The effect of surgical wide excision and amniotic membrane transplantation with adjuvant topical mitomycin C treatment in recurrent conjunctival--corneal intraepithelial neoplasia.
To investigate the effect of surgical wide excision and amniotic membrane transplantation with adjuvant mitomycin C 0.04% eye drops on recurrent conjunctival-corneal intraepithelial neoplasia (CCIN). The authors applied amniotic membrane transplantation after total surgical excision of a tumor to a patient with recurrent conjunctival-corneal intraepithelial neoplasia. The tumor co-existed as a conjunctival lesion and corneal opacity. After one week, the patient received mitomycin C 0.04% eye drops four times a day for one month to prevent recurrence. Ocular complications and recurrence were evaluated under slit lamp microscopy for one year. Corneal epithelium completely healed within one week after the surgery. Both conjunctival and corneal lesions were completely regressed and no recurrence has been found with follow-up to 24 months. Surgical wide excision and amniotic membrane transplantation with adjuvant topical MMC would be an effective treatment modality for treatment of recurrent CCIN.


Dlung: Unsupervised Few-Shot Diffeomorphic Respiratory Motion Modeling.
Lung image registration plays an important role in lung analysis applications, such as respiratory motion modeling. Unsupervised learning-based image registration methods that can compute the deformation without the requirement of supervision attract much attention. However, it is noteworthy that they have two drawbacks: they do not handle the problem of limited data and do not guarantee diffeomorphic (topology-preserving) properties, especially when large deformation exists in lung scans. In this paper, we present an unsupervised few-shot learning-based diffeomorphic lung image registration, namely Dlung. We employ fine-tuning techniques to solve the problem of limited data and apply the scaling and squaring method to accomplish the diffeomorphic registration. Furthermore, atlas-based registration on spatio-temporal (4D) images is performed and thoroughly compared with baseline methods. Dlung achieves the highest accuracy with diffeomorphic properties. It constructs accurate and fast respiratory motion models with limited data. This research extends our knowledge of respiratory motion modeling.


Intra-arterial injection of Mesobuthus tamulus venom elicits cardiorespiratory reflexes involving perivascular afferents.
Role of perivascular afferents for the cardiorespiratory alterations produced by Mesobuthus tamulus (BT) envenomation was examined in urethane-anaesthetized male rats. Blood pressure (BP), respiratory rate (RR) and heart rate (HR) were recorded after injecting BT venom/saline in the distal end of femoral artery for 60 min. In addition, paw oedema was also determined. Injection of venom produced an immediate (within 2 s) increase in RR followed by a decrease and finally a sustained increase up to 60 min. BP was increased (within 10 s) by 30-50%, which gradually declined but remained above the initial level up to 60 min. The bradycardiac response was late to occur (after 50 s) and the peak response was seen between 10 and 50 min, which remained at that level. There was oedema in the ipsilateral hind paw (venom injected side) as compared to contralateral side and saline control group. The oedema and cardiorespiratory changes were maximal at 1.0 mg/kg of venom. Pretreatment with indomethacin significantly attenuated the venom-induced responses and also blocked the paw oedema. Present experiments reveal that BT venom in a segment of an artery produces oedema by involving prostaglandins to sensitize the nociceptors present in perivascular tissues to evoke the cardiorespiratory reflexes.


Ehud Yairi: Reflections on a Career.
This is the second in a series of papers that provides an historical record in this journal of contributions made by the most influential researchers in the field of fluency disorders. The present paper reflects on the long and productive career of Ehud Yairi, outlining his many contributions to the field of stuttering, and his outstanding achievements and accomplishments. The paper is based on interviews with him during 2020, after the conclusion of his research career. His visionary, lifetime work has advanced our understanding of the nature, origins, and epidemiology of this disorder.


Measurement of an exciton Rabi rotation in a single GaN/Al(x)Ga(1-x)N nanowire-quantum dot using photoluminescence spectroscopy: evidence for coherent control.
Experimental observation of excited state exciton Rabi rotation in a single GaN quantum dot is presented. The dot is embedded in a site-controlled GaN/AlGaN nanowire. Damped oscillation is observed in the power-dependent spectra of the quantum-dot ground state upon resonant pumping of an excited state that had been identified by photoluminescence excitation spectroscopy. A discussion on the origins of the damping is given.


A comparison of rat femoral, sternebral and lumbar vertebral bone marrow fat content by subjective assessment and image analysis of histological sections.
A subjective assessment of the amount of fat within the available marrow space was made from histological sections of the femur, sternebrae and lumbar vertebrae in rats. The sternebrae and vertebrae showed considerably less variability than the femur. Comparison between subjective assessment and image analysis of femoral bone marrow fat showed that there is no great advantage to be gained from using the latter technique. It was concluded that evaluation of sternebral and vertebral bone marrow results in a more accurate assessment of fat content.


Cerebral vasomotor reactivity is significantly reduced in low-flow as compared to thromboembolic infarctions: the key role of the circle of Willis.
To test the hypothesis that cerebral vasomotor reactivity (CVMR) is significantly more reduced in patients with hemispheric low-flow infarctions than in brain infarctions due to arterio-arterial embolism, a series of 64 consecutive patients with internal carotid artery occlusions were studied. CVMR was calculated from relative changes of blood flow velocity within the middle cerebral artery (MCA) measured by transcranial Doppler ultrasonography (TCD) during hypo- and hypercapnia. The configuration of the circle of Willis (COW) was also determined by TCD using common carotid artery compression tests. Anterior, posterior or ophthalmic artery collateral flow, and absence or combinations of these, were differentiated. CT scans were categorized as showing either no infarction (group I; n = 20) or territorial (group II; n = 28), or low-flow infarctions (group III; n = 16). As compared to normal, CVMR was significantly reduced but equal in groups I and II, however, even more reduced in group III. CVMR was lowest, and low-flow infarctions were most frequent in patients whose collateral hemispheric blood supply was from the ophthalmic artery as opposed to patients with a complete or nearly complete COW. Our findings indicate that low-flow infarctions in extracranial ICA occlusions represent brain damage due to a critical reduction in cerebral perfusion pressure, as opposed to thromboembolically induced lesions. The configuration of the COW seems to play the key role. Our findings also support the view that the pattern of hemispheric infarction seen on CT indicates the pathogenesis of stroke.


Hepatitis A Virus, Hepatitis E Virus, and Rotavirus in Foods of Animal Origin Traded at the Borders of Brazil, Argentina, and Uruguay.
The aim of this study was to investigate hepatitis A virus (HAV), hepatitis E (HEV), and rotavirus (RV) in fresh and processed meat traded on the border of Brazil with Argentina and Uruguay. In total, 159 samples of raw and processed foods of animal origin were collected in Paso de los Libres, Argentina (n = 53 raw meat, n = 24 processed meat) and Rivera, Uruguay (n = 55 raw meat, n = 18 processed meat), or were seized by the Brazilian International Agricultural Surveillance System-VIGIAGRO (Brazil-Argentina border) (n = 8 raw meat, n = 1 bush meat). All samples were tested for the presence of HAV, HEV, and RV genomes. HAV genes were detected in 18.23% of samples and RV genes in 23.89%. No HEV-positive samples were detected. HAV was also detected in two of the VIGIAGRO samples. Processed meats from Argentina and Uruguay had a higher rate of HAV and RV than raw meat (P > 0.05). The median HAV in the Argentinian and Uruguayan samples was 6.9 × 104 and 3.5 × 103 copies/g, respectively. The presence of RV viral genes in raw meats from Argentina was significant, and this was not observed in processed meats. The presence of HAV and RV genes in a significant portion of products from Argentina and Uruguay is a potential source of human infection. This also indicates precarious conditions of acquisition, processing, and manipulation, which could be improved by improved regulation of food across borders.


Unusual surface distribution of concanavalin A reflects a cytoskeletal defect in neutrophils in Shwachman's syndrome.
Schwachman's syndrome is characterised by pancreatic insufficiency and frequent infections. Absolute polymorphonuclear leucocyte (PMN) counts are low in many patients, and the PMN show abnormal chemotaxis. It was postulated that a cytoskeletal defect might underlie these abnormalities, and a cytoskeleton-dependent function, the surface distribution and mobility of concanavalin-A receptors, was studied on neutrophils from Schwachman's syndrome patients. Approximately a third of the neutrophils in each patient showed a patched distribution of fluorescein-conjugated concanavalin A (FITC-con A) rather than the usual diffuse staining pattern. These patched neutrophils also bound larger amounts of FITC-con A than diffusely stained or capped PMN from the same patient. Antitubulin treatment did not alter the proportion of patched PMN. These findings suggest that a cytoskeletal defect underlies the patching of FITC-con A on the PMN surface. This defect could also contribute to the abnormal chemotaxis and frequent infections found in Shwachman's syndrome patients.


Caloric regulation and patterns of food choice in a patchy environment: the value and cost of alternative foods.
Rats in a laboratory foraging paradigm had 24-hr-per-day access to a feeder where they could search, by completing a fixed number of bar presses, for an opportunity to eat one of a pair of foods differing in caloric density (2.5, 3, 3.5, or 4 kcal/g) and, in Experiment 2, the price of food pellets (10 to 50 bar presses per pellet). The rats could either accept the opportunity, and eat a meal, or reject it in favor of further search. Daily caloric intake was relatively constant. The rats always included both foods in their diet, but, for any particular food, the degree of inclusion in the diet and of acceptance of meal opportunities, the meal size, and the rate of eating were all functions not only of the price and caloric value of that food but also of the price and value of the alternately-available food. The patterns of intake for one food relative to those for the other available food were strongly correlated with the relative rate of calorie intake during consumption of that food compared to the other. Although the rats appeared to be sensitive to the local rates of calorie flow, they did not maximize daily calories consumed per time spent feeding.


