Adiponectin and the risk of gastrointestinal cancers in East Asians: Mendelian randomization analysis.
Adiponectin is an important adipocytokine and has been associated with the risks of gastrointestinal cancers (GICs). Mendelian randomization (MR) analysis is needed to assess the causal relationships between adiponectin and GICs. We retrieved the summary data of genome-wide association studies for adiponectin and six types of GICs in East Asians. A series of quality control steps were performed to select the eligible genetic instrumental tools. Horizontal pleiotropy and between-SNP heterogeneity were tested to choose the primary MR method. We also conducted sensitivity analyses to test the robustness of the main findings. We detected neither heterogeneity nor horizontal pleiotropy for the eligible SNPs in all of the MR analyses. Inverse variance weighted (IVW) was therefore used as the primary method, and suggested that per 10% increase in log-transformed adiponectin level was significantly associated with a decreased risk of gastric cancer (odds ratio [OR] = 0.88, 95% CI 0.81, 0.96), whereas with an increased risk of hepatocellular carcinoma (OR = 1.26, 95% CI 1.09, 1.44) and of biliary tract cancer (OR = 1.54, 95% CI 1.12, 2.12). However, only the association between adiponectin and HCC risk was statistically significant after correction for multiple testing. No statistically significant association was detected between adiponectin and esophageal (OR = 1.05, 95% CI 0.89, 1.23), pancreatic (OR = 1.04, 95% CI 0.78, 1.37), and colorectal cancers (OR = 1.00, 95% CI 0.93, 1.07). Sensitivity analyses did not find contradictory results. High level of adiponectin may have a causal effect on and can serve as a biomarker for the carcinogenesis of gastric cancer, hepatocellular carcinoma, and biliary tract cancer.


Radiologic assessment of resectability and prognosis in esophageal carcinoma.
Utilizing double-contrast technique it is possible to detect the earliest malignant lesions of the esophagus even when the carcinoma is confined to the mucosa. In patients with carcinoma, it is also important to attempt to grade and classify the lesion in order to predict its resectability and prognosis. The resectability of a lesion is determined by the depth of invasion and by the presence or absence of lymph node metastases. The significant factors are the length of the lesion, its gross morphology, the character of its margins, and the depth of ulceration. Unfortunately, the depth of invasion is not necessarily directly related to the prognosis. In some carcinomas confined to the submucosa, lymph node metastases are already present, and these patients have a poor prognosis. The presence of lymph node metastases in early carcinoma can be suggested by the gross morphology of the lesion, its length, irregularity of the surface, and the presence of a complex lesion. Careful analysis of the radiographic features of the carcinoma can be valuable for the assessment of resectability and prognosis.


Investigations into the skin-irritant properties of resiniferonol ortho esters.
A series of esters were produced by partial synthesis from 9,13,14-orthophenylacetyl-resiniferonol. These compounds were tested for irritant effects by means of a mouse ear assay. All of the derivatives, including the parent compound, produced short-term inflammation of mice ears within 1-2 h and the effects did not persist for 24 h. This is in contrast to esters of structurally related tigliane diterpenes which produce a longer-term on mice ears. Highly potent irritants were synthesized which exhibited irritant doses 50% in the 0.0012-0.00021 nmol range. These esters were all substituted phenylacetates of the C-20 position of 9,13,14-orthophenylacethyl-resiniferonol. The meta or para positions of the phenylacetate moiety were substituted with electronegative groups for maximum activity. Compounds exhibiting substituted phenyl propionates at C20 were not irritants in the test used.


H3 phosphorylation-dependent structural changes in chromatin. Implications for the role of very lysine-rich histones.
Contrary to native H1/H5-containing chromatin where phosphorylation induces local structural changes affecting chromatin condensation, in stripped fibers phosphorylation of the totality of H3 molecules does not affect significantly chromatin conformation and DNA-protein interactions. Modification of H3 causes only a slight increase of flexibility of nucleosomal chains, despite important changes in histone topography revealed by immunochemical reactivity studies. We suggest that phosphorylation may only induce into the system the potential for dynamic change by modulating histone-histone interactions within and between nucleosomes, probably as a result of conformational change in the H3 protein. The signal for structural change would come from one or other factors (very lysine-rich histones, non-histones) that influence internucleosomal interactions at very specific locations in the chromatin, probably through protein-protein contacts. So, phosphorylation may modify a direct interaction between the N-terminal basic tail of H3 and very lysine-rich histones.


Proprioception retraining for a patient with chronic wrist pain secondary to ligament injury with no structural instability.
Case report. Previously published studies demonstrate the importance of the sensory innervation of the carpal ligaments and the implication for the sensorimotor control of the wrist. In addition, this case considers key rehabilitation concepts to include the dart-throwing motion and the stabilizing effect of the forearm muscles. To describe the rehabilitation program for a patient with chronic wrist pain, diagnosed with a partial tear of the dorsal intercarpal ligament and a sprain of the scapholunate ligament of the right wrist. The patient participated in a staged treatment plan over a 3-month period (20 sessions), which began with a focus on proprioceptive awareness and joint position sense retraining. The treatment progressed to strengthening of specific muscles to enhance stability of the wrist joint. The patient completed the Quick Disabilities of the Arm, Shoulder and Hand and the patient-rated wrist evaluation on initial evaluation, re-evaluation at ninth session, and discharge at 20th session. Raw scores in the Quick Disabilities of the Arm, Shoulder and Hand and the patient-rated wrist evaluation improved from 33 and 61.5 on initial evaluation to 18 and 17.5 on discharge, respectively. Sensorimotor techniques including proprioceptive retraining may improve pain, neuromuscular control, and functional outcomes in patients with chronic wrist pain due to ligament injury. The effectiveness of proprioceptive retraining needs to be evaluated in a well-designed randomized controlled trial recruiting this patient population. 5.


A clinical audit of anatomical side marker use in a pediatric medical imaging department: A quantitative and qualitative investigation.
The presence of a radiopaque or digital anatomical side marker (ASM) is an important diagnostic feature on radiographs and should be a routine feature on every radiographic image. Despite its importance, research has indicated numerous instances where ASMs were absent which have the potential to lead to adverse events. To date, few studies have systematically examined the use of ASMs in clinical practice and explored medical imaging professionals' perspectives on ASM use. This research aimed to address this knowledge gap. This investigation was conducted in two stages. Stage 1 involved a retrospective clinical audit of 421 randomly selected radiographs within 12-months at a pediatric medical imaging department. The data were analyzed for overall presence and type of marker use. Stage 2 comprised of semi-structured interviews with 11 radiographers to garner their perspectives on ASM use, and barriers and enablers to their use in clinical practice. The interviews were transcribed verbatim and thematically analyzed. The overall presence of ASMs (radiopaque and digital) was observed on 99 per cent of radiographs. There was a noticeable shift towards the use of digital (78.8 per cent) compared to radiopaque ASMs (20.2 per cent), highlighting the growing trend towards using ASM in post-processing. A handful of images (N = 4) did not include any ASMs. Semi-structured interviews revealed multifaceted barriers (time, infection precautions, and patient factors) and few enablers (professionalism, legal requirement) for ASM use. This investigation, informed by quantitative and qualitative research paradigms, has shed new light on an important area of radiography practice. While missing ASMs were a small feature, there continue to remain opportunities where best practice standards can be improved. The increasing use of digital ASMs potentially highlights a shift in clinical practice standards.


Comparative transcriptome analysis of muscular dystrophy models Large(myd), Dmd(mdx)/Large(myd) and Dmd(mdx): what makes them different?
Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of Mendelian diseases. The underlying pathophysiology and phenotypic variability in each form are much more complex, suggesting the involvement of many other genes. Thus, here we studied the whole genome expression profile in muscles from three mice models for MD, at different time points: Dmd(mdx) (mutation in dystrophin gene), Large(myd-/-) (mutation in Large) and Dmd(mdx)/Large(myd-/-) (both mutations). The identification of altered biological functions can contribute to understand diseases and to find prognostic biomarkers and points for therapeutic intervention. We identified a substantial number of differentially expressed genes (DEGs) in each model, reflecting diseases' complexity. The main biological process affected in the three strains was immune system, accounting for the majority of enriched functional categories, followed by degeneration/regeneration and extracellular matrix remodeling processes. The most notable differences were in 21-day-old Dmd(mdx), with a high proportion of DEGs related to its regenerative capacity. A higher number of positive embryonic myosin heavy chain (eMyHC) fibers confirmed this. The new Dmd(mdx)/Large(myd-/-) model did not show a highly different transcriptome from the parental lineages, with a profile closer to Large(myd-/-), but not bearing the same regenerative potential as Dmd(mdx). This is the first report about transcriptome profile of a mouse model for congenital MD and Dmd(mdx)/Large(myd). By comparing the studied profiles, we conclude that alterations in biological functions due to the dystrophic process are very similar, and that the intense regeneration in Dmd(mdx) involves a large number of activated genes, not differentially expressed in the other two strains.


Do patients with metastatic urothelial carcinoma benefit from docetaxel as second-line chemotherapy?
To evaluate the efficacy and toxicity of docetaxel regimen as second-line after failure of a platinum-based chemotherapy. Between May 2005 and June 2008, we retrospectively analyzed the data of 22 patients who had evidence of disease progression after one prior platinum-based regimen for metastatic urothelial carcinoma. Patients were treated with two different docetaxel dose schedules: (1) docetaxel 60 mg/m(2) every 21 days for unfit patients or (2) docetaxel 75 mg/m(2) every 21 days for fit patients. Median number of docetaxel cycles was three. Overall disease control rate was 18 %. Of the 22 patients, no patient achieved complete or partial response and four patients had stable disease. Median progression-free survival was 1.67 months and median overall survival was 3.12 months. Neutropenia was the most common adverse event. This study identifies that docetaxel as second-line chemotherapy has low activity and was associated with significant toxicity.


