Quantitative Fit Tested N95 Respirator-Alternatives Generated With CT Imaging and 3D Printing: A Response to Potential Shortages During the COVID-19 Pandemic.
Three-dimensional (3D) printing allows innovative solutions for personal protective equipment, particularly in times of crisis. Our goal was to generate an N95-alternative 3D-printed respirator that passed Occupational Safety and Health Administration (OSHA)-certified quantitative fit testing during the COVID-19 pandemic. 3D printed prototypes for N95 solutions were created based on the design of commercial N95 respirators. Computed tomography imaging was performed on an anthropomorphic head phantom wearing a commercially available N95 respirator and these facial contour data was used in mask prototyping. Prototypes were generated using rigid and flexible polymers. According to OSHA standards, prototypes underwent subsequent quantitative respirator fit testing on volunteers who passed fit tests on commercial N95 respirators. A total of 10 prototypes were 3D printed using both rigid (n = 5 designs) and flexible materials (n = 5 designs), Prototypes generated with rigid printing materials (n = 5 designs) did not pass quantitative respirator fit testing. Three of the five prototypes with flexible materials failed quantitative fit testing. The final two prototypes designs passed OSHA-certified quantitative fit tests with an overall mean fit factor of 138 (passing is over 100). Through rapid prototyping, 3D printed N95 alternative masks were designed with topographical facial computed tomography data to create mask facial contour and passed OSHA-certified quantitative respiratory testing when flexible polymer was used. This mask design may provide an alternative to disposable N95 respirators in case of pandemic-related shortages. Furthermore, this approach may allow customization for those that would otherwise fail fit testing on standard commercial respirators.


Transversus abdominis plane catheter bolus analgesia after major abdominal surgery.
Purpose. Transversus abdominis plane (TAP) blocks have been shown to reduce pain and opioid requirements after abdominal surgery. The aim of the present case series was to demonstrate the use of TAP catheter injections of bupivacaine after major abdominal surgery. Methods. Fifteen patients scheduled for open colonic resection surgery were included. After induction of anesthesia, bilateral TAP catheters were placed, and all patients received a bolus dose of 20 mL bupivacaine 2.5 mg/mL with epinephrine 5 μg/mL through each catheter. Additional bolus doses were injected bilaterally 12, 24, and 36 hrs after the first injections. Supplemental pain treatment consisted of paracetamol, ibuprofen, and gabapentin. Intravenous morphine was used as rescue analgesic. Postoperative pain was rated on a numeric rating scale (NRS, 0-10) at regular predefined intervals after surgery, and consumption of intravenous morphine was recorded. Results. The TAP catheters were placed without any technical difficulties. NRS scores were ≤3 at rest and ≤5 during cough at 4, 8, 12, 18, 24, and 36 hrs after surgery. Cumulative consumption of intravenous morphine was 28 (23-48) mg (median, IQR) within the first 48 postoperative hours. Conclusion. TAP catheter bolus injections can be used to prolong analgesia after major abdominal surgery.


Demographic characteristics of disability applicants: relationship to allowances.
This article highlights some of the causes underlying differences in disability allowances by sex and race. Among the causes are differences in labor-force patterns, the educational background, and the age distributions of the insured and applicant populations. More than half of the differences between the black and white applicants in the proportion of claims allowed is explained by differences in their age distributions. The lower proportion of claims allowed for black applicants may reflect the greater tendency fo the black insured population to apply for disability insurance benefits.


Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2.
The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we describe the development and employment of a new functional assay that measures neutralizing antibodies for SARS-CoV-2 and present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced antibody responses for key variants in an Asian volunteer cohort. We also present an accurate quantitation of serological responses for SARS-CoV-2 that exploits a unique set of in-house, recombinant human monoclonal antibodies targeting the viral Spike and nucleocapsid proteins and demonstrate a reduction in neutralizing antibody titres across all groups 6 months post-vaccination. We also observe a marked reduction in the serological binding activity and neutralizing responses targeting recently newly emerged Omicron variants including XBB 1.5 and highlight a significant increase in cross-protective neutralizing antibody responses following a third dose (boost) of vaccine. These data illustrate how key virological factors such as immune escape mutations combined with host demographic factors such as age and sex of the vaccinated individual influence the strength and duration of cross-protective serological immunity for COVID-19.


Increased nitric oxide in exhaled air: an early marker of asthma in non-smoking aluminium potroom workers?
To study exhaled nitric oxide (NO) as a marker of airway inflammation caused by potroom exposure, hypothesising that (a) workers exposed to potroom pollutants would have higher concentrations of NO in expired air than control subjects employed at the same plant but working outside of the potroom atmosphere, and (b) that concentrations of exhaled NO in potroom employees might be positively associated with concentrations of fluoride and exposure to dust. A study group comprising 186 male subjects (aged 24-63 years), employed in the potrooms of one Norwegian aluminium smelter, and 40 comparable control subjects (aged 25-60 years) recruited from the same plant, were examined by measurements of exhaled and nasal concentrations of NO, spirometry, and a questionnaire on respiratory symptoms as a part of an annual health surveillance programme. Estimates of exposure to fluorides and dust for selected job categories were obtained by means of personal samplers carried by the workers. In the non-smokers, the concentrations of exhaled NO were higher in the potroom workers than in the controls (median (interquartile range) 9.3 (6.2-15.6) v 5.7 (4.6-8.3) ppb, p=0.001). The two groups did not differ in spirometry and asthma-like symptoms. Non-smoking potroom workers with asthma-like symptoms had higher concentrations of exhaled NO than those with no symptoms (median (interquartile range) 21.0 (19.3-41. 4) v 8.5 (5.9-12.8) ppb, p=0.001), but had comparable spirometric values. In subjects who smoked, the concentrations of exhaled NO did not differ significantly between potroom workers and controls (median (interquartile range) 4.6 (3.3-8.0) v 4.0 (3.4-5.1) ppb. Exhaled NO was not significantly associated with either duration of employment or routine measurements of dust and fluorides. Exposure to potroom pollutants is associated with increased concentrations of exhaled NO in non-smoking subjects. Nitric oxide in exhaled air may be an early marker of airway inflammation in aluminium potroom workers.


The impact of Hurricane Maria on individuals living with non-communicable disease in Puerto Rico: the experience of 10 communities.
Coinciding with the rising non-communicable disease (NCD) prevalence worldwide is the increasing frequency and severity of natural hazards. Protecting populations with NCDs against natural hazards is ever more pressing given their increased risk of morbidity and mortality in disaster contexts. This investigation examined Hurricane Maria's impacts across ten lower SES municipalities in Puerto Rico with varying community characteristics and hurricane impacts to understand experiences of supporting individuals with NCD management in the six-month period following the hurricane. We conducted 40 qualitative interviews with mayors, first responders, faith leaders, community leaders, and municipal employees from 10 municipalities in Puerto Rico. Using QSR NVivo software, we deductively and inductively coded interview transcripts and undertook thematic analysis to characterize community-level hurricane impact and consequences for NCD management, and to identify convergent and divergent themes. Damages to infrastructure, including healthcare facilities and roadways, complicated the provision of timely health care for NCDs, patient transport, and pharmaceutical/medical supply chain continuity. Lengthy power outages at both healthcare facilities and private residences were barriers to healthcare service delivery, use of medical equipment, and storage of prescription medications with refrigeration, and led to a widespread mental health crisis. Cascading failures such as fuel shortages further compounded these challenges. The consequences of these impacts included the reported exacerbation of health conditions and loss of life among NCD patients. Study findings identify contributors to morbidity and mortality among individuals with NCDs following Hurricane Maria. With the growing frequency of catastrophic disasters from natural hazards, the experiences of communities that endured these impacts offer important lessons regarding policies and practices to better support community disaster resilience and address the evolving preparedness needs of NCD patients.


The lethal toxicity of Matacil 1.8 F to rainbow trout and its in vivo metabolism.
Fingerling rainbow trout (Salmo gairdneri Richardson) were used to determine the lethal toxicity of Matacil 1.8 F and Matacil 1.8 D ready-to-use formulations. The 96-h LC50s were 21.3 mg/l for water-based Matacil 1.8 F; 19.1 mg/l for oil-based Matacil 1.8 F; and 0.36 mg/l for Matacil 1.8 D. Aminocarb (4-dimethylamino-m-tolyl N-methylcarbamate) and MA (4-methylamino-m-tolyl N-methylcarbamate) were detected in fish tissue 96 h after exposure. More than 50% of the total residue (Aminocarb + MA) were the parent compound. The bioaccumulation ratio ranged from 1.70 to 3.32 at different concentrations of aminocarb. Both aminocarb and MA were rapidly eliminated after the fish had been transferred to clean water; the total residue declined by more than 90% in 72 h and became non-detectable in 96 h.


