Progesterone 6-hydroxylation is catalysed by cytochrome P-450 in the moderate thermophile Bacillus thermoglucosidasius strain 12060.
The moderate thermophile, Bacillus thermoglucosidasius, transforms progesterone into four metabolites. These are 6alpha- and 6beta-hydroxyprogesterone, androstenedione and testosterone. This is the first report of bacterial 6alpha-hydroxylation of steroids. The identity of the progesterone metabolites shows that there are three major types of transforming activity in this organism; C-17-C-20 lyase that cleaves the pregnane side chain of the substrate, C-17 oxidoreductase that interconverts the metabolites androstenedione and testosterone, and 6-hydroxylation. 6-hydroxylation activity was purified virtually to homogeneity and was shown to be catalysed by a cytochrome P-450 monooxygenase enzyme. This is the first report of a thermostable cytochrome P-450.


Effect of diagnosis, surveillance, and treatment of Barrett's oesophagus on health-related quality of life.
Barrett's oesophagus is a chronic precancerous condition that predisposes patients to the development of oesophageal adenocarcinoma, which, once invasive, carries a poor prognosis. This likelihood of a negative outcome has led to the development of robust surveillance and treatment pathways. The true effect of Barrett's oesophagus on life expectancy and the efficacy of long-term surveillance remains under debate. With these uncertainties and no reliable methods of individual risk stratification, patients must be continually monitored and thus carry the burden of this chronic disease. In this Review, we summarise the major findings concerning the patients' perspective of this disease and its care pathways. Health-related quality of life (HRQoL) measurement has become a valuable metric to assess the effects of disease, the quality of health-care delivery, and treatment efficacy across various disease settings. Research to date has shown significant reductions in HRQoL scores related to Barrett's oesophagus compared with controls from the general population. The scores of patients with Barrett's oesophagus seem to be similar to those of patients with gastro-oesophageal reflux disease. Symptom control appears to be important, but not the only factor, in maximising HRQoL. Most researchers have used generic and disease-specific HRQoL instruments because there are few outcome measures that are validated and reliable in patients with Barrett's oesophagus. These methodologies potentially overlook crucial unmeasured areas that are specific to patients with Barrett's oesophagus. Historically, follow-up care has left some patients with insufficient understanding of the disease, inaccurate perceptions of cancer risk, and an unnecessary psychological burden. A greater understanding of the prevalence of these factors and identification of follow-up needs specific to these patients will help to shape future health-care delivery and improve patient experience.


sIL-6R: more than an agonist?
On target cells, interleukin-6 (IL-6) interacts with its receptor complex consisting of the membrane-bound IL-6 receptor (IL-6R) and the signal transducing protein gp130. IL-6R can exist as a soluble protein (sIL-6R), which binds the ligand IL-6. This soluble complex can bind to gp130 on cells that lack the membrane-bound IL-6R and initiate signaling. This process is named transsignaling. The significance of transsignaling via sIL-6R is underlined by different publications and exceeds very probably the significance of the membrane-bound IL-6R. It is the general assumption that sIL-6R acts as an agonist in combination with IL-6 resulting in an enhancement of the IL-6 effects. In this article, we suppose 'non-agonistic' properties. There are several publications that give reasons to speculate that sIL-6R (a) has IL-6-antagonistic effects, (b) has orphan properties and (c) interacts with yet unknown binding partners different from IL-6. Knowledge about additional properties of sIL-6R will enlarge the biologic understanding of this molecule and might give an explanation for the sometimes contrasting effects of the cytokine IL-6.


Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.
The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.


Association of genetic variants in migraineurs with and without restless legs syndrome.
Several single-nucleotide polymorphisms (SNPs) are associated with restless legs syndrome (RLS). This study investigated whether or not additional SNP variants increase the risk of RLS in migraineurs and in migraine with aura (MA) and migraine without aura (MoA) subgroups. Migraineurs with and without RLS were genotyped using an Affymetrix array. We performed association analyses for the entire cohort and the MA and MoA subgroups, which were divided further into episodic migraine (EM) and chronic migraine (CM). Potential correlations between SNPs and clinical indices in migraineurs with RLS were examined by multivariate regression analysis. The rs77234324 and rs79004933 SNPs were found in migraineurs with (P = 2.57E-07) and without (P = 3.03E-07) RLS. The A allele frequency for rs77234324 (on LGR6) was 0.1321 in migraineurs with RLS and 0.0166 in those without RLS (odds ratio, 8.978). The T allele frequency for rs79004933 (in the intergenic region) was 0.1981 in migraineurs with RLS and 0.0446 in those without (odds ratio, 5.281). rs2858654, rs76770509, rs4243475 in UTRN, rs150762626, and rs2668375 were identified in migraine with and without RLS in the MoA subgroup (P = 7.56E-09, P = 2.30E-08, P = 1.19E-07, P = 6.86E-07, and P = 8.05E-07, respectively). There was a suggestion of an association between rs10510331 (P = 1.50E-06) and CM and EM in patients with MoA and RLS. Multivariate regression showed a significant relationship between rs79004933 and the Beck Depression Inventory score. rs77234324 in LGR6 and rs79004933 in the intergenic region were associated with RLS in migraineurs. Five SNPs increased the risk of RLS in patients with MoA.


Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia.
Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes.


Monitoring the total available calmodulin concentration in intact cells over the physiological range in free Ca2+.
We describe the design, characterization and application of a new genetically encoded fluorescent biosensor for intracellular detection of both free Ca(2+)-calmodulin and apocalmodulin, which together comprise the available calmodulin concentration. The biosensor binds both forms of calmodulin with an apparent Kd value of 3 microM, and has kinetic properties making it suitable for monitoring dynamic changes on a subsecond time scale. It can be used in conjunction with the fluorescent Ca(2+)-indicator, indo-1, allowing the available calmodulin and free Ca2+ concentrations to be monitored concurrently. We have determined an intracellular available calmodulin concentration of 8.8 +/- 2.2 microM under resting conditions in a human kidney cell line stably expressing the biosensor. Elevation of the intracellular free Ca2+ concentration by agonist, store-operated Ca(2+)-entry or ionophore results in Ca(2+)-dependent consumption of the available calmodulin. A plot of normalized values for the available calmodulin concentration versus the free Ca2+ concentration fits a consumption curve with a cooperativity coefficient of 1.8 and a [Ca2+]50 of 850 nM. There is no detectible binding of calmodulin to the biosensor above a free Ca2+ concentration of approximately 4 microM, consistent with an available calmodulin concentration < or = 200 nM under these conditions, and an overall excess of calmodulin-binding sites.


Implementation of EPR-Youth, a Client-Accessible and Multidisciplinary Health Record; A Mixed-Methods Process Evaluation.
Client-accessible interdisciplinary health records potentially contribute to integrated care by facilitating collaboration and enhancing clients' involvement in care. To achieve this, three Dutch organizations providing 'care for youth' developed a fully client-accessible electronic patient record (EPR-Youth). To evaluate the implementation of EPR-Youth and to determine barriers and facilitators. A mixed methods design combined system data, process observations, questionnaires and focus group interviews. Target groups were parents, adolescents, professionals using EPR-Youth, and implementation stakeholders. Client-portal acceptability was high among all clients. Client-portal adoption rate was high and differed between age groups and educational levels. Professionals' doubts about acceptability, appropriateness and fidelity were partly due to lack of system knowledge. Implementation barriers were the complexity of co-creation, lack of clear leadership, and concerns about legal issues. Facilitators were clarifying vision and legal context, setting deadlines, and a pioneering spirit. The early implementation of EPR-Youth, the first Dutch client-accessible interdisciplinary electronic health record in 'care for youth' was successful. To enhance adoption among clients, group-specific barriers for portal-use should be determined. Professionals need additional training. Further research is needed to gain insight into client-portal access barriers. To benefit more from co-creation, an organizational change towards situational leadership is necessary.


Processing, polymorphism, and biological significance of P190, a major surface antigen of the erythrocytic forms of Plasmodium falciparum.
A detailed analysis of P190, a major surface associated protein of Plasmodium falciparum erythrocytic stages has been undertaken. We have demonstrated that this protein is recognised by two monoclonal antibodies, one of which recognises a constant feature (2.2) and one a variable feature (7.3). Cell free protein synthesis demonstrates that the variable 7.3 epitope is encoded in the structural gene for P190. The 7.3 epitope is only present on late trophozoites and schizonts whilst the 2.2 epitope is present on all erythrocytic stages. Labelling of synchronised cultures demonstrates that P190 is made only from 30 h onwards, (i.e. by trophozoites and schizonts). By pulse chase analysis we show that P190 undergoes processing and is lost at release/re-invasion, correlating with a lack of 7.3 immunofluorescence reactivity on rings. Sera from Nigeria recognise P190 from a Thai isolate of malaria. They also react with purified P190 in a micro-ELISA assay. A model for the role of P190 in re-invasion is presented, and the possible clinical significance of this protein is discussed.


Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones.
An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum.