UVA-mediated downregulation of MMP-2 and MMP-9 in human epidermal keratinocytes.
While human dermal fibroblasts increase the expression and secretion of distinct matrix metalloproteinases (MMPs) in response to ultraviolet (UV) irradiation, much less is known about regulation of MMPs with regard to normal human epidermal keratinocytes (NHEK). In this in vitro study, the effect of ultraviolet A (UVA) irradiation on gelatinase expression and secretion by NHEK was investigated. Irradiation of NHEK with non-toxic doses of UVA resulted in a dose-dependent downregulation of MMP-2 (gelatinase A) and MMP-9 (gelatinase B). A single dose of 30JUVA/cm(2) lowered MMP-2 activity to 26% and MMP-9 activity to 33% compared with mock-irradiated cells at 24h after irradiation. Downregulation of MMP-2 and MMP-9 steady-state mRNA levels was observed at 4h after UVA irradiation. The inhibitory effect of UVA on gelatinases was mediated by UVA-generated singlet oxygen (1O(2)). These findings suggest an inverse response to UVA irradiation in NHEK than in fibroblasts.


Stabilization, Rolling, and Addition of Other Extracellular Matrix Proteins to Collagen Hydrogels Improve Regeneration in Chitosan Guides for Long Peripheral Nerve Gaps in Rats.
Autograft is still the gold standard technique for the repair of long peripheral nerve injuries. The addition of biologically active scaffolds into the lumen of conduits to mimic the endoneurium of peripheral nerves may increase the final outcome of artificial nerve devices. Furthermore, the control of the orientation of the collagen fibers may provide some longitudinal guidance architecture providing a higher level of mesoscale tissue structure. To evaluate the regenerative capabilities of chitosan conduits enriched with extracellular matrix-based scaffolds to bridge a critical gap of 15 mm in the rat sciatic nerve. The right sciatic nerve of female Wistar Hannover rats was repaired with chitosan tubes functionalized with extracellular matrix-based scaffolds fully hydrated or stabilized and rolled to bridge a 15 mm nerve gap. Recovery was evaluated by means of electrophysiology and algesimetry tests and histological analysis 4 months after injury. Stabilized constructs enhanced the success of regeneration compared with fully hydrated scaffolds. Moreover, fibronectin-enriched scaffolds increased muscle reinnervation and number of myelinated fibers compared with laminin-enriched constructs. A mixed combination of collagen and fibronectin may be a promising internal filler for neural conduits for the repair of peripheral nerve injuries, and their stabilization may increase the quality of regeneration over long gaps.


Morphological changes and serological reactions in cultured Leishmania donovani promastigotes.
Promastigotes of Leishmania donovani cultured in liquid media gradually changed from a majority of elongated forms through a predominance of intermediate spindle-shaped parasites to a majority of round forms, often aflagellate. Quantitative and qualitative differences among these subpopulations, separated on Percoll gradients, could be demonstrated when they were run on SDS-PAGE gels and stained from proteins or carbohydrates. When cultures containing a majority of one or other form were used as antigenic substrate in serological tests (ELISA and immunofluorescence) the older, round forms were more highly reactive with patients' sera. These forms may represent different phases of the parasite, related to function, and the density variations would provide a convenient method to separate them.


Pitx3 deficiency produces decreased dopamine signaling and induces motor deficits in Pitx3(-/-) mice.
Midbrain dopamine (DA) neurons are involved in cognition, control of motor activity, and emotion-related behaviors. Degeneration of DA neurons particularly in the substantia nigra is a hallmark of Parkinson's disease. The homeobox transcription factor, Pitx3, plays a critical role in the development, function, and maintenance of midbrain DA neurons. We found that in young adult Pitx3-null mice, Pitx3(-/-), there was decreased tyrosine hydroxylase staining, indicating a loss of DA neurons particularly in the substantia nigra. In addition, fast-scan cyclic voltammetry and microdialysis assays of DA release indicated that the lack of Pitx3 caused a significant reduction of striatal DA release. Tonic DA release was impaired more significantly than the phasic DA release induced by burst firing of DA neurons. Furthermore, behavioral tests revealed that Pitx3(-/-) mice displayed abnormal motor activities, including impaired motor coordination and decreased locomotion. In summary, these data provide further evidence that Pitx3 is specifically required for DA-related function and, if impaired, Pitx3 could contribute during the pathogenesis of Parkinson's disease.


Interplay between Brain BDNF and Glutamatergic Systems: A Brief State of the Evidence and Association with the Pathogenesis of Depression.
The excitatory neurotransmitter glutamate system and the brain-derived neurotrophic factor (BDNF) system are principally involved in phenomena of cellular and synaptic plasticity. These systems are interacting, and disclosing mechanisms of such interactions is critically important for understanding the machinery of neuroplasticity and its modulation in normal and pathological situations. The short state of evidence in this review addresses experimentally confirmed connections of these mechanisms and their potential relation to the pathogenesis of depression. The connections between the two systems are numerous and bidirectional, providing for mutual regulation of the glutamatergic and BDNF systems. The available data suggest that it is complex and well-coordinating nature of these connections that secures optimal synaptic and cellular plasticity in the normal brain. Both systems are associated with the pathogenesis of depression, and the disturbance of tight and well-balanced associations between them results in unfavorable changes in neuronal plasticity underlying depressive disorders and other mood diseases.


Bisphosphonate treatment of osteoporosis.
Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. Bisphosphonates reduce the risk of fracture quickly. The risk of radiographic vertebral deformities is reduced after 1 year of treatment with risedronate [68]. The risk of clinical vertebral fractures is reduced after 1 year of treatment with alendronate [69] and just 6 months' treatment with risedronate [157]. The antifracture effect of risedronate has been shown to continue through 5 years of treatment [158]. Alendronate and risedronate are approved by the FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for prevention (risedronate) and treatment (alendronate and risedronate) of glucocorticoid-induced osteoporosis. Alendronate is also approved for treatment of osteoporosis in men. Other bisphosphonates (etidronate for oral use, pamidronate and zoledronate for intravenous infusion) are also available and can be used off label for patients who cannot tolerate approved agents. Although bisphosphonates combined with estrogen or raloxifene produce greater gains in bone mass compared with single-agent treatment, the use of two antiresorptive agents in combination cannot be recommended because the benefit on fracture risk has not been demonstrated and because of increased cost and side effects.


Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity.
This study aimed to explore the neuroprotective effect of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein on early brain injury caused by subarachnoid hemorrhage (SAH) and the relevant mechanisms in experimental rats, expecting to understand whether MANF was a potential therapeutic target for SAH treatment. A perforation model of SAH was introduced into the study. Recombinant human MANF (rh-MANF) and protein kinase B (Akt) inhibitor (MK2206) were used to explore the effect and the mechanisms. Multiple approaches for systemic assessment were employed in the research, including the Garcia test, the SAH grade, Evans blue (EB) dye leakage, brain-water content (BWC), the rotarod test, and the Morris water-navigation task, as were biotechniques, such as immunohistochemistry, Western blot, transmission electron microscopy, and flow cytometry. MANF was mainly expressed in rat neurons, and its expression increased significantly at 3 h after SAH induction and peaked at 24 h. Stereotactic injection of rh-MANF into the cerebroventricle significantly increased the level of MANF, p-Akt, p-mouse double minute 2 homolog (p-MDM2), and B-cell lymphoma 2 (Bcl-2) in brain tissue, whereas it down-regulated the expression of P53, Bcl-2-associated X protein (Bax), and cleaved caspase-3, which indicated that neuronal apoptosis was remarkably suppressed. Expression of matrix metallopeptidase 9 (MMP-9) was also suppressed by the rh-MANF injection. Furthermore, neurologic deficits, EB dye leakage, and BWC were reduced, and long-lasting neuroprotection was noted with rh-MANF administration. The antiapoptotic and blood-brain barrier (BBB) protective effect could be offset by administering MK2206. MANF could alleviate neuronal apoptosis by activating Akt-dependent prosurvival pathway and abate BBB damage via MMP-9 suppression. MANF showed not only transient but also long-lasting neuroprotective properties. The rh-MANF as a potential drug for treating SAH might be of clinical use.-Li, T., Xu, W., Gao, L., Guan, G., Zhang, Z., He, P., Xu, H., Fan, L., Yan, F., Chen, G. Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity.


Treatment and outcomes for anxiety disorders among children and adolescents: a review of coping strategies and parental behaviors.
This article reviews the current literature on the treatment of anxiety disorders in children and adolescents and describes the factors that are essential to address in treatment. Coping deficits and parental behaviors are highlighted as factors that contribute to anxiety in youth. Interventions for anxious youth are described, with particular emphasis on cognitive-behavioral therapy for anxiety disorders. Finally, a review of the longitudinal course of anxiety and suggestions for future directions in treatment and research are provided.


Comparative study of the subjective and objective grading of ptosis surgery outcomes.
To assess the results of blepharoptosis surgery in our hospital by subjective and objective grading of the outcome and comparing them to determine their degree of corelation. Retrospective interventional case series report supplemented by postal questionnaires and telephonic patient surveys. The study included 107 eyelids of 78 patients. Using a simple grading system, surgical outcome was objectively graded as good, suboptimal, or poor. Outcome was also defined according to the patients' perspective as good, suboptimal, or poor. Level of agreement between the subjective and objective grading of the outcome was measured using a weighted kappa analysis. The objective results were classed as good-68/107 (63.5%), suboptimal--18 eyelids (16.8%), and poor--21 eyelids (19.6%). The subjective results were obtainable in 91 eyelids and were good--54/91 (59.3%), suboptimal--8/91 (8.7%), and poor--29/91 (32%). A mismatch between objective and subjective outcomes was seen in 16 eyelids. We saw a statistically significant corelation between the objective grading and the patients' perspective (P<0.001). Our overall ptosis surgery results are comparable with rates previously reported. The subjective and objective outcomes of ptosis surgery may sometimes vary, but nevertheless exhibit substantive agreement when measured by this simple grading system.


