high energy efficiency. Moreover, the rate of CO production by Bi-CMEC ranges from approximately 0.1-0.5 mmol·cm(-2)·h(-1) at an applied overpotential of η ≈ 250 mV for a cathode with surface area equal to 1.0 cm(2). This CO evolution activity is much higher than that afforded by other non-noble metal cathode materials and distinguishes Bi-CMEC as a superior and inexpensive platform for electrochemical conversion of CO2 to fuel.


Activationless electron transfer through the hydrophobic core of cytochrome c oxidase.
Electron transfer (ET) within proteins occurs by means of chains of redox intermediates that favor directional and efficient electron delivery to an acceptor. Individual ET steps are energetically characterized by the electronic coupling V, driving force DeltaG, and reorganization energy lambda. lambda reflects the nuclear rearrangement of the redox partners and their environment associated with the reactions; lambda approximately 700-1,100 meV (1 eV = 1.602 x 10(-19) J) has been considered as a typical value for intraprotein ET. In nonphotosynthetic systems, functional ET is difficult to assess directly. However, using femtosecond flash photolysis of the CO-poised membrane protein cytochrome c oxidase, the intrinsic rate constant of the low-DeltaG electron injection from heme a into the heme a(3)-Cu(B) active site was recently established at (1.4 ns)(-1). Here, we determine the temperature dependence of both the rate constant and DeltaG of this reaction and establish that this reaction is activationless. Using a quantum mechanical form of nonadiabatic ET theory and common assumptions for the coupled vibrational modes, we deduce that lambda is <200 meV. It is demonstrated that the previously accepted value of 760 meV actually originates from the temperature dependence of Cu(B)-CO bond breaking. We discuss that low-DeltaG, low-lambda reactions are common for efficiently channeling electrons through chains that are buried inside membrane proteins.


Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis.
The folate antagonist methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA), but its mechanism of action with regard to the impact on folate metabolism remains elusive. The aim of the present study was to investigate the cellular pharmacologic impact of MTX on peripheral blood cells, by comparing MTX-treated RA patients to MTX-naive RA patients and healthy controls. Gene expression microarray data were used to investigate the expression of 17 folate pathway genes by peripheral blood cells from a cohort of 25 RA patients treated with MTX, 10 MTX-naive RA patients starting treatment with MTX, and 15 healthy controls (test cohort). Multiplex real-time polymerase chain reaction was used to validate the results in an independent cohort, consisting of 151 RA patients treated with MTX, 28 MTX-naive RA patients starting treatment with MTX, and 24 healthy controls (validation cohort). Multiple folate metabolism-related genes were consistently and significantly altered between the 3 groups in both cohorts. Concurrent with evidence of an immune-activation gene signature in MTX-naive RA patients, significant up-regulation of the folate-metabolizing enzymes γ-glutamyl hydrolase and dihydrofolate reductase, as well as the MTX/folate efflux transporters ABCC2 and ABCC5, was observed in the MTX-naive RA group compared to healthy controls. Strikingly, MTX treatment of RA patients normalized these differential gene expression levels to the levels observed in healthy controls. These results suggest that under inflammatory conditions, basal folate metabolism in the peripheral blood cells of RA patients is markedly up-regulated, and treatment with MTX restores folate metabolism to normal levels. Identification of this novel gene signature provides insight into the mechanism of action of MTX, thus paving the way for development of novel folate metabolism-targeted therapies.


Identifying monkeypox: do dental professionals have adequate knowledge and awareness?
The emergence of monkeypox has presented a new challenge for health agencies around the globe. There is significant increase in the number of cases that too in non-endemic countries with more than 18000 cases reported worldwide. The present study was conducted to assess knowledge and awareness regarding monkeypox among dental professionals. The present cross-sectional study among 410 subjects who were residing in a northern state of the country. Informed consent was obtained from all the subjects. Study sample was selected on the basis of Systematic random sampling methodology. A self-designed close-ended questionnaire written in English and verified by experts was utilized for the study. The questionnaire was delivered personally to study subjects to collect the required information. Chi-square test and ANOVA were used for statistical analysis. One-fourth (24.8%) of the subjects never heard about monkeypox disease. Negative response was given by 44.8% of subjects regarding resemblance of monkeypox with small pox. Only 31.2% of subjects had knowledge regarding oral manifestations of the disease. High knowledge scores were reported by only 28% of subjects. Higher knowledge levels were significantly related to education level and working profile of study subjects. Online media (Internet) was preferred as the main source to obtain more information by 42.2 of subjects. There was low level of knowledge regarding monkeypox among study subjects. There is an urgent need for dental professionals to keep themselves updated with recent knowledge on new emerging infectious diseases.


Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort.
Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7-9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDD's carcinogenic potency based on such data.


Future Challenges for Physical Therapy during and after the COVID-19 Pandemic: A Qualitative Study on the Experience of Physical Therapists in Spain.
This qualitative exploratory study addressed the perspectives of Spanish physical therapists (PTs) regarding (a) the organization of their work during the first wave of the pandemic; (b) their role within the intensive care units (ICUs); (c) management of COVID-19 survivors; (d) potential future challenges identified for the physical therapy profession. Thirty PTs who had worked at a National Public Hospital in Madrid during the first COVID-19 outbreak were recruited by purposeful sampling and snowball techniques. In-depth interviews and researcher field notes were used to collect data. Interviews were transcribed verbatim. An inductive thematic analysis was used to identify emerging themes. After identifying 1110 codes, four themes emerged. Throughout the first wave of the pandemic, the role and work of PTs in hospitals experienced a change. These changes took place at their organizational level, affecting the distribution of PTs in the hospital, and the role of PTs in front-line COVID units such as ICUs, as well as direct management of outpatients at the onset of the pandemic, and after discharge from the ICUs. This situation has led to PTs foreseeing challenges and developing new expectations concerning their role and the physical therapy profession in the future.


A humanized leucine zipper-TRAIL hybrid induces apoptosis of tumors both in vitro and in vivo.
Evidence suggests that stimulating apoptosis in malignant cells without inflicting collateral damage to the host's normal tissues is a promising cancer therapy. Chemo- and radiation therapies that, especially if combined, induce apoptosis in tumor cells have been used for treating cancer patients for decades. These treatments, however, are limited in their ability to discriminate between malignant and non-malignant cells and, therefore, produce substantial healthy tissue damage and subsequent toxic side-effects. In addition, as a result of these therapies, many tumor types acquire an apoptosis-resistant phenotype and become more aggressive and metastatic. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) has been considered a promising and reliable selective inducer of apoptosis in cancerous cells. TRAIL, however, is not uniformly effective in cancer and multiple cancer cell types are considered resistant to natural TRAIL. To overcome this deficiency of TRAIL, we have earlier constructed a yeast-human hybrid leucine zipper-TRAIL in which the yeast GCN4-pII leucine zipper was fused to human TRAIL (GCN4-TRAIL). This construct exhibited a significantly improved anti-tumor apoptotic activity and safety, but is potentially immunogenic in humans. Here, we report a novel, potent, and fully human ATF7 leucine zipper-TRAIL (ATF7-TRAIL) fusion construct that is expected to have substantially lower immunogenicity. In solution, ATF7-TRAIL exists solely as a trimer with a Tm of 80°C and is active against cancer cells both in vitro and in vivo, in a mouse tumor xenograft model. Our data suggest that our re-engineered TRAIL is a promising candidate for further evaluation as an antitumor agent.