A surgical technique for safely placing a drug delivery catheter into the pons of primates: preliminary results of carboplatin infusion.
We sought to develop a neurosurgical procedure to access the pons with a drug delivery device for chronic therapy and collect preliminary data on the toxicity of direct infusions of carboplatin in primates. We made midline incisions on five cynomolgus monkeys, identified the inion, made a burr hole 2.5 cm below the inion, and inserted a catheter through the cerebellum into the roof of the pons. Pumps that infused saline for 90 days or carboplatin solutions for 30 to 35 days at 10 microl/d were placed subcutaneously in the low cervical/high thoracic region. Monkeys were assessed by computed tomography and magnetic resonance imaging, laboratory studies, daily neurological observation, postmortem examinations, and histopathology. Monkeys infused with saline and 82 microg of carboplatin remained neurologically intact throughout the infusion periods. Serial imaging showed that the catheter tip was in the pons and revealed no evidence of hemorrhage, edema, or migration. Two monkeys infused with up to 850 microg of carboplatin showed hyperintense magnetic resonance imaging signals at Days 15 and 18 and neurological deficits at approximately Week 3. Platinum levels greater than 10 ng/mg tissue were detected over a distance of 1 cm in tissue slices. Histopathology demonstrated significant tissue necrosis around the tip of the catheter. The pons of monkeys is safely accessed with a catheter for drug delivery by using a posterior midline approach. Clinical observations, radiographic imaging, and laboratory tests of animals infused with saline for 3 months or 0.26 mg/ml of carboplatin for 1 month were unremarkable. Neurotoxicity was seen with dose levels of 2.6 mg/ml of drug for 1 month. This procedure offers opportunities for examining the toxicity of brainstem antitumor therapy in primates.


Recent Findings Unravel Genes and Genetic Factors Underlying Leptosphaeria maculans Resistance in Brassica napus and Its Relatives.
Among the Brassica oilseeds, canola (Brassica napus) is the most economically significant globally. However, its production can be limited by blackleg disease, caused by the fungal pathogen Lepstosphaeria maculans. The deployment of resistance genes has been implemented as one of the key strategies to manage the disease. Genetic resistance against blackleg comes in two forms: qualitative resistance, controlled by a single, major resistance gene (R gene), and quantitative resistance (QR), controlled by numerous, small effect loci. R-gene-mediated blackleg resistance has been extensively studied, wherein several genomic regions harbouring R genes against L. maculans have been identified and three of these genes were cloned. These studies advance our understanding of the mechanism of R gene and pathogen avirulence (Avr) gene interaction. Notably, these studies revealed a more complex interaction than originally thought. Advances in genomics help unravel these complexities, providing insights into the genes and genetic factors towards improving blackleg resistance. Here, we aim to discuss the existing R-gene-mediated resistance, make a summary of candidate R genes against the disease, and emphasise the role of players involved in the pathogenicity and resistance. The comprehensive result will allow breeders to improve resistance to L. maculans, thereby increasing yield.


Efficacy of sunitinib in patients with metastatic renal cell carcinoma: initial experience in two Chinese centers.
The advent of targeted therapy has proved a milestone in the history of metastatic renal cell carcinoma treatment, and several guidelines now recommend sunitinib as first- or second-line treatment. But little is known about its efficacy in Asian patients. The aim of this article was to evaluate the efficacy of sunitinib monotherapy in patients with metastatic renal cell carcinoma treated at two Chinese centers. One hundred and forty-one patients with metastatic renal cell carcinoma were included in the study. Of them, 119 patients received single-agent sunitinib as first-line therapy and the remaining 22 patients received it as second-line therapy. One hundred and twenty patients received sunitinib in a dosage of 50 mg orally once daily on a 4-2 schedule (4 weeks on treatment, 2 weeks off), while 21 patients received 37.5 mg/day continuously until either disease progression or unacceptable toxicity occurred. The overall response rate, survival outcomes, and safety were evaluated. Over a median follow-up time of 23 months (16 cycles; range 2-45 months), complete responses, partial responses, and stable disease lasting two cycles or longer were achieved in 2.8%, 24.1%, and 60.3% of patients respectively (objective response rate 26.9%; overall benefit 87.2%). The median progression-free survival was 14.2 months (range 3-39 months). During the study, 53 patients died and the median survival time was 13.5 months (range 7-25 months). Dose modification or treatment interruption due to adverse events was required in 36.9% of the patients. The most common adverse events were hand-foot syndrome (71.4%), thrombocytopenia (68.8%), hypertension (47.1%), and fatigue (46.3%). Sunitinib had a favorable efficacy/tolerability profile in Chinese patients with metastatic renal cell carcinoma.


Virtue Ethics and Integration in Evidence-Based Practice in Psychology.
The policy statement for evidence-based practice in psychology is the most important document in contemporary psychotherapy. In its current form, evidence-based practice in psychology gives scientific research precedence in psychotherapy practice. However, psychotherapy practice's complexity warrants reflection beyond the limits of science. The importance of clinical expert is not recognised in the current policy statement. The clinical expert is necessary to translate psychological research into clinical practice. It is also crucial to identify, clarify and include patient preferences in psychotherapy practice. This paper argues that virtue ethics is a useful theoretical framework for conceptualising clinical expertise. Clinical expertise is conceptualised as the meta-capacity of practical wisdom (phronesis) and the virtues necessary for integrating best available research, clinical expertise and patient preferences.


Bat influenza viruses transmit among bats but are poorly adapted to non-bat species.
Major histocompatibility complex class II (MHC-II) molecules of multiple species function as cell-entry receptors for the haemagglutinin-like H18 protein of the bat H18N11 influenza A virus, enabling tropism of the viruses in a potentially broad range of vertebrates. However, the function of the neuraminidase-like N11 protein is unknown because it is dispensable for viral infection or the release of H18-pseudotyped viruses. Here, we show that infection of mammalian cells with wild-type H18N11 leads to the emergence of mutant viruses that lack the N11 ectodomain and acquired mutations in H18. An infectious clone of one such mutant virus, designated rP11, appeared to be genetically stable in mice and replicated to higher titres in mice and cell culture compared with wild-type H18N11. In ferrets, rP11 antigen and RNA were detected at low levels in various tissues, including the tonsils, whereas the wild-type virus was not. In Neotropical Jamaican fruit bats, wild-type H18N11 was found in intestinal Peyer's patches and was shed to high concentrations in rectal samples, resulting in viral transmission to naive contact bats. Notably, rP11 also replicated efficiently in bats; however, only restored full-length N11 viruses were transmissible. Our findings suggest that wild-type H18N11 replicates poorly in mice and ferrets and that N11 is a determinant for viral transmission in bats.


Rickettsia Sca2 Recruits Two Actin Subunits for Nucleation but Lacks WH2 Domains.
The Rickettsia ∼1800-amino-acid autotransporter protein surface cell antigen 2 (Sca2) promotes actin polymerization on the surface of the bacterium to drive its movement using an actin comet-tail mechanism. Sca2 mimics eukaryotic formins in that it promotes both actin filament nucleation and elongation and competes with capping protein to generate filaments that are long and unbranched. However, despite these functional similarities, Sca2 is structurally unrelated to eukaryotic formins and achieves these functions through an entirely different mechanism. Thus, while formins are dimeric, Sca2 functions as a monomer. However, Sca2 displays intramolecular interactions and functional cooperativity between its N- and C-terminal domains that are crucial for actin nucleation and elongation. Here, we map the interaction of N- and C- terminal fragments of Sca2 and their contribution to actin binding and nucleation. We find that both the N- and C-terminal regions of Sca2 interact with actin monomers but only weakly, whereas the full-length protein binds two actin monomers with high affinity. Moreover, deletions at both ends of the N- and C-terminal regions disrupt their ability to interact with each other, suggesting that they form a contiguous ring-like structure that wraps around two actin subunits, analogous to the formin homology-2 domain. The discovery of Sca2 as an actin nucleator followed the identification of what appeared to be a repeat of three Wiskott-Aldrich syndrome homology 2 (WH2) domains in the middle of the molecule, consistent with the presence of WH2 domains in most actin nucleators. However, we show here that contrary to previous assumptions, Sca2 does not contain WH2 domains. Instead, our analysis indicates that the region containing the putative WH2 domains is folded as a globular domain that cooperates with other parts of the Sca2 molecule for actin binding and nucleation.


Quality of life and symptom experience measurement tools in adults with atrial fibrillation: a scoping review protocol.
The objective of this scoping review is to identify and map measurement tools for evaluating disease-specific quality of life and symptoms in adults with atrial fibrillation. The review will also identify key concepts that differentiate quality of life from symptom experience. Quality of life is a broad concept influenced by physical health, psychological state, degree of independence, and social/functional status. Symptoms of a chronic disease may influence quality of life through their effect on an individual's perception of physical health. Symptom experience is distinct from quality of life; however, the distinction is ill-defined, resulting in conceptual overlap in the measurement tools used to assess these concepts in patients with atrial fibrillation. Included manuscripts will describe a scale, index, questionnaire, checklist, or other form of measurement tool designed to assess quality of life or symptom experience in adults with atrial fibrillation or supraventricular arrhythmia. Peer-reviewed research manuscripts and systematic reviews, gray literature, and conceptual/theoretical papers will be included. The review will follow the JBI methodology for scoping reviews. MEDLINE, CINAHL, PsycINFO, the Cochrane Database of Systematic Reviews, and Embase will be searched, as well as Google Scholar, MedNar, and OpenGrey. Articles will be considered if they are published in English, Danish, Swedish, or Norwegian, with no date limitation. The title and abstract of each article will be independently screened by two authors, followed by full-text review of remaining articles, according to the inclusion criteria. Data will be independently extracted by two authors using a data extraction tool.


A wavelet-based noise reduction algorithm and its clinical evaluation in cochlear implants.
Noise reduction is often essential for cochlear implant (CI) recipients to achieve acceptable speech perception in noisy environments. Most noise reduction algorithms applied to audio signals are based on time-frequency representations of the input, such as the Fourier transform. Algorithms based on other representations may also be able to provide comparable or improved speech perception and listening quality improvements. In this paper, a noise reduction algorithm for CI sound processing is proposed based on the wavelet transform. The algorithm uses a dual-tree complex discrete wavelet transform followed by shrinkage of the wavelet coefficients based on a statistical estimation of the variance of the noise. The proposed noise reduction algorithm was evaluated by comparing its performance to those of many existing wavelet-based algorithms. The speech transmission index (STI) of the proposed algorithm is significantly better than other tested algorithms for the speech-weighted noise of different levels of signal to noise ratio. The effectiveness of the proposed system was clinically evaluated with CI recipients. A significant improvement in speech perception of 1.9 dB was found on average in speech weighted noise.