Potassium efflux from single skinned skeletal muscle fibers.
The efflux of 42K from single, skinned (sarcolemma removed) skeletal muscle fibers has been determined. Isotope washout curves are kinetically complex and can be fit as the sum of three exponentials, including a fast component (k = 0.25 s-1) with a pool size equivalent to 91% of the fiber volume, an intermediate component (k = 0.08 s-1) equivalent to 6% of the fiber volume, and a slow component (k = 0.008 s-1) equivalent to 0.5% of fiber volume. Only the intermediate kinetic component is significantly affected by pretreatment of fibers with detergent. Efflux curves from detergent-treated fibers could be fit as the sum of two exponentials with coefficients and rate constants comparable to those of the fast and slow component of washout of untreated controls. Similarly the washout of [14C]sucrose can be described as the sum of two exponentials. We conclude that the intermediate component of 42K washout results from the movement of ions from a membrane bound space within the skinned fiber. Because of its relative volume, the sarcoplasmic reticulum seems to be a reasonable choice as a structural correlate for this component. Our estimate of the potassium permeability for the sarcoplasmic reticulum (SR) based on the efflux data is 10(-7) cm/s. This value is less than previous estimates from isolated preparations.


99mTechnetium-labeled cardiac scintigraphy for suspected amyloidosis: a review of current and future directions.
Cardiac amyloidosis (CA) is an underdiagnosed form of restrictive cardiomyopathy leading to a rapid progression into heart failure. Evaluation of CA requires a multimodality approach making use of echocardiography, cardiac magnetic imaging, and nuclear imaging. Technetium (Tc)-labeled cardiac scintigraphy has witnessed a resurgence in its application for the workup of CA. Advancements in disease-modifying therapies have fueled the rapid adoption of cardiac scintigraphy using bone tracers and the need for transformative novel studies. The goal of this review is to present diagnostic utility, currently recommended protocols, as well as a glimpse into the rapid evolution of Tc-labeled cardiac scintigraphy in the diagnosis of CA.


Expression of chemokine receptor CXCR4 is closely correlated with clinical outcome in human nasopharyngeal carcinoma.
The CXC chemokine receptor 4 (CXCR4) has been reported to be involved in the development and progression of nasopharyngeal carcinoma (NPC). However, the role of CXCR4 in clinical outcome and prognosis of NPC patients remains controversial. In the present study, we investigated and reviewed the expression of CXCR4 in NPC tissues and then analyzed the definitive role of CXCR4 in clinical outcome and prognosis. Here, we found that the expression level of CXCR4 was significantly higher in NPC cancer specimens (61/98) than that in paired non-tumor tissues (p < 0.001). Together with our pathological analysis, statistic analysis revealed that CXCR4 expression was indeed closely correlated with UICC stage (p = 0.000), N stage (p = 0.019), and metastasis (p = 0.000). Most importantly, the systematic review combined with our survival and multivariate analysis that revealed high expression of CXCR4 was obviously associated with poor overall survival (OS) (p = 0.000) and progression-free survival (PFS) (p = 0.000) and can act as an independent prognostic factor in NPC patients. In conclusion, this study suggests that CXCR4 is highly activated and expressed in the development of NPC and may be recommended as an indicator in the diagnosis of NPC. Thus, targeting of CXCR4 gene or protein could be used as a potential therapy for NPC.


Vascular relaxation, aging and thyroid hormones.
Previous work indicates vascular can be studied in vitro and that there is a marked age-associated decrease in the ability of rat aortic strips to relax in response to beta-adrenergic agonists. The present studies were aimed at better understanding the role of thyroid hormones in vascular relaxation and aging. Removal of the thyroid gland from young rats resulted in a decrease in the ability of isoproterenol to relax the aorta. Relaxation caused by nitroglycerin, a non-specific relaxant, was not impaired by thyroidectomy. In 22-month-old rats, isoproterenol caused no relaxation unless exogenous thyroid hormones were administered. Hypophysectomy seven months prior to testing improved the ability of thyroid hormones to restore isoproterenol relaxation of the aorta. The loss of relaxation with age could be due in part to a pituitary mediated loss of responsiveness of aortic tissue to thyroid hormones. The data provide new evidence for the importance of thyroid hormones in beta-adrenergic receptor mediated vascular relaxation and demonstrate that the loss of aortic relaxation with aging can be reversed.


Verification of DICOM GSDF in complex backgrounds.
While previous research has determined the contrast detection threshold in medical images, it has focused on uniform backgrounds, has not used calibrated monitors, or has involved a low number of readers. With complex clinical images, how the Grayscale Standard Display Function (GSDF) affects the detection threshold and whether the median background intensity shift has been minimized by GSDF remains unknown. We set out to determine if the median background affected the detection of a low-contrast object in a clustered lumpy background, which simulated a mammography image, and to define the contrast detection threshold for these complex images. Clustered lumpy background images were created of different median intensities and disks of varying contrasts were inserted. A reader study was performed with 17 readers of varying skill level who scored with a five-point confidence scale whether a disk was present. The results were analyzed using reader operating characteristic (ROC) methodology. Contingency tables were used to determine the contrast detection threshold. No statistically significant difference was seen in the area under the ROC curve across all of the backgrounds. Contrast detection fell below 50 % between +3 and +2 gray levels. Our work supports the conclusion that Digital Imaging and Communications in Medicine GSDF calibrated monitors do perceptually linearize detection performance across shifts in median background intensity. The contrast detection threshold was determined to be +3 gray levels above the background for an object of 1° visual angle.


Areas of enduring COVID-19 prevalence: drivers of prevalence and mitigating strategies.
UK local authorities that experienced sustained high levels of COVID-19 between 1st March 2020 and 28th February 2021 were described by the UK Scientific Advisory Group for Emergencies as areas of enduring prevalence. This research was carried out in order to examine the views of local authority Directors of Public Health, who played a crucial role in the local response to COVID-19, on reasons for sustained high levels of prevalence in some areas, alongside an investigation of the mitigation strategies that they implemented during the course of the pandemic. Interviews were conducted with Directors of Public Health in 19 local authority areas across England, between July and November 2021. This included nine areas identified as areas of enduring prevalence and ten 'comparison' areas. The outcomes of this study suggests that the geographical differences in prevalence rates are strongly influenced by health inequalities. Structural factors including deprivation, employment, and housing, due to their disproportionate impact on specific groups, converged with demographic factors, including ethnicity and age, and vaccination rates, and were identified as the main drivers of enduring prevalence. There are key differences in these drivers both within and, to a lesser extent, between local authorities. Other than these structural barriers, no major differences in facilitators or barriers to COVID-19 mitigation were identified between areas of varying prevalence. The main features of successful mitigation strategies were a locally tailored approach and partnership working involving local authority departments working with local health, community, voluntary and business organisations. This study is the first to add the voices of Directors of Public Health, who played a crucial role in the local COVID-19 response. Areas of enduring prevalence existed during the pandemic which were caused by a complex mix of structural factors related to inequalities. Participants advised that more research is needed on the effectiveness of mitigation strategies and other measures to reduce the impact of structural inequalities, to better understand the factors that drive prevalence. This would include an assessment of how these factors combine to predict transmission and how this varies between different areas.


Functional identification of rub52 gene involved in the biosynthesis of rubradirin.
An open reading frame, rub52, has been identified as a gene encoding thymidine diphospho-glucose 2,3-dehydratase by sequence analysis of the rubradirin biosynthetic gene cluster of Streptomyces achromogenes var. nibradiris NRRL3061. The gene codes for a protein consisting of 458 amino acids with calculated molecular mass of 50862 Da. The gene was amplified and heterologously expressed in Escherichia coli as a soluble His-tagged fusion protein. C-2 deoxygenation functionality of thymidine diphospho-4-keto-6-deoxyglucose was assigned to the rub52 gene product from in vitro enzyme assay.


High-throughput process development: determination of dynamic binding capacity using microtiter filter plates filled with chromatography resin.
Steadily increasing demand for more efficient and more affordable biomolecule-based therapies put a significant burden on biopharma companies to reduce the cost of R&D activities associated with introduction of a new drug to the market. Reducing the time required to develop a purification process would be one option to address the high cost issue. The reduction in time can be accomplished if more efficient methods/tools are available for process development work, including high-throughput techniques. This paper addresses the transitions from traditional column-based process development to a modern high-throughput approach utilizing microtiter filter plates filled with a well-defined volume of chromatography resin. The approach is based on implementing the well-known batch uptake principle into microtiter plate geometry. Two variants of the proposed approach, allowing for either qualitative or quantitative estimation of dynamic binding capacity as a function of residence time, are described. Examples of quantitative estimation of dynamic binding capacities of human polyclonal IgG on MabSelect SuRe and of qualitative estimation of dynamic binding capacity of amyloglucosidase on a prototype of Capto DEAE weak ion exchanger are given. The proposed high-throughput method for determination of dynamic binding capacity significantly reduces time and sample consumption as compared to a traditional method utilizing packed chromatography columns without sacrificing the accuracy of data obtained.


Success and failure in gonorrhea control.
This article has shown that all the necessary components for successful control of gonorrhea are available. In developed countries, general improvements in economic conditions and advances in treatment and diagnosis have resulted in the lowest incidence rates of gonorrhea ever. Within these countries, however, control is failing, and gonorrhea is becoming hyperendemic among specific populations who tend to be disadvantaged and marginalized and who may have limited access to health care. Managing gonorrhea in individual patients and ensuring that their sexual partners receive appropriate treatment will contribute to reducing the transmission of infection in the community. Innovative school- and community-based interventions targeted to vulnerable populations will further help to reduce the incidence and contribute to improvements in the sexual health of the population.