A gap analysis of SDG 3 and MDG 4/5mortality health targets in the six Arabic countries of North Africa: Egypt, Libya, Tunisia, Algeria, Morocco, and Mauritania.
The United Nations Assembly adopted the Sustainable Development Goals to succeed the Millennium Development Goals in September 2015. From a European perspective, the development of health in the countries of North Africa are of special interest as a critical factor of overall social development in Europe's Mediterranean partners. In this paper, we address the mortality related SDG-3 targets, the likelihood to achieve them until 2030 and analyze how they are defined. We projected mortality trends from 2000-2015 to 2030, based on mortality estimates by inter-agency groups and the WHO in mother and child health, non-communicable diseases, and road traffic mortality. The gap analysis compares the time remaining until 2030 to the time needed to complete the target assuming a linear trend of the respective indicator. A delay of not more than 3.75 years is considered likely to achieve the target. The SDG-3 targets of a Maternal Mortality Ratio below 70 per 100 000 live births and an U5MR below 25 per 1 000 live births have been achieved by Egypt, Libya, and Tunisia. Libya and Tunisia have also achieved the target for Newborn Mortality with Egypt close to achieving it as well. Algeria and Morocco are generally on track for most of the indicators, including deaths from non-communicable diseases and suicide rates; however, all of the countries are lagging when it comes to deadly Road Traffic Injuries for 2030. Mauritania is the only North African country which is not likely to reach the 2030 targets for any of the mortality indicators. Although mortality statistics may be incomplete there is an impressive gradient from East to West showing Mauritania and deadly road traffic injuries as the most problematic areas. Given the large differences between countries baselines, we consider it preferable to set realistic targets to be achieved until 2030.


Konjac ceramide (kCer) regulates keratinocyte migration by Sema3A-like repulsion mechanism.
Previously, we proposed the following mechanism for konjac ceramide (kCer)-mediated neurite outgrowth inhibition: kCer binds to Nrp as a Sema3A agonist, resulting in Nrp1/PlexA complex formation and activation of the Sema3A signaling pathway to induce phosphorylation of CRMP2 and microtubule depolymerization. The Sema3A/Nrp1 signaling pathway is known to be also expressed in normal human keratinocytes. To determine whether kCer can function in human keratinocytes as it does in neurites, that is, if it can bind to Nrp1 in place of Sema3A, we studied the effect of kCer on HaCaT cell migration activity. Using a trans-well chamber assay, we compared the effects of Sema3A and kCer on serum-derived cell migration activity. kCer showed Sema3A-like suppression of cell migration activity and induction of cellular Cofilin phosphorylation. In addition, kCer and Sema3A inhibited histamine (His)-enhanced migration of immature HaCaT cells. We have demonstrated that kCer does not interact with histaime receptors H1R or H4R directly, but we speculate that kCer may transduce a signal downstream of the His signaling pathway.


Mitochondrial plasticity with exercise training and extreme environments.
Mitochondria form a reticulum in skeletal muscle. Exercise training stimulates mitochondrial biogenesis, yet an emerging hypothesis is that training also induces qualitative regulatory changes. Substrate oxidation, oxygen affinity, and biochemical coupling efficiency may be regulated differentially with training and exposure to extreme environments. Threshold training doses inducing mitochondrial upregulation remain to be elucidated considering fitness level.


Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release.
Activation of metabotropic glutamate receptors (mGluRs) has diverse effects on the functioning of vertebrate synapses. The cellular mechanisms that underlie these changes, however, are largely unknown. The role of presynaptic mGluRs in modulating Ca(2+) dynamics and regulating neurotransmitter release was investigated at the vestibulospinal-reticulospinal (VS-RS) synapse in the lamprey brain stem. Application of the specific Group I mGluRs antagonist 7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) reduced the amplitude of consecutive high-frequency evoked excitatory postsynaptic currents (EPSCs). A series of experiments using techniques of electrophysiology and calcium imaging were carried out to determine the cellular mechanisms by which this phenomenon occurs. Concentration-dependent increases in the pre- and postsynaptic [Ca(2+)](i) were seen with the application of mGluR agonists. Similarly, high-frequency stimulation of axons caused a Group I mGluR-dependent enhancement in presynaptic Ca(2+) transients. Application of mGluR agonist caused a depolarization of the presynaptic elements, while thapsigargin decreased the high-frequency stimulus- and agonist-induced rises in [Ca(2+)](i). These data suggest that both membrane depolarization and the release of Ca(2+) from intracellular stores potentially play a role in mGluR-induced Ca(2+) signaling. To determine the effect of this modulation of Ca(2+) dynamics on spontaneous glutamate release, miniature EPSCs were recorded from postsynaptic reticulospinal neurons. A potent Group I mGluR agonist, (S)-homoquisqualic acid, caused a large increase in the frequency of events. These results demonstrate the presence of presynaptic Group I mGluRs at the VS-RS synapse. Activation of these receptors leads to a rise in [Ca(2+)](i) and enhances the spontaneous and evoked release of glutamate. Taken together, these studies highlight the importance of synaptic activation of these facilitatory autoreceptors in both short-term plasticity and synaptic transmission.