A shared antigenic determinant between natural killer cells and nervous tissue.
Considerable evidence for shared antigenic determinants between nervous elements and lymphocytes has accumulated. It has also been suggested that this cross-recognition may be involved in the pathogenesis of human neurological diseases such as myasthenia gravis and multiple sclerosis. We report here evidence that a marker for natural killer (NK) cells, anti-Leu-7 (HNK-1), specifically binds to components of human and rodent central nervous tissue as well as peripheral nervous tissue, especially to myelin sheaths. In contrast, another NK-cell marker (VEP13) did not react with nervous tissue. Since NK-cell function is impaired in a population of multiple sclerosis patients, the observed cross-reactivity indicates that autosensitization against myelin may simultaneously cause a defect of NK-cell function. Furthermore, the shared antigenic determinant may help to identify a hitherto undefined nervous tissue antigen and simultaneously increase the knowledge about the nature of NK-cell antigens.


Transurethral needle ablation of the prostate: an alternative minimally invasive therapeutic concept in the treatment of benign prostate hyperplasia.
Alternative minimally invasive methods treating benign prostate hyperplasia (BPH) have become more and more important. Transurethral needle ablation (TUNATM) has been demonstrated to be effective in both canine and the human prostate. The goal of our study was to prove the safety, feasibility and tolerance of this new procedure. In this prospective nonrandomized study, 33 patients underwent TUNATM-treatment. One, 3 and 6 months postoperatively, follow-up examinations were carried out assessing urodynamic parameters such as urinary flow rates, residual urine levels, and IPSS-scores. During the last visit additional cystomanometry and urethrocystoscopy were done. Six months postoperatively IPSS-score and residual urine volumes were decreased by 50% (range: 1-72%) and 75% (range: 12-97%). Improvement in maximum flow rate was 63% (range: 5-125%). No serious postoperative complications occurred. After a short 'learning period' most of the treatments where performed as an out-patient-procedure so the patients could leave the hospital without the need for indwelling catheters. The TUNATM appears to be a minimally invasive and safe out-patient procedure for the treatment of selected cases of BPH.


Pediatric stomas, tubes, and appliances.
Pediatric patients with ostomies are a challenge to health care providers. An ostomy is not without problems. Knowledge of surgical techniques and a commitment to the care and management of the stoma and appliances are needed to prevent and manage complications. Ongoing patient education is paramount for compliance and prevention of problems. An experienced individual trained in stoma care must be available as a resource to provide support and answer questions or concerns of patients and their families.


Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes.
In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including once-weekly (QW) formulations have been incorporated into type 2 diabetes (T2D) clinical guidelines, making it essential that pharmacists and healthcare professionals (HCPs) have a clear understanding of their safety profiles. Currently, three QW GLP-1 RAs are approved and marketed in the United States for the treatment of T2D: dulaglutide, exenatide extended-release and semaglutide. This review provides pharmacists and HCPs with collated data related to potential safety and tolerability issues when patients use QW GLP-1 RAs, enabling patient education and treatment optimization. This is a narrative review comparing the safety and tolerability of the three QW GLP-1 RAs, using data from Phase 3 clinical trials. Extracted safety data included gastrointestinal (GI) adverse events (AEs), hypoglycaemia, injection-site reactions, pancreatitis, neoplasms, gallbladder events, and diabetic retinopathy (DR) and/or its complications (DRCs). A total of 30 trials were identified for inclusion; eight were head-to-head trials involving another GLP-1 RA; of these, six compared GLP-1 RAs with different dosing regimens (QW vs once-daily or twice-daily), and two were direct QW vs QW GLP-1 RA comparisons. The most commonly reported AEs were GI events (notably nausea, vomiting and diarrhoea), but there was variation between the three QW drugs. These were generally mild-to-moderate in severity and transient. Risk of hypoglycaemia, injection-site reactions, pancreatitis, neoplasms and gallbladder events was generally low across the GLP-1 RAs investigated. Overall rates of DR or DRC were low across the trials. Only in one trial (SUSTAIN 6) there were significantly more DRC events reported in patients treated with QW semaglutide (3.0%) compared with placebo (1.8%). This was likely due to the rapid improvement in glucose control in patients with pre-existing DR enrolled within that trial. This review puts the latest clinical data from the marketed QW GLP-1 RAs into context with results from older Phase 3 trials, to enable pharmacists and HCPs to make informed treatment decisions. Each of the three QW GLP-1 RAs has their own safety profile, which should be considered when choosing the optimal treatment for patients.


Driving external chemistry optimization via operations management principles.
Confronted with the need to significantly raise the productivity of remotely located chemistry CROs Pfizer embraced a commitment to continuous improvement which leveraged the tools from both Lean Six Sigma and queue management theory to deliver positive measurable outcomes. During 2012 cycle times were reduced by 48% by optimization of the work in progress and conducting a detailed workflow analysis to identify and address pinch points. Compound flow was increased by 29% by optimizing the request process and de-risking the chemistry. Underpinning both achievements was the development of close working relationships and productive communications between Pfizer and CRO chemists.


A computer program for the analysis of crossover designs.
We describe a program, CROSS, which we have written to obtain potency estimates and other parameters for bioassay data from assays of crossover design. The program permits testing of all assays for statistical validity and calculates the complete analysis of variance for assays of balanced design. The form of data input and the complete documentation of assay results make this program particularly useful for anyone carrying out crossover assays on a routine basis. The analysis of variance presented is also useful for more general biological or medical situations.


The group-based law enforcement mistrust scale: psychometric properties of an adapted scale and implications for public health and harm reduction research.
Negative encounters with law enforcement-direct and vicarious-fuel mistrust. When considered as part of the 'risk environment' in public health and harm reduction research, law enforcement mistrust may have broad implications. For example, fearing arrest may prevent someone from calling 911 when witnessing an overdose or lead to syringe-sharing and community spread of HIV. For people in the US who identify as Black or African American, these effects may compound, given the ways in which communities of color have been overpoliced. The purpose of this study is to investigate the psychometrics of an adapted scale of law enforcement mistrust-the Group-Based Law Enforcement Mistrust Scale (GBLEMS)-and evaluate its associations with racial and ethnic identity and experiences with law enforcement. This cross-sectional survey took place in a small city in the Western United States where only 3% of the population is Black or African American. The sample included Black or African American and Hispanic and Latina women at risk of HIV, and members of their social networks, yielding a diverse sample across racial, ethnic, and gender identities (N = 219). The GBLEMS is a 12-item scale adapted from the Group-Based Medical Mistrust Scale (GBMMS; Thompson et al. 2004). The current analysis evaluated the psychometric properties of the GBLEMS (reliability, exploratory factor analysis) and its associations with demographics, other race-based constructs, and experiences with law enforcement. The GBLEMS demonstrated strong reliability (Cronbach's alpha = 0.92) and exploratory factor analysis indicated that items loaded onto two factors-mistrust and disparities in treatment. There was also support for the scale's construct validity. As hypothesized, GBLEMS scores were higher among respondents who identify as Black or African American, and among those who reported other experiences of racial discrimination, medical mistrust, and negative encounters with law enforcement. This study yielded support for the reliability and validity of the GBLEMS as a multi-item, two-factor scale measuring group-based law enforcement mistrust. When framing public health and harm reduction research in terms of the risk environment, law enforcement mistrust may be important to measure as part of a comprehensive approach that addresses persistent racial disparities.


Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. Three causative genes are known: ENG (HHT-1), ACVRL1 (HHT-2), and SMAD4 (mutated in HHT in association with juvenile polyposis). Gastrointestinal bleeding is the most common symptom after epistaxis. The stomach and the duodenum are the main gastrointestinal sites of telangiectases. Our aim was to explore gastrointestinal tract of consecutive HHT patients to assess distribution, number, size, and type of telangiectases in relation to genotype. HHT patients underwent gastroduodenoscopy, video capsule endoscopy, and colonoscopy. Molecular analysis of ENG and ACVRL1 was performed to identify the disease-causing mutation. Twenty-two patients (13 men; mean age: 59 ± 9 years) were analyzed: 7 with HHT-1, 13 with HHT-2, and 2 undefined. Gastrointestinal telangiectases were identified as follows: at gastroduodenoscopy in 86% of HHT-1 patients and in 77% of HHT-2 patients, at video capsule endoscopy in all HHT-1 patients and in 84% of HHT-2 patients, and at colonoscopy in 1 patient for each group. HHT-1 showed multiple telangiectases with a higher prevalence, more relevant in the duodenum. Our data demonstrate extensive involvement of the gastrointestinal tract with a more severe association in HHT-1. Gastroduodenoscopy provides significant information on gastrointestinal involvement, and video capsule endoscopy may be added in selected patients. Colonic polyps/adenomas were identified as occasional findings.


Establishment of human glial cell lines chronically infected with the human immunodeficiency virus.
Human malignant glioma cells were cotransfected with an infectious molecular clone of the human immunodeficiency virus (HIV) and a selectable drug resistance gene (neo). HIV/neo-positive cell clones were maintained in continuous culture for over 5 months and showed the following characteristics: (i) expression of HIV antigens as detected by indirect immunofluorescence staining in 80-90% of cells; (ii) efficient production of HIV RNA and infectious progeny virus; (iii) minimal cytopathic effects (notably in cell morphology), in contrast to HIV-infected T lymphocytes. These results demonstrate that certain glial cells originating from human brain can support a chronic infection with HIV comparable to that observed in T lymphoid cell lines. The cell lines provide an in vitro model system for studies on the mechanism and biological effects of HIV infection in glial cells, and offer an alternative source of the virus that has not been Adapted to lymphocytes or macrophages.