Fractal interwoven resonator based penta-band metamaterial absorbers for THz sensing and imaging.
This paper presents a unique penta-band metamaterial absorber platform for terahertz imaging systems.The proposed fractal metamaterial absorber (FMMA) consists of fractal triangle section metasurfaces. By combining fractal resonators posing different operation skills in the same unit cell, the absorber shows multiband spectral response. The proposed unit cell structure operates at five near perfect absorption modes corresponding to the frequency bands of 1.1 THz, 3.4 THz, 4.9 THz, 5.9 THz, and 7.8 THz, respectively. Based on the fractal metamaterial absorber array, we also propose a sensing pixel design for bimaterial cantilever array sensing systems. The single pixel assembles 4x6 fractal resonator array and [Formula: see text]-Al bimaterial microcantilevers. The sensing region of the FMMA pixel can bend the bimaterial cantilevers effectively at multiple modes, enhancing the imaging capacity. The effective medium theory is executed to visualize the constitute parameters during the absorption and reveal the origin of the rising modes. The absorption mechanism is also discussed based on the surface current distributions and electric field profiles. The numerical outcomes prove that the proposed fractal metamaterial unit cell is a promising candidate as an absorbing platform for THz band sensing and imaging applications. The derived iterative formula used in the fractal design procedure is explained for further investigations of microelectromechanical systems (MEMS) compatible compact absorber arrays.


Use of multivariate analysis to evaluate antigenic relationships between US BVDV vaccine strains and non-US genetically divergent isolates.
Bovine viral diarrhea virus (BVDV) comprises two species, BVDV-1 and BVDV-2. But given the genetic diversity among pestiviruses, at least 22 subgenotypes are described for BVDV-1 and 3-4 for BVDV-2. Genetic characterization is generally accomplished through complete or partial sequencing and phylogeny, but it is not a reliable method to define antigenic relationships. The traditional method for evaluating antigenic relationships between pestivirus isolates is the virus neutralization (VN) assay, but interpretation of the data to define antigenic relatedness can be difficult to discern for BVDV isolates within the same BVDV species. Data from this study utilized a multivariate analysis for visualization of VN results to analyze the antigenic relationships between US vaccine strains and field isolates from Switzerland, Italy, Brazil, and the UK. Polyclonal sera were generated against six BVDV strains currently contained in vaccine formulations, and each serum was used in VNs to measure the titers against seven vaccine strains (including the six homologous strains) and 23 BVDV field isolates. Principal component analysis (PCA) was performed using VN titers, and results were interpreted from PCA clustering within the PCA dendrogram and scatter plot. The results demonstrated clustering patterns among various isolates suggesting antigenic relatedness. As expected, the BVDV-1 and BVDV-2 isolates did not cluster together and had the greatest spatial distribution. Notably, a number of clusters representing antigenically related BVDV-1 subgroups contain isolates of different subgenotypes. The multivariate analysis may be a method to better characterize antigenic relationships among BVDV isolates that belong to the same BVDV species and do not have distinct antigenic differences. This might be an invaluable tool to ameliorate the composition of current vaccines, which might well be important for the success of any BVDV control program that includes vaccination in its scheme.


Anticoagulation: a surgical perspective.
Heparin combines with antithrombin III, and the resulting complex inactivates several clotting factors (all are serine proteases) in the coagulation cascade, but the most important steps are inhibition of the conversion of factor X to Xa and the antithrombin effect. Heparin pharmacokinetics are poorly understood, but when the usual doses are given intravenously, heparin is rapidly removed from the blood and has a half-life of approximately 90 minutes. Warfarin is not a true anticoagulant but is readily absorbed after oral administration. It interrupts the coagulation mechanism by interfering with the vitamin K-dependent synthesis of prothrombin and factors VII, IX, and X. This process takes 4 to 5 days. The drug has a long half-life, and its activity is enhanced or blunted by many chemicals. The effective treatment of thromboembolism with heparin, followed by warfarin, requires a basic understanding of the complex pharmacologic aspects and drug interactions.


The role of social media for blood donor motivation and recruitment.
Social media platforms have become an important lifestyle aspect. Therefore, we implemented communication via social media platforms to recruit new donors and to motivate repeat donors. Here, we report a survey among donors of our blood donation facility to evaluate the impact of different strategies for donor motivation from the donors' perspective. During 8 consecutive weeks, all whole blood donors were asked to participate. The survey consisted of a questionnaire including the demographic items sex, age, number of prior donations, and 14 potential motivators for blood donation. Social media included the items "Facebook" and "Jodel" (German local mobile application). Of 3320 consecutive donors, 2920 (88%) participated in the survey. Social media motivated 7.4% of our donors, among them mainly young and female donors. For first-time donors (FTDs; n = 157) the three strongest motivational factors were friends and/or relatives (73%), social media (15%), and "I do not need additional motivation" (11%). Repeat donors (n = 2693) most often stated that they do not need additional motivation (72%) and only 7% were motivated by social media. Social media have become the second most important motivator to recruit FTDs beside relatives and friends who are by far the main motivators for FTDs. For repeat donors, social media play a less important role. Social media are becoming increasingly important for transfusion services.


Prevalence and sociodemographic characteristics of self-reported suicidal behaviours in Latvia in 2010: A population-based study.
The fact that Latvia is among the countries with the highest suicide mortality rates in the European Union highlights the importance of research in this field. The aims of the study were to determine the 2010 prevalence of self-reported suicidal behaviours in Latvia, to identify sociodemographic risk factors and to examine sequences for reporting of suicidal behaviours. Computer assisted personal interviews were carried out to gather information on a representative sample of the Latvian population aged 18 to 64 (n = 2816). The study sample was selected using a combination of stratified random sampling and quota methods. Last year prevalence of any type of suicidal behaviour was 18.5% - nearly threefold lower than observed in 2000 (52.6%). Middle age, non-cohabitation status and lower level of education were significant risk factors for serious types of suicidal behaviour (suicidal ideation, suicidal plans, suicide attempts) among men, but only lower level of education was for women. Risk factors regarding mild types of suicidal behaviour (life-weariness, death wishes) were the same for men and women: older and middle aged, non-cohabitation status, and lower level of education. A total of 79.6% reported a continuous pattern of suicidal behaviours. Several sociodemographic risk factors for suicidal behaviours have been found. Further research is needed to clarify additional risk factors, especially in the high-risk groups studied and specific determinants contributing to reduction in prevalence of suicidal behaviours and suicide mortality in Latvia.


Lyme disease in a child presenting with bilateral facial nerve palsy: MRI findings and review of the literature.
We report a 7-year-old boy with neuroborreliosis presenting with headache and bilateral facial nerve palsy. MRI demonstrated tentorial and bilateral facial and trigeminal nerve enhancement.


The therapeutic effect of CD133(+) cells derived from human umbilical cord blood on neonatal mouse hypoxic-ischemic encephalopathy model.
Brain damage at birth can cause lifelong neurodevelopmental deficits. Recently, stem cell therapies have been used in several fields of medicine. We previously reported that CD133(+) cells, endothelial progenitor cells derived from human umbilical cord blood, induce nerve extension in an ex vivo hypoxic-ischemic encephalopathy model. Here, we used an in vivo model to examine the effect of CD133(+) cells in neonatal hypoxic-ischemic encephalopathy. Hypoxic-ischemic brain lesions were induced in neonatal severe combined immunodeficiency mice using the Rice-Vannucci method. CD133(+) cells were administered by intraperitoneal injection 24h after injury. Immunohistochemical analysis revealed that intraperitoneally transplanted CD133(+) cells migrate towards the brain 48h after injection. Moreover, in CD133(+) cell-treated animals, motor function improved and the brain was protected from the hypoxic-ischemic insult compared with untreated animals. Our results suggest that CD133(+) cells derived from human umbilical cord blood have therapeutic potential in neonatal hypoxic-ischemic encephalopathy.


Subarachnoideal blood spread following epidural blood patch given to treat spontaneous intracranial hypotension: Can it cause neurological complications?
(1) To determine the frequency of subarachnoid blood spread following epidural blood patch (EBP) in a cohort of subjects with spontaneous intracranial hypotension (SIH). (2) To describe the outcome of these patients. In a cohort of 106 patients exhibiting SIH, spiral spinal CT scans were obtained post-lumbar EBP and neuroradiological data was reviewed for evidence of subarachnoideal bleeding. Subarachnoideal blood spread was detected on spinal CT scans following EBP in 9 of 106 patients with SIH. All patients exhibited a complete recovery and no neurological complications were observed. A low incidence of subarachnoideal blood spread was observed following EBP given to treat SIH. Instances of subarachnoideal blood spread were not associated with neurological complications or altered efficacy of the EBP procedure.