Clinical application of bell retinoscopy.
The procedure of bell retinoscopy is described in detail, including changes in motion, color, and brightness of reflex. The responses are divided into eight categories. Suggestions are included to guide and direct the optometrist in prescribing lenses on the basis of bell retinoscopy.


A new method for the control of discrete nonlinear dynamic systems using neural networks.
A new controller design method for nonaffine nonlinear dynamic systems is presented in this paper. An identified neural network model of the nonlinear plant is used in the proposed method. The method is based on a new control law that is developed for any discrete deterministic time-invariant nonlinear dynamic system in a subregion Phi(x) of an asymptotically stable equilibrium point of the plant. The performance of the control law is not necessarily dependent on the distance between the current state of the plant and the equilibrium state if the nonlinear dynamic system satisfies some mild requirements in Phi(x). The control law is simple to implement and is based on a novel linearization of the input-output model of the plant at each instant in time. It can be used to control both minimum phase and nonminimum phase nonaffine nonlinear plants. Extensive empirical studies have confirmed that the control law can be used to control a relatively general class of highly nonlinear multiinput-multioutput (MIMO) plants.


Pseudomonas mangiferae sp. nov., isolated from bark of mango tree in Thailand.
An aerobic, Gram-stain-negative, rod-shaped bacterium, designated DMKU BBB3-04T, was isolated from bark of mango tree . Colonies were circular, convex with entire margins when grown on nutrient agar medium for 2 days. The bacterium was motile by means of lophotrichous flagella and produced black-brown pigment. The strain grew at 12-40 °C (optimum, 28-30 °C) and at pH 6.0-8.0 (pH 6.5). Growth was observed in the presence of up to 5 % (w/v) NaCl. Strain DMKU BBB3-04T showed the highest 16S rRNA gene sequence similarity to Pseudomonas furukawaii KF707T (97.1 %), Pseudomonas indica NBRC 103045T (97.0 %), Pseudomonas tarimensis MA-69T (96.9 %) and Pseudomonas azotifigens 6H33bT (96.8 %), suggesting that strain DMKU BBB3-04T should be classified within the genus Pseudomonas. Analysis of strain DMKU BBB3-04T was also performed using three housekeeping genes (gyrB,rpoB and rpoD) and further confirmed the phylogenetic assignment of the strain. The major fatty acids found in strain DMKU BBB3-04T were summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c), C16 : 0 and summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c) (35, 22 and 19 %, respectively). The major polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The respiratory quinone was Q-9. The DNA G+C content of the strain DMKU BBB3-04T was 67.6 mol%. On the basis of phenotypic characteristics, chemotaxonomic data and phylogenetic analysis, strain DMKU BBB3-04T is considered to represent a novel species in the genus Pseudomonas. We propose the name Pseudomonasmangiferae sp. nov. for this novel species. The type strain of the novel species is DMKU BBB3-04T (=TBRC 7080T=JCM 32061T).


Catheter-Related Staphylococcus aureus Bacteremia and Septic Thrombosis: The Role of Anticoagulation Therapy and Duration of Intravenous Antibiotic Therapy.
Catheter-related septic thrombosis is suspected in patients with persistent central line-associated bloodstream infection (CLABSI) after 72 hours of appropriate antimicrobial therapy. The clinical diagnosis and management of this entity can be challenging as limited data are available. We retrospectively studied the clinical characteristics of patients with Staphylococcus aureus catheter-related septic thrombosis and the outcomes related to different management strategies. This retrospective study included patients with CLABSI due to S. aureus who had concomitant radiographic evidence of catheter site thrombosis treated at our institution between the years 2005 and 2016. We collected data pertaining to patients' medical history, clinical presentation, management, and outcome within 3 months of bacteremia onset. A total of 128 patients were included. We found no significant difference in overall outcome between patients who had deep vs superficial thrombosis. Patients with superficial thrombosis were found to have a higher rate of pulmonary complications (25% vs 6%; P = .01) compared with those with deep thrombosis. Patients who received less than 28 days of intravascular antibiotic therapy had higher all-cause mortality (31 vs 5%; P = .001). A multivariate logistic regression analysis identified 2 predictors of treatment failure: ICU admission during their illness (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.08-6.99; P = .034) and not receiving anticoagulation therapy (OR, 0.24; 95% CI, 0.11-0.54; P < .001). Our findings suggest that the presence of S. aureus CLABSI in the setting of catheter-related thrombosis may warrant prolonged intravascular antimicrobial therapy and administration of anticoagulation therapy in critically ill cancer patients.


Database-driven semigrand canonical Monte Carlo method: Application to segregation isotherm on defects in alloys.
The application of existing semigrand canonical ensemble Monte Carlo algorithms to alloys requires the chemical potential difference values between pairs of atomic species in the alloys as inputs. However, finding the appropriate values for a target system at a desired temperature and bulk composition is a time-consuming task consisting of multiple test runs to determine the chemical potential differences. This problem becomes more serious when dealing with systems containing three or more atomic species, such as medium- and high-entropy alloys, due to the increase of the number of chemical potential differences that need to be calculated. Here we propose a method for sampling from the semigrand canonical ensemble that relies on energy databases acting as an external atomic reservoir at the desired temperature and composition. Given these energy databases, the desired bulk composition and corresponding chemical potential differences can be satisfied in a "single" Monte Carlo simulation. Moreover, the energy databases shed light on the underlying energetics of alloys, reflecting their local chemical ordering. We demonstrate the validity of this method using analyses of segregation isotherms at grain boundaries and dislocations in two alloy systems: Fe-1-at.-%-Si and NiCoCr medium-entropy alloy. We also discuss the possibly relevant information contained in such energy databases.


Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer.
Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC.


Impact of a training program on disaster preparedness among paramedic students of a tertiary care hospital of North India: A single-group, before-after intervention study.
Disaster can occur at any time any place. Disaster preparedness plays an important role to reduce the loss of a community/country. The aim of this interventional study was to ascertain the impact of a video-based educational intervention program on improvement in knowledge and attitude of paramedical students in a hospital. A pre-post study (interventional study design) was conducted on paramedic students. Our study period was 6 months which was divided into Phases I, II, and III. For administrative purpose, we included all paramedical students, and our sample size was 119. The baseline assessment of knowledge and attitude of paramedic students was done by a pretested questionnaire (Observation 1) with having a baseline scoring. After that, intervention Phase 1 was implemented, and later, end line observation (Observation 2) was made. Changes in knowledge and attitude were observed by the score difference (Observation 2-Observation 1). Descriptive statistics were calculated, and the mean of cumulative score was compared using the Wilcoxon signed-rank test. We applied Mann-Whitney U-test for finding associations between dependent variables with an independent variable using SPSS version 22 (IBM, Chicago, USA) software. Our baseline results showed that most of our participants had average knowledge (54.6%), followed by poor knowledge (24.4%). Approximately one-fifth (21.0%) of the participants had good knowledge regarding disaster preparedness. A significant improvement was observed in cumulative score (P < 0.005). A significant difference was observed in knowledge and attitude with respect to age and courses (P < 0.05). Forty percent of the students responded that they would like to get trained by that mock drill, and 26.1% were interested in disaster preparedness workshops in the future. Our present study results indicate that the overall knowledge and attitude level of the students was average and required improvement. A similar result was reported in some studies conducted globally for the same purpose. All of our students perceived that training for disaster preparedness is necessary for all health facilities, and it is important to have an emergency plan and disaster management committee. Regarding training methods, most of our students liked our interactive audiovisual method. However, their preferred methods were mock drill and workshops. It can be arranged in the future for them.


Estimating the proportion of all observed birth defects occurring in pregnancies terminated by a second-trimester abortion.
Prenatal termination of pregnancy may underestimate risks or cause bias in epidemiological studies of birth defects if such studies measure only defects diagnosed postnatally. We aimed to estimate the proportion of all fetuses with birth defects terminated in the second trimester of pregnancy-overall and for specific defects. The study comprised all pregnancies ending in a singleton birth, miscarriage, or termination of pregnancy for which health care services were sought, as recorded in Danish medical registries between 1 January 2007 and 31 December 2011. Of the 420,090 pregnancies, 307,637 fetuses survived until gestational week 12 or beyond; of these, 296,373 (96%) ended in a live birth or stillbirth and 11,264 (4%) ended in a second-trimester termination. The prevalence of birth defects among live births and stillbirths was 3% (9,790/296,373); the corresponding prevalence among second-trimester-terminated pregnancies was 14% (1,563/11,264). Although only 4% of all pregnancies ended in a second-trimester termination, 14% (1,563/11,353) of pregnancies with birth defects were ended by a second-trimester termination. The groups of birth defects with the highest proportion of second-trimester terminations were defects of the nervous system (347/740; 48%) and abdominal wall (58/149; 39%). For many types of birth defects, however, that proportion was less than 10%. The proportion of terminated pregnancies carrying birth defects is considerably greater than the corresponding proportion for pregnancies that end as live births or stillbirths. The proportion of birth defects unobserved at birth due to second-trimester terminations depends on type of defect and lethality.