A multidrug-resistant Stenotrophomonas maltophilia clinical isolate from Kamuzu Central Hospital, Malawi.
Stenotrophomonas maltophilia is a significant opportunistic pathogen that is associated with high mortality in immunocompromised individuals. In this study, we describe a multidrug-resistant (MDR) S. maltophilia clinical isolate from Kamuzu Central Hospital (KCH), Lilongwe, Malawi. A ceftriaxone and meropenem nonsusceptible isolate (Sm-MW08), recovered in December 2017 at KCH, was referred to the National Microbiology Reference Laboratory for identification. In April 2018, we identified the isolate using MALDI Biotyper mass spectrometry and determined its antimicrobial susceptibility profile using microdilution methods. Sm-MW08 was analysed by S1-PFGE, PCR, and Sanger sequencing, in order to ascertain the genotypes that were responsible for the isolate's multidrug-resistance (MDR) phenotype. Sm-MW08 was identified as S. maltophilia and exhibited resistance to a range of antibiotics, including all β-lactams, aminoglycosides (except arbekacin), chloramphenicol, minocycline, fosfomycin and fluoroquinolones, but remained susceptible to colistin and trimethoprim-sulfamethoxazole. The isolate did not harbour any plasmid but did carry chromosomally-encoded blaL1 metallo-β-lactamase and blaL2 β-lactamase genes; this was consistent with the isolate's resistance profile. No other resistance determinants were detected, suggesting that the MDR phenotype exhibited by Sm-MW08 was innate. Herein, we have described an MDR S. maltophilia from KCH in Malawi, that was resistant to almost all locally available antibiotics. We therefore recommend the practice of effective infection prevention measures to curtail spread of this organism.


Comparison Between a Combined Transrectal and Transperineal Approach and a Transrectal Approach for Prostate Rebiopsy.
To evaluate whether a combination method involving the transrectal (TR) and transperineal (TP) approach can increase the cancer detection rate relative to the TR approach regarding repeat prostate biopsy. One thousand and nineteen patients underwent initial prostate biopsies and 298 repeat prostate biopsies. All initial biopsies were conducted transrectally. Of the repeat biopsies, 179 (60.1%) were performed using the combined transrectal and transperineal (TR+TP) approach; 113 (37.9%) were carried out transrectally. All biopsies were performed under ultrasound guidance using a 16-gauge core biopsy needle; 651 were diagnosed as prostate cancer; 224 patients underwent radical prostatectomies (RPs). We evaluated the cancer detection rates between the biopsy methods in the repeat biopsy cohort and compared the clinical and pathological features of the RP specimens between the initial and repeat biopsy groups. A median of 12 and 20 cores were obtained in the initial and repeat biopsy patients, respectively. Cancer detection rates regarding biopsies 1, 2, 3, 4 and 5 were 49.2% (551/1,119), 34.7% (75/216), 33.3% (20/60), 26.7% (4/15) and 14.3% (1/7), respectively. There were no significant differences between the TR and the TR+TP approach (32.7% vs. 33.5%). RP specimens diagnosed using repeat biopsies showed more anterior dominant tumors relative to those diagnosed using the initial biopsies (59.5% vs. 35.9%; p<0.001). The TR+TP combination approach could not increase cancer detection rates relative to the TR approach in the repeat biopsy cohort. However, 16-gauge needle biopsy demonstrated acceptable cancer detection rates in the comparatively small number of biopsy cores.