PTEN expression in melanoma: relationship with patient survival, Bcl-2 expression, and proliferation.
Inactivation of the tumor suppressor gene, phosphatase and tensin homologue (PTEN), is a major alteration in preclinical melanoma models. We investigated the clinical relevance of PTEN expression in the primary melanoma patients with extended follow-up. We correlated PTEN expression with clinicopathologic variables and outcome in 127 primary melanomas (median follow-up, 12.8 years). We evaluated the associations between PTEN expression and proliferation and resistance to apoptosis (assessed by Ki-67 and Bcl-2, respectively). We also examined the effect of a favorable phenotype, defined as retained PTEN, low proliferative index, and low expression of Bcl-2 on disease-free survival and overall survival. Altered PTEN, Bcl-2, and Ki-67 expressions were observed in 55 of 127 (43.3%), 61 of 127 (48%), and 43 of 114 (37.7%) of cases, respectively. Decreased PTEN expression correlated significantly with the ulceration (P = 0.01). Rates of disease-free survival and overall survival in patients with favorable phenotype were 72% and 74% at 5 years versus 64% and 64% in patients with an unfavorable phenotype. At 10 years, the rates of disease-free survival and overall survival were 72% and 68% for patients with a favorable phenotype but declined to 60% and 55% in patients with an unfavorable phenotype. However, relationships between both PTEN and Bcl2 and patient survival were not significant as well as the associations between PTEN and Bcl-2 or Ki-67. Our data suggest that altered PTEN expression is common in primary melanomas and is associated with aggressive tumor behavior. However, PTEN alone provided limited prognostic value. Our findings show the need to examine molecular alterations identified in preclinical studies using an adequately large cohort of patients with extended follow-up to better assess the magnitude of their clinical relevance.


Ophthalmoplegia plus, an electro-oculographic study.
To find out whether the central structures governing conjugate eye movements are affected in ophthalmoplegia plus (OP), we conducted an electro-oculographic study in 6 patients suffering from OP with varying degrees of extraocular involvement and with mitochondrial changes in the skeletal musculature. All the patients presented alterations of the smooth pursuit and saccadic movements, of optokinetic nystagmus as well as of the vestibular reflexes and of visuovestibular interaction, thus confirming impairment of the central oculomotor structures and particularly of those of the archicerebellum and brainstem. These data suggest a supranuclear component in the pathogenesis of ophthalmoplegia and are in accord with the findings of brainstem spongiosis in OP, which in turn seem to express a multisystem pathological state of the mitochondria.


Behavioral and Social Research to Accelerate the Geroscience Translation Agenda.
Geroscience is the study of how to slow biological aging to extend healthspan and longevity. Geroscience has not heretofore incorporated behavioral or social-science methods or findings into its agenda, but the current expansion of the agenda to human trials of anti-aging therapies will be greatly aided by behavioral and social science. This article recommends some ways in which geroscience can be augmented through collaboration with behavioral and social science to: accomplish translation from animal models to humans; inform the design of clinical trials of anti-aging therapies; develop outcome measures for evaluating efficacy of anti-aging therapies, and reduce and not exacerbate health disparities.


Contrast echocardiography as a useful additional diagnostic tool in evaluating a primary cardiac tumor.
The current report describes a case of a primary cardiac lymphoma. For early and appropriate treatment of a cardiac mass it is not only important to determine its localization and extension but also to differentiate between malignant and benign lesions. This report demonstrates that not only transthoracic echocardiography but also the other different forms of echocardiography such as transesophageal echocardiography, as well as contrast and intracardiac echocardiography, are useful tools in the diagnostic workup of cardiac masses.


Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients.
Estrogen is thought to play a protective role against neurodegeneration through a variety of mechanisms including the activation of growth factors, the control of synaptic plasticity, and the reduction of response to various insults, such as iron and glutamate. Increasing evidence indicates an increased level of extracellular glutamate and a down-regulation of glutamate transporters in Alzheimer's disease (AD). In this study, we show that glutamate uptake in astrocytes derived from Alzheimer's patients is significantly lower than that from non-demented controls. Estrogen treatment increases glutamate uptake in a dose-dependent pattern. Two glutamate transporters, GLT-1 and GLAST, are expressed in the astrocytes. Up-regulation of the glutamate transporters is induced by estrogen treatment in AD astrocytes only. Our data suggest that the action of estrogen on glutamate uptake by astrocytes might contribute to its potential neuroprotective role in AD.


Ultrasound and Near-Infrared Light Dual-Triggered Upconversion Zeolite-Based Nanocomposite for Hyperthermia-Enhanced Multimodal Melanoma Therapy via a Precise Apoptotic Mechanism.
High reactive oxygen species (ROS) generation efficiency and induction of targeted cell apoptosis are recognized as key objectives to achieve a highly efficient strategy for cancer therapy with minimum side effects of inflammatory reactions. However, it is still a challenge to realize higher therapeutic efficiency with a cell apoptosis model. Herein, we present strong upconversion luminescent biosafe cores derived from Linde Type A (LTA) zeolites and modification with targeted/therapeutic drugs for multimodal therapy, in which sonodynamic therapy (SDT) combined with photodynamic therapy (PDT) increases therapeutic efficiency especially in deep sites of tumor via producing cytoplasmic ROS and mitochondrial superoxide and photothermal therapy (PTT) enhances PDT effects via higher fluorescence resonance energy transfer (FRET) efficacy attributed to an increased temperature. Furthermore, the transcriptomic analysis reveals that cellular internalization of the nanosystem can lead to tumor ablation via cell apoptosis. We expect that the multimodal therapy based on LTA zeolite drug nanocarriers could be applied in the cancer therapeutics in the near future.


Identification of Candidate Genes Regulating Carcass Depth and Hind Leg Circumference in Simmental Beef Cattle Using Illumina Bovine Beadchip and Next-Generation Sequencing Analyses.
Genome-wide association studies are a robust means of identifying candidate genes that regulate economically important traits in farm animals. The aim of this study is to identify single-nucleotide polymorphisms (SNPs) and candidate genes potentially related to carcass depth and hind leg circumference in Simmental beef cattle. We performed Illumina Bovine HD Beadchip (~670 k SNPs) and next-generation sequencing (~12 million imputed SNPs) analyses of data from 1252 beef cattle, to which we applied a linear mixed model. Using a statistical threshold (p = 0.05/number of SNPs identified) and adopting a false discovery rate (FDR), we identified many putative SNPs on different bovine chromosomes. We identified 12 candidate genes potentially annotated with the markers identified, including CDKAL1 and E2F3, related to myogenesis and skeletal muscle development. The identification of such genes in Simmental beef cattle will help breeders to understand and improve related traits, such as meat yield.


An energetic analysis of host plant selection by the large milkweed bug, Oncopeltus fasciatus.
The large milkweed bug, Oncopeltus fasciatus, is a specialized seed feeder that has been observed completing nymphal development in the field on only a small proportion of its potential host species within the genus Asclepias. In central Missouri only two of the six milkweed species studied, A. syriaca and A. verticillata, commonly supported nymphal O. fasciatus growth in the field. The seed of all six species, however, was equally suitable food for bugs reared in the laboratory. In laboratory preference tests, adult bugs chose to feed on the largest seeds, A. hirtella, but such a preference could not explain the observed field feeding patterns.One explanation to account for the observed host plant selection is based upon an energetic analysis. Only A. syriaca provided enough seed biomass for a clutch of O. fasciatus nymphs to develop on a single plant, and only A. verticillata grew in high enough density that a clutch could find sufficient food within the limited range of nymphal movement. These results illustrate a corollary of the resource concentration hypothesis: within a plant group whose members share similar secondary plant chemistries, the only species that will be viable hosts for a specialized herbivore are those that provide the minimal resource density necessary for the completion of nymphal development.In central Missouri, O. fasciatus has specialized on a critical resource density, not traits of individual Asclepias species. The appearance of host selection within the potential host plant spectrum is the result of a characteristic growth form, seed output, and dispersion pattern for each milkweed species that makes some species much more likely than others to produce sufficient seed resources.


Design, fabrication, and applications of bioinspired slippery surfaces.
Bioinspired slippery surfaces (BSSs) have attracted considerable attention owing to their antifouling, drag reduction, and self-cleaning properties. Accordingly, various technical terms have been proposed for describing BSSs based on specific surface characteristics. However, the terminology can often be confusing, with similar-sounding terms having different meanings. Additionally, some terms fail to fully or accurately describe BSS characteristics, such as the surface wettability of lubricants (hydrophilic or hydrophobic), surface wettability anisotropy (anisotropic or isotropic), and substrate morphology (porous or smooth). Therefore, a timely and thorough review is required to clarify and distinguish the various terms used in BSS literature. This review initially categorizes BSSs into four types: slippery solid surfaces (SSSs), slippery liquid-infused surfaces (SLISs), slippery liquid-like surfaces (SLLSs), and slippery liquid-solid surfaces (SLSSs). Because SLISs have been the primary research focus in this field, we thoroughly review their design and fabrication principles, which can also be applied to the other three types of BSS. Furthermore, we discuss the existing BSS fabrication methods, smart BSS systems, antifouling applications, limitations of BSS, and future research directions. By providing comprehensive and accurate definitions of various BSS types, this review aims to assist researchers in conveying their results more clearly and gaining a better understanding of the literature.