Sealing effect of a polysaccharide nanosheet for murine cecal puncture.
Recent developments in nanobiotechnology have led us to develop a method of producing a free-standing polymer nanosheet composed of polysaccharides (ie, polysaccharide nanosheet) with a thickness of tens of nanometers. Owing to its enormous aspect ratio, the polysaccharide nanosheet is semi-absorbent and has a physical adhesive strength 7.5-fold greater than that of conventional films of >1 microm thickness. Herein, we have investigated the therapeutic sealing effect of this polysaccharide nanosheet on murine cecal puncture as a wound dressing material. Murine cecum was punctured and then overlapped with the polysaccharide nanosheet. Thereafter, we evaluated its sealing effect on bacterial peritonitis as well as the protection offered by the polysaccharide nanosheet against bacterial permeability using an in vitro transmembrane assay. The 39-nm-thick polysaccharide nanosheet overlapped tightly the perforated cecum. No adhering agents were required because of the ability of the polysaccharide nanosheet to adhere to the tissue surface by physical adsorption (eg, van der Waals interaction). Sealing the perforated cecum with the polysaccharide nanosheet increased survival rate without postoperative adhesion by comparison with untreated mice (90 vs 30%; P < .01). These data were supported by the improvement in peritonitis related to bacterial counts, white blood cell counts, and the serum tumor necrosis factor level. Moreover, using an in vitro transmembrane assay, we showed that the polysaccharide nanosheet inhibited effectively bacterial penetration. We have demonstrated the potential clinical benefits of the nanosheet-type biomaterial that can be used for repairing a cecal colotomy without chemical bonding agents.


[Clostridium difficile infecion--diagnostics, prevention and treatment].
Clostridium difficile is the most common cause of an antibiotic-associated diarrhoea. Frequency of Clostridium difficile infections (CDI) increased in the last decade. This study presents current preventive measure i.e. hand washing, disposable gloves. Additionally, the article presents diagnostic methods: detection glutamine dehydrogenase (GDH), toxins A and B, cytotoxicity neutralization test, polymerase chain reaction methods (PCR) i.e. nucleic acid amplification test (NAAT) and stool culture. Moreover available methods of treatment were presented depending on severity of CDI e.i. metronidazole, vancomycin, fidaxomicin, rifaximin. Furthermore, the review provides information about alternative methods of treatment in view of new hypervirulent strains of C. difficile and increasing resistance to commonly used antibiotics, including: fuscid acid, bacitracin, probiotics, non-toxigenic strains, immunoglobulins, monoclonal antibodies, vaccines, toxins binders and fecal transplant.


Investigation of a synthetic diamond detector response in kilovoltage photon beams.
An important characteristic of radiation dosimetry detectors is their energy response which consists of absorbed-dose and intrinsic energy responses. The former can be characterized using Monte Carlo (MC) simulations, whereas the latter (i.e., detector signal per absorbed dose to detector) is extracted from experimental data. Such a characterization is especially relevant when detectors are used in nonrelative measurements at a beam quality that differs from the calibration beam quality. Having in mind the possible application of synthetic diamond detectors (microDiamond PTW 60019, Freiburg, Germany) for nonrelative dosimetry of low-energy brachytherapy (BT) beams, we determined their intrinsic and absorbed-dose energy responses in 25-250 kV beams relative to a 60 Co beam, which is usually the reference beam quality for detector calibration in radiotherapy. Three microDiamond detectors and, for comparison, two silicon diodes (PTW 60017) were calibrated in terms of air-kerma free in air in six x-ray beam qualities (from 25 to 250 kV) and in terms of absorbed dose to water in a 60 Co beam at the national metrology laboratory in Sweden. The PENELOPE/penEasy MC radiation transport code was used to calculate the absorbed-dose energy response of the detectors (modeled based on blueprints) relative to air and water depending on calibration conditions. The MC results were used to extract the relative intrinsic energy response of the detectors from the overall energy response. Measurements using an independent setup with a single ophthalmic BEBIG I25.S16 125 I BT seed (effective photon energy of 28 keV) were used as a qualitative check of the extracted intrinsic energy response correction factors. Additionally, the impact of the thickness of the active volume as well as the presence of extra-cameral components on the absorbed-dose energy response of a microDiamond detector was studied using MC simulations. The relative intrinsic energy response of the microDiamond detectors was higher by a factor of 2 in 25 and 50 kV beams compared to the 60 Co beam. The variation in the relative intrinsic energy response of silicon diodes was within 10% over the investigated photon energy range. The use of relative intrinsic energy response correction factors improved the agreement among the absorbed dose to water values determined using microDiamond detectors and silicon diodes, as well as with the TG-43 formalism-based calculations for the 125 I seed. MC study of microDiamond detector design features provided a possible explanation for inter-detector response variation at low-energy photon beams by differences in the effective thickness of the active volume. MicroDiamond detectors had a non-negligible variation in the relative intrinsic energy response (factor of 2) which was comparable to that in the absorbed-dose energy response relative to water at low-energy photon beams. Silicon diodes, in contrast, had an absorbed-dose energy dependence on photon energy that varied by a factor of 6, whereas the intrinsic energy dependence on beam quality was within 10%. It is important to decouple these two responses for a full characterization of detector energy response especially when the user and reference beam qualities differ significantly, and MC alone is not enough.


Advanced life support in obstetrics (ALSO) and post-partum hemorrhage: a prospective intervention study in Tanzania.
To evaluate the impact of Advanced Life Support in Obstetrics (ALSO) training on staff performance and the incidences of post-partum hemorrhage (PPH) at a regional hospital in Tanzania. Prospective intervention study. A regional, referral hospital. A total of 510 women delivered before and 505 after the intervention. All high- and mid-level providers involved in childbirth at the hospital attended a two-day ALSO provider course. Staff management was observed and post-partum bleeding assessed at all vaginal deliveries for seven weeks before and seven weeks after the training. PPH (blood loss ≥500ml), severe PPH (blood loss ≥1000ml) and staff performance to prevent, detect and manage PPH. The incidence of PPH was significantly reduced from 32.9 to 18.2%[RR 0.55 (95%CI: 0.44-0.69)], severe PPH from 9.2 to 4.3%[RR 0.47 (95%CI: 0.29-0.77)]. The active management of the third stage of labor was also significantly improved. There was a significant decrease in episiotomies. By visual estimation, staff identified one in 25 of the PPH cases before the ALSO training and one in five after the training. A significantly higher proportion of women with PPH had continuous uterine massage, oxytocin infusion and bimanual compression of the uterus after the training. A two-day ALSO training course can significantly improve staff performance and reduce the incidence of PPH, at least as evaluated by short-term effects.


Hoffa's fat pad impingement treated arthroscopically: related findings on preoperative MRI in a case series of 62 patients.
The morphology of painful impingement of the infrapatellar fat pad (Hoffa's disease), which is characterized by inflammation, swelling, hypertrophy, fibrosis, and/or calcifications, has been well described. The purpose of this study was to investigate whether corresponding characteristic MRI findings could be assessed in patients with infrapatellar fat pad impingement. This study includes 62 patients with secondary symptomatic Hoffa's fat pad impingement. In these patients, the fat pad was partially resected until no impingement could be determined at full knee movement. Within a maximum of 3 months before arthroscopic surgery, patients had standardized MR imaging using a 1.5 Tesla unit with the following sequences: sagittal T1-TSE, coronal STIR-TSE, transversal fat-suppressed PD-TSE, and sagittal fat-suppressed PD-TSE (Siemens Magnetom Avanto syngo MR B 15). In this case series, the preoperative MRI appearance of the fat pad was evaluated and compared with a cohort of 255 patients without fat pad impingement but with various knee disorders at arthroscopy as well as the same standardized MRI protocol. In patients with Hoffa's fat pad impingement, morphologic changes such as localized edema of the superior and/or posterior part of the fat pad, a deep fluid-filled infrapatellar bursa, non-visualization of vertical and/or horizontal clefts, fibrosis, and calcifications were noted on MR imaging with remarkable frequency. Besides a significant enlargement of the fat pad, each of these MRI findings was significantly associated with impingement of Hoffa's fat pad (P < 0.05). Besides a moderate kappa score for the detection of intrahoffatic calcifications and vertical clefts, kappa values for each finding showed good inter-observer agreement. Results of logistic regression revealed that edema of Hoffa's fat pad was one of the most important diagnostic MRI criteria for the diagnosis of Hoffa's fat pad impingement. MR imaging allows identification of several changes that may be related to a symptomatic impingement of Hoffa's fat pad. In patients who are suspected of having infrapatellar fat pad impingement, such MRI findings should be considered and distinguished from other causes of anterior knee pain.


Cancer risk in men exposed in utero to diethylstilbestrol.
An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.


Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis.
Experimental renovascular hypertension or supravalvular aortic constriction results in left ventricular hypertrophy and impaired minimum coronary vascular resistance. However, these experimental models expose the coronary arteries to increased intra-arterial pressure, so that hypertensive vascular changes might be responsible for the impaired minimum coronary resistance. This study was performed to test the hypothesis that left ventricular hypertrophy in the absence of increased coronary pressure results in abnormalities of myocardial perfusion. Aortic valve stenosis was produced by plication of the noncoronary aortic cusp of 11 dogs at 6-8 weeks of age. Studies were carried out when the animals reached adulthood; mean left ventricular:body weight ratio was 7.1 +/- 0.4 as compared to 4.4 +/- 0.3 g/kg in 11 normal dogs (P less than 0.01). Under quiet resting conditions, myocardial blood flow measured with microspheres was significantly greater than normal in dogs with aortic stenosis. However, during maximum coronary vasodilation with adenosine, mean left ventricular blood flow in dogs with hypertrophy (3.29 +/- 0.39) was substantially less than in normal dogs (6.19 +/- 0.54 ml/min per g; P less than 0.01), whereas minimum coronary resistance was increased from 14.1 +/- 1.7 in normal dogs to 23.7 +/- 5.4 mmHg. min X g/ml (P less than 0.01). To examine the response of myocardial perfusion to cardiac stress, blood flow was measured during pacing at 200 and 250 beats/min. Compared with normal dogs, animals with hypertrophy had a subnormal increase in myocardial blood flow during tachycardia; this perfusion deficit was most marked in the subendocardium. These data demonstrate that left ventricular hypertrophy alone, without increased coronary artery pressure, is associated with impaired minimum coronary vascular resistance and with abnormalities of myocardial blood flow during pacing stress.


Anti-endotoxin agents. 2. Pilot high-throughput screening for novel lipopolysaccharide-recognizing motifs in small molecules.
Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are an integral part of the outer leaflet of the outer-membrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS is simple, comprising of two protonatable cationic functions separated by about 15 A, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, we employ high-throughput screening methods, using a novel fluorescent probe displacement method. Searches in three-dimensional structure databases yielded about approximately 4000 commercially available small molecules, each possessing two cationic functions spaced approximately 15 A apart. Approximately 400 such compounds have been screened in an effort to validate the method by which high-affinity endotoxin binders can be identified. We show that the IC50 values that are obtained from the fluorescence-based primary screen are correlated both to the enthalpy of binding, as measured by isothermal titration calorimetry, as well as to biological potency in vitro assays. By performing rapid toxicity screens in tandem with the bioassays, lead compounds of interest can be easily identified for further systematic structural modifications and SAR studies.


Free radical oxidation of polyunsaturated lipids: New mechanistic insights and the development of peroxyl radical clocks.
The peroxidation of lipids in biological membranes has been implicated in both the onset and development of most degenerative diseases. The primary products of this autoxidation process are usually lipid hydroperoxides. They form as a consequence of a free radical chain reaction: lipid peroxyl radicals propagate the chain by rate-limiting H-atom abstraction from another lipid. Studies of the mechanism of lipid peroxidation are a specific part of a wider effort to understand the more general phenomenon of hydrocarbon autoxidation, which dates back some 70 years. However, the autoxidation of lipids is generally much more complicated than that of other hydrocarbons because of additional reaction pathways afforded by a variety of uniquely positioned unsaturated bonds. Indeed, polyunsaturation is an important aspect of many of the most relevant of physiological lipids, such as linoleate and arachidonate. In this Account, we present our current understanding of the mechanism of unsaturated lipid peroxidation, effectively updating our Account on the same topic published 25 years ago. Our more recent work has, in large part, been stimulated by the discovery of the nonconjugated linoleate hydroperoxide as a product under certain autoxidation conditions. The identification of this long-elusive bis-allylic hydroperoxide prompted our kinetic characterization of the reaction leading to its formation. The product distributions obtained from autoxidations of newly synthesized model compounds, which vary in either the substitution of the bis-allylic moiety or the configuration of the double bonds, have provided key insights into the overall mechanism. These insights have in turn been reinforced by the results of theoretical calculations. The picture that emerges is one wherein the delocalized carbon-centered radicals, which arise as intermediates in these reactions, first associate with dioxygen to form pre-reaction complexes. These complexes then collapse through transition state structures that maximize the orbital interactions between the delocalized radical SOMO and dioxygen. The energies of these transition states are influenced by steric effects; thus, there are distinct changes in product distribution in the autoxidation of dienes having different substitution patterns. The radical-dioxygen complexes are also intermediates in the isomerization of allylperoxyl and pentadienylperoxyls, helping explain the high regio- and stereochemical fidelity of these processes. We have taken advantage of the rapid fragmentation of nonconjugated peroxyl radicals to develop a powerful peroxyl radical clock methodology, which can be used to determine rate constants for reactions of peroxyl radicals with molecules having rate constants ranging from 1 to 10(7) M(-1) s(-1). We can make use of this methodology to address various questions, both fundamental and applied, relating to lipid peroxidation and its inhibition by radical-trapping antioxidants.


Biomonitoring the spatial and historical variations of persistent organic pollutants (POPs) in an industrial region.
Several persistent organic pollutants (POPs) like polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), and polybrominated diphenyl ethers (PBDEs) were measured in needle, branch, bark, and tree ring samples in pine samples collected at 27 sites (21 industrial, 6 background) in Aliaga industrial region in Turkey. Soil, litter, and air samples were also collected to investigate the relationships between the air and soil, litter, and tree components. Concentrations decreased with distance from the sources and the lowest ones were measured at background sites. The spatial distribution of POPs indicated that the major sources in the region are the iron-steel, ship-breaking, petrochemical plants and the petroleum refinery. Significant correlations between the air concentrations and, soil, litter, and tree components indicated the interaction of these compartments with air. Observed increasing trends of POPs in the tree-ring samples were representative for the variations in anthropogenic emissions and resulting atmospheric concentrations in Aliaga region. These results indicated that tree components, litter and soil could be used to determine the spatial variations while tree rings could be used to investigate the historical trends of atmospheric POPs in a region. POP amounts (mg/ha) stored in different tree components, litter, and soil were also inventoried. Among the tree components, generally, the highest amounts were stored in the stem followed by needles. For the overall inventory, the highest amounts were stored in soil for PCNs, PBDEs, and PCBs while highest PAH amounts were stored in trees, indicating that in addition to soil, vegetation is also an important reservoir for POPs.


Murine Astrovirus Infection and Transmission in Neonatal CD1 Mice.
Murine astrovirus (MuAstV) is a recently identified, widespread infection among laboratory mice. Our goal was to determine the duration of MuAstV infection, susceptibility of pups, and efficacy of soiled-bedding sentinels and environmental monitoring. Eight CD1 dams and their litters of 3-d-old pups and 8 CD1 dams and their litters of 13-d-old mice were inoculated orally with MuAstV. Neither dams nor offspring demonstrated any clinical signs, and MuAstV had little to no effect on weight gain in pups. MuAstV RNA was detected in feces from 15 of the 16 dams through postnatal day (PND) 21, and 9 dams were still shedding MuAstV at PND 42. MuAstV RNA was highest in intestines of mice. Low levels of MuAstV RNA were sporadically detected in the spleen, liver, and kidney. MuAstV was detected in 97% of feces from 3- to 9-wk-old mice born to infected dams. Several weanlings became pregnant, and intestines from their pups were MuAstV-negative at PND 0 through 5. Weekly swabs of cages housing MuAstV-infected mice were MuAstV-positive through PND 42. Swabs of the rear exhaust manifold of the ventilated rack were MuAstV-positive at 21 through 56 d after inoculation. In addition, 98% of sentinels that received soiled bedding from dams and their litters and 83% of sentinels that received soiled bedding from weaned mice were MuAstV-positive. Feces from most sentinels exposed to soiled bedding that had been stored for 1, 2 or 3 wk before addition of the sentinels were MuAstV-positive.


A standardized framework to evaluate the quality of studies using TDABC in healthcare: the TDABC in Healthcare Consortium Consensus Statement.
This Consensus Statement introduces a standardized framework, in a checklist format, to support future development and reporting of TDABC studies in healthcare, and to encourage their reproducibility. Additionally, it establishes the first formal networking of TDABC researchers through the creation of the TDABC in Healthcare Consortium. A consensus group of researchers reviewed the most relevant TDABC studies available in Medline and Scopus databases to identify the initial elements of the checklist. Using a Focus Group process, each element received a recommendation regarding where in the scientific article section it should be placed and whether the element was required or suggested. A questionnaire was circulated with expert researchers in the field to provide additional recommendations regarding the content of the checklist and the strength of recommendation for each included element. The TDABC standardized framework includes 32 elements, provides recommendations where in the scientific article to include each element, and comments on the strength of each recommendation. All 32 elements were validated, with 21 elements classified as mandatory and 11 as suggested but not mandatory. This is the first standardized framework to support the development and reporting of TDABC research in healthcare and to stablish a community of experts in TDABC methodology. We expect that it can contribute to scale strategies that would result in cost-savings outcomes and in value-oriented strategies that can be adopted in healthcare systems and institutions.


Evaluation of radioimmunoassay and in vitro colony assay techniques for determination of colony-stimulating factor and inhibitory activity in murine serum and tissue.
These studies have evaluated a newly developed radioimmunoassay (RIA) for the measurement of colony-stimulating factor (CSF) in murine serum and other biologic fluids. The routine in vitro agar gel bioassay for CSF is influenced by high molecular weight serum lipoproteins and low molecular weight tissue-derived materials that are inhibitory to colony formation. Studies with normal serum revealed that in all cases, the levels of CSF detected by the RIA were equal to or greater than levels measured by the bioassay. Dose curves with varying quantities of serum had linear responses in the RIA but not the colony assay. Using Sephadex G-150 chromatography, the murine serum was separated into CSF active and CSF inhibitory peaks as determined by bioassay. Evaluation of these fractions by RIA indicated that the assay was unaffected by the serum inhibitors. Likewise, experiments with tissue lysates indicated that the RIA was not influenced by the low molecular weight tissue inhibitors. Instead, the radioimmunoassay revealed low levels of CSF that were not detectable by bioassay. These observations indicate that the RIA is superior to the bioassay for the estimation of CSF in murine serum and other biologic materials.


