Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5.
Six hundred sixteen eyes with recent severe diabetic vitreous hemorrhage reducing visual acuity to 5/200 or less for at least 1 month were randomly assigned to either early vitrectomy or deferral of vitrectomy for 1 year. The proportion of eyes with visual acuity of 10/20 or better was higher in the early vitrectomy group than in the deferral group throughout the 4-year follow-up period. Up to the 18-month visit, the early group had a higher proportion of eyes with visual acuity of no light perception. An increased chance of obtaining good vision with early vitrectomy was clearly present in the type I diabetes group, particularly in patients who developed severe vitreous hemorrhage after less than 20 years of diabetes, a patient group tending to have more severe proliferative retinopathy. This advantage was not found in the type II diabetes group, in which patients were older and tended to have less severe retinopathy. The findings of this and previous Diabetic Retinopathy Vitrectomy Study reports support early vitrectomy in eyes known or suspected to have very severe proliferative diabetic retinopathy as a means of increasing the chance of restoring or maintaining good vision.


Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials.
This study evaluated the association of time in range (TIR) of 70-180 mg/dL (3.9-10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials. In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications. Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51-78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25-56), for each 10 percentage points lower TIR (P < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics. Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A1c remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics-especially when measured with continuous glucose monitoring-add value as outcome measures in many studies.


Relating the size of molecularly defined clusters of tuberculosis to the duration of symptoms.
Molecular profiling of Mycobacterium tuberculosis isolates has improved recognition of tuberculosis case clusters, but the determinants of cluster size are unknown. We hypothesized that longer duration of symptoms prior to initiation of tuberculosis therapy would be associated with increased cluster size. All patients with tuberculosis in Harris County, Texas, identified between 10/1/95 and 12/31/97 through a prospective population-based project were interviewed, had their medical records reviewed, and had M. tuberculosis isolates molecularly characterized. There were 506 symptomatic, evaluable patients in 74 clusters, ranging in size from 2 patients (32 clusters) to 61 patients (1 cluster). The median duration of symptoms was 46 days (range, 1-471 days). There was no association between the log-transformed duration of symptoms and cluster size in univariate or multivariate analysis. In multivariate analysis, age and HIV coinfection were inversely related to cluster size, but only weakly. The size of molecularly defined clusters of tuberculosis was not related to the duration of symptoms of most patients who belonged to clusters.


High prevalence of cyclooxygenase 2 expression in papillary thyroid carcinoma.
Cyclooxygenase-2 (COX-2) seems to play a role in the development and carcinogenesis of papillary thyroid carcinoma. Its incidence of expression and potential application as a tumor marker remain to be elucidated. Immunohistochemical staining for COX-2 expression was performed for 30 papillary thyroid carcinoma (PTC) and 40 benign thyroid specimens. COX-2 mRNA expression was analyzed using a reverse transcriptase-polymerase chain reaction (RT-PCR) for paired fresh frozen tissues removed from surgically resected PTC specimens. COX-2 expression was detected by immunohistochemistry in 27 of 30 (90%) PTC but was absent in 40 benign thyroid specimens, including 27 nodular hyperplasia, 7 follicular adenoma and 6 lymphocytic thyroiditis. Two of the three COX-2 negative carcinomas were follicular variant of PTC. RT-PCR analysis confirmed COX-2 mRNA over-expression in 14 of 20 (70%) paired specimens of PTC. Real-time quantitative RT-PCR showed that the level of COX-2 mRNA expression was significantly higher in PTC than in both the adjacent non-cancerous tissues and the benign thyroid specimens. COX-2 is frequently expressed in PTC but not in benign thyroid specimens. COX-2 expression may serve as a useful molecular marker for PTC in cases of diagnostic difficulty.