Exogenous lipoid pneumonia due to silent aspiration following surgery and radiotherapy for cancer of the tongue.
A man with a history of cancer of the base of the tongue presenting with hemoptysis, recurrent pneumonia and crazy-paving patterns on CT was ultimately diagnosed with lipoid pneumonia, subsequently found to be associated with use of fish oil capsules and possible Parkinson's disease. Pulmonary alveolar proteinosis and invasive mucinous adenocarcinoma as differential diagnoses were considered and dismissed. Risk of aspiration and lipoid pneumonia should be considered in patients with similar radiological findings and history.


Increased intracranial arterial tortuosity is associated with worse cardiovascular outcome in patients with Loeys-Dietz syndrome.
The aim of our study was to evaluate the association between intracranial arterial tortuosity and cardiovascular outcome in patients with Loeys-Dietz syndrome (LDS). We performed a retrospective analysis of all patients with genetically confirmed LDS who underwent at least one brain MRA at our institution (n = 32); demographic and clinical features were evaluated in relation to the tortuosity of intracranial arteries as measured by tortuosity index (TI), which was calculated using the formula: [(centerline length) / (straight-line length)-1] × 100. Receiver operating characteristic curve analysis for intracranial TI and the binary end point of aortic surgery showed vertebrobasilar TI (VBTI) to be the best classifier among the examined arterial segments (AUC = 0.822). Patients with higher VBTI showed a greater incidence of aortic surgery (p < 0.001) and underwent more surgical and endovascular procedures (p = 0.006), with a higher rate of operations (p = 0.002). Kaplan-Meier analysis showed a significantly longer surgery-free survival in patients with lower arterial tortuosity (p < 0.001). At multivariate analysis, higher VBTI was associated with an increased risk of surgery (p < 0.001), which was independent of gene mutation and patient age. Increased VBTI is a marker of adverse cardiovascular outcome in patients with LDS, which can be easily measured on brain MRA, and may be useful in the management of this heterogeneous patient population.


Correlates of disparities in syringe return ratios: A cross-sectional study of a syringe services program in New York.
Predictors of syringe exchange behavior are critical to informing secondary prevention measures needed to attenuate risk of blood-borne infections among persons who inject drugs (PWID). Participants included PWIDs who attended a syringe services program in New York from 2015 to 2017 (n = 1777). We analyzed the syringe return ratio (receipts/returns) with two distinct but related methodological strategies-threshold logistic regression and quantile regression-to identify correlates of disparities in syringe return ratios. The majority of participants were white males negative for HIV (90% white, 63% male, 76% HIV-). Logistic and quantile regression models showed that the correlates of disparate syringe return ratios (i.e., magnitude and directionality of differences) changed across different percentile groups and quantile levels, respectively. At the median threshold, being single, urbanicity, and older age were associated with higher return ratios. Syringe return ratio disparities were more pronounced among subgroups of nontypical PWIDs (with extremely low or high return ratios) especially by urbanicity, race, relationship status, and type of housing. Irrespective of urbanicity classification, correlates of syringe return ratios such as older age, Black race, single relationship status, and unstable housing appear to be critical to informing targeted secondary prevention initiatives that promote harm reduction behavior.


Reversible tenfod reduction in mitochondria DNA content of human cells treated with ethidium bromide.
Cells of the human line VA2-B in suspension culture have been treated with very low concentrations of ethidium bromide for the purpose of reducing the amount of mitochondrial DNA (mit-DNA) per cell. Cells maintained in the presence of 5 ng/ml ethidium bromide grew at a normal rate for three days; thereafter, their doubling time gradually increased to a stable value of about 60 h. In these cells, the rate of 3H thymidine incorporation into mit-DNA decreased very rapidly to approximately 60% of the normal, and remained thereafter at this level, while the amount of mit-DNA per cell stabilized around a level of 70--80% of the control. In cells long-term treated with 5 ng/ml ethidium bromide, the rate of mitochondrial protein synthesis was about 35% of the normal, and the cytochrome c oxidase activity about 50% of the control. Cells treated with 20 ng/ml of the drug underwent 3--4 cell doublings at control rates, then gradually stopped growing, and eventually died. In these cells, the rate of incorporation of 3H thymidine into mit-DNA was reduced to 50% of the control value after 10 min treatment with ethidium bromide, and became barely detectable after three cell doublings. At this time, the cells had on the average less than 10% of the control amount of mit-DNA, the rate of mitochondrial protein synthesis was reduced to 3% of the normal, and the specific activities of cytochrome c oxidase and rutamycin-sensitive ATPase were less than 20% of the control values. In spite of these marked changes, the cells exhibited only a 20--30% loss in cell viability, as estimated by cloning efficiency, after three days of exposure to the drug. Cells treated with ethidium bromide at 20 ng/ml for three days, and then transferred to drug-free medium, recovered a near-to-normal growth rate and cloning efficiency and a near-to-normal rate of synthesis and amount of mit-DNA in about five days.


ARSD, a novel ERα downstream target gene, inhibits proliferation and migration of breast cancer cells via activating Hippo/YAP pathway.
Advanced breast cancer (BC), especially basal like triple-negative BC (TNBC), is a highly malignant tumor without viable treatment option, highlighting the urgent need to seek novel therapeutic targets. Arylsulfatase D (ARSD), localized at Xp22.3, is a female-biased gene due to its escaping from X chromosome inactivation (XCI). Unfortunately, no systematic investigation of ARSD on BC has been reported. In this study, we observed that ARSD expression was positively related to ERα status either in BC cells or tissue specimens, which were associated with good prognosis. Furthermore, we found a set of hormone-responsive lineage-specific transcription factors, FOXA1, GATA3, ERα, directly drove high expression of ARSD through chromatin looping in luminal subtype BC cells. Opposingly, ARSD still subjected to XCI in TNBC cells mediated by Xist, CpG islands methylation, and inhibitory histone modification. Unexpectedly, we also found that ectopic ARSD overexpression could inhibit proliferation and migration of TNBC cells by activating Hippo/YAP pathway, indicating that ARSD may be a molecule brake on ERα signaling pathway, which restricted ERα to be an uncontrolled active status. Combined with other peoples' researches that Hippo signaling maintained ER expression and ER + BC growth, we believed that there should exist a regulative feedback loop formation among ERα, ARSD, and Hippo/YAP pathway. Collectively, our findings will help filling the knowledge gap about the influence of ARSD on BC and providing evidence that ARSD may serve as a potential marker to predict prognosis and as a therapeutic target.


Intestinal transfer of sodium [14C]taurocholate in streptozotocin-treated rats.
The effect of streptozotocin (SZ) administration on sodium [14C]taurocholate (TC) transmural transfer was studied in the everted rat ileum. The excretion of fecal bile acids was also studied in living rats injected with that compound. The viability of the preparation used for the in vitro experiments was evaluated by light microscopy and by the rate of glucose uptake by tissue from the mucosal fluid. The results obtained showed that TC transfer to the serosal fluid was impaired after 24 h of SZ injection, as well as the active transport observed in control preparations. The amount of TC accumulated in the intestinal tissue was also diminished. In addition, total ATPase activity of tissue was decreased, and intracellular electrolyte concentration was altered. Therefore, a slower saturation of binding sites could be responsible for the effects of SZ on TC tissue accumulation, and a decreased ATPase activity for the impairment of the TC concentrative transport system. The results observed in vitro were supported by data in vivo because fecal bile acid excretion was significantly diminished in SZ-treated rats.


Mechanisms in biomedical ontology.
The concept of a mechanism has become a standard proposal for explanations in biology. It has been claimed that mechanistic explanations are appropriate for systems biology, because they occupy a middle ground between strict reductionism and holism. Because of their importance in the field a formal ontological description of mechanisms is desirable. The standard philosophical accounts of mechanisms are often ambiguous and lack the clarity that can be provided by a formal-ontological framework. The goal of this paper is to clarify some of these ambiguities and suggest such a framework for mechanisms. Taking some hints from an "ontology of devices" I suggest as a general approach for this task the introduction of functional kinds and functional parts by which the particular relations between a mechanism and its components can be captured.


Association between histological diaphragm atrophy and ultrasound diaphragm expiratory thickness in ventilated patients.
Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients. Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed. Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 μm2). Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous.


Acute atherosis. A histopathological hallmark of immune aggression?
Acute atherosis is a maternal vascular lesion observed regularly in cases of pre-eclampsia and idiopathic intrauterine growth retardation. This vasculopathy is characterized by fibrinoid necrosis of the vessel wall, an accumulation of lipid-laden macrophages, and a mononuclear perivascular infiltrate. Similar vascular lesions are seen in the decidual vessels of patients with autoimmune diseases, and in renal, cardiac and hepatic homograft rejection. Immunohistochemical studies often reveal extensive vascular deposition of IgM and complement in acute atherosis-like lesions. Granular deposition of immunoglobulins and complement within the vessel walls and mononuclear perivascular infiltrate may be a histopathological hallmark of a maternal immunological aggression against fetal tissues.


Viscoelastic properties of bone as a function of water content.
Stress relaxation of bovine femur was investigated as a function of water content, phi. As found for bone and bone collagen [Sasaki et al. (1993) J. Biomech. 26, 1369-1376], all the relaxation curves measured were described by a linear combination of a Kohlrausch-Williams-Watts (KWW) function and a simple exponential decay (Debye) function: G(t)/Gi = A1 exp[- (t/tau 1)beta] + A2 exp(= t/tau 2), A1 + A2 = 1, 0 < or = beta < or = 1, where Gi is an initial value of the relaxation shear modulus G(t), A1 and A2 are portions of KWW and Debye relaxations, respectively, and tau 1 and tau 2 are relaxation times of respective relaxations. Shear modulus values in the relaxation described by the KWW function (KWW relaxation) depend remarkably on phi while those in Debye relaxation are almost constant for increasing phi. phi dependencies of A1, tau 1 and beta are explained by assuming that the elementary process for the KWW relaxation would be a rearranging process of local disorders in the collagen molecular array. The relaxation rate for the Debye relaxation (= 1/tau 2) decreases linearly with phi. This linear relation between tau 2-1 and phi was well described on the basis of the concept of non-elasticity of a solid by the nuclearion of microcracks at the area of stress concentration.