[Model for the functional instruction of swallowing].
It is difficult to teach students about the mechanism of swallowing. There are three phases of swallowing; oral phase, pharyngeal phase and esophageal phase. The bolus of food is propelled to back of mouth by the tongue and the swallowing reflex happens. After nasopharynx and mouth closure, the glottal closure occurs, then hyoid and larynx are lifted by the contractions of suprahyoid and thyrohyoid muscles. As for the epiglottis, it is compressed by the tongue and inclines downward. As the larynx is lifted upward and anteriorly, slight vacuum is caused in the lower pharynx and upper esophagus at the same time, and pharyngeal constrictor compress bolus, therefore, the bolus passes the piriform fossa, and is inhaled into the esophagus. This time, we made a model in order to explain this complicated mechanism. The mandible is made of paper clay by using a metallic plate in it. The tongue, the soft palate, and the epiglottis are made by using the EVA (Ethylene Vinyl Acetate) sheet. Styloglossus, suprahyoid, thyrohyoid muscles are made with the wire. Moreover, a movable wooden chip represents the contraction of the pharyngeal constrictor muscles. The spring is put in the trachea in order to lift the larynx. The upper part of esophageal constrictor is made with spring plates.


[Topical aspects of standardization in anesthesiology and intensive care].
Implementation of standards and practice protocols is one of the most challenging problems of anesthesiology and intensive care. Several important issues regarding the process of standards development, their structure, goals, and targets, anticipated results and benefits, as well as clinical and theoretical limitations are discussed. The situation associated with the standardization at the national level is presented with parallel highlighting of future perspectives.


Oxidative stress biology and cell injury during type 1 and type 2 diabetes mellitus.
Diabetes mellitus (DM) affects approximately 170 million individuals worldwide and is expected to alter the lives of at least 366 million individuals within a future span of 25 years. Of even greater concern is the premise that these projections are underestimated since they assume obesity levels will remain constant. Type 1 insulin-dependent DM accounts for only 5-10 percent of all diabetics but represents a highly significant health concern, since this disorder begins early in life and leads to long-term complications. In contrast, Type 2 DM is recognized as the etiology of over 80 percent of all diabetics and is dramatically increasing in incidence as a result of changes in human behavior and increased body mass index. Yet, the pathological consequences of these disorders that involve the both the neuronal and vascular systems are intimately linked through the pathways that mediate oxidative stress. Here we highlight some of the relevant oxidative pathways that determine insulin resistance through reactive oxygen species, mitochondrial dysfunction, uncoupling proteins, and endoplasmic reticulum stress. These pathways are ultimately linked to protein kinase B (Akt) and the insulin signaling pathways that determine the initial onset of glucose intolerance and the subsequent course to apoptotic cell injury. Through the elucidation of these targets, improvement in current strategies as well as the development of future clinical applications can move forward for both the prevention and treatment of Type 1 and Type 2 DM.


Gene-environment interaction in molar-incisor hypomineralization.
Molar incisor hypomineralization (MIH) is an enamel condition characterized by lesions ranging in color from white to brown which present rapid caries progression, and mainly affects permanent first molars and incisors. These enamel defects usually occur when there are disturbances during the mineralization or maturation stage of amelogenesis. Both genetic and environmental factors have been suggested to play roles in MIH's development, but no conclusive risk factors have shown the source of the disease. During head and neck development, the interferon regulatory factor 6 (IRF6) gene is involved in the structure formation of the oral and maxillofacial regions, and the transforming growth factor alpha (TGFA) is an essential cell regulator, acting during proliferation, differentiation, migration and apoptosis. In this present study, it was hypothesized that these genes interact and contribute to predisposition of MIH. Environmental factors affecting children that were 3 years of age or older were also hypothesized to play a role in the disease etiology. Those factors included respiratory issues, malnutrition, food intolerance, infection of any sort and medication intake. A total of 1,065 salivary samples from four different cohorts were obtained, and DNA was extracted from each sample and genotyped for nine different single nucleotide polymorphisms. Association tests and logistic regression implemented in PLINK were used for analyses. A potential interaction between TGFA rs930655 with all markers tested in the cohort from Turkey was identified. These interactions were not identified in the remaining cohorts. Associations (p<0.05) between the use of medication after three years of age and MIH were also found, suggesting that conditions acquired at the age children start to socialize might contribute to the development of MIH.


Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity.
The specificity with which the genetic code is read in protein synthesis, and with which other highly specific biosynthetic reactions take place, can be increased above the level available from free energy differences in intermediates or kinetic barriers by a process defined here as kinetic proofreading. A simple kinetic pathway is described which results in this proofreading when the reaction is strongly but nonspecifically driven, e.g., by phosphate hydrolysis. Protein synthesis, amino acid recognition, and DNA replication, all exhibit the features of this model. In each case, known reactions which otherwise appear to be useless or deleterious complications are seen to be essential to the proofreading function.


Characterization of the non-permissive infection of rabbit cornea cells by vesicular stomatitis virus.
Rabbit cornea cells (RC-60) restrict the reproduction of vesicular stomatitis virus (VSV) (Thacore & Youngner, 1975). In cells infected with VSV alone, an inhibition in the synthesis of VSV genome RNA is observed. A number of parameters which could affect virus RNA synthesis have been examined: virus transcription and post-transcriptional modification, translation, modification of proteins and migration of the G protein to the surface of the cell; they all appear to be normal, although somewhat diminished, in the restricted system. In these cells, therefore, it is the replication of VSV RNA that is directly inhibited, although limited synthesis of both (+) and (-) strand genome length RNA does occur. When the cells are co-infected with rabbit poxvirus (RPV) as a helper virus, however, VSV production is normal. Our studies suggest that RPV plays a role in the maturation as well as in the replication of VSV RNA in RC-60 cells. Certain mutants of RPV have been found to lack the helper function and are unable to convert the RC-60 cells into a permissive host for VSV. These mutants should facilitate the elucidation of the mechanism by which RPV is able to overcome the restriction in these cells.


The anthrax protective antigen (PA63) bound conformation of a peptide inhibitor of the binding of lethal factor to PA63: as determined by trNOESY NMR and molecular modeling.
Anthrax protective antigen (PA) is one of the three proteins produced by the gram positive bacteria Bacillus anthracis collectively known as the "anthrax toxin" (Ascenzi, P.; Visca, P.; Ippolito, G.; Spallarossa, A.; Bolognesi, M.; et al. Anthrax toxin: a tripartite lethal combination. FEBS Lett. 2002, 531, 384-388). The role played by PA in anthrax intoxication is to transport the two enzymes lethal factor (LF) and edema factor (EF) into the cell. Collier and co-workers (Mourez, M.; Kane, R. S.; Mogridge, J.; Metallo, S.; Deschatelets, P.; et al. Designing a polyvalent inhibitor of anthrax toxin. Nat. Biotechnol. 2001, 958). reported the isolation of two peptides via phage display that bind to the PA63 heptamer and inhibit its interaction with LF and EF, and thereby prevent the transport of LF and EF into the cell. One of these peptides, His-Thr-Ser-Thr-Try-Trp-Trp-Leu-Asp-Gly-Ala-Pro (P1), was selected for structural investigation on the basis of its ability to prevent the binding of LF to the PA63 heptamer bundle. Two-dimensional trNOESY experiments coupled with NOE restrained simulated annealing calculations were used to determine the PA63-bound conformation of P1. On binding to PA63, P1 adopts a helical conformation involving residues 3-9 while the C- and N-terminal residues exhibit dynamic fraying.


Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies.
Immune thrombocytopenia purpura (ITP) is characterized by destruction of circulating platelets and the presence of antiplatelet antibodies. Many of the current immunomodulatory therapies act by reducing platelet destruction and usually do not have a lasting effect. This prospective, exploratory study characterized patients with ITP by identifying their demographic and comorbid clinical factors, use of treatments, serologic markers of autoimmunity, and possible relationships between platelet counts, concentrations of endogenous thrombopoietin (eTPO), and the presence of circulating anti-TPO antibodies. Data including medical history and laboratory evaluations were collected at a single patient visit on 205 patients (19 children, 186 adults). Reported histories revealed a 5% rate of thrombotic/ischemic events. Autoimmune markers including direct antiglobulin test and antinuclear antibodies were found more frequently than in the normal population; antiplatelet antibody testing was not done. eTPO concentrations were comparable to concentrations found in healthy volunteers. Our study confirmed that no significant inverse correlation occurred between circulating concentrations of eTPO and platelet counts in patients with ITP (Spearman r = -0.15). Two of the 205 patients tested (1%) had neutralizing activity of recombinant human TPO in a biological assay; however, this activity was confirmed to be anti-TPO antibody in only 1 patient.


Roles of Sulfur Metabolism and Rhodanese in Detoxification and Anti-Oxidative Stress Functions in the Liver: Responses to Radiation Exposure.
Organisms must confront various environmental stresses. The liver is central to protecting against such stresses in mammals, and it has many detoxification and anti-oxidative stress functions. Radiation is a source of oxidative stress and is known to affect the liver and induce anti-oxidative responses. The detoxification enzyme rhodanese, which is also called thiosulfate sulfurtransferase (TST), has been demonstrated to be induced in the liver in response to radiation. Cyanide detoxification is a function of the liver, and rhodanese is a key enzyme involved in sulfur metabolism in that detoxification. Though the anti-oxidative stress system in which sulfur molecules such as thiol compounds are involved has attracted attention as a defense against radiation, detoxification enzymes may have other roles in this defense. Understanding how these functions are affected by alterations of sulfur metabolism (including thiol compounds) after irradiation would help uncover their roles in defense against cancer and other deleterious health effects, as well as environmental stress responses. This article reviews the roles of sulfur-related metabolism in oxidative stress regulation and detoxification for recovery from liver damage after radiation exposure, with particular attention to recent findings of sulfur-related enzymes such as rhodanese, which is unique in sulfur metabolism.