Specific esponse to 5-HT2 agonists by arterioles linked to Meth A tumors in mice.
Using intravital microscopy, we compared the responses to serotonin [5-hydroxytryptamine (5-HT)] and to a specific 5-HT2 agonist [1-(2,5-dimethoxy-4-bromo-phenyl)-2-aminopropane (DOB)] by normal arterioles and by the host-modified arterioles feeding a Meth A tumor implanted into the flank of female BALB/c mice. Topical and intravenous administration of 5-HT (10(-6) to 10(-4) M and 0.01-10 micrograms) or DOB (5 x 10(-7) to 5 x 10(-5) M and 0.01-10 micrograms) induced arteriolar constriction, which was far more pronounced for the arterioles feeding the tumor. This larger degree of vasoconstriction in tumor-feeding vs. normal arterioles was not found with norepinephrine. We also compared tumor growth and the mouse life span in three groups of mice, which were given 1 mg of serotonin or 0.74 mg DOB or saline solution. 5-HT or DOB both reduced tumor growth drastically compared with the controls (P less than 0.001), and survival rates were significantly higher in the 5-HT or DOB-treated groups (P less than 0.001). We conclude that 5-HT2-serotoninergic agonists are of particular pharmacological interest, since their vasoconstrictive action on the microvasculature feeding the tumors is much greater than in normal tissue and may interfere with tumor growth.


Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers.
Peptides play a crucial role as biological vectors for targeted drug delivery. In particular, in cases of specific receptor expression, peptides are highly potent carriers for drug targeting approaches. Kidney-targeted peptides require specific attention because of the necessity of fine-tuning their behavior with respect to extraction and retention in the complex architecture of the kidneys. To enable optimal carrier capacity and targeting specificity, this study focuses on pharmacokinetic profiles of different kidney-specific peptides and examines the impact of drug conjugation. γ-Scintigraphy was used to compare the pharmacokinetics and specificity prior to and after drug conjugation of the model drug α-lipoic acid. The results revealed that drug conjugation dramatically affects the targeting specificity, in the worst case leading to a total loss of kidney specificity. Nevertheless, efficient drug transport was achieved with the novel kidney carrier (KKEEE)3K, even with a multiple-drug loading of α-lipoic acid after intraveous and intraperitoneal administration. In contrast to other peptidic molecules, (KKEEE)3K demonstrated its significant potential as a promising carrier candidate for kidney-targeted drug delivery to proximal tubule cells, especially for the treatment of severe kidney diseases.


The Midlife Transition, Depression, and Its Clinical Management.
The World Health Organization estimates that more than 260 million people are affected by depression worldwide, a condition that imposes a significant burden to individuals, their families, and society. Women seem to be disproportionately more affected by depression than men, and it is now clear that some women may experience windows of vulnerability for depression at certain reproductive stages across their life span, including the midlife transition. For some, age, the presence of cardiovascular or metabolic problems, and the emergence of significant, bothersome vasomotor symptoms and sleep problems may result in a compounded, deleterious impact on well-being and overall functioning.


Design and pilot validation of A-gear: a novel wearable dynamic arm support.
Persons suffering from progressive muscular weakness, like those with Duchenne muscular dystrophy (DMD), gradually lose the ability to stand, walk and to use their arms. This hinders them from performing daily activities, social participation and being independent. Wheelchairs are used to overcome the loss of walking. However, there are currently few efficient functional substitutes to support the arms. Arm supports or robotic arms can be mounted to wheelchairs to aid in arm motion, but they are quite visible (stigmatizing), and limited in their possibilities due to their fixation to the wheelchair. The users prefer inconspicuous arm supports that are comfortable to wear and easy to control. In this paper the design, characterization, and pilot validation of a passive arm support prototype, which is worn on the body, is presented. The A-gear runs along the body from the contact surface between seat and upper legs via torso and upper arm to the forearm. Freedom of motion is accomplished by mechanical joints, which are nearly aligned with the human joints. The system compensates for the arm weight, using elastic bands for static balance, in every position of the arm. As opposed to existing devices, the proposed kinematic structure allows trunk motion and requires fewer links and less joint space without compromising balancing precision. The functional prototype has been validated in three DMD patients, using 3D motion analysis. Measurements have shown increased arm performance when the subjects were wearing the prototype. Upward and forward movements were easier to perform. The arm support is easy to put on and remove. Moreover, the device felt comfortable for the subjects. However, downward movements were more difficult, and the patients would prefer the device to be even more inconspicuous. The A-gear prototype is a step towards inconspicuousness and therefore well-received dynamic arm supports for people with muscular weakness.