Transient acrosomal hypoplasia of spermatozoa and male fertility.
Successful pregnancy was established despite previous demonstration of acrosomal hypoplasia. Although initial studies of sperm function and electron microscopic evaluation of the semen documented the presence of severe structural abnormalities, the condition proved to be transient in nature.


Tuberculosis: feeding the enemy.
The nutrition of intracellular Mycobacterium tuberculosis is particularly experimentally intractable. In this issue of Chemistry and Biology, using 13C labeling with a new method of data analysis, Beste and colleagues provide direct evidence for the nutrients and pathways used by this ancient enemy of humanity.


Determinants of exercise adherence and maintenance among patients with hypertension: a narrative review.
Treatment options for hypertension have been evolving over time. However, prevalence rates keep increasing and perpetuate hypertension as a major cardiovascular risk factor. Exercise training is effective in reducing blood pressure, cardiovascular disease risk factors and mortality, besides improving quality of life. However, participation rates for hypertensive patients remain shockingly low and adherence to exercise training tends to decline following exercise programs. These trends emphasize the need to deepen our knowledge of modifiable intrapersonal, interpersonal, and socioeconomic and environmental factors that help explain exercise adherence among people with hypertension. The present review focuses on the determinants of adherence and long-term maintenance of a physically active lifestyle in hypertensive individuals.


Ganglion Cell Complex Thinning in Young Gaucher Patients: Relation to Prodromal Parkinsonian Markers.
Patients with Gaucher disease (GD) have an increased risk for parkinsonism. Retinal thinning has been described in parkinsonism as an early nonmotor feature. Scarce reports have addressed retinal thickness changes in GD. The objectives of this study were to compare ganglion cell complex (GCC) thickness in adolescents and young adults (AYAs) with GD with healthy control subjects, and to correlate it with the presence of parkinsonian features (PFs), clinical prodromal markers of parkinsonism, severity score index (SSI), and glucosylsphingosine (Lyso-GL-1). This study included 48 AYAs with GD (11-29 years), 11 with manifest PFs (Group 1) and 37 with no PFs (Group 2), and 48 matched healthy control subjects (Group 3). Age of GD onset, disease duration, medication history, history of constipation, SSI, and hematological assessment were done. Neurocognitive evaluation included Parts I, II, and III of the Unified Parkinson's Disease Rating Scale (UPDRS), Wechsler Adult and Intelligence Scale and Wechsler Intelligence Scale for Children, Beck Depression Inventory (BDI), rapid eye movement sleep behavior disorder (RBD) scale, Munich Parasomnia Screening scale, and the olfactory dysfunction scale. Molecular analyses of the acid GBA gene and Lyso-GL-1 were done. Participants underwent full ophthalmological examination and optical coherence tomography with GCC thickness measurement. GCC was significantly thinner in Group 1 than in Groups 2 and 3 (P < 0.001), whereas no significant difference was found between Groups 2 and 3 (P = 0.977). In addition, a significant interocular GCC thickness difference was found among the studied AYAs with GD (P = 0.007). GCC correlated positively with total intelligence quotient (P < 0.001) and negatively with Lyso-GL-1 (P = 0.019), UPDRS (P = 0.004), and BDI (P = 0.029), but not with SSI (P = 0.874), GD type (P = 0.85), or genotype (P = 0.842). A significant negative relationship was found between GCC thickness and PFs (P = 0.001), parasomnia (P = 0.003), constipation (P = 0.031), RBD (P = 0.044), and hyposmia (P = 0.033). GCC thinning may be a promising biomarker for central nervous system neurodegeneration that has the potential to monitor early PFs among people with GD. © 2020 International Parkinson and Movement Disorder Society.


Assessment of breast cancer response to neoadjuvant chemotherapy: is volumetric MRI a reliable tool?
The purpose of this study was to evaluate the reliability of volumetric magnetic resonance imaging (MRI) in breast cancer size assessment before, during and after neoadjuvant chemotherapy (NAC). Volumetric MRI measures performed on 15 patients with breast cancer were compared with volumes reckoned upon mean lesional diameters, using the same MRI data. Concordance correlation coefficient (CCC), Bland & Altman plots, RECIST evaluation and Cohen's Kappa were assessed, to evaluate the agreement between the two methods. CCC was computed before (0.9357), during (0.8053) and after (0.7499) NAC, in all examinations pooled together (0.8617), and on final tumor volume as a percentage of baseline volume (0.9224). In 2/15 (13.3%) cases RECIST assessment was different. Cohen's Kappa was 0.787 (CI(95%)=0.513-1.062). In summary, volumetric MRI is a reliable tool to assess breast cancer size before, during and after NAC. Further investigations are needed to understand whether improvements in surgical planning are feasible.


P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology.
High-risk (HR) human papillomaviruses (HPVs) are the main agents involved in the pathogenesis of cervical preinvasive and invasive lesions. Their regression or persistence is paramount in the progression or regression of preinvasive lesions. Therefore, the diagnosis of the presence or absence of HR-HPV is essential in the prognosis and follow-up of low-grade and high-grade squamous intraepithelial lesions. Human papillomavirus DNA and messenger RNA can be identified by a variety of molecular methods; however, their clinical use has limitations. The fact that p16(INK4a) is a surrogate marker for the presence of HR-HPV is well established. However, the clinical usefulness of p16(INK4a) is currently limited by the lack of immunohistologic and cytologic standardization of a scoring system. This article presents an overview illustrating this shortcoming based on relevant literature data.


Discovery and widespread occurrence of polyhalogenated 1,1'-dimethyl-2,2'-bipyrroles (PDBPs) in marine biota.
Polyhalogenated 1,1'-dimethyl-2,2'-bipyrroles (PDBPs) are halogenated natural products (HNPs) previously shown to bioaccumulate in marine mammals and birds. Since their discovery in 1999, six hexahalogenated and a few lesser halogenated congeners have been identified in diverse marine mammal samples. Here we report the identification of 17 additional hexahalogenated PDBPs in the blubber extract of a humpback dolphin (Sousa chinensis) from Queensland, Australia. Thirteen of these new PDBPs were also detected in an Australian sea cucumber (Holothuria sp.). Additional samples were also tested positive on several new PDBPs, including an Australian venus tuskfish (Choerodon venustus) as well as a white whale (Delphinapterus leucas) and a sperm whale (Physeter macrocephalus) from the Northern Hemisphere. GC/ECNI-MS-SIM quantification of the molecular ions was carried out with the help of synthesized standards. The sum concentration of PDBPs was 1.1 mg/kg lipid in the humpback dolphin and 0.48 mg/kg lipid in the sea cucumber.


1-Methyl-2-pyrrolidinone (NMP) does not induce structural and numerical chromosomal aberrations in vivo.
1-Methyl-2-pyrrolidinone induces aneuploidy in yeast, but only under special treatment conditions. Other genotoxic effects have not been found in vitro, and in vivo no data are available in the literature. Therefore, NMP was investigated in the mouse micronucleus test and the Chinese hamster bone marrow test for structural and numerical chromosomal aberrations. These tests can detect both types of alterations as demonstrated by appropriate positive control substances (cyclophosphamide, vincristine sulfate and benomyl). NMP at single oral doses up to 3800 mg/kg body weight (approximately 80% of the LD50) did not lead to an increase either in micronucleated erythrocytes or in structural or numerical chromosomal aberrations when bone marrow was sampled 16, 24 and 48 h after treatment in the micronucleus test or after 24 and 48 h for karyotype analysis.


Association between number of medications and mortality in geriatric inpatients: a Danish nationwide register-based cohort study.
To explore the association between the number of medications and mortality in geriatric inpatients taking activities of daily living and comorbidities into account. A nationwide population-based cohort study was performed including all patients aged ≥ 65 years admitted to geriatric departments in Denmark during 2005-2014. The outcome of interest was mortality. Activities of daily living using Barthel Index (BI) were measured at admission. National health registers were used to link data on an individual level extracting data on medications, and hospital diseases. Patients were followed to the end of study (31/12/2015), death, or emigration, which ever occurred first. Kaplan-Meier survival curves were used to estimate crude survival proportions. Univariable and multivariable analyses were performed using Cox regression. The multivariable analysis were adjusted for age, marital status, period of hospital admission, BMI, and BI (model 1), and additionally either number of diseases (model 2) or Charlson comorbidity index (model 3). We included 74,603 patients (62.8% women), with a median age of 83 (interquartile range [IQR] 77-88) years. Patients used a median of 6 (IQR 4-9) medications. Increasing number of medications was associated with increased overall, 30-day, and 1-year mortality in all three multivariable models for both men and women. For each extra medication, the mortality increased by 3% in women and 4% in men in the fully adjusted model. Increasing number of medications was associated with mortality in this nationwide cohort of geriatric inpatients. Our findings highlight the importance of polypharmacy in older patients with comorbidities.


Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo-cleavage agents.
Sulfonyloxyl radicals, readily generated upon UV irradiation of p-pyridine sulfonyl ethanone oxime derivatives, effectively cleave DNA, in a pH independent manner, and under either aerobic or anaerobic conditions. p-Pyridine sulfonyl ethanone oxime derivatives were synthesized from the reaction of p-pyridine ethanone oxime with the corresponding sulfonyl chlorides in good to excellent yields. All compounds, at a concentration of 100μM, were irradiated at 312nm for 15min, after incubation with supercoiled circular pBluescript KS II DNA and resulted in extended single- and double- strand cleavages. The cleavage ability was found to be concentration dependent, with some derivatives exhibiting activity even at nanomolar levels. Besides that, p-pyridine sulfonyl ethanone oxime derivatives showed good affinity to DNA, as it was observed with UV interaction and viscosity experiments with CT DNA and competitive studies with ethidium bromide. The compounds interact to CT DNA probably by non-classical intercalation (i.e. groove-binding) and at a second step they may intercalate within the DNA base pairs. The fluorescence emission spectra of pre-treated EB-DNA exhibited a significant or moderate quenching. Comparing with the known aryl carbonyloxyl radicals the sulfonyloxyl ones are more powerful, with both aryl and alkyl sulfonyl substituted derivatives to exhibit DNA photo-cleaving ability, in significantly lower concentrations. These properties may serve in the discovery of new leads for "on demand" biotechnological and medical applications.