Is It Safe to Perform Endoscopic Retrograde Cholangiopancreatography in Decompensated Cirrhosis?
Endoscopic retrograde cholangiopancreatography (ERCP) is treatment modality of choice for management of pancreatobiliary disorders. However, safety of ERCP in the patients with cirrhosis is not adequately studied. This study was aimed to evaluate adverse events in the patients with cirrhosis undergoing ERCP and the predictors of adverse events and mortality. The present study was a retrospective analysis of patients with cirrhosis who underwent ERCP from January 2012 to December 2016. Binary logistic regression analysis was performed to ascertain the risk factors for adverse events and mortality at 1 month. A total of 261 patients underwent ERCP (80.8% men, mean age 53.49 ± 12.6years). There were 36 (16.1%) overall adverse events in patients undergoing ERCP for biliary indication, whereas no adverse event in pancreatic indication. On univariate analysis, ascites, encephalopathy, high Child-Pugh-Turcotte (CTP) and model for end-stage liver disease (MELD) score, and creatinine levels were significantly associated; however, on multivariable analysis, CTP class C (p value 0.033; odds ratio [OR] 3.5, 95% confidence interval [CI] 1.1-11.5) and MELD > 18 (p value 0.004; OR 5.6, 95% CI 1.7-17.9) were independent risk factors for adverse events. There were 19 (8.5%) mortalities. On univariate analysis, presence of ascites, encephalopathy, cholangitis, biliary sphincterotomy, high CTP, low albumin, and high creatinine were significantly associated, whereas, on multivariable analysis, presence of cholangitis (p 0.017; OR 3.8, 95% CI 1.3-11.4) was associated increased mortality. Although endoscopic sphincterotomy might be safe for the patients with cirrhosis undergoing ERCP; advanced liver cirrhosis may be independent risk factor for post-ERCP adverse events. Cholangitis at admission is an independent risk factor for mortality.


High prevalence of early asymptomatic venous thromboembolism in anticoagulated COVID-19 patients hospitalized in general wards.
Coronavirus disease 2019 (COVID-19) is associated with coagulation activation and high incidence of venous thromboembolism (VTE) in severe patients despite routine thromboprophylaxis. Conflicting results exist regarding the epidemiology of VTE for unselected anticoagulated COVID-19 patients hospitalized in general wards. The aim of this study was to evaluate the prevalence of asymptomatic deep venous thrombosis (DVT) in unselected patients with COVID-19 recently hospitalized in general wards. We performed a systematic complete doppler ultrasound (CDU) at a median 4 days after admission in 42 consecutive COVID-19 patients hospitalized in general wards of our university hospital, irrespective of D-Dimer level, and retrospectively collected clinical, biological and outcome data from electronic charts. Thromboprophylaxis was systematically applied following a French national proposal. In our population, the prevalence of asymptomatic DVT was 19% (8/42 patients), with distal thrombosis in 7/8 cases and bilateral DVT in 4/8 cases. Symptomatic pulmonary embolism was detected in 4 (9.5%) patients, associated to DVT in one case. Compared to patients without DVT, patients with DVT were older and experienced poorer outcomes. In conclusion, prevalence of asymptomatic DVT is high in the first days of hospitalization of unselected COVID-19 patients in general wards and may be related to poor prognosis. Individualized assessment of thromboprophylaxis and early systematic screening for DVT is warranted in this context.


Increasing Competence in Pressure Injury Prevention Using Competency-Based Education in Adult Intensive Care Unit.
There is a significant focus on pressure injury prevention to promote better patient outcomes and control health care cost. In 2016, the institution's pressure injury quarterly prevalence survey showed that two-thirds of the patients surveyed who developed unit-acquired pressure injury stage 2 and greater were in the adult intensive care units. The quality improvement project used a pre- and postintervention design. The adult medical intensive care unit (MICU) executed a competency-based education project to increase staff implementation of pressure injury prevention. Following initiation of competency-based education, staff documentation of pressure injury prevention implementation increased, and unit-acquired pressure injury stage 2 and greater rates were reduced. The use of a competency-based education program may be effective in increasing pressure injury prevention in the intensive care unit.


Investigations on the vibrational modes and non-linear optical properties of 4-Fluoro Chalcone crystal.
Organic Nonlinear Optical (NLO) crystals of 4-fluorochalcone (4FC) were synthesized and grown by slow evaporation solution growth method. The grown crystals have been characterised by powder X-ray diffraction, factor group analysis, FTIR, FT-Raman, UV-Vis Spectroscopy, powder SHG and Vickers microhardness tests. Theoretical quantum chemical analysis were performed to determine the first order hyperpolarizability (β) and HOMO-LUMO analysis of the title compound were computed by GAUSSIAN 03 package.


The non-coding competing endogenous RNAs in acute myeloid leukemia: biological and clinical implications.
Acute myeloid leukemia (AML) is a hematologic carcinoma that has seen a considerable improvement in patient prognosis because of genetic diagnostics and molecularly-targeted therapies. Nevertheless, recurrence and drug resistance remain significant obstacles to leukemia treatment. It is critical to investigate the underlying molecular mechanisms and find solutions. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), circular RNAs, long non-coding RNAs, and pseudogenes, have been found to be crucial components in driving cancer. The competing endogenous RNA (ceRNA) mechanism has expanded the complexity of miRNA-mediated gene regulation. A great deal of literature has shown that ncRNAs are essential to the biological functions of the ceRNA network (ceRNET). NcRNAs can compete for the same miRNA response elements to influence miRNA-target RNA interactions. Recent evidence suggests that ceRNA might be a potential biomarker and therapeutic strategy. So far, however, there have been no comprehensive studies on ceRNET about AML. What is not yet clear is the clinical application of ceRNA in AML. This study attempts to summarize the development of research on the related ceRNAs in AML and the roles of ncRNAs in ceRNET. We also briefly describe the mechanisms of ceRNA and ceRNET. What's more significant is that we explore the clinical value of ceRNAs to provide accurate diagnostic and prognostic biomarkers as well as therapeutic targets. Finally, limitations and prospects are considered.


Visualization of Chromatin Dynamics by Live Cell Microscopy Using CRISPR/Cas9 Gene Editing and ANCHOR Labeling.
The organization of the eukaryotic nucleus facilitates functional chromatin contacts which regulate gene transcription. Despite this being extensively studied through population-based chromatin contact mapping and microscopic observations in single cells, the spatiotemporal dynamics of chromatin behavior have largely remained elusive. The current methods to label and observe specific endogenous genomic loci in living cells have been challenging to implement and too invasive to biological processes. In this protocol, we describe the use of a recently developed DNA labelling strategy (ANCHOR) with CRISPR/Cas9 gene editing, to discreetly label genes for live cell imaging to study chromatin dynamics. Our approach improves on some of the fundamental shortfalls associated with current labelling strategies and has the potential for multiplexed observations.


Er:YAG laser ablation of tissue: effect of pulse duration and tissue type on thermal damage.
The thermal damage caused by 2.94-micron Er:YAG laser ablation of skin, cornea, aorta, and bone was quantified. The zone of residual thermal damage produced by normal-spiking-mode pulses (pulse duration approximately 200 microseconds) and Q-switched pulses (pulse duration approximately 90 ns) was compared. Normal-spiking-mode pulses typically leave 10-50 microns of collagen damage at the smooth wall of the incisions; however, at the highest fluences (approximately 80J/cm2) tears were produced in cornea and aorta and as much as 100 microns of damaged collagen is found at the incision edge. Q-switched pulses caused less thermal damage, typically 5-10 microns of damage in all tissues.


Reinnervation of frog sympathetic ganglia with somatic nerve fibres.
The formation of synapses in the last two ganglia of the sympathetic chain of the frog Rana esculenta was investigated after anastomosing the 6th spinal nerve to the denervated ganglia in order to evaluate the reinnervation of deafferented sympathetic neurons with somatic cholinergic axons. The same ganglia were examined both electrophysiologically and morphologically from 25 to 280 days after the operation. In response to electrical stimulations of the anastomosed spinal nerve, synaptic transmission was analysed with intracellular microelectrodes placed into B or C sympathetic neurons. Synaptic density was quantified using electron microscopy by a synaptic index defined as the ratio of the number of synapses encountered to the number of perykarya examined. After ganglionic deafferentation, post-synaptic membrane differentiations persisted without any pre-synaptic element and an index of the 'vacated' post-synaptic differentiations was calculated. Although somatic axons were growing into all ganglia studied, no sign of neuronal reinnervation was detected in ganglia of 8 of the 31 frogs (26%) taken from 29 to 210 days after the anastomosis. Moreover, in 18 out of 31 frogs (58%) analysed at different times after the operation, the ganglia were reinnervated with regenerating preganglionic axons in spite of care taken to avoid it. However, even after 3 months, certain neurons of these ganglia were not reinnervated and the synaptic index approximated the value of normal ganglia only in the 8th ganglion. In addition, post-synaptic membrane differentiations could still persist and coexist with normal synapses. It was only beyond three months after the anastomosis that the ganglia of 5 of the 31 frogs (16%) were reinnervated with regenerating somatic axons. Reinnervated B and C neurons were polyinnervated. But in 3 out of these 5 frogs the ganglia were also reinnervated with preganglionic axons and several B and C neurons received a double reinnervation. The synaptic indices were far from the value of normal ganglia except for the 8th ganglion of one frog reinnervated by both types of axons and the indices of vacated differentiations were close to that of ganglia with no reinnervated neurons. Contrary to mammals, frog somatic axons are, therefore, relatively ineffective at reinnervating sympathetic neurons, probably because in amphibian ganglia, synapses between the pre- and post-synaptic elements require higher specificity.


Influence of Single and Combined Mixtures of Metal Oxide Nanoparticles on Eggplant Growth, Yield, and Verticillium Wilt Severity.
Verticillium wilt, caused by Verticillium dahliae, is one of the major diseases of eggplants. Nanoparticles (NPs) of CuO, Mn2O3, and ZnO were sprayed alone onto leaves of young eggplants and in different combinations and rates, and then seedlings were transplanted into soil infested with V. dahliae in the greenhouse and field between 2015 and 2018. All combinations of NPs were consistently less effective than CuO NPs applied alone at 500 µg/ml at increasing disease suppression, biomass, and fruit yield. CuO NPs were associated with an increase in fruit yield (17 and 33% increase) and disease suppression (28 and 22% reduction) in 2016 and 2017, respectively, when compared with untreated controls. However, this effect was negated in the greenhouse and field experiments when CuO NPs were combined with Mn2O3. Combining NPs of CuO with ZnO resulted in variable effects; amendments increased growth and suppressed disease in greenhouse experiments, but results were mixed in the field. Leaf tissue analyses from the greenhouse experiments showed that Cu concentration in leaves was reduced when CuO NPs were combined with other NPs, even when application rates were the same amount. A simple competition for entry sites may explain why combinations of CuO NPs and Mn2O3 NPs reduced efficacy but does not explain the lack of inhibition between Cu and Zn. NPs of CuO performed better than their larger bulk equivalent, and studies on application rate found 500 µg/ml was optimal. No phytotoxicity, as determined, by leaf burning, necrotic spots, or dead apical buds was noted even at the highest combined rates of 1,500 µg/ml.