On-line effects of quadripulse transcranial magnetic stimulation (QPS) on the contralateral hemisphere studied with somatosensory evoked potentials and near infrared spectroscopy.
To evaluate on-line effects of quadripulse stimulation (QPS) over the primary motor cortex (M1) on cortical areas in the contralateral hemisphere. QPS consisted of 24 bursts of transcranial magnetic stimulation (TMS) pulses with an inter-burst interval of 5 s for 2 min (for on-line effect study) or 360 bursts for 30 min (for after-effect study). Each burst consisted of four TMS pulses (i.e. QPS) separated by an interstimulus interval of 5 or 50 ms (QPS-5 or QPS-50). QPSs were delivered over the left M1. Experiment 1 [on-line effect on somatosensory evoked potential (SEP)]: Left median nerve SEPs were recorded before, during and after QPS. Experiment 2 (after effect on SEP): After-effects of QPS were evaluated by following up SEPs after the QPS sessions. Experiment 3 (on-line effect on NIRS): Near infrared spectroscopy (NIRS) was also recorded at the right hemisphere during all QPS paradigms. Both QPS-5 and QPS-50 enlarged a cortical component of the contralateral SEP during stimulation. On the other hand, concerning the after effects, QPS-5 over M1 potentiated the contralateral SEP and QPS-50 tended to depress it. In NIRS study, both QPS-5 and QPS-50 induced a significant oxy-Hb decrease (deactivation pattern) at the right hemisphere during stimulation whereas sham stimulations unaffected them. We have shown the unidirectional on-line effects evoked by QPS-5 and QPS-50 on both SEP and NIRS, and bidirectional after effects on SEP at the contralateral hemisphere. The discrepancy between on-line effect and after effect may be explained by the differences in the underlying mechanisms between them. The former may be mainly explained by pure electrophysiological property changes in the membrane or synapses. The latter may be explained by synaptic efficacy changes which need some protein syntheses at least partly. Another discrepancy shown here is the direction of on-line effects. Electrophysiological (SEP) function was potentiated by both QPSs whereas hemodynamic (NIRS) function was depressed. This may be explained by which sensory areas contribute to NIRS or SEP generation.


Impaired respiratory function and heightened pulmonary inflammation in episodic binge ethanol intoxication and burn injury.
Clinical data indicate that cutaneous burn injuries covering greater than 10% of the total body surface area are associated with significant morbidity and mortality, in which pulmonary complications, including acute respiratory distress syndrome (ARDS), contribute to nearly half of all patient deaths. Approximately 50% of burn patients are intoxicated at the time of hospital admission, which increases days on ventilators by 3-fold, and doubles the length of hospitalization, compared to non-intoxicated burn patients. The most common drinking pattern in the United States is binge drinking, where an individual rapidly consumes alcoholic beverages (4 for women, 5 for men) in 2 h. An estimated 38 million Americans binge drink, often several times per month. Experimental data demonstrate that a single binge-ethanol exposure, prior to scald injury, impairs innate and adaptive immune responses, thereby enhancing infection susceptibility and amplifying pulmonary inflammation, neutrophil infiltration, and edema, and is associated with increased mortality. Since these characteristics are similar to those observed in ARDS burn patients, our study objective was to determine whether ethanol intoxication and burn injury and the subsequent pulmonary congestion affect physiological parameters of lung function, using non-invasive and unrestrained plethysmography in a murine model system. Furthermore, to mirror young adult binge-drinking patterns, and to determine the effect of multiple ethanol exposures on pulmonary inflammation, we utilized an episodic binge-ethanol exposure regimen, where mice were exposed to ethanol for a total of 6 days (3 days ethanol, 4 days rest, 3 days ethanol) prior to burn injury. Our analyses demonstrate mice exposed to episodic binge ethanol and burn injury have higher mortality, increased pulmonary congestion and neutrophil infiltration, elevated neutrophil chemoattractants, and respiratory dysfunction, compared to burn or ethanol intoxication alone. Overall, our study identifies plethysmography as a useful tool for characterizing respiratory function in a murine burn model and for future identification of therapeutic compounds capable of restoring pulmonary functionality.


Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults.
Background. Prosthetic joint infections (PJIs) significantly complicate joint arthroplasties. Propionibacterium acnes is an increasingly recognized PJI pathogen, yet limited clinical and therapeutic data exist. We sought to examine characteristics of P. acnes shoulder PJIs and compare surgical and nonsurgical management outcomes. Methods. A retrospective analysis of P. acnes shoulder PJIs was conducted at an academic center in Baltimore, Maryland from 2000 to 2013. Results. Of 24 cases of P. acnes shoulder PJIs, 92% were diagnosed after extended culture implementation; 42% in the delayed and 46% in the late postsurgical period. Joint pain and diminished function were the predominant presenting clinical signs. Erythrocyte sedimentation rate and C-reactive protein elevations occurred in 47% and 44%, respectively. All tested isolates were susceptible to β-lactams, moxifloxacin, vancomycin, and rifampin. Clindamycin resistance was identified in 6%. Of the antibiotic-only treated cases, 67% had a favorable clinical outcome compared with 71% (P = 1.0) of cases with a combined antibiotic-surgical approach. Favorable outcome with and without rifampin therapy was 73% and 60% (P = .61), respectively. Conclusions. Propionibacterium acnes PJI diagnoses increased with extended culture. Inflammatory markers were elevated in a minority of cases. Isolates maintained broad antimicrobial susceptibility. Compared to combined antibiotic-surgical approaches, antibiotic-only approaches were similarly successful in selected cases.


An assay suitable for high throughput screening of anti-influenza drugs.
We developed a novel drug screening system for anti-influenza A virus by targeting the M2 proton channel. In the SPP (Single Protein Production) system, E. coli cell growth occurs only in the presence of effective M2 channel inhibitors, and thus simple measurement of cell growth was used as readouts for drug screening. Two potential inhibitors for M2 (V27A) mutant were verified using this method, which inhibit both the mutant and wild-type M2 channels.


Costs of storing colour and complex shape in visual working memory: Insights from pupil size and slow waves.
We investigated the impact of perceptual processing demands on visual working memory of coloured complex random polygons during change detection. Processing load was assessed by pupil size (Exp. 1) and additionally slow wave potentials (Exp. 2). Task difficulty was manipulated by presenting different set sizes (1, 2, 4 items) and by making different features (colour, shape, or both) task-relevant. Memory performance in the colour condition was better than in the shape and both condition which did not differ. Pupil dilation and the posterior N1 increased with set size independent of type of feature. In contrast, slow waves and a posterior P2 component showed set size effects but only if shape was task-relevant. In the colour condition slow waves did not vary with set size. We suggest that pupil size and N1 indicates different states of attentional effort corresponding to the number of presented items. In contrast, slow waves reflect processes related to encoding and maintenance strategies. The observation that their potentials vary with the type of feature (simple colour versus complex shape) indicates that perceptual complexity already influences encoding and storage and not only comparison of targets with memory entries at the moment of testing.


Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.
A healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high-fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (GlycoHi) were fed a low fat or HFD for 16 weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, GlycoHi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome.


Increasing drug solubility by means of bile salt-phosphatidylcholine-based mixed micelles.
Study of the solubilization of commercial grades of soya phosphatidylcholine (SPC) with different purities by bile salts (BS) indicated that only highly pure grades of SPC are suitable for the preparation of clear solutions of BS/SPC-mixed micelles (BS/SPC-MM). The solubilizing capacity of different BS towards SPC increased in the following order; Sodium cholate (SC) < sodium deoxycholate (SDC) < sodium glycocholate (SGC). Moreover, egg phosphatidylcholine (EPC) was solubilized to a higher extent than SPC. Furthermore, the solubility study of different drugs in the prepared MM showed substantial enhancement of solubility, the extent of which is essentially affected by the chemical nature of the drug and the composition of MM. Benzodiazepine drugs such as clonazepam, tetrazepam, diazepam, and lorazepam displayed higher affinity for MM compared with BS alone, whereas steroidal drugs, such as estradiol, prednisolone and progesterone, compared with benzodiazepines, displayed relatively higher affinity for BS alone. The solubilizing capacity of MM for the different drugs was increased to different degrees by the addition of benzyl alcohol which was comparable to the solubility of the drug in pure benzyl alcohol. The interaction between benzyl alcohol and the drug in MM could be proved by NMR.


NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?
Nitric oxide is a major endothelium-derived vascular smooth muscle relaxing factor; its synthesis from L-arginine is selectively inhibited by L-NG-methylarginine. To assess whether basal nitric oxide release contributes to blood pressure regulation in vivo, we have investigated the cardiovascular effects of L-NG-methylarginine in the anesthetized guinea pig. L-NG-methylarginine (0.1-10 mg/kg, i.v. bolus) elicited a sustained, dose-dependent, increase in arterial pressure and a moderate bradycardia. L-arginine (30 mg/kg i.v.) prevented or reversed the pressor effect of L-NG-methylarginine, while atropine (2 mg/kg) abolished the associated bradycardia. In contrast, L-arginine did not attenuate the pressor effect of norepinephrine or angiotensin. Our findings suggest that basal nitric oxide production is sufficient to modulate peripheral vascular resistance; hence nitric oxide may play a role in arterial pressure homeostasis.


Complications From Subdural Drains in Burr Hole Drainage of Chronic and Subacute Subdural Haematomas: A Single-Centre Experience.
Introduction The use of drains following the burr-hole evacuation of chronic (CSDH) and subacute subdural haematomas (SASDH) is a well-established practice offering a significant reduction in recurrence rates and improvement of survival. The purpose of this work is to investigate the complication rate of subdural drains following the burr-hole evacuation of CSDH and SASDH. Methods A retrospective review of the clinical records of all patients managed surgically for CSDH or SASDH was conducted. Patients over 18 years, that met the criteria for surgical evacuation, were included in this study. Patients admitted for CSDH or SASDH but managed either conservatively or with craniotomy were excluded from further analysis. Results A total of 97 cases, with a mean age at the time of diagnosis of 78.25 years were identified in which 122 drains were used. Three complications, two acute subdural haematomas, and one case of drain-associated seizures were identified, yielding an overall complication rate of 3%. Conclusion The use of intradural drains is associated with a small, yet not negligible, possibility of serious complications.