Successful endoscopic sclerotherapy for anastomotic tumor hemorrhage: A case report.
A 71-year-old male developed anastomotic tumor bleeding after subtotal gastrectomy (Billroth II), and the surgery was refused due to coronary atherosclerotic heart disease. Endoscopic sclerotherapy (ES) in the treatment of esophagogastric variceal bleeding has been commonly reported, but few in non-variceal upper gastrointestinal bleeding. As far as we know, endoscopic sclerotherapy for malignant tumor hemorrhage has not been reported. Here a valuable case is presented: endoscopic sclerotherapy was performed on the anastomotic tumor bleeding, which is an effective try in a particular period.


The erythroblastic island niche: modeling in health, stress, and disease.
Erythropoiesis is one of the most demanding processes in the body, with more than 2 million red blood cells produced every second. Multiple hereditary and acquired red blood cell disorders arise from this complex system, with existing treatments effective in managing some of these conditions but few offering a long-term cure. Finding new treatments relies on the full understanding of the cellular and molecular interactions associated with the production and maturation of red blood cells, which take place within the erythroblastic island niche. The elucidation of processes associated within the erythroblastic island niche in health and during stress erythropoiesis has relied on in vivo modeling in mice, with complexities dissected using simple in vitro systems. Recent progress using state-of-the-art stem cell technology and gene editing has enabled a more detailed study of the human niche. Here, we review these different models and describe how they have been used to identify and characterize the cellular and molecular pathways associated with red blood cell production and maturation. We speculate that these systems could be applied to modeling red blood cell diseases and finding new druggable targets, which would prove especially useful for patients resistant to existing treatments. These models could also aid in research into the manufacture of red blood cells in vitro to replace donor blood transfusions, which is the most common treatment of blood disorders.


Repairing damaged myocardium: evaluating cells used for cardiac regeneration.
Cellular cardiomyoplasty has raised hopes of regenerating mechanical function in the heart. Several cell sources have been investigated for their ability to repair the damaged heart, providing reason for optimism. Multiple mechanisms have been proposed for the beneficial effects of the delivered cells; however, true reversal of cardiac damage implies the generation of new contractile myocytes. The assessment of a cell's ability to regenerate contractile cells requires a defined set of criteria that, if met, define success. Here we review data from the four primary players in cellular cardiomyoplasty (skeletal myoblasts, bone marrow cells, embryonic stem cells, and resident cardiac stem cells) and assess their potential to differentiate into contractile myocytes as indicated by their ability to meet such specified milestones. Both animal studies and clinical trials suggest that current experimental approaches to cellular cardiomyoplasty yield short-term improvement, although it may be independent of cell type used. However, the mechanisms underlying this salutary effect, as well as its persistence in the longer term, have remained elusive.


The suitability of a membrane diffusion growth chamber for studying bacterial interaction.
Rates of diffusion of nutrients and metabolites through 0.1 micron pore diameter polycarbonate membranes are so low that the use of membrane-separated systems to study bacterial interaction seems to have little application. Effective nutrient availability throughout the system is very dependent on membrane area/medium volume ratio. An attempt to demonstrate a known interaction in the membrane diffusion chamber was not successful.


Effects of Hatchery Rearing on the Structure and Function of Salmonid Mechanosensory Systems.
This paper reviews recent studies on the effects of hatchery rearing on the auditory and lateral line systems of salmonid fishes. Major conclusions are that (1) hatchery-reared juveniles exhibit abnormal lateral line morphology (relative to wild-origin conspecifics), suggesting that the hatchery environment affects lateral line structure, perhaps due to differences in the hydrodynamic conditions of hatcheries versus natural rearing environments, and (2) hatchery-reared salmonids have a high proportion of abnormal otoliths, a condition associated with reduced auditory sensitivity and suggestive of inner ear dysfunction.


Effects of treatments for drooling on caries risk in children and adolescents with cerebral palsy.
Neuromuscular impairment makes individuals with cerebral palsy (CP) more prone to drooling. Among the treatment options, there are procedures that interfere with saliva production. It is imperative to evaluate the effect of the different modalities since the reduction in salivary flow rate/production may exacerbate the risk of dental caries. The aim of this study was to compare the effects of different treatments for drooling on caries risk and salivary parameters in children and adolescents with CP. A total of 142 children and adolescents with CP, aged 6 to 18 years, were assigned to groups based on the different treatments they had received for drooling: G1-anticholinergic drugs (n = 18), G2-botulinum toxin injection (n = 16), G3-salivary glands surgery (n = 16), G4-no treatment (n = 42), and G5-non-drooling subjects (n = 50). All participants were evaluated on the Simplified Oral Hygiene Index, and for the prevalence of dental caries (decayed, missing, and filled teeth index and white spot lesions). Unstimulated whole saliva was collected, and salivary flow rate and osmolality were measured. Chi-square, ANOVA and Poisson regression were calculated. Prevalence ratios and their respective 95 % confidence intervals were obtained. The significance level was fixed at 5%. No differences were found in the decayed, missing, and filled teeth index (p = 0.128) and Simplified Oral Hygiene Index (p = 0.674) among the different groups. G3 presented significantly higher percentages of WSL (p < 0.001), lower values of salivary flow rate (p < 0.001), and higher values of osmolality (p < 0.001). The white spot lesion prevalence ratio was higher only for G3 (Prevalence ratio = 14.36; IC 95% = 4.64-44.40; p < 0.001). Children and adolescents with CP who had received surgical treatment for drooling exhibited higher number of white spot lesions because of the reduced salivary flow rate and higher salivary osmolality.


Social interactions lead to motility-induced phase separation in fire ants.
Collections of fire ants are a form of active matter, as the ants use their internal metabolism to self-propel. In the absence of aligning interactions, theory and simulations predict that active matter with spatially dependent motility can undergo motility-induced phase separation. However, so far in experiments, the motility effects that drive this process have come from either crowding or an external parameter. Though fire ants are social insects that communicate and cooperate in nontrivial ways, we show that the effect of their interactions can also be understood within the framework of motility-induced phase separation. In this context, the slowing down of ants when they approach each other results in an effective attraction that can lead to space-filling clusters and an eventual formation of dynamical heterogeneities. These results illustrate that motility-induced phase separation can provide a unifying framework to rationalize the behavior of a wide variety of active matter systems.


Pudendal nerve conduction to evaluate organic erectile dysfunction.
This study aimed to evaluate the value of testing pudendal nerve conduction in men with erectile dysfunction. This open prospective study was conducted on 150 men with documented erectile dysfunction of at least 6 mo of duration, all of whom underwent pudendal nerve conduction by the same investigator. Only patients with erectile dysfunction and low back pain (n = 9) showed statistically significant prolonged pathologic pudendal nerve conduction latency of 43.1 msec/div (SD +/- 11.3 msec/div, P < 0.05). There were no correlations between the pudendal nerve conduction latency in patients suffering from erectile dysfunction associated with diabetes mellitus, local trauma, pelvic surgery, or antihypertensive drugs. Pudendal nerve conduction may contribute valuable information to the evaluation of patients with erectile dysfunction caused by neurologic deficits as manifested by low back pain.


Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women.
Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Selective estrogen receptor modulators may be an alternative to bisphosphonates for treating rebound resorption after discontinuing denosumab. This study aimed to investigate the effects of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. This retrospective observational study included 61 patients who received 12-month follow-up raloxifene therapy after denosumab discontinuation. The primary endpoint was the bone mineral density change. The secondary endpoints were the changes in bone turnover markers and the incidence of new vertebral fractures. Raloxifene administration for 12 months after denosumab discontinuation resulted in a significantly lower bone mineral density at all sites compared to the level at 6 months after the last denosumab treatment (lumbar spine, - 5.48%; femoral neck, - 2.95%; total hip, - 3.52%; all, p < 0.001). The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Marked increases in the bone turnover markers from baseline were noted after switching to raloxifene. However, no new vertebral fractures occurred during raloxifene treatment. Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. Therefore, raloxifene administered sequentially after denosumab discontinuation was not effective in preventing rebound phenomenon.


Measuring the effect of ambient noise directionality and split-beam processing on the convergence of the cross-correlation function.
Measurements of ambient noise have been used to infer information about the ocean acoustic environment. In recent years the correlation of ambient noise has been shown to give estimates of the travel time of acoustic paths between the sensors recording the noise. A number of issues affect the results of the noise correlation. This paper presents the results of noise correlation of the two horizontally separated arrays of sensors in the 2010 ambient noise experiment. Using the experimental data, the effects on the convergence of the noise correlation are examined with respect to the size and shape of the arrays, the length of time used, and the directionality of the noise field.