Improving the nurse-family partnership in community practice.
Evidence-based preventive interventions are rarely final products. They have reached a stage of development that warrant public investment but require additional research and development to strengthen their effects. The Nurse-Family Partnership (NFP), a program of nurse home visiting, is grounded in findings from replicated randomized controlled trials. Evidence-based programs require replication in accordance with the models tested in the original randomized controlled trials in order to achieve impacts comparable to those found in those trials, and yet they must be changed in order to improve their impacts, given that interventions require continuous improvement. This article provides a framework and illustrations of work our team members have developed to address this tension. Because the NFP is delivered in communities outside of research contexts, we used quantitative and qualitative research to identify challenges with the NFP program model and its implementation, as well as promising approaches for addressing them. We describe a framework used to address these issues and illustrate its use in improving nurses' skills in retaining participants, reducing closely spaced subsequent pregnancies, responding to intimate partner violence, observing and promoting caregivers' care of their children, addressing parents' mental health problems, classifying families' risks and strengths as a guide for program implementation, and collaborating with indigenous health organizations to adapt and evaluate the program for their populations. We identify common challenges encountered in conducting research in practice settings and translating findings from these studies into ongoing program implementation. The conduct of research focused on quality improvement, model improvement, and implementation in NFP practice settings is challenging, but feasible, and holds promise for improving the impact of the NFP.


Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians.
Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6,617 MetS and 3,476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages-discovery phase (N = 2,158) and replication phase (N = 7,935). We discovered two variants within/near the CETP gene-rs1800775 and rs3816117-associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus-rs16890462 in the vicinity of SFRP1 gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome.


TransMiner: mining transitive associations among biological objects from text.
Associations among biological objects such as genes, proteins, and drugs can be discovered automatically from the scientific literature. TransMiner is a system for finding associations among objects by mining the Medline database of the scientific literature. The direct associations among the objects are discovered based on the principle of co-occurrence in the form of an association graph. The principle of transitive closure is applied to the association graph to find potential transitive associations. The potential transitive associations that are indeed direct are discovered by iterative retrieval and mining of the Medline documents. Those associations that are not found explicitly in the entire Medline database are transitive associations and are the candidates for hypothesis generation. The transitive associations were ranked based on the sum of weight of terms that co-occur with both the objects. The direct and transitive associations are visualized using a graph visualization applet. TransMiner was tested by finding associations among 56 breast cancer genes and among 24 objects in the calpain signal transduction pathway. TransMiner was also used to rediscover associations between magnesium and migraine.


GRNOPC1: the world's first embryonic stem cell-derived therapy. Interview with Jane Lebkowski.
Geron's Chief Scientific Officer, Jane Lebkowski, discusses the long road to clinical trials and the next steps for GRNOPC1. The long-awaited clinical trial of Geron's GRNOPC1 therapy for spinal cord injury has been one of the biggest stories in regenerative medicine over the past few years. The trial initially received the go-ahead from the US FDA in early 2009, but was put on clinical hold soon afterwards when an increased frequency of cysts was found in an animal experiment. Revision in release criteria and additional prospective animal studies allayed these concerns and the clinical hold was finally lifted in June 2010. The Phase I clinical trial enrolled its first patient in October 2010. As the world's first human trial of an embryonic stem cell-derived therapy, the trial has generated a huge amount of attention.


Molecular marker linkage map for apple.
Linkage maps for two apple clones, White Angel and Rome Beauty, were constructed using isozyme and DNA polymorphisms segregating in a population produced from a Rome Beauty x White Angel cross. The linkage map for White Angel consists of 253 markers arranged in 24 linkage groups and extends over 950 cM. The Rome Beauty map contains 156 markers on 21 linkage groups. The White Angel map was taken as the standard, and we were able to identify linkage groups in Rome Beauty homologous to 13 White Angel linkage groups. The location of several genes not segregating in the Rome Beauty x White Angel population could be determined on the basis of known linkages with segregating markers. Hence, the standard map for apple now contains about 360 markers, with most linkage groups saturated at 10-15 cM. The double pseudotestcross format of the mapping population permitted the comparison of recombination frequencies in male and female parents in certain regions of the genome where appropriate markers were available. The recombination frequencies observed for the approximately 170 cM that were comparable gave no indication that a sex-related difference in recombination rate was characteristic of apple.