Relación entre práctica de actividad física en el tiempo libre y rendimiento académico en alumnos(as) de 5° de Primaria a 4° de ESO.
Los objetivos del presente estudio fueron establecer la relación de la práctica de ejercicio físico en el tiempo libre con la práctica de los padres, el rendimiento académico, la importancia que le dan a la asignatura de educación física (EF) y la influencia que consideran que tiene sobre su rendimiento académico; así como sobre la percepción que tienen de la importancia que le dan los padres a la EF. Para ello, un total de 867 niños y niñas de 5° de Primaria a 4° de la ESO (edad: 12.99 ± 1.90 años) diligenciaron un cuestionario previamente validado. El análisis estadístico mostró diferencias significativas al relacionar práctica deportiva de los alumnos con la práctica de sus padres y madres (p < 0.001), así como un mayor rendimiento académico entre los practicantes (p entre 0.008 y <0.001). En general, los alumnos le dieron la misma importancia a la EF que al resto de asignaturas, si bien los practicantes tenían una mejor percepción de la importancia de la EF (p = 0.002). En conclusión, hay una relación entre la práctica de ejercicio físico y el rendimiento académico, con la práctica de los padres y con la importancia que le dan ellos a la asignatura de EF, pero no con la que perciben que le dan sus padres.


Outpatient parenteral antibiotic therapy for fever and neutropenia.
The treatment of fever and neutropenia following chemotherapy lends itself well to outpatient parenteral antimicrobial therapy (OPAT). Patients prefer to be at home rather than hospitalized again. There is a clear cost advantage of outpatient therapy. With a quality program and careful patient selection, OPAT can be provided effectively and safely. The chances of an infection due to resistant bacteria also appear to be reduced. There are an increasing number of studies that support the use of empiric antibiotic therapy for the first fever in neutropenic patients. The choice of antimicrobial, dose, as well as vascular access and infusion devices must be tailored to the individual patient needs and circumstances.


Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors.
Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.


Relationship of C3 & C4 levels with filarial immune complexes in bancroftian filariasis.
C3 and C4 levels were determined by radial immuno-diffusion technique and filarial circulating immune-complexes by anti-C3 ELISA in microfilaraemic individuals and patients with clinical filariasis. Decreased levels of C3 and C4 were observed in both groups of filarial patients. Low levels of complement components were associated with low levels of circulating immune complexes.


Psychometric properties of the caregiving difficulty scale in mothers of children with cerebral palsy.
The Caregiving Difficulty Scale is used to measure the burden of caregiving experienced by mothers of children with cerebral palsy. This study aimed to identify the psychometric properties of the Caregiving Difficulty Scale using the Rasch model. Data collected from 206 mothers of children with cerebral palsy were analyzed. Unidimensionality, difficulty of item, rating scale appropriateness, and reliability using the separation index of the Caregiving Difficulty Scale were verified. Unidimensionality of all 25 items was identified through the item fit. Our analysis of item difficulty indicated that person ability and item difficulty are expressed as a similar logit extend. The use of the 5-point rating scale appeared to be appropriate. Outcome analysis revealed that the reliability was high based on the person and that the item separation level was acceptable. This study showed that the Caregiving Difficulty Scale could be a valuable tool for evaluating the caregiving burden in mothers of children with cerebral palsy.


Workplace Violence and Job Performance among Community Healthcare Workers in China: The Mediator Role of Quality of Life.
To explore the impact of workplace violence on job performance and quality of life of community healthcare workers in China, especially the relationship of these three variables. From December 2013 to April 2014, a total of 1404 healthcare workers were recruited by using the random cluster sampling method from Community Health Centers in Guangzhou and Shenzhen. The workplace violence scale, the job performance scale and the quality of life scale (SF-36) were self-administered. The structural equation model constructed by Amos 17.0 was employed to assess the relationship among these variables. Our study found that 51.64% of the respondents had an experience of workplace violence. It was found that both job performance and quality of life had a negative correlation with workplace violence. A positive association was identified between job performance and quality of life. The path analysis showed the total effect (β = -0.243) of workplace violence on job performance consisted of a direct effect (β = -0.113) and an indirect effect (β = -0.130), which was mediated by quality of life. Workplace violence among community healthcare workers is prevalent in China. The workplace violence had negative effects on the job performance and quality of life of CHCs' workers. The study suggests that improvement in the quality of life may lead to an effective reduction of the damages in job performance caused by workplace violence.


The Cushing syndrome induced by bronchial carcinoid tumors.
To define the clinical spectrum of bronchial carcinoid tumors in patients presenting with the Cushing syndrome, to evaluate the role of chest radiographs and computed tomography in their diagnosis, to review the characteristic histologic features, and to determine patient outcome. Retrospective analysis of consecutive patients. A referral-based medical center. Fifteen consecutive patients with the Cushing syndrome evaluated at the Mayo Clinic with histologically proven bronchial carcinoid tumors. Clinical, radiographic, and histologic features. The Cushing syndrome was the initial clinical presentation, and bronchial carcinoid tumors were found later in all 15 patients. The diagnosis of carcinoid tumor was proved histologically in all cases. Ten biopsies showed typical carcinoid tumors, three were histologically atypical, and three were metastatic. Corticotropin was detected by immunostaining in seven of these tumors. Biochemical analysis showed marked elevations of circulating corticotropin with a mean serum value of 156 +/- 58 pmol/L (normal, 4 to 22 pmol/L). Additional clinical features included hypokalemia in six patients and glucocorticoid response to either high-dose dexamethasone or metyrapone in 6 of 13. These hormonally active carcinoid tumors were frequently radiographically occult, with 10 of 15 patients initially having normal chest radiographs. Computed tomography was successful in locating carcinoid tumors in five patients with negative chest radiographs evaluated after 1980. All five remaining patients with normal chest radiographs evaluated before 1980 eventually developed nodular lesions on standard chest radiography from 1 to 10 years later. Ten patients achieved complete remission and two patients, partial remission of the Cushing syndrome after surgical resection. Three patients continued to have symptomatic glucocorticoid excess due to metastatic disease. Although uncommon, the Cushing syndrome may be the initial clinical manifestation of an otherwise indolent bronchial carcinoid tumor. Radiographic imaging of occult lesions can be successfully accomplished with computed tomography. Surgical resection is curative in most patients with this disorder.


'A disease like any other' traditional, complementary and alternative medicine use and perspectives in the context of COVID-19 among the Congolese community in Belgium.
As a hard-hit area during the COVID-19 pandemic, Belgium knew the highest mortality among people from sub-Saharan African descent, compared to any other group living in the country. After migration, people often maintain traditional perceptions and habits regarding health and healthcare, resulting in a high prevalence of traditional, complementary and alternative medicine use among different migrant communities in northern urban settings. Despite being the largest community of sub-Saharan African descent in Belgium, little is known on ethnobotanical practices of the Belgian Congolese community. We therefore conducted an exploratory study on the use of medicinal plants in the context of COVID-19 and perceptions on this new disease among members of the Congolese community in Belgium. We conducted 16 in-depth semi-structured interviews with people of Congolese descent currently living in Belgium. Participants were selected using purposive sampling. Medicinal plant use in the context of COVID-19 was recorded through free-listing. Data on narratives, ideas and perceptions on the origin, cause/aetiology and overall measures against COVID-19 (including vaccination) were collected. Interview transcripts were analysed using thematic analysis. Four overarching themes emerged from our data. Firstly, participants perceived the representation of the severity of COVID-19 by the Belgian media and government-and by extend by all governmental agencies in the global north-as exaggerated. As a result, traditional and complementary treatments were seen as feasible options to treat symptoms of the disease. Fifteen forms of traditional, complementary and alternative medicine were documented, of which thirteen were plants. Participants seem to fold back on their Congolese identity and traditional knowledge in seeking coping strategies to deal with the COVID-19 pandemic. Finally, institutional postcolonial distrust did not only seem to lead to distrust in official messages on the COVID-19 pandemic but also to feelings of vaccination hesitancy. In the context of the COVID-19 pandemic, participants in our study retreated to, reshaped and adapted traditional and culture-bound knowledge. This study suggests that the fragile and sensitive relationship between sub-Saharan African migrant groups and other social/ethnic groups in Belgium might play a role in their sensitivity to health-threatening situations, such as the COVID-19 pandemic.


Engineering the Plant Secretory Pathway for the Production of Next-Generation Pharmaceuticals.
Production of biologics in plants, or plant molecular pharming, is a promising protein expression technology that is receiving increasing attention from the pharmaceutical industry. Previously, low expression yields of recombinant proteins and the realization that certain post-translational modifications (PTMs) may not occur optimally limited the widespread acceptance of the technology. However, molecular engineering of the plant secretory pathway is now enabling the production of increasingly complex biomolecules using tailored protein-specific approaches to ensure their maturation. These involve the elimination of undesired processing events, and the introduction of heterologous biosynthetic machinery to support the production of specific target proteins. Here, we discuss recent advances in the production of pharmaceutical proteins in plants, which leverage the unique advantages of the technology.