Quality of life and symptom distress after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/ HIPEC) for peritoneal surface malignancy can effectively control the disease, however it is also associated with adverse effects which may affect quality of life (QoL). To investigate early perioperative QoL after CRS/HIPEC, which has not been discussed in Taiwan. This single institution, observational cohort study enrolled patients who received CRS/HIPEC. We assessed QoL using the Taiwanese version of the MD Anderson Symptom Inventory (MDASI-T) and European Organization Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). Participants completed the questionnaires before CRS/HIPEC (S1), at the first outpatient follow-up (S2), and 3 mo after CRS/HIPEC (S3). Fifty-eight patients were analyzed. There was no significant perioperative difference in global health status. Significant changes in physical and role functioning scores decreased at S2, and fatigue and pain scores increased at S2 but returned to baseline at S3. Multiple regression analysis showed that age and performance status were significantly correlated with QoL. In the MDASI-T questionnaire, distress/feeling upset and lack of appetite had the highest scores at S1, compared to fatigue and distress/feeling upset at S2, and fatigue and lack of appetite at S3. The leading interference items were working at S1 and S2 and activity at S3. MDASI-T scores were significantly negatively correlated with the EORTC QLQ-C30 results. QoL and symptom severity improved or returned to baseline in most categories within 3 mo after CRS/HIPEC. Our findings can help with preoperative consultation and perioperative care.


Health care ethics: models of the provider-patient relationship.
Societal changes and ethical issues in health care have been responsible for the evolution of the models of the provider-patient relationship. As health care providers we must recognize the ethical and moral issues inherent in the provider-patient relationship and its impact on health care and our society today.


Imaging of abdominal and pelvic injuries from the Boston Marathon bombing.
The aim of this study is to describe the imaging findings of abdominal and pelvic injuries in victims of the Boston Marathon bombing. A retrospective review of 87 patients following the Boston Marathon bombing was performed to evaluate for abdominal and pelvic injuries on plain radiography or CT scans of the abdomen and pelvis. Imaging exams were evaluated for shrapnel, soft tissue injury, visceral damage, vascular disruption, and fractures. The injuries were classified as primary, secondary, tertiary, and quaternary blast injuries. Eleven of the 87 patients had positive findings in the abdomen or pelvis (M:F = 7:4, average age 34.6 years). There were 22 ball bearings, two nails, one screw, and two irregular metal fragments in the 11 patients with secondary blast (shrapnel) injuries. There was no peritoneal penetration or visceral injury seen in any of the patients. One patient had multiple transverse process fractures, representing tertiary blast injury. All but one patient had superficial penetrating abdominal or pelvic injuries secondary to shrapnel. There were no cases of bowel or solid visceral organ injuries due to the lack of peritoneal violation from the relatively low-powered explosions. Absence of peritoneal penetration by shrapnel indicates no need for laparotomy following low-powered explosions.


Pythium kandovanense sp. nov., a fungus-like eukaryotic micro-organism (Stramenopila, Pythiales) isolated from snow-covered ryegrass leaves.
Pythiumkandovanense sp. nov. (ex-type culture CCTU 1813T = OPU 1626T = CBS 139567T) is a novel oomycete species isolated from Lolium perenne with snow rot symptoms in a natural grassland in East-Azarbaijan province, Iran. Phylogenetic analyses based on sequence data from internal transcribed spacer (ITS)-rDNA, coxI and coxII mitochondrial genes clustered our isolates in Pythium group E as a unique, well supported clade. Pythium kandovanense sp. nov. is phylogenetically and morphologically distinct from the other closely related species in this clade, namely Pythium rostratifingens and Pythium rostratum. Pythium kandovanense sp. nov. can be distinguished from these two species by its cylindrical sporangia and lower temperatures for optimum and maximum growth rate. The development of zoospores released through a shorter discharge tube is an additional morphological feature which can be used to differentiate Pythium kandovanense sp. nov. from Pythium rostratifingens. Laboratory inoculation tests demonstrated the pathogenicity of Pythium kandovanense sp. nov. to L. perenne under wet cold (0-3 °C) conditions.


A case of extremely prolonged viral shedding: Could cell cultures be a diagnostic tool to drive COVID-19 patient discharge?
This study addressed the case of a patient with prolonged COVID-19 viral shedding, reported by Real-Time PCR, until 71 days from symptom onset. However, viral culture received negative results after 30 days from symptom onset. Therefore, viral culture may be a worthwhile test for patients requiring discharge, in particular for those presenting prolonged viral shedding.


The ketogenic diet in children with Glut1 deficiency syndrome and epilepsy.
The effects of a long-term ketogenic diet in children with Glut1 deficiency syndrome on metabolism are unknown. Our results indicate a characteristic effect of a long-term ketogenic diet on glucose and lipid homeostasis in Glut1 deficiency syndrome. Although serum lipids and apolipoproteins reflect a proatherogenic lipoprotein profile, adipocytokine constellation is not indicative of enhanced cardiovascular risk.


Symptoms, weight loss, and physical function in a lifestyle intervention study of older cancer survivors.
Many older cancer survivors are overweight or obese, with additional illness burden increasing functional decline, which may affect their ability to engage in lifestyle interventions. This study examined how overweight long-term survivors' symptom severity associated with comorbidity prior to a diet and exercise intervention was associated with post-intervention function and examined symptoms' effects on function through change in physical activity, diet quality, and weight status. This is a secondary data analysis of 514 breast, prostate, and colorectal cancer survivors who participated in the one-year home-based diet and exercise intervention Reach-Out to Enhance Wellness trial. Measures included symptoms, weight, physical activity, diet quality, overall physical function (PF), and basic and advanced lower extremity function (BLEF and ALEF). Simple and serial mediation analyses were conducted to examine direct effects of symptom severity on PF, BLEF, and ALEF and indirect effects of symptom severity through changes in diet quality, physical activity, and weight. Symptom severity was directly associated with lower functioning scores for PF (b=-0.63 p<0.001), BLEF (b=-0.33, p<0.001), and ALEF (b=-0.22, p<0.001). Indirect effects of symptom severity through weight loss, physical activity, and diet were not significant. Weight loss and physical activity were associated with higher PF and ALEF and diet quality was associated with higher BLEF. Symptom severity of older, overweight cancer survivors negatively affects physical function. However, greater weight loss and more physical activity were associated with higher functioning scores, regardless of symptom severity.


Can probability neglect bias promote social distancing during the COVID-19 pandemic?
The effectiveness of a stay-at-home order depends on the speed of behavioral changes that are triggered by risk perception. Probability neglect bias, one of the cognitive biases, may lead people to engage in social distancing. However, there is no empirical evidence of the relationship between probability neglect bias and social distancing. This study aims to examine the relationship between individual differences in susceptibility to probability neglect bias and the level of social distancing practice during the early stages of the COVID-19 outbreak in Japan. The level of engagement in social distancing was defined as the narrowing of life-space mobility. We conducted a web-based questionnaire survey among 1000 adults living in central Tokyo, Japan, at the beginning of the pandemic outbreak. Our results show that people had a strong fear of infection in the early pandemic stages. Approximately 60% of our subjects were influenced by probability neglect bias. People susceptible to probability neglect bias engaged in social distancing more intensely than those who were not susceptible after the state of emergency was lifted.


Testosterone and behavior: involvement of the hormone in psychotropic effects of baclofen.
We studied the effect of baclofen (GABA(B) receptor agonist) on the behavior of male mice with different levels of anxiety in tests for social and sexual contact and on blood testosterone levels. The drug reduced testosterone level and behavioral reaction to an unknown male in intact animals and did not modulate the hormone level and social contacts in anxious mice. In the test with receptive female, baclofen reduced testosterone level and sexual motivation in intact males and did not modulate the hormone level and initial sexual interest in anxious mice. Parallelism in the development of behavioral and endocrine components of the reaction to social and sexual stimuli confirms possible involvement of testosterone in psychotropic effects of baclofen.


Optical frequency-domain imaging microprofilometry with a frequency-tunable liquid-crystal Fabry-Perot etalon device.
An optical frequency-domain interference microscope with a liquid-crystal Fabry-Perot interferometer as an optical frequency-scan device was developed for microscopic three-dimensional shape measurements. The proposed system can perform absolute measurement of the discontinuous surface profile of a microscopic object without use of mechanically moving components such as a piezoelectric transducer or a grating spectrometer. Experimental results are presented that demonstrate the validity of the principle.


Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression.
Both activating and null mutations of proteins required for canonical WNT signaling have revealed the importance of this pathway for normal skeletal development. However, tissue-specific transcriptional mechanisms through which WNT signaling promotes the differentiation of bone-forming cells have yet to be identified. Here, we address the hypothesis that canonical WNT signaling and the bone-related transcription factor RUNX2/CBFA1/AML3 are functionally linked components of a pathway required for the onset of osteoblast differentiation. Our findings show that, in bone of the SFRP1 (secreted frizzled-related protein-1)-null mouse, which exhibits activated WNT signaling and a high bone mass phenotype, there is a significant increase in expression of T-cell factor (TCF)-1, Runx2, and the RUNX2 target gene osteocalcin. We demonstrate by mutational analysis that a functional TCF regulatory element responsive to canonical WNT signaling resides in the promoter of the Runx2 gene (-97 to -93). By chromatin immunoprecipitation, recruitment of beta-catenin and TCF1 to the endogenous Runx2 gene is shown. Coexpression of TCF1 with canonical WNT proteins resulted in a 2-5-fold activation of Runx2 promoter activity and a 7-8-fold induction of endogenous mRNA in mouse pluripotent mesenchymal and osteoprogenitor cells. This enhancement was abrogated by SFRP1. Taken together, our results provide evidence for direct regulation of Runx2 by canonical WNT signaling and suggest that Runx2 is a target of beta-catenin/TCF1 for the stimulation of bone formation. We propose that WNT/TCF1 signaling, like bone morphogenetic protein/transforming growth factor-beta signaling, activates Runx2 gene expression in mesenchymal cells for the control of osteoblast differentiation and skeletal development.