The recurrence of pterygium after different modalities of surgical treatment.
To assess and compare the recurrence rate of pterygium after limbal stem cell transplantation versus amniotic membrane transplantation (AMT) as ocular surface reconstructing measures in recurrent pterygium, also evaluation of the use of antimetabolite drugs as adjunctive therapy for AMT. Prospective randomized comparative study included 60 eyes of 48 patients with recurrent pterygia. Informed consents were taken from all patients. Primary pterygium excision was performed 6-15 months ago; the cases were divided randomly into three equal groups: Group 1: included 20 eyes with excision of the pterygium and application of limbal stem cell transplantation with conjunctival autograft, group 2: included 20 eyes with excision of the pterygium followed by AMT and group 3: included 20 eyes in which surgical excision of pterygium was followed by intra-operative application of low-dose of MMC (0.05%) for 3 min then using AMT. The study included 36 males and 12 females of age ranged from 28 to 52 years. The recurrence rate was 2 eyes in group 1 (10%) (limbal stem cell transplantation + conjunctival autograft), 6 eyes in group 2 (30%) (AMT) and 4 eyes (20%) in group 3 (MMC + AMT). The rate of recurrence was significantly different between the three groups (P < 0.001). Limbal stem cell transplantation together with conjunctival autografting proved to be more effective in prevention of pterygium recurrence and in rapid restoration of normal epithelial morphology. MMC in addition to AMT decreases the incidence of recurrence.


New insights from small rhythmic circuits.
Small rhythmic circuits, such as those found in invertebrates, have provided fundamental insights into how circuit dynamics depend on individual neuronal and synaptic properties. Degenerate circuits are those with different network parameters and similar behavior. New work on degenerate circuits and their modulation illustrates some of the rules that help maintain stable and robust circuit function despite environmental perturbations. Advances in neuropeptide isolation and identification provide enhanced understanding of the neuromodulation of circuits for behavior. The advent of molecular studies of mRNA expression provides new insight into animal-to-animal variability and the homeostatic regulation of excitability in neurons and networks.


Attachment insecurity moderates the relationship between disease activity and depressive symptoms in ulcerative colitis.
Among people with ulcerative colitis, depression occurs more frequently when inflammation is active. We hypothesized that individual differences in interpersonal style affect the risk that active disease will be accompanied by depressive symptoms. In this study, disease activity, depressive symptoms, and 2 dimensions of interpersonal style, attachment anxiety and attachment avoidance, were measured in 146 ulcerative colitis outpatients at time 1 and in 99 of these patients at a second time-point, 7 to 37 months later. Test-retest correlations of attachment anxiety (r = 0.83, P < 0.001) and attachment avoidance (r = 0.76, P < 0.001) confirmed that these dimensions are stable. There was a stepwise increase in the correlation between time 2 disease activity and depression from the lowest tercile of attachment anxiety (r = 0.00, P = 0.99), through the middle tercile (r = 0.36, P = 0.05), to the highest tercile (r = 0.52, P = 0.002). For attachment avoidance, disease activity and depression were only significantly correlated in the highest tercile (r = 0.49, P = 0.005). Attachment anxiety meets all tested criteria as a moderator of the relationship between disease activity and depressive symptoms. Further attention to interpersonal style as a moderator of depressive risk in ulcerative colitis is warranted.


Gastrointestinal cancer prevention policies in Iran: A policy analysis of agenda-setting using Kingdon's multiple streams.
Gastrointestinal cancers continue to claim the lives of thousands of individuals. Fortunately, primary prevention, which focuses on interventions to change unhealthy lifestyle behaviors, can lessen the negative effects and decrease the economic burden of these cancers. The purpose of this paper is to assess the likelihood of adopting gastrointestinal cancer prevention policies through the lens of Kingdon's theory of agenda setting. A qualitative study was conducted using document review and face-to-face interviews with 22 key informants from different stages of the policymaking process of gastrointestinal cancer prevention program in Iran. We used purposive sampling. Our analysis of documents and interview were guided based on Kingdon's multiple streams (problem stream, policy stream, and political stream). Based on the results of this study the important factors of problem stream are as below. The high cost of gastrointestinal cancer diagnostic services dramatically affect patient's financial affordability to essential cancer-related services. Consequently, most of the cancers show distant metastasis at the time of diagnosis, imposing catastrophic expenses to patients, society, and the health systems. In the policy stream, participants mentioned the importance of the cancer registry system in the country that provides a clear source of information for decision-makers to plan for early diagnostic services. Under the political stream, the national and international supports provide a favorable climate for this issue. Now that a window of opportunity for gastrointestinal cancer prevention policymaking is created, there is a need for greater efforts to strengthen the inter-sectoral collaboration. The presence of the policy entrepreneurs during this period can press for policy change, however, actors need political support from the highest level of the governance to push this issue on the agenda. This paper is seeking to have impact on the policies related to prevention of gastrointestinal cancers in Iran.


Dynamical Rearrangement of Human Epidermal Growth Factor Receptor 2 upon Antibody Binding: Effects on the Dimerization.
Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER family that is overexpressed in some of the most aggressive tumours. Although it is known that HER2 dimerization involves a specific region of its extracellular domain, the so-called "dimerization arm", the mechanism of dimerization inhibition remains uncertain. However, uncovering how antibody interactions lead to inhibition of HER2 dimerization is of key importance in understanding its role in tumour progression and therapy. Herein, we employed several computational modelling techniques for a molecular-level understanding of the interactions between HER and specific anti-HER2 antibodies, namely an antigen-binding (Fab) fragment (F0178) and a single-chain variable fragment from Trastuzumab (scFv). Specifically, we investigated the effects of antibody-HER2 interactions on the key residues of "dimerization arm" from molecular dynamics (MD) simulations of unbound HER (in a total of 1 µs), as well as ScFv:HER2 and F0178:HER2 complexes (for a total of 2.5 µs). A deep surface analysis of HER receptor revealed that the binding of specific anti-HER2 antibodies induced conformational changes both in the interfacial residues, which was expected, and in the ECDII (extracellular domain), in particular at the "dimerization arm", which is critical in establishing protein-protein interface (PPI) interactions. Our results support and advance the knowledge on the already described trastuzumab effect on blocking HER2 dimerization through synergistic inhibition and/or steric hindrance. Furthermore, our approach offers a new strategy for fine-tuning target activity through allosteric ligands.


Magnitude and possible risk factors of musculoskeletal disorders among street cleaners and solid waste workers: a cross-sectional study.
In the absence of a standardized work environment, insurance system, occupational safety measures and expanding workload an uptrend of musculoskeletal disorders secondary to occupational hazards is observed among a wide range of occupations in developing countries including street sweepers/cleaners. The aim of this study is to determine the burden and potential factors associated with musculoskeletal disorders among street cleaners/solid waste collectors in Gondar town, Ethiopia. A cross-sectional study design was used to determine the burden and identify potential risk factors of musculoskeletal disorders among street cleaners. Street cleaners (n = 422) working experience of at least one year were randomly selected from the community at their respective work sites (street). A face-to-face interview recorded the participant's response addressing socio-demographic, occupational, job satisfaction, disability related to basic ADL, physical measurements, and self-reported pain using the Nordic-Musculoskeletal questionnaire. The logistic regression model was created to identify potential factors associated with self-reported MSDs. The sample consists of women street sweepers/cleaners (100%, n = 422, response rate 100%) with at least one-year of work experience with a mean age of 37.03 ± 8.26. About 40% of women sweepers were illiterate and 95% reported no job satisfaction. The overall prevalence of MSDs was 73% (n = 308, 95% CI; 68.5, 77.2), among them nearly 65% reported having experienced disability in performing basic ADL in the past 12 months. Low back pain was the most prevalent region (n = 216, 70.1% case versus MSDs n = 308). In univariate and multivariate logistics analysis, being overweight/obese (AOR of 4.91 (95%, 2.22, 10.87)), age group 35 and above (AOR 2.534 (1.51, 4.26)), not-satisfied with job (AOR 2.66 (1.05, 6.75)), and street cleaning distance of longer than 2 km (AOR 2.82 (1.64, 4.83)) were significantly associated with self-reported musculoskeletal disorder.. This study demonstrated higher self-reported MSDs among street sweepers/cleaners. Modifiable predictors like overweight, lack of job satisfaction, and cleaning longer distance were identified to be associated. Hence, there is a need for ergonomic measures and policy to curb these factors to reduce the burden of MSD among women street sweepers.


Identification and characterization of an α-1,3 mannosidase from Elizabethkingia meningoseptica and its potential attenuation impact on allergy associated with cross-reactive carbohydrate determinant.
Core α-1,3 mannose is structurally near the core xylose and core fucose on core pentasaccharide from plant and insect glycoproteins. Mannosidase is a useful tool for characterization the role of core α-1,3 mannose in the composition of glycan related epitope, especially for those epitopes in which core xylose and core fucose are involved. Through functional genomic analysis, we identified a glycoprotein α-1,3 mannosidase and named it MA3. We used MA3 to treat allergen horseradish peroxidase (HRP) and phospholipase A2 (PLA2) separately. The results showed that after MA3 removed α-1,3 mannose on HRP, the reactivity of HRP with anti-core xylose polyclonal antibody almost disappeared. And the reactivity of MA3-treated PLA2 with anti-core fucose polyclonal antibody decreased partially. In addition, when PLA2 was conducted enzyme digestion by MA3, the reactivity between PLA2 and allergic patients' sera diminished. These results demonstrated that α-1,3 mannose was an critical component of glycan related epitope.


Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats.
Exogenously administered fructose-1,6-diphosphate (FDP) has been studied for its ability to protect tissue during hypoxia or ischemia. Recently, a clear effect of FDP on the central nervous system has raised the question whether FDP can get into the brain. FDP levels were measured in blood, brain, liver, kidney, muscle and fat after intraperitoneal administration of a single 0.5gkg(-1) dose of FDP to adult male Sprague-Dawley rats. A complete time course of the levels in blood and brain was determined. The levels of FDP in the blood and brain increase simultaneously, i.e. there is no lag in the increase in the brain. The levels of FDP fall to baseline in liver, kidney, muscle and fat by 12h, but remain elevated in blood and brain. However, levels in the blood at 12h are significantly decreased from the peak levels, while those in brain are not different from the peak levels, suggesting that the kinetics of FDP in blood and brain are quite different. Stripping the endothelial cells from the brain tissue sample did not change the levels of FDP indicating that FDP is not trapped in the capillary cells. Incubation of brain slices in a solution of FDP, followed by washing, raised tissue levels of FDP indicating that FDP is taken up into cells within the brain. Finally, the experiments demonstrate a significant increase in brain levels of FDP after oral administration. These data suggest that an oral formulation of FDP might be developed for treatment of neurological disease.