Intra- and extraganglionic nerve endings formed by neurosecretory cells of the cerebral ganglion of the earthworm (Lumbricus terrestris L.).
In the cerebral ( = supraesophageal, suprapharyngeal) ganglion of the earthworm, a number of neurosecretory Gomori-positive perikarya are bipolar; others are unipolar, or multipolar. Some of the neurosecretory cell processes project centrally into a fibrous zone; peripheral processes enter small nerves which leave the dorsocaudal aspect of the ganglion. In the central fibrous zone, the neurosecretory fibers form varicose Gomoripositive terminals. Here, also zinc-iodine-osmium (ZIO)-positive fibers and monoamine fluorescent fibers are found. With the electron microscope, nerve terminals containing synaptic vesicles and either large neurosecretory "peptidergic" granular vesicles (diameter more than 1500 A), or smaller granular vesicles (diameter about 1300 A, or 900 A) are observed. These axon endings mainly form axo-dendritic synapses. "Peptidergic" profiles are both pre- and postsynaptic. Some of the extraganglionic "peptideric" fibers appear to terminate around vessels, but most of them form terminals on the visceral muscle cells which surround the ganglion. We think that the central neurosecretory processes communicate with the fibers of the synaptic zone of the ganglion. The peripheral neurosecretory "peptidergic" fibers are supposed to form a primitive neurohemal area and/or to function as vasomotor nerves. The fibers innervating the visceral muscle cells may represent vegetative nerves.


Ultrasound-guided biopsy of greater omentum: an effective method to trace the origin of unclear ascites.
Thickened greater omentum is encountered with high frequency in patients with ascites. The purpose of our study was to assess the utility of greater omentum biopsy under the guidance of ultrasound (US) in tracing the origin of unclear ascites and differentiating benign and malignant ascites. We retrospectively reviewed our institutional database for all records of greater omentum biopsy cases. One hundred and ninety-four patients with unclear ascites and thickened greater omentum were included in the study. The sonograms of greater omentum were evaluated before undergoing the ultrasound-guided biopsy and a biopsy was considered successful if a specific benign or malignant diagnosis was rendered by the pathologist. Successful biopsy was rendered for 182 biopsy procedures (93.8%, 182/194) including tuberculosis (n=114), chronic inflammation (n=3), metastases (n=58), malignant mesothelioma (n=6) and pseudomyxoma peritonei (n=1). Twelve biopsies were non-diagnostic. According to the results of biopsy and follow-up, the sensitivity and specificity of biopsy in distinguishing malignant ascites from benign ascities were respectively 95.6% (65/68) and 92.9% (117/126). The greater omentum of 84 cases of tuberculous peritonitis showed "cerebral fissure" sign and was well seen as an omental cake infiltrated with irregular nodules when involved by carcinomatosis. No "cerebral fissure" sign was observed in peritoneal carcinomatosis. The sensitivity and specificity of this sign in indicating the existence of tuberculous peritonitis were 73.5% (89/121) and 100% (73/73). Moreover, if the specific "cerebral fissure" sign was combined with the biopsy results, the specificity of biopsy in distinguishing malignant ascites from benign ascits increased to 96.8% (122/126). Ultrasound-guided biopsy of greater omentum is an important and effective method to diagnose the unclear ascites for patients with thickened omentum if certain techniques could be paid attention to. "Cerebral fissure" sign of greater omentum was a specific sign in indicating the tuberculous peritonitis and could increase the specificity of biopsy in distinguishing malignant ascites from benign ascits if combined with the biopsy results.


Forest inventory and analysis: a national inventory and monitoring program.
Forests provide significant commodity and noncommodity values to the citizens of the United States. An important and substantial role in ensuring the continued health, productivity, and sustainability of these resources is a reliable and credible inventory and monitoring program. The Forest Inventory and Analysis (FIA) program of the US Forest Service has been monitoring and reporting on status, condition, and trends in the nation's forests for over 70 years and the Forest Health Monitoring (FHM) program for the last 11 years. Recent legislation included in the 1998 Farm Bill, along with efforts to integrate inventory and monitoring networks to deliver Criteria and Indicators of Sustainable Forests, are redefining the role and operation of the recently integrated FIA and FHM programs. This paper provides a brief history and a look at new directions for the enhanced FIA Program.


Upright T waves in lead aVR are associated with cardiac death or hospitalization for heart failure in patients with a prior myocardial infarction.
The aim of the present study was to clarify the prognostic significance of upright T waves (amplitude > 0 mV) in lead aVR in patients with a prior myocardial infarction (MI). We retrospectively examined 167 patients with a prior MI. The primary end point was cardiac death or hospitalization for heart failure. During a follow-up period of 6.5 ± 2.8 years, 34 patients developed the primary end point. A Kaplan-Meier analysis showed a lower primary event-free rate in patients with upright T waves in lead aVR than in those with nonupright T waves in lead aVR (P = 0.001). Univariate Cox proportional hazards regression analyses showed that age, gender, chronic kidney disease, anterior wall MI, upright T waves in lead aVR, left ventricular ejection fraction, loop diuretic use, and spironolactone use were significantly associated with the primary end point. A multivariate Cox proportional hazards regression analysis selected age [hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.05-1.16, P < 0.001], upright T waves in lead aVR (HR 3.10, 95% CI 1.23-7.82, P = 0.017), and loop diuretic use (HR 4.61, 95% CI 1.55-13.67, P = 0.006) as independent predictors of the primary end point. In conclusion, the presence of upright T waves in lead aVR is an independent predictor of cardiac death or hospitalization for heart failure in patients with a prior MI. The analysis of T-wave amplitude in lead aVR provides useful prognostic information in patients with a prior MI.


The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis.
TACC3 is a centrosomal/mitotic spindle-associated protein that is highly expressed in a cell cycle-dependent manner in hematopoietic lineage cells. During embryonic development, TACC3 is expressed in a variety of tissues in addition to the hematopoietic lineages. TACC3 deficiency causes an embryonic lethality at mid- to late gestation involving several lineages of cells. Hematopoietic stem cells, while capable of terminal differentiation, are unable to be expanded in vitro or in vivo in reconstitution approaches. Although gross alterations in centrosome numbers and chromosomal segregation are not observed, TACC3 deficiency is associated with a high rate of apoptosis and expression of the p53 target gene, p21(Waf1/Cip1). Hematopoietic stem cell functions, as well as deficiencies in other cell lineages, can be rescued by combining the TACC3 deficiency with p53 deficiency. The results support the concept that TACC3 is a critical component of the centrosome/mitotic spindle apparatus and its absence triggers p53-mediated apoptosis.


Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers.
To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer. Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidate TAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201)-restricted CTL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2-positive healthy donors and cancer patients. CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4(655-663) (FILPVLGAV) and CDH3-7(757-765) (FIIENLKAA) peptides could induce HLA-A2-restricted CTLs in Tgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A2-positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice. These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.


Pheromones Modulate Learning by Regulating the Balanced Signals of Two Insulin-like Peptides.
Social environment modulates learning through unknown mechanisms. Here, we report that a pheromone mixture that signals overcrowding inhibits C. elegans from learning to avoid pathogenic bacteria. We find that learning depends on the balanced signaling of two insulin-like peptides (ILPs), INS-16 and INS-4, which act respectively in the pheromone-sensing neuron ADL and the bacteria-sensing neuron AWA. Pheromone exposure inhibits learning by disrupting this balance: it activates ADL and increases expression of ins-16, and this cellular effect reduces AWA activity and AWA-expressed ins-4. The activities of the sensory neurons are required for learning and the expression of the ILPs. Interestingly, pheromones also promote the ingestion of pathogenic bacteria while increasing resistance to the pathogen. Thus, the balance of the ILP signals integrates social information into the learning process as part of a coordinated adaptive response that allows consumption of harmful food during times of high population density.


Experimental study on shear characteristics of the silty clay soil-ice interface.
During the spring thawing, the decrease of soil-ice interface strength by temperature may lead to slope instability. For this reason, some researchers have explored the relationship between temperature and soil-ice interface strength. However, previous studies have not systematically explored the change law of strength at the soil-ice interface from negative temperature to 0 °C. Therefore, direct shear tests were conducted at different shear temperatures and different moisture contents. The effects of temperature and moisture content on strength, cohesion, and internal friction angle are analyzed, while the shear failure mechanism of specimens at different temperatures is discussed according to the location of the shear failure surface. The results show that: Shear properties of soil ice specimens are related to the unfrozen moisture content. The strength of the sample decreases with increasing temperature, and the change in strength is most significant from - 2 to - 0 °C. The strength reduction in this range is from 21.8 to 74.8%, and the higher the moisture content the more obvious this phenomenon is. The shear index tends to decrease with the increase of unfrozen water content, and the greater the increase of unfrozen water, the faster the decrease of both, especially in stage 2. When the temperature is higher than - 5℃, the failure surface is located above the soil-ice interface, and the strength of the specimen is similar to that of the frozen soil. When the temperature is - 10℃, the shear damage surface appears at the soil-ice interface, and the strength of the specimen is determined by the strength of the soil-ice interface.