Allelotype of gastric adenocarcinoma.
Gastric adenocarcinoma is a leading cause of cancer mortality world-wide. Yet, the underlying molecular events important in the development of this cancer are largely undefined. Thus, we performed a comprehensive survey for allelic loss on our panel of xenografted human gastric carcinomas. Contaminating normal stromal cells of primary cancers often limit mutational analyses. Xenografted samples of our gastric carcinomas provided optimally enriched tumors for neoplasia that clearly and sensitively demonstrated genetic alterations. Additionally, total absence of allelic signals in these xenografted samples confirmed true loss of alleles rather than just allelic imbalance. Analysis of at least two highly polymorphic microsatellite markers per nonacrocentric chromosomal arm in our xenografted human gastric carcinomas demonstrated significant loss of heterozygosity well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. Several of these loci represent novel findings of significant loss in gastric cancers. On chromosome 17p, p53 is known to be inactivated either by mutation or deletion in a majority of gastric carcinomas. The critical target(s) of inactivation in gastric cancers at these other loci remain to be characterized.


Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma.
Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.


Effectiveness of zinc protoporphyrin/heme ratio and ferritin for assessing iron status in preterm infants.
Since iron is crucial for many tissue processes, we, therefore, aimed to assess ferritin and the zinc protoporphyrin to heme ratio (ZnPP/H) as indicators of iron status in preterm newborns, particularly during certain inflammatory episodes. From 170 preterm babies, paired ferritin and ZnPP/H measurements were collected twice (on the first postnatal day and six weeks later). To compare these measures and assess the impact of anemia, sepsis, and packed red blood cell transfusion (PRBT), three different scenarios were considered. Compared to the non-anemic group, the anemic patients' serum ferritin level was considerably lower (p = 0.044), whereas the anemic patients' ZPP/H ratio was significantly greater (p < 0.001). In neonates with sepsis, ferritin levels were considerably greater in both anemic and non-anemic septic neonates compared to neonates without sepsis (p < 0.001 for each). Regarding ZPP/H ratio, no appreciable variations were found between the two groups. In addition, serum ferritin significantly increased following each PRBT (p < 0.001 for each). As a result of each PRBT, the ZPP/H ratio considerably decreased (p < 0.001). As a measure of iron status during particular inflammatory processes like infection and PRBT, ZnPP/H may be more accurate.


Knowledge and Impact of COVID-19 on Middle-Aged and Older People Living with HIV in Lima, Peru.
COVID-19 has had an unprecedented worldwide impact, and Peru has had one of the highest COVID-19 case rates despite implementation of an early strict nationwide quarantine. Repercussions on Peru's healthcare system may impact vulnerable populations, particularly people with HIV (PWH). We explored knowledge of COVID-19 and the socioeconomic and health impact of the pandemic among middle-aged and older PWH. A cross-sectional telephone survey was administered to 156 PWH age ≥40 years receiving care in one of two large HIV clinics in Lima, Peru. The majority of PWH (age 52 ± 7.7 years, 41% female, 65% completed secondary school or less) were knowledgeable regarding COVID-19 symptoms and prevention methods. Nearly half of those employed prior to the pandemic reported job loss. Female sex (unadjusted prevalence ratio [PR] 1.85 [95%CI 1.27-2.69]), low educational level (PR 1.62 [1.06-2.48]) and informal work (PR 1.58 [1.06-2.36]) were risk factors for unemployment but not in adjusted models. Increased anxiety was reported in 64% and stress in 77%. COVID-19 has had a substantial socioeconomic and mental health impact on PWH living in Lima, Peru, particularly those with lower educational levels and informal workers. Efforts are needed to ensure continued medical care and socioeconomic support of PWH in Peru.


Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome.
Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband's dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. KEY MESSAGE: Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.


Nowcasting India's Quarterly GDP Growth: A Factor-Augmented Time-Varying Coefficient Regression Model (FA-TVCRM).
Governments, central banks, private firms and others need high frequency information on the state of the economy for their decision making. However, a key indicator like GDP is only available quarterly and that too with a lag. Hence decision makers use high frequency daily, weekly or monthly information to project GDP growth in a given quarter. This method, known as nowcasting, started out in advanced country central banks using bridge models. Nowcasting is now based on more advanced techniques, mostly dynamic factor models. In this paper we use a novel approach, a Factor Augmented Time Varying Coefficient Regression (FA-TVCR) model, which allows us to extract information from a large number of high frequency indicators and at the same time inherently addresses the issue of frequent structural breaks encountered in Indian GDP growth. One specification of the FA-TVCR model is estimated using 19 variables available for a long period starting in 2007-08:Q1. Another specification estimates the model using a larger set of 28 indicators available for a shorter period starting in 2015-16:Q1. Comparing our model with two alternative models, we find that the FA-TVCR model outperforms a Dynamic Factor Model (DFM) model and a univariate Autoregressive Integrated Moving Average (ARIMA) model in terms of both in-sample and out-of-sample Root Mean Square Error (RMSE). Further, comparing the predictive power of the three models using the Diebold-Mariano test, we find that FA-TVCR model outperforms DFM consistently. In terms of out-of-sample forecast accuracy both the FA-TVCR model and the ARIMA model have the same predictive accuracy under normal conditions. However, the FA-TVCR model outperforms the ARIMA model when applied for nowcasting in periods of major shocks like the Covid-19 shock of 2020-21.


Pleural space infections after image-guided percutaneous drainage of infected intraabdominal fluid collections: a retrospective single institution analysis.
Percutaneous drainage of infected intraabdominal fluid collections is preferred over surgical drainage due to lower morbidity and costs. However, it can be a challenging procedure and catheter insertion carries the potential to contaminate the pleural space from the abdomen. This retrospective analysis demonstrates the clinical and radiographic correlation between percutaneous drainage of infected intraabdominal collections and the development of iatrogenic pleural space infections. A retrospective single institution analysis of 550 consecutive percutaneous drainage procedures for intraabdominal fluid collections was performed over 24 months. Patient charts and imaging were reviewed with regard to pleural space infections that were attributed to percutaneous drain placements. Institutional review board approval was obtained for conduct of the study. 6/550 (1.1%) patients developed iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections. All 6 patients presented with respiratory symptoms and required pleural space drainage (either by needle aspiration or chest tube placement), 2 received intrapleural fibrinolytic therapy and 1 patient had to undergo surgical drainage. Pleural effusion cultures revealed same bacteria in both intraabdominal and pleural fluid in 3 (50%) cases. A video with a dynamic radiographic sequence demonstrating the contamination of the pleural space from percutaneous drainage of an infected intraabdominal collection is included. Iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections occur at a low incidence, but the pleural empyema can be progressive requiring prompt chest tube drainage, intrapleural fibrinolytic therapy or even surgery. Expertise in intraabdominal drain placements, awareness and early recognition of this complication is critical to minimize incidence, morbidity and mortality in these patients.


High-throughput chemical and chemoenzymatic approaches to saccharide-coated magnetic nanoparticles for MRI.
There is a need for biofunctionalised magnetic nanoparticles for many biomedical applications, including MRI contrast agents that have a range of surface properties and functional groups. A library of eleven adducts, each formed by condensing a reducing sugar with a catechol hydrazide, for nanoparticle functionalisation has been created using a high-throughput chemical synthesis methodology. The enzymatic transformation of an N-acetylglucosamine (GlcNAc) adduct into an N-acetyllactosamine adduct by β-1,4-galactosyltransferase illustrates how chemoenzymatic methods could provide adducts bearing complex and expensive glycans. Superparamagnetic iron oxide nanoparticles (8 nm diameter, characterised by TEM, DLS and SQUID) were coated with these adducts and the magnetic resonance imaging (MRI) properties of GlcNAc-labelled nanoparticles were determined. This straightforward approach can produce a range of MRI contrast agents with a variety of biofunctionalised surfaces.