"Learning about your residents": how assisted living residence medication aides decide to administer pro re nata medications to persons with dementia.
This study identified how unlicensed staff members decide to administer medications prescribed pro re nata (PRN) to residents of assisted living (AL) settings designated for persons with dementia. Theories of knowledge, including explicit and implicit knowledge, discretion, and judgment, guided the analysis. Data were collected and analyzed using qualitative methods. The staff members responsible for medication administration were shadowed for 6 consecutive days in three Oregon ALs. In-person interviews were conducted with 16 staff members, and residents' medication records were reviewed. Medication aides' decisions to administer PRN medications were informed by resident request, interpretation of resident-specific actions, training and experience, and setting-specific practices. The theme, learning about your residents, was consistent across settings. By administering PRN medications, medication aides play an important role in the daily care and comfort of AL residents with dementia. Policy makers need information about whether to permit unlicensed staff to administer medications and the level of training to require. This research suggests that training should recognize the tacit knowledge of practicing medication aides. Despite the role that PRN medications can play in the daily comfort and well-being of AL residents, little is known about as-needed medications prescribed versus those actually used across settings; also needed is an understanding of how other health professionals are involved in treatment plans that include medications.


Clinical significance of early-diastolic tissue velocity imaging of lateral mitral annulus for prognosis of nonischemic left ventricular dysfunction.
We explored the potential of tissue velocity imaging (TVI) for prognosis of nonischemic left ventricular (LV) dysfunction (LVD). We reviewed 138 nonischemic LVD patients (58 ± 14 years) who underwent both cardiac magnetic resonance (CMR) and echocardiography. Septal and lateral mitral annular TVI data were compared with late gadolinium enhancement (LGE) on CMR. During a mean follow-up of 24 months, recovery (>15%) of LV ejection fraction and clinical outcomes (cardiovascular death and heart failure hospitalization) were assessed. LGE was commonly observed in the basal anteroseptal, inferoseptal, and inferior segments, but infrequently observed in the anterolateral segment. LGE was associated with lower early diastolic, septal (Sep-e' = 5.2 ± 2.0 vs 6.9 ± 2.0 cm/s, P = .031) and lateral (Lat-e' = 7.3 ± 3.0 vs 9.5 ± 2.0 cm/s, P < .001) TVI. The relationship between Lat-e' and anterolateral LGE (area under the curve, AUC 0.834) was much better than that between Sep-e' and inferoseptal LGE (AUC 0.699). The 60 patients with LVD reversibility revealed higher Lat-e' (9.8 ± 2.0 vs 6.7 ± 2.2 cm/s, P < .001) and lower LGE burden (7.3 ± 9.0 vs 22 ± 10%, P < .001), while Lat-e' ≤ 7.8 cm/s appeared unfavorable for 31 events patients. On multivariate analyses, Lat-e' (HR 0.79, 95% CI 0.63-0.99, P = .044) and LVD reversibility (HR 0.53, 95% CI 0.16-0.90, P = .018) were still meaningful together with LGE segments and burden. Lat-e' was related with LVD reversibility and a significant predictor of clinical outcomes.


Efficacy of two levofloxacin-containing second-line therapies for Helicobacter pylori: a pilot study.
An ideal second-line therapeutic regimen for the treatment of patients who do not respond to standard triple therapy is currently being investigated. In this study, we aimed to investigate the efficacy of two levofloxacin-containing second-line therapies for Helicobacter pylori (H. pylori). One hundred and forty eight consecutive H. pylori -positive patients who did not respond to the standard triple therapy (77 female, 71 male) were enrolled in the study. The patients were randomized consecutively to two-second-line therapy groups; 73 to the levofloxacin-containing sequential (LCS) and 75 to the levofloxacin-containing quadruple (LCQ) therapy group. The LCS therapy group received pantoprazole 40 mg and amoxicillin 1,000 mg twice daily for 5 days followed by pantoprazole 40 mg twice daily and metronidazole 500 mg three times daily and levofloxacin 500 mg one time daily for 7 days. The LCQ therapy group received pantoprazole 40 mg twice daily, tetracycline 500 mg four times daily, bismuth subcitrate 300 mg four times daily and levofloxacin 500 mg one time daily for 10 days. H. pylori eradication was confirmed by stool antigen testing at least 6 weeks after cessation of therapy. Side-effects and compliance were assessed by a questionnaire. Intention-to-treat cure rates were: 82.2% (95%CI; 73-91) and 90.6% (95%CI; 79-95) in the LCS and LCQ therapy, respectively. Per protocol cure rates were: 85.7% (95%CI; 75-92) and 93.1% (95%CI; 85-98) in the LCS and LCQ therapy, respectively. No statistically significant difference was found between two groups (p = .1). No differences in compliance or adverse effects were demonstrated between two groups. This prospective trial demonstrates that both levofloxacin-containing sequential therapy and levofloxacin-containing quadruple therapy regimens have higher H. pylori eradication rates and are well tolerated. The levofloxacin-containing quadruple therapy is likely the best treatment option for a second-line therapy, at least in the Turkish population.


Renal artery aneurysm secondary to Candida albicans in four kidney allograft recipients.
Infection is a frequent cause of morbidity and mortality in solid organ transplant recipients. It may occur at different periods after transplantation. We report four cases of mycotic aneurysms due to Candida albicans (CA) in renal transplant recipients occurring early after kidney transplantation. Four patients (three men, one woman) aged from 24 to 55 years who underwent cadaveric renal transplantation from three different donors developed a mycotic aneurysm at 9 to 90 days after transplantation. In all cases aneurysms were located at the anastomosis between the renal graft artery and the iliac axis. The clinical presentations were fever in three cases, including endocarditis in one patient or deterioration of graft function in two cases and hemorrhagic shock secondary to a ruptured renal artery in the fourth case, which led to death. The arterial aneurysm was discovered at autopsy. The diagnosis of a mycotic aneurysm was based on morphological investigations: echotomography, spiral computed tomography, and arteriography. In all cases bacteriological studies (blood culture, culture of the aneurysmal wall and content) isolated CA. In three patients CA was isolated from the preservation solution; it was of the same phenotype as the one isolated from the aneurysm in one recipient. Antifungal therapy was started in patients who lived, but all kidney transplants had to be removed. Anatomical results of arterial reconstructions were satisfactory in all cases and remained so during the follow-up. The insidious presentation and clinical course of mycotic aneurysms due to CA require a high degree of suspicion to make the correct diagnosis.


Production and characterization of recombinant dengue virus type 4 envelope domain III protein.
Dengue fever, a mosquito-borne viral disease has become a major worldwide public health problem with a dramatic expansion in recent years. Cultivation process for production of recombinant dengue virus type 4 envelope domain III (rDen 4 EDIII) protein in Escherichia coli was developed for its diagnostic use as well as for further studies in immunoprophylaxis. The dissolved oxygen level was maintained at 20-30% of air saturation. The culture was induced with 1mM of isopropyl beta-d-thiogalactoside when dry cell weight was 13.78 g l(-1) and cells were further grown for 4h to reach 17.31 g l(-1) of culture. The protein was overexpressed in the form of insoluble inclusion bodies. The rDen 4 EDIII protein was purified by affinity chromatography and analyzed by SDS-PAGE. The final yield of purified rDen 4 EDIII protein in this method was approximately 196 mg l(-1) of culture. The purified protein was recognized in Western blot analysis and enzyme-linked immunosorbent assay (ELISA) with dengue infected human serum samples. These results show that the product has the potential to be used for the diagnosis of dengue infection or for further studies in vaccine development. This production system may also be suitable for the high yield of other recombinant dengue proteins.


Multidimensional Family Therapy for Justice-Involved Young Adults with Substance Use Disorders.
The present study explored the acceptability, feasibility, fidelity, and outcomes of a young adult adaptation of multidimensional family therapy (MDFT), an evidence-based family treatment originally developed for adolescents. Participants included 22 individuals between the ages of 19 to 25 who were enrolled in a criminal drug court program. MDFT was found to be feasible and was delivered with strong fidelity to young adults and their families. Participants reported high satisfaction with MDFT, and 95% completed treatment. Analyses revealed statistically significant decreases in substance use on all indicators from baseline to the 6-month follow-up. Significant improvements were also noted in vocational functioning, including a 73% increase in full-time employment from baseline to 6-month follow-up. Criminal justice outcomes included a significant decrease in legal risk, and 86% of study participants had no rearrests from baseline through the 18-month follow-up period. The article concludes with recommendations for implementing family-based interventions with young adults, as well as future research directions in this important area.


Radical scavengers from the entomogenous deuteromycete Beauveria amorpha.
The culture medium of Beauveria amorpha Hohn. exhibited strong radical scavenging properties. Activity-directed fractionation assisted by a radical scavenging assay on TLC afforded two active compounds which were identified as 6-methyl-2,4-dihydroxyphenyl 4-O-methyl-beta-D-glucopyranoside (1) and (-)-terredionol (2). Compound 1 displays radical scavenging and lipid peroxidation inhibitory activity comparable to those of TroloxC, ascorbic acid or quercetin.