Area method for the estimation of partition coefficients for physiological pharmacokinetic models.
A new technique, the area method, is derived for the determination of partition coefficients for both blood-flow limited and membrane limited physiological pharmacokinetic models. This method was compared to a standard technique by Monte Carlo simulation. Partition coefficients were calculated for the blood-flow limited case for both eliminating and noneliminating organs. It was found that the area method compared favorably to a standard technique and was less prone to error. This may be attributed to the more subjective interpretation as to which data points are included in the terminal phase, since the standard method relies on the accurate determination of the terminal slope for the calculation of partition coefficients. Both methods are satisfactory for the calculation of partition coefficients with the area method being more accurate and precise.


Structural diversity in binary superlattices self-assembled from polymer-grafted nanocrystals.
Multicomponent nanocrystal superlattices represent an interesting class of material that derives emergent properties from mesoscale structure, yet their programmability can be limited by the alkyl-chain-based ligands decorating the surfaces of the constituent nanocrystals. Polymeric ligands offer distinct advantages, as they allow for more precise tuning of the effective size and 'interaction softness' through changes to the polymer's molecular weight, chemical nature, architecture, persistence length and surrounding solvent. Here we show the formation of 10 different binary nanocrystal superlattices (BNSLs) with both two- and three-dimensional order through independent adjustment of the core size of spherical nanocrystals and the molecular weight of densely grafted polystyrene ligands. These polymer-brush-based ligands introduce new energetic contributions to the interparticle potential that stabilizes various BNSL phases across a range of length scales and interparticle spacings. Our study opens the door for nanocrystals to become modular elements in the design of functional particle brush solids with controlled nanoscale interfaces and mesostructures.


Computed Tomography Evaluation of the Arterial Supply to Segment 4 of the Liver.
In a setting of living-donor liver transplant and patients undergoing extended hepatic resections for both primary and metastatic liver tumors, preoperative assessment of hepatic arterial anatomy is very important because of the risk of ischemic complications in the event of inadvertent injury to the arterial supply. Anatomical variations in hepatic arterial supply to the liver are very common and seen in nearly half the population. Identifying anomalous origin of segment 4 hepatic artery is vital since this vessel can cross the transection plane and can result in liver ischemia and liver failure. The purpose of our study is to study the variations in hepatic arterial anatomy to segment 4 of the liver in the Indian population. A retrospective evaluation of 637 consecutive computed tomography (CT) angiograms over a period of 1 year was performed, and we analyzed the arterial supply to segment 4 of the liver. We found that the arterial supply to segment 4 of the liver originated from left hepatic artery (LHA) in majority of cases, 76.3%. LHA along with the accessory LHA supplied this segment in 6.4%, whereas the accessory LHA solely supplied this segment in 0.4%. The right hepatic artery (RHA) was seen to supply this segment in 10.2%. Dual supply with branches from the RHA and LHA was seen in 6.6% of patients. Preoperative mapping of segment 4 hepatic arterial supply using CT angiography will act as a roadmap to surgeons as they attempt to carefully dissect and preserve this segments' arterial supply. Depending on the anatomical variation, surgical techniques will vary to ensure safety of segment 4 arterial supply.


Gray matter heterotopia and acute necrotizing encephalopathy in trichothiodystrophy.
Trichothiodystrophy was diagnosed in a 3-year-old male presenting with speech delay, brittle hair, chronic neutropenia, and a history of febrile convulsions. Cranial magnetic resonance imaging revealed a focal subcortical and periventricular gray matter heterotopia. An acute encephalopathy with status epilepticus and coma occurred when he was 4 years of age during an upper respiratory tract infection. Magnetic resonance imaging revealed multifocal T2-weighted hypersignal lesions involving mainly the thalami, hippocampi, midbrain, and pons. Analysis of cerebrospinal fluid revealed hyperproteinorachia without pleocytosis. Results of an extensive metabolic evaluation of this acute brain injury, resembling the syndrome of acute necrotizing encephalopathy of childhood described in Japan, were negative. Focal neuronal migration disorder and acute encephalopathy with symmetric thalamic involvement are newly described neurologic manifestations of syndromes with trichothiodystrophy, which suggests that these conditions may have a common genetic background.


The Role of Dermal Regenerative Templates in Complex Lower Extremity Wounds.
Dermal regenerative templates (DRTs) provide an option for management of complex lower extremity wounds. DRTs may be used to achieve definitive wound closure by serving as a scaffold for local tissue infiltration. Healing with a DRT interface leads to histologic and structural properties similar to native skin. DRTs can be applied over deep wounds with exposed critical structures that may have required a local or free flap. DRTs are a valuable option for lower extremity limb reconstruction.


Popliteal aneurysm: a celebration of the bicentennial of John Hunter's operation.
Analysis of the original documents on Hunter's operation revealed that Hunter himself never realized the theoretical implications of his operation, particularly that collateral circulation could develop following ligation of the main arterial trunk of a limb. This operation, however, marks a monumental step in the history of vascular surgery. Even though supplanted only one century later by Matas' obliterating endoaneurysmorraphy, this technique became the first efficient means of managing popliteal aneurysms, the prognosis of which had been absolutely disastrous until that time, leading to either amputation or death in most cases.


Photo-elasticity of silk fibroin harnessing whispering gallery modes.
Silk fibroin is an important biomaterial for photonic devices in wearable systems. The functionality of such devices is inherently influenced by the stimulation from elastic deformations, which are mutually coupled through photo-elasticity. Here, we investigate the photo-elasticity of silk fibroin employing optical whispering gallery mode resonation of light at the wavelength of 1550 nm. The fabricated amorphous (Silk I) and thermally-annealed semi-crystalline structure (Silk II) silk fibroin thin film cavities display typical Q-factors of about 1.6 × 104. Photo-elastic experiments are performed tracing the TE and TM shifts of the whispering gallery mode resonances upon application of an axial strain. The strain optical coefficient K' for Silk I fibroin is found to be 0.059 ± 0.004, with the corresponding value for Silk II being 0.129 ± 0.004. Remarkably, the elastic Young's modulus, measured by Brillouin light spectroscopy, is only about 4% higher in the Silk II phase. However, differences between the two structures are pronounced regarding the photo-elastic properties due to the onset of β-sheets that dominates the Silk II structure.


Chlamydia ophthalmia neonatorum in Cameroon.
In the Ndoungué Hospital in Cameroon 449 new-born babies were examined for a month to check on the occurrence of ophthalmia neonatorum. Silver nitrate eyedrops 1% were applied at birth. The incidence of ophthalmia neonatorum was 19.4%; Chlamydia was found in 8 cases (incidence 1.8%) and gonococci in 4 cases (0.9%). Chemical conjunctivitis was suspected in 13 cases (2.9%). Slight conjunctivitis was seen in 68 cases and severe conjunctivitis in 19 cases (4.2%). A sexually transmitted agent was demonstrated in 6% of the slight cases and in 42% of the severe cases. Ophthalmia neonatorum due to Chlamydia was significantly more frequently severe and without specific features than those due to other agents. Although silver nitrate is still considered to be one of the most effective prophylactic measures for gonococcal ophthalmia neonatorum, in 4 cases this disease still developed. Silver nitrate is ineffective against Chlamydia and is also often the cause of a chemical conjunctivitis. The search is advocated for more efficient medicines in Africa which are effective against both Chlamydia and resistant gonoccoci.


Unsymmetrical polysulfidation via designed bilateral disulfurating reagents.
Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


The effects of phorbol ester on mouse blastomeres: a role for protein kinase C in compaction?
The effects of phorbol myristate acetate (PMA) and other activators of protein kinase C on the cytoskeletal organization of mouse oocytes and early embryos have been examined. The effects observed depended on the developmental stage on exposure to PMA. PMA had little effect on the cytoskeletal or microvillous organization of unfertilized oocytes. Interphase cells from embryos prior to compaction showed limited disruption and loss of microvilli when exposed to PMA and foci of polymerized actin remained visible in the cytocortex of embryos up to the early 8-cell stage. When compacted late 8-cell embryos were exposed to PMA, most microvilli were lost and little polymerized actin remained in the cytocortex. PMA also caused loss of microtubules from compact 8-cell embryos under some experimental conditions. Intercellular flattening was both prevented and reversed. The relevance of these observations to the rearrangement of cell-cell contacts and cytoskeletal organization seen during compaction at the 8-cell stage is discussed and a possible role for protein kinase C in the generation of cell polarity proposed.


Author Correction: A machine-learning heuristic to improve gene score prediction of polygenic traits.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


The influence of substrate peptide length on human beta-tryptase specificity.
Combinatorial chemistry approach was applied to design chromogenic substrates of human beta-tryptase. The most active substrate, Ala-Ala-Pro-Ile-Arg-Asn-Lys-ANB-NH(2), was selected from among over 9 million heptapeptides. The amide of 5-amino-2-nitrobenzoic acid (ANB-NH(2)) attached at the C-terminus served as a chromophore. In order to determine the optimal length of the tryptase substrate, a series of N-terminally truncated fragments of this substrate was synthesized. Pro-Ile-Arg-Asn-Lys-ANB-NH(2), with the determined value of the specificity constant (k(cat)/K(M)) above 9 x 10(6) M(-1) s(-1), appeared to be the most specific substrate of tryptase. This substrate was twice as active as the parent heptapeptide substrate. We postulate that the optimal size of the pentapeptide substrate for the interaction with human beta-tryptase is associated with the unique structure of this proteinase, comprising four almost identical monomer subunits arranged in a square flat ring with its substrate pockets faced inside, forming a tetramer with a central pore that can be penetrated by this short peptide.