Interleukin‑37 is increased in peripheral blood mononuclear cells of coronary heart disease patients and inhibits the inflammatory reaction.
It has been universally acknowledged that interleukin‑37 (IL‑37) has an immunosuppressive effect on various inflammatory disorders. However, whether IL‑37 participates in the acute inflammation associated with coronary heart disease (CHD) has not yet been clarified. In the present study, the association between the serum levels of IL‑37 and the clinical indexes of CHD were analysed. In addition, the anti‑inflammatory effects of IL‑37 on peripheral blood mononuclear cells (PBMCs) were studied in CHD patients. PBMCs from 46 healthy controls (HCs) and 92 CHD patients were cultured in vitro and stimulated using the recombinant IL‑37 protein. The protein levels, as well as the mRNA expression of inflammatory cytokines (TNF‑α, IL‑1β, IL‑6, and IL‑17) were analysed by enzyme‑linked immunosorbent assay (ELISA) and real‑time polymerase chain reaction (RT‑PCR). Spearman's correlation test was performed to examine the association between the serum level of IL‑37 and the levels of pro‑inflammatory cytokines, certain clinical indexes, and disease activity during CHD. Compared to the HCs, the CHD patients, especially those with acute myocardial infarction, exhibited higher levels of IL‑37 in their PBMCs and sera. Serum levels of IL‑37 were associated with the levels of IL‑17, IL‑6, and TNF‑α, and clinical indexes such as the left ventricular ejection fraction (LVEF), amino‑N‑terminal pro‑plasma brain natriuretic peptide (NT‑proBNP) levels, and cardiac troponin T (cTnT) levels in CHD patients. Compared to the HC group, the production of inflammatory cytokines such as IL‑17, IL‑6, TNF‑α, and IL‑1β increased in the PBMCs of CHD patients and significantly decreased after the stimulation of the cells with recombinant IL‑37. The IL‑37 levels in CHD patients were high, and were correlated with the levels of CHD‑related pro‑inflammatory cytokines and disease activity. Notably, the expression of CHD‑related pro‑inflammatory cytokines in the PBMCs of CHD patients decreased following the stimulation of the cells with recombinant IL‑37, indicating that IL‑37 exerts anti‑inflammatory effects during CHD.


Superficial venous interventions: assessing the risk of DVT.
Understand the potential consequences of deep vein thrombosis (DVT) in patients undergoing superficial venous interventions, the proper way to assess DVT risk in patients with superficial venous disease and the appropriate management of patients stratified by risk level. Review of published literature Because DVT can have major long-term consequences, DVT risk should be assessed as a routine part of the preprocedure evaluation of venous disease. Chronic venous disease may have multiple contributing factors amenable to treatment in both the superficial and deep venous systems. Superficial venous interventions should be deferred in patients at particularly high risk for DVT, but may be performed with appropriate countermeasures for DVT prophylaxis in patients at moderate risk.


At-line quantification of bioactive antibody in bioreactor by surface plasmon resonance using epitope detection.
We report an innovative at-line method to monitor concentration of bioactive antibody (i.e., antibody with conserved antigen-binding activity) secreted during bioreactor culture by the use of surface plasmon resonance (SPR)-based biosensor technology. In a first series of experiments, conditions for SPR-based measurements were validated off-line by monitoring bioactive antibody concentration in conditioned medium from 500-ml baffled flask hybridoma cell cultures. A fully automated experimental setup in which the SPR-based biosensor was harnessed to a bioreactor was then used at-line to monitor the concentration of bioactive antibody produced in a 3.5-L bioreactor. Quantitative SPR measurements performed both at-line and off-line were in excellent agreement with quantitative Western blotting followed by densitometry analyses. Thus, our experimental study confirms that SPR biosensors can be applied to at-line quantification of correctly folded proteins that are secreted by cells cultured in a bioreactor. Our experimental approach represents a novel and robust analytical strategy to be applied to the control and optimization of the production of bioactive secreted proteins.


A Novel Mouse Model of Nonalcoholic Steatohepatitis Suggests that Liver Fibrosis Initiates around Lipid-Laden Macrophages.
While the interaction of cells such as macrophages and hepatic stellate cells is known to be involved in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), the mechanism remains unclear. This study employed a high-fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis to investigate the pathogenesis of fibrosis. Two mouse strains: C57BL/6J, the one susceptible to obesity, and A/J, the one relatively resistant to obesity, developed hepatic histologic features of NASH, including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis, after 9 weeks of HFCC diet. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in the C57BL/6J mice. A/J mice fed HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light was used to visualize the Maltese cross, cholesterol crystals within the aggregated macrophages. Fibrosis developed in a ring shape from the periphery of the aggregated macrophages such that the starting point of fibrosis could be visualized histologically. Matrix-assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine [P-18:1 (11Z)/18:0] and phosphatidylethanolamine [18:0/20:2 (11Z, 14Z)], in aggregated macrophages adjacent to the fibrotic lesions. In conclusion, the HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.


Development, performance evaluation, and clinical application of a Rapid SARS-CoV-2 IgM and IgG Test Kit based on automated fluorescence immunoassay.
The ongoing coronavirus disease 2019 (COVID-19) epidemic has made a huge impact on health, economies, and societies all over the world. Although reverse transcription-polymerase chain reaction (RT-PCR)-based nucleic acid detection has been primarily used in the diagnosis of COVID-19, it is time-consuming with limited application scenarios and must be operated by qualified personnel. Antibody test, particularly point-of-care antibody testing, is a suitable complement to nucleic acid test as it provides rapid, portable, and cost-effective detection of infections. In this study, a Rapid Antibody Test Kit was developed based on fluorescence immunochromatography for the sensitive, accurate, and automated detection of immunoglobulin M (IgM) and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human serum, plasma, and whole blood samples within 10 min. The sensitivity, specificity, precision, and stability of the test kit were of good performance. No cross-activity and no interference was observed. In the multiple-center parallel study, 223 samples from hospitalized patients were used to evaluate the clinical specificity of the test. Both SARS-CoV-2 IgM and IgG achieved a clinical specificity of 98.21%. The clinical sensitivities of SARS-CoV-2 IgM and IgG were 79.54% and 87.45%, respectively, among 733 reverse transcription-polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 samples. For the combined IgM and IgG assays, the sensitivity and specificity were 89.22% and 96.86%, respectively. Our results demonstrate that the combined use of IgM and IgG could serve as a more suitable alternative detection method for patients with COVID-19, and the developed kit is of great public health significance for the prevention and control of the COVID-19 pandemic.


Physiological and anatomical evidence for an inhibitory trigemino-oculomotor pathway in the cat.
During blink down-phase, the levator palpebrae superioris (levator) muscle is inactivated, allowing the orbicularis oculi muscle to act. For trigeminal reflex blinks, the excitatory connections from trigeminal sensory nuclei to the facial nucleus have been described, but the pathway whereby the levator is turned off have not. We examined this question by use of both physiological and anatomical approaches in the cat. Intracellular records from antidromically activated levator motoneurons revealed that periorbital electrical stimulation produced bilateral, long latency inhibitory postsynaptic potentials (IPSPs). Central electrical stimulation of the principal trigeminal nucleus produced shorter latency IPSPs. Intracellular staining revealed that these motoneurons reside in the caudal central subdivision and have 10 or more poorly branched dendrites, which extend bilaterally into the surrounding supraoculomotor area. Axons penetrated in this region could be activated from periorbital and central electrodes. Neurons labeled from tracer injections into the caudal oculomotor complex were distributed in a crescent-shaped band that lined the ventral and rostral aspects of the pontine trigeminal sensory nucleus. Double-label immunohistochemical procedures demonstrated that these cells were not tyrosine hydroxylase-positive cells in the Kölliker-Fuse area. Instead, supraorbital nerve afferents displayed a similar crescent-shaped distribution, suggesting they drive these trigemino-oculomotor neurons. Anterograde labeling of the trigemino-oculomotor projection indicates that it terminates bilaterally, in and above the caudal central subdivision. These results characterize a trigemino-oculomotor pathway that inhibits levator palpebrae motoneurons in response to blink-producing periorbital stimuli. The bilateral distributions of trigemino-oculomotor afferents, levator motoneurons, and their dendrites supply a morphological basis for conjugate lid movements.


[Effect of cold-light bleaching technique on human permanent teeth enamel surface].
To study the effects of the cold-light bleaching technique on crystals and microstructure of the dental enamel. The human premolars extracted for orthodontic reasons were treated by a standard cold-light bleaching procedure. After the treatment, all samples were detected by high resolution micro-area X-ray diffractometer, Fourier transform infrared spectroscope and scanning electron microscope. After the permanent teeth were treated with cold-light bleaching technique, the enamels' crystal dimension, crystallinity decreased and irregular surfaces and shallow disk pits appeared. The cold-light bleaching technique could lead to the changes of crystals and microstructure in the surface layer of dental enamel.


The Tmod cellular logic gate as a solution for tumor-selective immunotherapy.
Immune cells that are engineered with receptors to integrate signals from multiple antigens offer a promising route to achieve the elusive property of therapeutic selectivity in cancer patients. Several types of multi-signal integrators have been described, among them mechanisms that pair activating and inhibitory receptors which are termed NOT gates by analogy to logical operations performed by machines. Here we review one such NOT-gated signal integrator called the Tmod system which is being developed for patients with solid tumors. Coupled with rigorous selection for patients with defined lesions in their tumor genomes (loss of heterozygosity), the Tmod approach presents an unusual opportunity to create truly selective therapies for certain cancer patients. Several of these agents are advancing toward the clinic, supported by a large body of quantitative preclinical data.