Heterogeneity within the nonstructural protein 5-encoding region of hepatitis C viruses from a single patient.
Nucleotide (nt) sequence heterogeneity of the hepatitis C virus (HCV) genome derived from a single carrier was investigated. A polymerase chain reaction (PCR) product of 311 bp in the putative nonstructural protein 5-encoding region was directly sequenced, while part of a PCR product was cloned, and sequence analyses were carried out for 27 independent clones. Although 14 of the 27 clones were conserved, ten other types of nt sequences were found. The difference was at most 3 nt (1.1%). A directly determined sequence showed the major sequence of the cloned products. Since most of the nt changes occurred in the third letter of a codon, these nt changes might not have originated from random misincorporation during the PCR. These results of natural divergence of genome population in a single carrier suggest that HCV is a typical RNA virus with a quasi-species nature due to high mutation rates.


Effect of hyperlipidaemia to accelerate intervertebral disc degeneration in the injured rat caudal disc model.
Dyslipidaemia is a well-known risk factor for the development of atherosclerosis, however, little is known about the effect of dyslipidaemia on intervertebral disc degeneration (IVDD). Thus, the purpose of this study is to investigate the relationship between dyslipidaemia and IVDD, and to identify the possible mechanism by which dyslipidaemia aggravates the degeneration of intervertebral discs. Hyperlipidaemia rats were induced, thirty male Wistar rats were randomly divided into two groups: normal chow diet control group (CON) and high-fat diet group (HFD) for 8 weeks. And then, a rat disc degeneration model was established, rats were divided into three experimental groups: the normal chow diet + sham surgery group (CON-Sham); the normal chow diet + needle puncture group (CON-NP); and the high-fat diet + needle puncture group (HFD-NP), all rats were continually fed with normal chow diet or HFD 8 weeks. At the end of the experiment, the discs were harvested and histomorphological analysis, immunohistochemistry staining, real-time PCR and western blot were performed for all groups. The degenerative histological score of disc in the HFD-NP group was significantly higher than the CON-NP group. Immunohistochemical analysis revealed remarkable reductions in aggrecan and collagen type II expressions, and significant increases in IL-1β, TNF-α, MMP-13, HIF-1α and P65 expression in the HFD-NP group. RT-PCR and western blot analysis showed that the mRNA levels and protein expressions of MMP-13 and TIMP-1 were higher in the HFD-NP group. Hyperlipidaemia resulted in an exaggerated degenerative changes and altered expression and transcription of the degeneration-associated molecules in the rat disc tissue. These results raise the possibility that hyperlipidaemia may accelerate the progression of disc degeneration.


Microbial induction of B and T cell areas in rabbit appendix.
Gut-associated lymphoid tissue (GALT) development requires interaction with the intestinal microbiota. Because murine secondary lymphoid tissue development is driven by positive feedback interactions between B cells and stromal cells, we used in situ hybridization to determine whether intestinal commensals influence such interactions during rabbit appendix development. The features of positive feedback interactions we examined (CXCL13 mRNA expression, B cell accumulation and FDC differentiation) increased during early follicle development, but stalled in the absence of intestinal commensals. These features were reinitiated by commensals that stimulated follicle development and intrafollicular B cell proliferation. Our results suggest that rabbit appendix follicles develop in two phases: an initial phase of B cell recruitment to nascent follicles, possibly through positive feedback interactions, and a subsequent phase of intrafollicular B cell proliferation stimulated by intestinal commensals. In addition, we found that intestinal commensals stimulate appendix CCL21 mRNA expression and T cell area formation.


Curcumin treatment protects rat retinal neurons against excitotoxicity: effect on N-methyl-D: -aspartate-induced intracellular Ca(2+) increase.
Curcumin, an extract from the plant Curcuma longa with well-known antioxidant and anti-inflammatory activities, was tested as protective agent against excitotoxicity in rat retinal cultures. A 24 h-treatment with curcumin reduced N-methyl-D: -aspartate (NMDA)-mediated excitotoxic cell damage, estimated as decrease of cell viability and increase in apoptosis. The protection was associated with decrease of NMDA receptor-mediated Ca(2+) rise and reduction in the level of phosphorylated NR1 subunit of the NMDA receptor. These results enlighten a new pharmacological action of the plant extract, possibly mediated by a modulation of NMDA receptor activity.


Improved time efficiency and accuracy in diffusion tensor microimaging with multiple-echo acquisition.
In high-field NMR microscopy rapid single-shot imaging methods, for example, echo planar imaging, cannot be used for determination of the apparent diffusion tensor (ADT) due to large magnetic susceptibility effects. We propose a pulse sequence in which a diffusion-weighted spin-echo is followed by multiple gradient-echoes with additional diffusion weighting. These additional echoes can be used to calculate the ADT and T*2 maps. We show here that this results in modest but consistent improvements in the accuracy of ADT determination within a given total data acquisition time. The method is tested on excised, chemically fixed rat spinal cords.


Associations Between Career Satisfaction, Personal Life Factors, and Work-Life Integration Practices Among US Surgeons by Gender.
Burnout among US surgeons is alarmingly high, particularly among women, and work-life integration conflicts contribute to career dissatisfaction. To evaluate associations between surgical career satisfaction and personal life factors such as time requirements for outside interests, household chores, and parenting responsibilities and to explore similarities and differences between men and women. This cross-sectional survey study of practicing US surgeons was conducted between June 4 and August 1, 2018. The 257-item online survey was sent to 25 748 fellows of the American College of Surgeons. A 31-item subanalysis was performed from August 13 to November 4, 2019. Degree of career satisfaction was measured on a 5-point Likert scale. Professional and personal life factors associated with career satisfaction were evaluated with gender-stratified multivariable proportional odds models. Among 3807 respondents, 3166 self-identified as male (83%) and 639 (17%) as female. Fewer women reported career satisfaction (483 [77%] vs 2514 [82%]) and relatively more women reported problematic interruption of personal life owing to work (315 [50%] vs 1381 [45%]). A higher proportion of women reported being primarily responsible for meal preparation (282 [46%] vs 355 [12%]) and housekeeping (149 [24%] vs 161 [5%]). On multivariable analyses, factors independently associated with career satisfaction were generally similar between genders. Stronger collegial support of work-life integration efforts was significantly associated with higher career satisfaction for both genders (P < .001), although the odds ratio (OR) for women was higher than for men (OR, 4.52; 95% CI, 2.60-7.87 vs OR, 2.45; 95% CI, 1.88-3.21). For men and women, increasing age was significantly associated with higher career satisfaction (men: OR, 1.04; 95% CI, 1.03-1.05; P < .001; women: OR, 1.04; 95% CI, 1.02-1.06; P = .001), and insufficient time for family owing to work was associated with lower satisfaction (men: OR, 0.66; 95% CI, 0.49-0.90; P = 009; women: OR, 0.49; 95% CI, 0.30-0.81; P = .006). For women only, there was a significant association between primary responsibility for at least 1 household chore and lower career satisfaction (OR, 0.66; 95% CI, 0.45-0.98; P = .04). In this study, although women had relatively lower surgical career satisfaction than men, the associations between career satisfaction and personal life factors were largely similar. Collegial support of work-life integration efforts appeared to be the most influential factor, particularly for women. Optimization of work-life integration may not only decrease physician burnout but also promote gender equity in surgery.


The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer.
Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFalpha and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies.


A new case of acute nonlymphocytic leukemia (French-American-British subtype M1) with double minutes and c-MYC amplification.
Herein, we present a new case of acute nonlymphocytic leukemia (ANLL) French-American-British M1 subtype with presence of multiple double minutes (dmin) derived from the amplification of the c-MYC oncogene. A review of dmins in ANLL is presented.


Microfluidic Encapsulation of Ovarian Follicles for 3D Culture.
The ovarian follicle that contains one single oocyte is the fundamental functional tissue unit of mammalian ovary. Therefore, isolation and in vitro culture of ovarian follicles to obtain fertilizable oocytes are regarded as a promising strategy for women to combat infertility. In this communication, we performed a brief survey of studies on microfluidic encapsulation of ovarian follicles in core-shell hydrogel microcapsules for biomimetic 3D culture. These studies highlighted that recapitulation of the mechanical heterogeneity of the extracellular matrix in ovary is crucial for in vitro culture to develop early pre-antral follicles to the antral stage, and for the release of cumulus-oocyte complex (COC) from antral follicles in vitro. The hydrogel encapsulation-based biomimetic culture system and the microfluidic technology may be invaluable to facilitate follicle culture as a viable option for restoring women's fertility in the clinic.


Quantitative analysis of videokymography in normal and pathological vocal folds: a preliminary study.
Videokymography (VKG) captures high-speed images of the vocal folds independently of the periodicity of the acoustic signal. The aim of this study was to preliminarily assess a software package that can objectively measure specific parameters of vocal fold vibration. From August 2009 until December 2010, we prospectively evaluated 40 subjects (Group A, 18 normal subjects; Group B, 14 patients with benign lesions of the middle third of the vocal fold, such as polyps and cysts; Group C, 8 patients treated by endoscopic excision of vocal fold benign lesions) by videoendoscopy, videolaryngostroboscopy, and VKG. A VKG camera was coupled to a 70° telescope and video was recorded during phonation. Images were objectively analyzed by a post-processing software tool (VKG-Analyser) with a user-friendly interface developed by our group. Different parameters were considered, including the ratio between the amplitude of the vibration of one vocal fold with respect to the contralateral (R(amp)), the ratio between the period of one vocal fold vibration and the opposite one (R(per)), and the ratio between the duration of the open and closed phase within a glottal cycle (R(oc)). Mean values for R(amp), R(per), and R(oc) in Group A were 1.05, 1.04, and 1.35, respectively; in Group B were 1.63, 0.92, and 0.97, respectively; and in Group C were 1.13, 0.91, and 1.85, respectively. Quantitative analysis of videokymograms by the herein presented tool, named VKG-Analyser, is useful for objective evaluation of the vibratory pattern in normal and pathologic vocal folds. Important future developments of this tool for the study of both physiologic and pathologic patterns of vocal fold vibration can be expected.


Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance.
Dose [-concentration]-effect relationships can be obtained by fitting a predictive pharmacokinetic (PK)-pharmacodynamic (PD) model to both concentration and effect observations. Either a model can befit simultaneously to all the data ("simultaneous" method), or first a model can befit to the PK data and then a model can be fit to the PD data, conditioning in some way on the PK data or on the estimates of the PK parameters ("sequential" method). Using simulated data, we compare the performance of the simultaneous method with that of three sequential method variants with respect to computation time, estimation precision, and inference. Using NONMEM, under various study designs, observations of one type of PK and one type of PD response from different numbers of individuals were simulated according to a one-compartment PK model and direct Emax PD model, with parameters drawn from an appropriate population distribution. The same PK and PD models were fit to these observations using simultaneous and sequential methods. Performance measures include computation time,fraction of cases for which estimates are successfully obtained, precision of PD parameter estimates, precision of PD parameter standard error estimates, and type-I error rates of a likelihood ratio test. With the sequential method, computation time is less, and estimates are more likely to be obtained. Using the First Order Conditional Estimation (FOCE) method, a sequential approach that conditions on both population PK parameter estimates and PK data, estimates PD parameters and their standard errors about as well as the "gold standard" simultaneous method, and saves about 40% computation time. Type-I error rates of likelihood ratio test for both simultaneous and sequential approaches are close to the nominal rates.


High-grade anal intraepithelial neoplasia among HIV-1-infected men screening for a multicenter clinical trial of a human papillomavirus vaccine.
High-grade anal intraepithelial neoplasia (HGAIN) is the precursor lesion to invasive anal cancer. Human papillomavirus (HPV) vaccination holds great promise for preventing anal cancer. We examined 235 HIV-1-infected men screening for participation in a multisite clinical trial of a quadrivalent HPV vaccine. All participants had anal swabs obtained for HPV testing and cytology and high-resolution anoscopy with biopsies of visible lesions to assess for HGAIN. HPV types 16 and 18 were detected in 23% and 10%, respectively; abnormal anal cytology was found in 56% and HGAIN in 30%. HGAIN prevalence was significantly higher in those with HPV16 detection compared to those without (38% vs 17%; P = .01). Use of antiretroviral therapy and nadir and current CD4+ cell count were not associated with abnormal anal cytology or HGAIN. HGAIN is highly prevalent in HIV-infected men. Further studies are needed on treatment and prevention of HGAIN.


Binding of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors, to guinea pig lung membranes.
Arachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesuf onyl)propyl-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D4 and thromboxane A2 receptors was examined in radioligand binding assays. YM158 inhibited [3H]leukotriene D4 and [3H]U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) binding to guinea pig lung membrane preparations, with Ki values of 0.64+/-0.06 nM for leukotriene D4 and 5.0+/-0.88 nM for thromboxane A2 receptors. The Hill coefficients (nH) did not significantly differ from unity, indicating that this antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (alpha1-, alpha2-, beta-adrenoceptors, histamine, 5-HT, muscarinic, sigma), C5a, opioid, Ca2+ channel, K+ channel, protein kinase C, bradykinin, endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D4 and thromboxane A2 receptors, and this has potential clinical and research applications.


Functional electrical stimulation as an orthotic means for the rehabilitation of paraplegic patients.
In rehabilitating paraplegic patients the restoration of locomotion is often planned to enable the disabled person to use the wheelchair as little as possible or eventually even to abandon it. This objective is more easily obtained in those with incomplete spinal lesions. Applied with the view of restoring locomotion are various types of orthoses, but in the present paper the authors deal with functional electrical stimulation (hereinafter FES) as a means of restoring locomotion, demonstrating the advantages of FES over the use of classical orthoses. The paper offers an outline of the methodology of FES in spinal neural lesions, discusses the criteria of patient selection, giving indications and contraindications. The authors conclude by stating their belief that this treatment represents a new way of rehabilitating spinal paralysed patients which will sooner or later become part of the routine rehabilitation of paraplegic patients.


Effects of maxillary advancement and impaction on nasal airway function.
The effects of Le Fort I osteotomy on the nasal airway are controversial. This study aimed to evaluate nasal airway changes after Le Fort I. 25 patients underwent conventional Le Fort I osteotomy and were separated into three groups depending on the type of surgery they underwent. 11 patients needed maxillary impaction, 9 underwent maxillary advancement, and 5 had both maxillary impaction and advancement. Rhinological examinations, anterior rhinomanometry and acoustic rhinometry were carried out 1 week before surgery and 3 months after that. Wilcoxon and χ(2) tests were used for data analysis. The samples included 19 females and 6 males with a mean age of 22.4 ± 3.32 years. Rhinomanometric assessment showed that total nasal airflow was increased from 406 ± 202 ml/s to 543 ± 268 ml/s in all three groups. Significant decrease in nasal airway resistance was seen in all three groups. Acoustic rhinometry revealed a significant decrease in total nasal volume but an increase in the cross-sectional areas of isthmus nasi (IN) and inferior concha. The rhinomanometric measurements showed improvements in the total nasal airflow after Le Fort I osteotomy with alar base cinch suture in cases where the impaction was not higher than 5.5mm.


Differential characteristics of the middle latency auditory evoked magnetic responses to interstimulus intervals.
The human middle latency auditory evoked magnetic fields were recorded with different interstimulus intervals (ISI) to investigate the differential natures of P30m and the P50m, including whether the P50m source was spatially different or not from the P30m source. Twenty right-handed healthy subjects participated in the experiment. Auditory magnetic responses were recorded in the 0.5 s ISI (ISI were between 0.4 and 0.6 s) and the 1.5 s ISI conditions (ISI were between 1 and 2 s). Tone bursts were presented to the right ears 880 times consecutively for each condition. The P30m and the P50m responses were investigated, and the dipole source localization was performed. The P50m latency was significantly prolonged, while the P30m latency did not vary in the shorter ISI. Both P50m and P30m amplitudes were significantly reduced in the shorter ISI. The P50m was located significantly more anteriorly than P30m. These results suggest the existence of differential characteristic and spatially different magnetic responses in the middle latency range. This study has revealed one aspect of the different natures between P30m and P50m, and may provide a key for auditory perceptional processes in humans.


Characterizing the nonlinear growth of large-scale structure in the Universe
The local Universe displays a rich hierarchical pattern of galaxy clusters and superclusters. The early Universe, however, was almost smooth, with only slight 'ripples' as seen in the cosmic microwave background radiation. Models of the evolution of cosmic structure link these observations through the effect of gravity, because the small initially overdense fluctuations are predicted to attract additional mass as the Universe expands. During the early stages of this expansion, the ripples evolve independently, like linear waves on the surface of deep water. As the structures grow in mass, they interact with each other in nonlinear ways, more like waves breaking in shallow water. We have recently shown how cosmic structure can be characterized by phase correlations associated with these nonlinear interactions, but it was not clear how to use that information to obtain quantitative insights into the growth of structures. Here we report a method of revealing phase information, and show quantitatively how this relates to the formation of filaments, sheets and clusters of galaxies by nonlinear collapse. We develop a statistical method based on information entropy to separate linear from nonlinear effects, and thereby are able to disentangle those aspects of galaxy clustering that arise from initial conditions (the ripples) from the subsequent dynamical evolution.


Synthesis, characterisation and biological activity of thienoyl- and furanoyl-derived schiff-base compounds with 3d metal ions.
Cobalt(ll), copper(ll), nickel(ll) and zinc(ll) metal complexes of 2-carboxybenzylidene thienoylhydrazide HL(1) and 2-carboxybenzylidene furenoylhydrazide HL(2) of the type [M(L)(2).Cl(2)] have been prepared where M = Co(ll) and Ni(ll) and L = HL(1) and HL(2) (Fig 1) and characterized by their physical, analytical and spectral studies. The different mode of chelation of the ligands with metals and the effect of these metals on their biological properties is discussed.


A strategy for discovery of novel broad-spectrum antibacterials using a high-throughput Streptococcus pneumoniae transcription/translation screen.
The authors report the development of a high-throughput screen for inhibitors of Streptococcus pneumoniae transcription and translation (TT) using a luciferase reporter, and the secondary assays used to determine the biochemical spectrum of activity and bacterial specificity. More than 220,000 compounds were screened in mixtures of 10 compounds per well, with 10,000 picks selected for further study. False-positive hits from inhibition of luciferase activity were an extremely common artifact. After filtering luciferase inhibitors and several known classes of antibiotics, approximately 50 hits remained. These compounds were examined for their ability to inhibit Escherichia coli TT, uncoupled S. pneumoniae translation or transcription, rabbit reticulocyte translation, and in vitro toxicity in human and bacterial cells. One of these compounds had the desired profile of broad-spectrum biochemical activity in bacteria and selectivity versus mammalian biochemical and whole-cell assays.


Antibody-drug conjugate [ADC] treatment of leukaemia.
Three ADCs: Mylotarg, Besponda and Lumoxiti have improved overall survival and event=free survival as well as reduced relapse in 3 types of Leukaemia: AML, ALL and HCL, respectively. Lessons from these three SOC successful ADCs should guide other new ADCs in addressing the ADC-related off target toxicity due to the cytotoxic payload that limits their therapeutic index by using the successful approach of administrating lower doses in a fractionated regimen over time in separate days of the cycle to reduce the severity and frequency of the ADC-related serious toxicities that include ocular damage, long-term peripheral neuropathy and hepatic toxicity etc.


Significant decrease of mortality due to anastomotic leaks following esophageal resection: management makes the difference.
Anastomotic leakage is the most frequent cause of postoperative mortality following esophageal surgery. However, no gold standard for diagnosing and managing leakage has been established. Continuous clinical judgment is extremely important; therefore, to optimize the management of leakage, we established a special group for decision-making in cases of suspected leakage in the early postoperative period. Between January 2010 and December 2016, 234 consecutive patients underwent elective esophageal resection with a thoracoabdominal incision. In 2014, we established a group consisting of a surgeon, surgical endoscopist, and anesthesiologist for decision-making in cases of suspected leakage. They discussed emerging problems and decided on further diagnostics or therapy. The data were documented prospectively and compared to the years prior to 2014. Two hundred and thirty-four consecutive patients were enrolled in the study, 110 in the years 2010-2013 (group A), and 124 in the years 2014-2016 (group B). Neither patients' characteristics nor the rate of anastomotic leakage differed significantly between the two study groups. The hospital mortality rate was 10% (11 patients) in group A and 4.8% (six patients) in group B. Most interestingly, mortality due to anastomotic leakage was 35% in group A (9/26), whereas it decreased significantly to 6.5% (2/31 patients) (P < 0.001) in group B. Our data clearly demonstrated that optimizing the management of anastomotic leakage by making team decisions can lead to a significant decrease in mortality.