Preclinical evaluation of a phosphorothioate oligonucleotide in the retina of rhesus monkey.
Overexpression of vascular endothelial growth factor (VEGF) has been strongly implicated in the development of choroidal neovascularization (CNV) in patients with age-related macular degeneration. In this study, a phosphorothioate oligonucleotide (PS-oligo) targeting both human and rat VEGF(165) genes upstream of the translation initiation code, named DS135 in this study, was evaluated for its uptake dynamics and retinal tolerance after intravitreal (IV) and subretinal (SR) injections in the rhesus monkey. Intravitreal and SR injections of a fluorescent-labeled DS135 (FL-DS135) resulted in both dose- and time-dependent uptake and persistence, and FL-DS135 remained detectable in the retina for at least 3 weeks after injection. Ophthalmic examination showed transient vitreous haze after IV delivery of a high dose but not with a low dose of FL-DS135. Histologic examination showed no evidence of retinal degeneration with respect to IV delivery. After SR delivery, however, dose-related cellular infiltration, transient residual fluid, and slight distortion of the neuroretina were observed. The biologic efficacy of DS135 was further assessed in a laser-induced CNV model, and development of CNV was determined by fluorescein angiography and histologic examination. Incomplete inhibition of CNV formation was observed after IV and SR injection of DS135, but no statistically significant difference was achieved when compared with dose-matched control of PS-oligo. Analysis of fluorescein angiogram and histologic examination showed less than 30% incidence of CNV development in this monkey model. Our study demonstrated that PS-oligos can be successfully introduced into the retina, although with potential limitations, after SR delivery. DS135, a PS-oligo targeting the VEGF gene upstream of the translation initiation code, partially inhibited CNV formation. An improved CNV model is necessary for further confirmation of the full therapeutic potency of DS135 before clinical application.


Synthesis of 2,3-dihydronaphtho[2,3-d][1,3]thiazole-4,9-diones and 2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones and novel ring contraction and fusion reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] into 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones.
Treatment of N-substituted 2-(methylamino)naphthoquinones 3 and -anthracene-1,4-diones 4 with S2Cl2 and DABCO in chlorobenzene gave the corresponding 2,3-dihydronaphtho[2,3-d][1,3]thiazole-4,9-diones 1 and 2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones 2 by triethylamine addition, in high to moderate yields. The DABCO replacement for N-ethyldiisopropylamine in the reaction of anthracene-1,4-diones 4 led unexpectedly to the corresponding 2-thioxo-2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones 10. The reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] 1d, 2d with Et3N in chlorobenzene under reflux yielded 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones 15, 16, i.e., ring contraction and fusion products. A plausible mechanism was proposed for the formation of the products.


A Novel Faster-Acting, Dry Powder-Based, Naloxone Intranasal Formulation for Opioid Overdose.
To examine the pharmacokinetics and safety of FMXIN001, a new intranasal powder-based naloxone formulation, in comparison to Narcan® nasal liquid spray. FMXIN001, was developed by blending drug microspheres with larger lactose monohydrate particles, that serve as diluent and carrier, as well as a disaggregating agent. Scanning electron microscopy and X-ray were used to characterize the formulation and in vitro deposition was investigated using a nasal cast. We compared the pharmacokinetics and safety of FMXIN001 versus Narcan® in two clinical trials: a pilot study with 14 healthy adults and a pivotal trial in 42 healthy adults (NCT04713709). The studies were open-label, single-dose, randomized, two-period, two-treatment, two-sequence crossover studies to assess the pharmacokinetics and safety of FMXIN001 versus Narcan® nasal spray. FMXIN001 comprises naloxone microspheres (5-30 μM) and lactose particles (40-240 μM). Upon in vitro testing, naloxone deposits mainly to the middle turbinates region and the upper part of the nasal cavity of a nasal cast. In human subjects, FMXIN001 produced significantly higher exposure at the initial time points of 4, 10, and 30 min, post-administration, compared to Narcan®. Both treatments were safe and well tolerated. FMXIN001, powder-based spray, results in similar overall exposure to Narcan®, but with more rapid absorption in the first 30 min. FMXIN001 is expected to have a shorter onset of action for a more effective therapeutic intervention to manage opioid overdose. Rapid administration of naloxone in cases of opioid overdose is imperative, given the alarming increase in mortality rates.


Tetany following resuscitation after abruptio placentae.
Serum ionized calcium and magnesium are normally decreased during later stages of pregnancy. A further rapid decline may be caused by the rapid infusion of blood bank products in which citrate is used as an anticoagulant/preservative. Tetany, as reported here, may be precipitated by such infusions. A gravid woman presented in hemorrhagic shock due to abruptio placentae. Rapid infusion of packed red blood cells and fresh frozen plasma precipitated signs of tetany, muscle rigidity, posturing, high airway pressure during mechanical ventilation, etc. Ionized calcium and magnesium blood levels were very low (0.58 mmol/L and 1.0 mg/dL, respectively), but responded to rapid electrolyte administration. Binding of calcium and magnesium by citrate may lead to hypo-ionized calcemic and hypomagnesemic tetany after rapid replacement of blood products in the pregnant patient. This consequence is worsened when extreme alkalemia due to respiratory or metabolic causes is also present.


Explainable machine learning predictions of dual-target compounds reveal characteristic structural features.
Compounds with defined multi-target activity play an increasingly important role in drug discovery. Structural features that might be signatures of such compounds have mostly remained elusive thus far. We have explored the potential of explainable machine learning to uncover structural motifs that are characteristic of dual-target compounds. For a pharmacologically relevant target pair-based test system designed for our study, accurate prediction models were derived and the influence of molecular representation features of test compounds was quantified to explain the predictions. The analysis revealed small numbers of specific features whose presence in dual-target and absence in single-target compounds determined accurate predictions. These features formed coherent substructures in dual-target compounds. From computational analysis of specific feature contributions, structural motifs emerged that were confirmed to be signatures of different dual-target activities. Our findings demonstrate the ability of explainable machine learning to bridge between predictions and intuitive chemical analysis and reveal characteristic substructures of dual-target compounds.


Bilateral neuralgic amyotrophy complicating Weil's disease.
The case of a patient with leptospirosis (treated with trimethoprim) with late neurological complications manifesting as a bilateral plexus syndrome is described. The probable reasons for the continued weakness, in this patient, of the muscles supplied by the anterior interosseus nerve, despite improvement in the proximal muscles, are briefly discussed.


Epidemiology of hepatitis B and the role of vaccination.
Hepatitis B virus (HBV) is a major cause of morbidity and mortality with a disproportionate impact on Asia and Africa. Current guidelines recommend screening at-risk populations for chronic HBV infection so that diagnosed individuals can be linked to appropriate hepatitis care. The vast majority of infected individuals are undiagnosed and untreated, and are at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. In individuals who are not yet infected, the HBV vaccine is safe and highly effective at preventing disease transmission. Countries with successful vaccination programs have been able to dramatically reduce their HBV prevalence. A concerted effort to screen, treat, and vaccinate at-risk individuals has the potential to eliminate HBV as a public health threat by 2030.


Integrating multiple factors to optimize watchtower deployment for wildfire detection.
Traditional human-vision-based watchtower systems are being gradually replaced by the machine-vision-based watchtower system. The visual range of machine-vision-based watchtower is smaller than the range of traditional human-vision-based watchtower, which has led to a sharp increase in the number of towers that should be deployed. Consequently, the overlapping area between watchtowers is larger and overlaps are more frequent than in conventional watchtower networks. This poses an urgent challenge: identifying the optimal locations for deployment. If the number of required watchtowers must be increased to extend the detection coverage, overlaps among watchtowers are inevitable and result in viewshed redundancy. However, this redundancy of the viewshed resources of the watchtowers has not been utilized in the design of fire detection systems. Moreover, fire ignition factors, such as climatic factors, fuels, and human behaviour, cause the fire occurrence risk to differ among forest areas. Thus, the fire risk map of the area should also be considered in watchtower deployment. A fire risk model is used as the first step in producing the fire risk map, which is used to propose a new watchtower deployment model for optimizing the watchtower system by integrating viewshed analysis, location allocation, and multi-coverage of the high-fire-risk area while considering the budget constraints for providing optimal coverage. We use a real dataset of a forest park to evaluate the applicability of our approach. The proposed approach is evaluated against the FV-NB (Full coVerage with No Budget constraint) algorithm and the XV-B (maXimum possible coVerage with a Budget constraint) algorithm in terms of performance. The evaluation results demonstrate that our approach realizes higher coverage gain and excellent multiple-coverage of the fire risk area by integrating the viewshed and the fire risk level into location allocation while satisfying requirements on the overall coverage and budget. The proposed approach is more suitable in the environments with moderate watchtower density, in which overlapping areas are frequent. It offers as much as 8.9-17.3% improvement of multiple-coverage of the high-fire-risk area.