Tortoises develop and overcome position biases in a reversal learning task.
The capability of animals to alter their behaviour in response to novel or familiar stimuli, or behavioural flexibility, is strongly associated with their ability to learn in novel environments. Reptiles are capable of learning complex tasks and offer a unique opportunity to study the relationship between visual proficiency and behavioural flexibility. The focus of this study was to investigate the behavioural flexibility of red-footed tortoises and their ability to perform reversal learning. Reversal learning involves learning a particular discrimination task, after which the previously rewarded cue is reversed and then subjects perform the task with new reward contingencies. Red-footed tortoises were required to learn to recognise and approach visual cues within a Y-maze. Once subjects learned the visual discrimination, tortoises were required to successfully learn four reversals. Tortoises required significantly more trials to reach criterion (80% correct) in the first reversal, indicating the difficulty of unlearning the positive stimulus presented during training. Nevertheless, subsequent reversals required a similar number of sessions to the training stage, demonstrating that reversal learning improved up to a point. All subjects tested developed a position bias within the Y-maze that was absent prior to training, but most were able to exhibit reversal learning. Red-footed tortoises primarily adopted a win-stay choice strategy while learning the discrimination without much evidence for a lose-shift choice strategy, which may explain limits to their behavioural flexibility. However, improving performance across reversals while simultaneously overcoming a position bias provides insights into the cognitive abilities of tortoises.


P-selectin mediates spontaneous leukocyte rolling in vivo.
Rolling represents the initial step leading to leukocyte extravasation from blood vessels during an inflammatory reaction. In vitro studies indicate that P-selectin could be one of the ligands on endothelium involved in the rolling phenomenon, although the molecular determinants responsible for this transient attachment in vivo are still undefined. Our objectives were to develop a blocking monoclonal antibody against canine P-selectin and to use it to investigate the role of P-selectin in leukocyte rolling in vivo using the technique of intravital microscopy. P-selectin was immunoaffinity purified from canine platelets and used for the production of monoclonal antibodies. One of the hybridomas generated, MD6, was shown by enzyme-linked immunosorbent assay and by flow cytometry to bind preferentially to stimulated platelets and to completely prevent binding of stimulated platelets to neutrophils. Visualization of canine mesenteric venules by intravital microscopy showed that administration of MD6 resulted in a marked inhibition in the number of rolling leukocytes (18.96 +/- 9.92 v 156.40 +/- 19.50 leukocytes/min, P < .05; 88.3% +/- 6.0% inhibition). Control antibody MD3 (which recognizes a nonfunctional epitope of canine P-selectin) had no effect on the number of rolling leukocytes or on their rolling velocity. These results show for the first time that P-selectin plays an essential role in leukocyte rolling in vivo, and therefore may be a key participant of the inflammatory response.


Chemical composition and in vitro antibacterial and antiproliferative activities of the essential oil from the leaves of Psidium myrtoides O. Berg (Myrtaceae).
In this study, the chemical composition and antibacterial and antiproliferative potential of the essential oil obtained from fresh leaves of Psidium myrtoides (PM-EO) against oral pathogens and human tumour cell lines were investigated for the first time. GC-FID and GC-MS analyses showed that trans-β-caryophyllene (30.9%), α-humulene (15.9%), α-copaene (7.8%), caryophyllene oxide (7.3%) and α-bisabolol (5.3%) are the major constituents of PM-EO. The antibacterial activity of PM-EO against a panel of oral pathogens was investigated in terms of their minimal inhibitory concentrations (MIC) using the broth microdilution method. PM-EO displayed moderate activity against Streptococcus mitis (MIC = 100 μg/mL), S. sanguinis (MIC = 100 μg/mL), S. sobrinus (MIC = 250 μg/mL), and S. salivarius (MIC = 250 μg/mL), and strong activity against S. mutans (MIC = 62.5 μg/mL). The antiproliferative activity in normal (GM07492A, lung fibroblasts) and tumour cell lines (MCF-7, HeLa, and M059 J) was performed using the XTT assay. PM-EO showed 50% inhibition of normal cell growth at 359.8 ± 6.3 μg/mL. Antiproliferative activity was observed against human tumour cell lines, with IC50 values significantly lower than that obtained for the normal cell line, demonstrating IC50 values for MCF-7 cells (254.5 ± 1.6 μg/mL), HeLa cells (324.2 ± 41.4 μg/mL) and M059 J cells (289.3 ± 10.9 μg/mL). Therefore, the cytotoxicity of PM-EO had little influence on the antibacterial effect, since it showed antibacterial activity at lower concentrations. Our results suggest that PM-EO is a promising source of new antibacterial and antitumour agents.


Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases.
Fifty-six cases of this uncommon neoplastic manifestation are presented. These cases represent 0.065% of 86,589 new cases of malignant disease seen at The Princess Margaret Hospital from 1968 to 1982. There were 29 men and 27 women. The median age at presentation was 58 years. Three major groups were identified: inguinal disease, 24 cases; unilateral inguinal plus iliac disease, 16 cases; local plus systemic disease, 16 cases. Pathologic subtypes were anaplastic, 24; squamous, 11; adenocarcinoma, nine; melanoma, nine; and others, three. Survival at 5 years for all patients was 27%. Among 40 patients who presented with inguinal and inguinal plus iliac disease, survival was 37.5% at 5 years. Initial treatment following biopsy was radiation in 35, lymph node dissection in eight, and chemotherapy in four. Excisional biopsy only was performed in nine cases. There were no treatment-related deaths. The findings observed in this study, in which radiation therapy was employed as initial management in the majority of cases, suggests that radiation therapy is a valid alternative to surgery in the management of this disease.


Merits and pitfalls of mifepristone in Cushing's syndrome.
Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). Retrospective study of patients treated in seven European centers. Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.


[Postural evaluation in women with chronic pelvic pain].
to evaluate by photogrammetry, postural changes in women with chronic pelvic pain. thirty women with complaint of chronic pelvic pain and 37 without it, in a total of 67 women, were evaluated. The evaluation was realized through anamnesis, fixed markers in defined anatomical sites, and frontal, posterior, left and right lateral photographies. Photo analysis has been done by the software CorelDraw, version 11.0. Quantitative values for postural analysis of the ankle, the knee in the saggittal plan, pelvis, lumbar lordosis, thoracic kyphosis, adducted/abducted scapula, shoulders, head and third finger on the floor test were obtained. The qualitative variables studied were the knee (varus, valgus or normal), the presence or not of winged scapula and leveling of shoulders. The Statistical Package for Social Sciences, version 16.0 was used for the statistical analyses. Fisher's exact test and Monte-Carlo method were used to compare the qualitative variables, and for the quantitative data, t or Mann-Whitney test was used. The comparisons among continuous data, corrected for possible confusion variables were realized by the univariate covariance analysis. Significance level was established at 0.05 or 5%. there were significant differences between cases and controls for protruded head (47.5 and 52.0 masculine, respectively; p<0.0001) and for protruded shoulders (1.9 and 1.6 cm, respectively; p=0.03). The other variables did not show significant differences. based on these results, attention to head and shoulder posture, to antalgic postures and to the emotional factor is recommended. Women with chronic pelvic pain should be treated, taking into consideration individual muscle-skeletal changes, and social and emotional conditions.


Microvascular approach to function and appearance of large orbital maxillary defects.
Forty-three patients with major three-dimensional orbitomaxillary defects underwent 48 free-tissue transfers for defects arising from resection of a neoplasm or trauma. Defects were complex, involving the malar skin, mandible, lateral nasal wall, orbit, palate, and brain. A three-dimensional approach attempting to recreate the midface by folding the flaps was the usual method, with subsequent revisions if necessary. Ten patients had simultaneous free bone grafts and 6 had vascularized bone grafts. There were three flap failures and four perioperative deaths. Excluding the 4 deaths, the results were assessed as excellent in 25 patients, good in 12, and poor in 2. Free-tissue transfer is a reliable method of providing enough tissue at one initial operation to satisfy complex three-dimensional defects of the orbitomaxillary region. Followed by minor revision, it provides a means of restoring function and appearance without multiple staged procedures with a high risk of failure.