Knee angle-dependent oxygen consumption during isometric contractions of the knee extensors determined with near-infrared spectroscopy.
Fatigue resistance of knee extensor muscles is higher during voluntary isometric contractions at short compared with longer muscle lengths. In the present study we hypothesized that this would be due to lower energy consumption at short muscle lengths. Ten healthy male subjects performed isometric contractions with the knee extensor muscles at a 30, 60, and 90 degrees knee angle (full extension = 0 degrees ). At each angle, muscle oxygen consumption (m.VO2) of the rectus femoris, vastus lateralis, and vastus medialis muscle was obtained with near-infrared spectroscopy. m.VO2 was measured during maximal isometric contractions and during contractions at 10, 30, and 50% of maximal torque capacity. During all contractions, blood flow to the muscle was occluded with a pressure cuff (450 mmHg). m.VO2 significantly (P < 0.05) increased with torque and at all torque levels, and for each of the three muscles. m.VO2 was significantly lower at 30 degrees compared with 60 degrees and 90 degrees and m.VO2 was similar (P > 0.05) at 60 degrees and 90 degrees . Across all torque levels, average (+/- SD) m.VO2 at the 30 degrees angle for vastus medialis, rectus femoris, and vastus lateralis, respectively, was 70.0 +/- 10.4, 72.2 +/- 12.7, and 75.9 +/- 8.0% of the average m.VO2 obtained for each torque at 60 and 90 degrees . In conclusion, oxygen consumption of the knee extensors was significantly lower during isometric contractions at the 30 degrees than at the 60 degrees and 90 degrees knee angle, which probably contributes to the previously reported longer duration of sustained isometric contractions at relatively short muscle lengths.


Myocarditis Associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Case Report and Review of the Literature.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) is a clinical syndrome that can be life-threatening, depending on the organs involved. Although DRESS commonly presents with skin lesions, myocarditis and pericarditis associated with DRESS, although rare, can be fatal. A case of DRESS associated with myocarditis is presented with a review of the literature of 43 reported cases of DRESS associated with myocarditis that included the present case, to evaluate the effectiveness of treatment of DRESS with corticosteroids. CASE REPORT A 33-year-old man presented with fever, diarrhea, and a diffuse maculopapular rash, four weeks after being treated with antibiotics and a nonsteroidal anti-inflammatory drug (NSAID). He developed renal failure, liver dysfunction, and profound hypotension with severe left ventricular dysfunction that required mechanical cardiac support. A diagnosis was made of myocarditis associated with DRESS syndrome. After treatment began with prednisolone, the skin rash, multi-organ dysfunction, and cardiogenic dysfunction resolved. CONCLUSIONS Myocarditis is a rare complication associated with DRESS, but when it is suspected, urgent echocardiography should be performed, particularly when hemodynamic instability occurs. Early diagnosis, removal of the causative agent, and treatment with corticosteroids are important to reduce mortality from cardiac involvement in patients with DRESS.


SOS3 function in plant salt tolerance requires N-myristoylation and calcium binding.
The salt tolerance gene SOS3 (for salt overly sensitive3) of Arabidopsis is predicted to encode a calcium binding protein with an N-myristoylation signature sequence. Here, we examine the myristoylation and calcium binding properties of SOS3 and their functional significance in plant tolerance to salt. Treatment of young Arabidopsis seedlings with the myristoylation inhibitor 2-hydroxymyristic acid caused the swelling of root tips, mimicking the phenotype of the salt-hypersensitive mutant sos3-1. In vitro translation assays with reticulocyte showed that the SOS3 protein was myristoylated. Targeted mutagenesis of the N-terminal glycine-2 to alanine prevented the myristoylation of SOS3. The functional significance of SOS3 myristoylation was examined by expressing the wild-type myristoylated SOS3 and the mutated nonmyristoylated SOS3 in the sos3-1 mutant. Expression of the myristoylated but not the nonmyristoylated SOS3 complemented the salt-hypersensitive phenotype of sos3-1 plants. No significant difference in membrane association was observed between the myristoylated and nonmyristoylated SOS3. Gel mobility shift and (45)Ca(2)+ overlay assays demonstrated that SOS3 is a unique calcium binding protein and that the sos3-1 mutation substantially reduced the capacity of SOS3 to bind calcium. The resulting mutant SOS3 protein was not able to interact with the SOS2 protein kinase and was less capable of activating it. Together, these results strongly suggest that both N-myristoylation and calcium binding are required for SOS3 function in plant salt tolerance.