A community-based survey on massage therapy in Saudi Arabia.
Massage therapy (MT) is the physical manipulation of the soft tissues. It primarily consists of manual or hands-on techniques such as applying fixed or movable pressure, holding, and moving muscles and body tissues. MT is beneficial for pain relief, sport-related injury rehabilitation, stress reduction, and to address psychological disorders. MT is the most prevalent form of complementary and alternative (CAM) therapy worldwide. The aim of this study was to evaluate the knowledge, attitudes, and perceptions regarding MT among the Saudi community. A cross-sectional online survey using WhatsApp©, Google Forms©, Facebook©, and Twitter© was conducted among the general community of the Kingdom of Saudi Arabia (KSA) to assess the knowledge, attitudes, and perceptions regarding MT. Data was collected using a 20-item, self-administered questionnaire consisting of a series of both closed-ended and Likert-type questions. A total of 436 respondents completed the survey. Most of the respondents were female 84.2% (n = 367). Approximately 65% resided in the central region of KSA. The majority of the respondents, 81.4%, believed that MT is effective, 27.7% thought that MT leads to complications, and more than half of the residents, 55.7%, believed that patients should consult with their physicians prior to MT. The most common reasons for MT were to treat muscle pain, for relaxation purposes, to treat bone and joint pain, and backache relief, which were reported by 49%, 20%, 19%, and 16% of the participants, respectively. The knowledge, attitudes, and perceptions of the Saudi population towards MT are insufficient in some aspects. The establishment of community-based health education programs to improve knowledge of MT is recommended.


Foot and ankle imaging in the athlete.
Foot and ankle injuries are among the most common of all sports-related injuries. Many injuries are simplistic from a diagnostic standpoint, whereas others require a high level of suspicion and the use of appropriate diagnostic imaging modalities. Whether a professional athlete or a weekend warrior, all athletes want minimal disruption to their sporting activity and a quick return to competition. An accurate diagnosis aids in the development of an appropriate rehabilitation program and in return to activity. This article reviews the more common foot and ankle injuries seen in the podiatrist's office and the preferred imaging modalities used to evaluate them.


Stochastic subwavelength structures on poly(methyl methacrylate) surfaces for antireflection generated by plasma treatment.
Subwavelength structures of sufficient height-to-width aspect ratio are adequate for reduction of the Fresnel reflection of surfaces. In the case of low-pressure plasma-treated polymers, the self-organized features are stochastically distributed on the surface area with unequal shapes. Common descriptions use effective medium theory along with a continuously altering volume filling factor that together lead to a lateral homogeneous layer with a depth-dependent refractive index. We use a fixed gradient function for the refractive index for reverse engineering of in situ measured broadband optical data, and we compare the results with nonoptic methods.


Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity.
Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD.


Tri-axial dynamic acceleration as a proxy for animal energy expenditure; should we be summing values or calculating the vector?
Dynamic body acceleration (DBA) has been used as a proxy for energy expenditure in logger-equipped animals, with researchers summing the acceleration (overall dynamic body acceleration--ODBA) from the three orthogonal axes of devices. The vector of the dynamic body acceleration (VeDBA) may be a better proxy so this study compared ODBA and VeDBA as proxies for rate of oxygen consumption using humans and 6 other species. Twenty-one humans on a treadmill ran at different speeds while equipped with two loggers, one in a straight orientation and the other skewed, while rate of oxygen consumption (VO2) was recorded. Similar data were obtained from animals but using only one (straight) logger. In humans, both ODBA and VeDBA were good proxies for VO2 with all r(2) values exceeding 0.88, although ODBA accounted for slightly but significantly more of the variation in VO2 than did VeDBA (P<0.03). There were no significant differences between ODBA and VeDBA in terms of the change in VO2 estimated by the acceleration data in a simulated situation of the logger being mounted straight but then becoming skewed (P = 0.744). In the animal study, ODBA and VeDBA were again good proxies for VO2 with all r(2) values exceeding 0.70 although, again, ODBA accounted for slightly, but significantly, more of the variation in VO2 than did VeDBA (P<0.03). The simultaneous contraction of muscles, inserted variously for limb stability, may produce muscle oxygen use that at least partially equates with summing components to derive DBA. Thus, a vectorial summation to derive DBA cannot be assumed to be the more 'correct' calculation. However, although within the limitations of our simple study, ODBA appears a marginally better proxy for VO2. In the unusual situation where researchers are unable to guarantee at least reasonably consistent device orientation, they should use VeDBA as a proxy for VO2.


Metagenomic analysis reveals the efficient digestion mechanism of corn stover in Angus bull rumen: Microbial community succession, CAZyme composition and functional gene expression.
Ruminant rumen is a biological fermentation system that can efficiently degrade lignocellulosic biomass. The knowledge about mechanisms of efficient lignocellulose degradation with rumen microorganisms is still limited. In this study, composition and succession of bacteria and fungi, carbohydrate-active enzymes (CAZymes), and functional genes involved in hydrolysis and acidogenesis were revealed during fermentation in Angus bull rumen via metagenomic sequencing. Results showed that degradation efficiency of hemicellulose and cellulose reached 61.2% and 50.4% at 72 h fermentation, respectively. Main bacterial genera were composed of Prevotella, Butyrivibrio, Ruminococcus, Eubacterium, and Fibrobacter, and main fungal genera were composed of Piromyces, Neocallimastix, Anaeromyces, Aspergillus, and Orpinomyces. Principal coordinates analysis indicated that community structure of bacteria and fungi dynamically changed during 72 h fermentation. Bacterial networks with higher complexity had stronger stability than fungal networks. Most CAZyme families showed a significant decrease trend after 48 h fermentation. Functional genes related to hydrolysis decreased at 72 h, while functional genes involved in acidogenesis did not change significantly. These findings provide a in-depth understanding of mechanisms of lignocellulose degradation in Angus bull rumen, and may guide the construction and enrichment of rumen microorganisms in anaerobic fermentation of waste biomass.


DNA damage detection by an archaeal single-stranded DNA-binding protein.
Archaeal DNA repair pathways are not well defined; in particular, there are no convincing candidate proteins for detection of DNA mismatches or the bulky lesions removed by excision repair pathways. Single-stranded DNA-binding proteins (SSBs) play a central role in DNA replication, recombination and repair. The crenarchaeal SSB is a monomer with a single oligonucleotide-binding fold for single-stranded DNA binding coupled to a flexible C-terminal tail reminiscent of bacterial SSB that mediates interactions with other proteins. We demonstrate that Sulfolobus solfataricus SSB can melt DNA containing a mismatch or DNA lesion specifically in vitro. We suggest that a potential role for SSB in archaea is the detection of DNA damage due to local destabilisation of the DNA double helix, followed by recruitment of specific repair proteins. Proteins interacting specifically with a single-stranded DNA:SSB complex include several known or putative DNA repair proteins and DNA helicases.


Effects of indiscriminate foraging by tropical hummingbirds on pollination and plant reproductive success: experiments with two tropical treelets (Rubiaceae).
In cloud forest at Monteverde, Costa Rica, two common treelets (Palicourea lasiorrachis and Cephaelis elata, both Rubiaceae) depend simultaneously on one hummingbird population (Lampornis calolaema) for pollination. Both species are distylous and self-incompatible. In laboratory experiments, we examined possible effects of indiscriminate foraging by hummingbirds among flowers of both species, as observed in the field, on pollination of Palicourea. In each of 35 trials, captive L. calolaema probed 2 flowers from pin plants of Palicourea followed by 20 thrum flowers of the same species, with either 0, 2, or 10 Cephaelis flowers intervening. We assessed pollen transfer by staining and counting pin pollen tubes growing in thrum styles; counts of 0, 1, or ≥2 pollen tubes relate directly to seed output (0, 1, or 2 seeds per fruit, respectively). Intervening Cephaelis flowers sharply reduced pollen receipt by thrum flowers of Palicourea and reduced some aspects of pollen dispersal from pins as well, thereby curtailing maternal and paternal reproductive potential of Palicourea. Such effects of interspecific pollen loss on reproductive output may lead to strong competition among some, though not all, combinations of plant species pollinated by L. calolaema or of other plant combinations that share animal pollinators.


Evaluation of Renal Blood Flow in Dogs during Short-Term Human-Dose Epoprostenol Administration Using Pulsed Doppler and Contrast-Enhanced Ultrasonography.
Prostacyclin is an in vivo bioactive substance that regulates renal blood flow (RBF). Information regarding how epoprostenol, a prostacyclin preparation, affects RBF in dogs is lacking. We investigated the effects of short-term epoprostenol administration on RBF in six healthy dogs under anesthesia by administering it intravenously at human doses-2, 5, and 10 ng/kg/min for 20 min. RBF was evaluated before and during epoprostenol administration using pulsed Doppler ultrasonography, and renal perfusion was evaluated using contrast-enhanced ultrasonography. Effects on renal and systemic circulation were evaluated by measuring systolic arterial, mean arterial, diastolic arterial, pulmonary arterial, mean right atrial, and pulmonary capillary wedge pressures; heart rate; and cardiac output. Kruskal-Wallis and Bonferroni multiple comparison tests and Spearman's rank correlation coefficient were used for statistical analyses. As epoprostenol dosage increased, the peak systolic and end diastolic velocity of the renal artery, maximum and minimum venous flow velocities of the interlobular and renal veins, and heart rate all tended to increase, although not significantly. Our results indicate that human-dose epoprostenol administration in dogs does not cause significant changes in renal or systemic circulation. However, the human doses used may have been too low to produce a clinical effect in dogs.