Interest of the combined measurement of selected urinary proteins in the diagnosis approach in nephrology.
Determination of the protein composition of urine is a non-invasive method helping to diagnose renal lesions and evaluate therapeutic interventions. We present here five observations that highlight the performance and relevance of urine protein analysis combining selected glomerular and tubular protein measurements. Total urine protein level and measurements of urinary IgG, albumin, transferrin alpha-1 microglobulin and retinol binding protein were performed on a urine sample by immunonephelometry. The results were normalized for urine creatinine concentration and integrated in the MDI interpretation software that provides a "urine protein profile" (UPP). Sequential UPP were performed in two patients with drug-induced tubular toxicity. One resolved after drug withdrawal. The second concomitantly developped glomerular lesions and repeated UPP was warranted to follow evaluation of the distinct renal lesions. Two cases illustrate two distinct clinical situations in patients with multiple myeloma, respectively myeloma cast nephropathy and toxic acute tubular necrosis. Those differential diagnoses were early anticipated by UPP. In one case, UPP was in favour of the presence of large amount of urinary monoclonal light chain excretion before performing urine electrophoresis analysis and renal biopsy while this was not in the other case. In the last case, we compared sequential UPP, renal function and kidney biopsies in a patient with a diagnosis of membranous nephropathy, and demonstrated a good correlation between urine glomerular and tubular protein excretion and progression of the renal lesions. The use of the UPP in clinical practice, particularly through the accurate quantification of tubular markers, is a more efficient tool for the diagnosis and follow-up of renal diseases than the less sensitive semi-quantitative urine electrophoresis or combined assays of both total proteinuria and albuminuria.


Community subgroups in dyspepsia and their association with weight loss.
A link between dyspepsia symptoms and weight loss is controversial. We aimed to determine whether or not weight loss is a marker of dyspepsia. Independent community-based cross-sectional studies. Subjects were randomly selected from the general population in Sydney, Australia. All subjects completed validated community health surveys. Two distinct data collections were used; the first as a training sample (N = 888) and the second as a validation sample to confirm the findings of the first (N = 2,907). The study was focused on weight loss, which was categorized as (a) any weight loss, (b) substantive weight loss (> or =3 kg), and (c) weight loss expressed as percentage of body weight. All dyspepsia symptoms studied were positively associated with weight loss although the strength of association did vary. Nausea and vomiting were most strongly associated with weight loss as were meal-related complaints such as postprandial fullness. Similarly, clusters formed based on symptoms were strongly differentiated in terms of weight loss with clusters characterized by nausea, vomiting, and early satiety/postprandial fullness reporting 25-30% weight loss prevalence over the previous 3 months compared with around 10% prevalence in clusters characterized by low dyspepsia symptom burden. Weight loss > or =3 kg followed a similar pattern but with a prevalence approximately half that of any weight loss, while weight loss expressed as percentage of body weight followed the same pattern. Dyspepsia symptoms are clearly and, in some cases, strongly associated with weight loss, both any loss of weight and substantive weight loss. Weight loss should be considered a warning symptom of dyspepsia.


Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.
To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.


Rapid isolation and characterization of microsatellites in the critically endangered mountain bongo (Tragelaphus eurycerus isaaci).
High-throughput sequencing tools promise to revolutionize many aspects of genetic research, e.g. by allowing the identification of functional adaptive genetic variation. However, the expense and expertise required to apply these tools to basic conservation questions is a challenge for applications outside academia, resulting in a so-called 'conservation genomics gap' (Shafer et al. 2015). The conservation genetics paradigm is that, basic information about inbreeding and gene flow are often critical to inform conservation management of small populations (Ouborg et al. 2010). This information is often needed quickly and ideally should be accessible to workers without special expertise in genomics (DeSalle and Amato 2004). While the inferential power of highthroughput sequencing to interrogate the genome is profound, the cost for population analysis is higher (though decreasing) than for traditional neutral markers. Thus, the use of neutral markers is still relevant in conservation applications. However, this assumes that neutral markers have been discovered and characterized for a given species of conservation concern, which is often untrue for nonmodel organisms. Here, we use a fast, cost-efficient, high-throughput sequencing method (Illumina MiSeq) to rapidly identify and characterize microsatellites in the mountain bongo (Tragelaphus eurycerus isaaci), which has a clear and timely conservation imperative but lacks any described neutral markers.


Is ADHD a valid diagnosis in older adults?
ADHD is a neurodevelopmental syndrome that often persists into adulthood. It is possible that different criteria are necessary for older adults than younger adults: the manifestations of ADHD could change with age; other conditions with onset in later life share presenting symptoms with ADHD; different contextual challenges and patterns of compensatory support may exist. For these reasons, we reviewed evidence for the validity of DSM ADHD criteria in adulthood for individuals over the age of 50. Specifically, we evaluated evidence that the DSM criteria for ADHD identify a valid syndrome in older adults based on clinical presentation, laboratory or testing findings, absence of alternate diagnosis to explain symptoms, course of the syndrome, or familial presence of the condition. We found evidence that various ADHD criteria identify subjects with clinical presentations similar to that seen in younger adults, but only 92 well-described cases have been reported in the literature. ADHD traits also may be less common in the general population of older adults than in younger adults, suggesting that the threshold for an atypical burden of ADHD traits may be lower in older populations. Future research can establish a richer basis for validity of diagnostic criteria for ADHD in older adults.


Polyphenols as Promising Drugs against Main Breast Cancer Signatures.
Breast cancer is one of the most common neoplasms worldwide, and in spite of clinical and pharmacological advances, it is still a clinical problem, causing morbidity and mortality. On the one hand, breast cancer shares with other neoplasms some molecular signatures such as an imbalanced redox state, cell cycle alterations, increased proliferation and an inflammatory status. On the other hand, breast cancer shows differential molecular subtypes that determine its prognosis and treatment. These are characterized mainly by hormone receptors especially estrogen receptors (ERs) and epidermal growth factor receptor 2 (HER2). Tumors with none of these receptors are classified as triple negative breast cancer (TNBC) and are associated with a worse prognosis. The success of treatments partially depends on their specificity and the adequate molecular classification of tumors. New advances in anticancer drug discovery using natural compounds have been made in the last few decades, and polyphenols have emerged as promising molecules. They may act on various molecular targets because of their promiscuous behavior, presenting several physiological effects, some of which confer antitumor activity. This review analyzes the accumulated evidence of the antitumor effects of plant polyphenols on breast cancer, with special attention to their activity on ERs and HER2 targets and also covering different aspects such as redox balance, uncontrolled proliferation and chronic inflammation.


Domestic extremists: dealing with demonstrators.
The security department of any healthcare facility faces delicate security problems. In addition to guarding staff and the facility, security professionals must protect the patients. This duty becomes even more difficult, says the author, when hospitals become political and moral battlegrounds for demonstrators.


[Nocardia endocarditis in aortic and tricuspid native valves].
Nocardia endocarditis in native valve is an uncommon infection that usually arises in immunodepressed patients. We report a 51-year-old man diagnosed as having Nocardia endocarditis in aortic and tricuspid native valves, which received antimicrobial therapy and required aortic valve replacement. In 6 month follow up the patient remained asymptomatic with good clinical evolution.


Anatomical variations and developmental anomalies of the thyroid gland in Ethiopian population: a cadaveric study.
Because of its embryonic origin, the thyroid gland is predisposed to multiple anatomical variations and developmental anomalies. These include the pyramidal lobe, the origin of levator glandular thyroidae, the absence of the isthmus, ectopic thyroid, accessory thyroid tissues, etc. These anatomical variations are clinically significant to surgeons, anatomists, and researchers. The present study was designed to report anatomical variations and developmental anomalies of the thyroid gland in Ethiopian population. The study was conducted on 40 cadavers used for routine dissection classes. The thyroid gland was exposed and observed for any variations and developmental anomalies. The length, width, and thickness of the lobes were measured using a vernier caliper. Differences in the incidence of pyramidal lobe and absence of the isthmus between sexes were tested using a Pearson chi-square test. The mean length, width, and thickness of the right lobe were 4.24 cm, 1.8 cm, and 1.6 cm, respectively, whereas it was 4.08 cm, 1.8 cm, and 1.6 cm, respectively for that of the left lobe. The pyramidal lobe was noted in 52.5% of the cadavers. The levator glandulae thyroidae were prevalent in 40% of the cadavers. The isthmus mainly overlies the 2nd to 4th tracheal rings and was absent in 7.5% of the cadavers. Accessory thyroid tissue and double pyramidal lobes were noted in 2.5% of the cadavers. Most of the variations of the thyroid gland were seen frequently in female but it was not statically significant. Different clinically important and rare variations of the thyroid gland were found.


Angiotensin-converting enzyme 2 (ACE2) proteins of different bat species confer variable susceptibility to SARS-CoV entry.
The discovery of SARS-like coronavirus in bats suggests that bats could be the natural reservoir of SARS-CoV. However, previous studies indicated the angiotensin-converting enzyme 2 (ACE2) protein, a known SARS-CoV receptor, from a horseshoe bat was unable to act as a functional receptor for SARS-CoV. Here, we extended our previous study to ACE2 molecules from seven additional bat species and tested their interactions with human SARS-CoV spike protein using both HIV-based pseudotype and live SARS-CoV infection assays. The results show that ACE2s of Myotis daubentoni and Rhinolophus sinicus support viral entry mediated by the SARS-CoV S protein, albeit with different efficiency in comparison to that of the human ACE2. Further, the alteration of several key residues either decreased or enhanced bat ACE2 receptor efficiency, as predicted from a structural modeling study of the different bat ACE2 molecules. These data suggest that M. daubentoni and R. sinicus are likely to be susceptible to SARS-CoV and may be candidates as the natural host of the SARS-CoV progenitor viruses. Furthermore, our current study also demonstrates that the genetic diversity of ACE2 among bats is greater than that observed among known SARS-CoV susceptible mammals, highlighting the possibility that there are many more uncharacterized bat species that can act as a reservoir of SARS-CoV or its progenitor viruses. This calls for continuation and expansion of field surveillance studies among different bat populations to eventually identify the true natural reservoir of SARS-CoV.


[Primary squamous cell carcinoma of the breast: rare form carcinoma].
Primary squamous cell carcinoma (SCC) is a rare form of breast carcinoma. Incidence is reported to be 0.1-3.6%. We report a case of a young woman, 37-year-old, with history of a lump in the upper outer quadrant of the left breast with ulceration of the skin surface. Menarche occurred at age of 12. The patient was married, had two deliveries and had her first child at age of 26. She did not use contraceptive pills. Diagnosis of the tumour of the breast was made at the Department of surgery in General Hospital in Bijeljina in September 2007. Clinical examination, mammography and ultrasonography were performed. Physical examination revealed a circumscribed and firm mass measuring 60 x 60 x 80 mm. Mammogram showed a round, high-density mass with almost regular but partially irregular margin. Ultrasonogram of the left breast tumor identified an irregularly shaped hypoechoic lesion. After clinical staging of the disease, we performed incision biopsy of the skin and tumour of the left breast with histopathology examination (standard hematoxylin and eosin). Patient had estrogen and progesteron receptors negative and was HER2/neu negative. After histopathology, patient's case was presented to the working group for breast tumors which decided to start with the neoadjuvant chemotherapy using platinum. After six cycles of neoadjuvant chemotherapy, regression of breast tumor was confirmed. Working group decided that radical mastectomy of left breast should be performed.


LncRNA MIR503HG Promotes High-Glucose-Induced Proximal Tubular Cell Apoptosis by Targeting miR-503-5p/Bcl-2 Pathway.
More than half of microRNAs are located in genes. LncRNAs are host genes of intronic microRNAs that regulate intracellular splicing to form pre-miRNAs that are processed to mature miRNAs. MicroRNAs work as partners or antagonists of their host lncRNAs by fine-tuning their target genes. However, whether lncRNA-MIR503HG (miR-503 host gene) is co-transcribed with miR-503 and affects miR-503 splicing, thereby affecting its target gene Bcl-2 expression and cell mitochondrial apoptotic pathway in diabetic nephropathy (DN) is currently unknown. Human proximal tubular (HK-2) cells cultured in high glucose were transfected with lncRNA MIR503HG overexpression/inhibition plasmid and miR-503 mimics/inhibitor. Real-time quantitative PCR was used to measure the expression levels of lncRNA MIR503HG, pre-miR-503, miR-503 and Bcl-2. Western blot was used to measure the protein expressions of Bcl-2, Bax, Cytc and cleaved-caspase 9/3. Annexin V/PI flow cytometry was used to measure apoptosis. Host lncRNA MIR503HG was co-transcribed with miR-503. MIR503HG regulated the expression of miR-503 by affecting miR-503 splicing synthesis. In the presence of high glucose, the expression levels of lncRNA MIR503HG and miR-503 were up-regulated in HK-2 cells cultured in high glucose. Bcl-2 expression was inhibited and levels of apoptosis-related proteins Cytc and Bax were increased in HK-2 cells cultured in high glucose, all of which promoted the caspase cascade reaction, leading to increased caspase-9 and caspase-3 shear fragments inducing apoptosis of the mitochondrial pathway. Inhibition of MIR503HG led to a reduction in miR-503 expression, up-regulated its target gene Bcl-2, inhibited the expression levels of Bax and other apoptosis-related proteins and attenuated HK-2 cell apoptosis induced by high glucose. Co-transfection of miRNA-503 partially offset the effect of MIR503HG-siRNA. MIR503HG indirectly regulates Bcl-2 by promoting the co-transcription of miRNA-503 to participate high-glucose-induced proximal tubular cell apoptosis, providing a new target for diabetic nephropathy treatment.


Practical considerations for conducting dental clinical trials in primary care.
There is increasing importance placed on conducting clinical trials in dentistry to provide a robust evidence base for the treatment provided, and models of care delivered. However, providing the evidence upon which to base such decisions is not straightforward, as the conduct of these trials is complex. Currently, only limited information is available about the strategies to deliver successful clinical trials in primary care settings, and even less available on dental clinical trials. Considerable knowledge and experience is lost once a trial is completed as details about effective management of a trial are generally not reported or disseminated to trial managers and researchers. This leads to loss of vital knowledge that could assist with the effective delivery of new trials. The aim of this study is to examine the conduct and delivery of five dental clinical trials across both Australia and the UK and identify the various factors that impacted upon their implementation. Findings suggest that early stakeholder engagement, and well-designed and managed trials, lead to improved outcomes for researchers, clinic staff and patients, and increases the potential for future dissemination and translation of information into practice.


Ductal carcinoma in situ of the breast.
Ductal carcinoma in situ of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup in the breast cancer family; it is projected that more than 39,000 new cases will be diagnosed in the United States during 1999. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Genetic changes routinely precede morphologic evidence of malignant transformation. Medicine must learn how to recognize these genetic changes, exploit them, and in the future, prevent them.


Kinetics of 76Br-labeled anti-CEA antibodies in pigs; aspects of dosimetry and PET imaging properties.
A monoclonal antibody labeled with the positron-emitting radionuclide 76Br (T(1/2) 16.2 h) has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini-pigs were injected intravenously with 46-75 MBq of the 76Br-labeled anti-CEA antibody 38S1, and the whole-body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest 76Br concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, mean+/-maximum error), 0.84+/-0.16, followed by liver, 0.74+/-0.28, and small intestine, 0.55+/-0.05, while the effective dose equivalent was 0.41+/-0.03 mSv/MBq. The PET imaging properties of 76Br in a two-dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of 18F. In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW ("full width at half-maximum") value of the point spread function was 7.7+/-0.2 mm for 76Br and 6.0+/-0.1 mm for 18F. In conclusion, radioimmuno PET using 76Br-labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy beta+ spectrum in the 76Br decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.


Pat1 promotes processing body assembly by enhancing the phase separation of the DEAD-box ATPase Dhh1 and RNA.
Processing bodies (PBs) are cytoplasmic mRNP granules that assemble via liquid-liquid phase separation and are implicated in the decay or storage of mRNAs. How PB assembly is regulated in cells remains unclear. Previously, we identified the ATPase activity of the DEAD-box protein Dhh1 as a key regulator of PB dynamics and demonstrated that Not1, an activator of the Dhh1 ATPase and member of the CCR4-NOT deadenylase complex inhibits PB assembly in vivo (Mugler et al., 2016). Here, we show that the PB component Pat1 antagonizes Not1 and promotes PB assembly via its direct interaction with Dhh1. Intriguingly, in vivo PB dynamics can be recapitulated in vitro, since Pat1 enhances the phase separation of Dhh1 and RNA into liquid droplets, whereas Not1 reverses Pat1-Dhh1-RNA condensation. Overall, our results uncover a function of Pat1 in promoting the multimerization of Dhh1 on mRNA, thereby aiding the assembly of large multivalent mRNP granules that are PBs.


The role and utility of measuring red blood cell methotrexate polyglutamate concentrations in inflammatory arthropathies--a systematic review.
Evidence regarding the relationship between red blood cell methotrexate polyglutamate concentration and response to treatment and adverse drug reactions in patients using methotrexate for inflammatory arthropathies is complex and in some respects appears conflicting. Accordingly, we undertook a systematic analysis of available evidence to determine the clinical utility of dosing methotrexate to a target red blood cell methotrexate polyglutamate concentration. A systematic literature review was conducted to identify all studies that had reported an association between red blood cell methotrexate polyglutamate concentration and disease activity or adverse drug reactions in users of methotrexate for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis or psoriatic arthritis. No randomised controlled trials were identified. Thirteen studies (ten in patients with rheumatoid arthritis and three in patients with juvenile idiopathic arthritis) were identified. All studies evaluated an association between red blood cell methotrexate polyglutamate concentration and response to treatment, and eight evaluated an association with toxicity. Eight studies identified lower disease activity with at least one higher red blood cell methotrexate polyglutamate concentration, although there was at least moderate potential for bias in all of these studies. Relatively large increases in concentration appeared to be required to produce a meaningful reduction in disease activity. Only one study identified an association between red blood cell methotrexate polyglutamate concentration and methotrexate-induced side effects, although studies were likely underpowered to detect this type of association. The manner in which data were presented in the included studies had many limitations that hampered its conclusive assessment, but red blood cell methotrexate polyglutamate concentrations appear to be a potentially useful guide to treatment in patients with inflammatory arthropathies, but the specific polyglutamate that should be monitored and how monitoring could be integrated into treat-to-target approaches should be clarified before it can be routinely implemented.