Updating OMERACT Core Set of Domains for ANCA-associated Vasculitis: Patient Perspective Using the International Classification of Function, Disability, and Health.
Aspects of antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) prioritized by patients with AAV were described using the International Classification of Function, Disability, and Health (ICF). Items identified during 14 individual interviews were incorporated into an ICF-based questionnaire administered to participants of 2 vasculitis patient symposia: 36 in the United Kingdom and 63 in the United States. Categories identified as at least "moderately relevant" by ≥ 5% of subjects included 44 body functions, 14 body structures, 35 activities and participation, 31 environmental factors, and 38 personal factors. Identified categories differ from those identified by the current Outcome Measures in Rheumatology (OMERACT) core set and those prioritized by vasculitis experts.


Annexin 1: an endogenous anti-inflammatory protein.
A hallmark of inflammation is the mobilization of blood-borne leukocytes across microvessels to kill and remove the invading pathogen. For its damaging potential, leukocyte movement is finely regulated, and endogenous pathways exist to ensure the time dependency of this process. Annexin 1 and its receptor(s) are one example of these pathways.


Distinct populations of rotaviruses circulating among neonates and older infants.
We obtained three stool specimens from each of 371 neonates. Two specimens were obtained between days 1 and 3 after birth, while they were in the hospital, and one specimen was obtained between days 6 and 14 after birth, after they had been discharged from the hospital. Seventy neonates excreted human rotavirus (HRV) while they were in the hospital, and the incidence rate for the cohort was 0.094 episodes per infant day. The incidence rate of community-acquired neonatal infections was markedly reduced to 0.022 episodes per infant day, with eight additional episodes of infection being detected after the infants were discharged from the hospital. Nevertheless, this was higher than the incidence of community-acquired HRV infection of 0.0037 episodes per infant day previously estimated by serology for the same cohort during the subsequent 2 years of infancy. None of the 78 episodes of neonatal HRV infection was accompanied by diarrhea. There were at least 44 distinct electropherotypes of HRV circulating among older infants in the community during the study period, and they comprised at least four different serotypes. Despite the genetic and antigenic diversity of the prevalent HRV isolates, only five electropherotypes with either serotype 2 or 4 specificity were isolated from the neonates, while serotype 1 and 3 viruses were not detected. Two of these electropherotypes, including one which was isolated from 57 of the 78 infants with episodes of infection, were isolated exclusively from the neonates. The other three electropherotypes were also isolated from the older infants; one was a major electropherotype and two were minor electropherotypes which were prevalent among the older infants. These results suggest that distinct populations of HRV cocirculate among neonates and older infants.


Effects of retained diaphyseal plates on forearm bone density and grip strength.
Numerous complications have been attributed to elective plate removal following successful treatment of both bone diaphyseal forearm fractures, yet the effects of retained implants are not known. Fourteen patients were reviewed for residual forearm grip strength (FGS) and bone mineral density (BMD) following uneventful union. Patients were analyzed in two groups based upon time from fixation: group I, > 2 years but < or = 5 years, and group II, > 5 years. In group I, mean 2.6 years follow-up (n = 6), mean FGS ratios (patient values/age matched general population means) were 0.65 and 0.77, respectively, for plated and normal limbs (p = 0.08). The mean BMD ratios of plated/normal sides adjacent to the plate were 0.99 (ulna) and 1.02 (radius); these values were not significantly different from more proximal forearm BMD ratios (p = 0.92 ulna; p = 0.44, radius). In group II, mean 8.4 years (n = 8), mean FGS ratios were 0.97 and 1.09, respectively, for plated and normal limbs (p > 0.05). The BMD ratio was 1.04 adjacent to the plate; this was not significantly different from the ratios measured away from the plate (p > 0.4). We conclude that retained forearm plates can be well tolerated and that their routine removal is not indicated based on FGS or BMD.


A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.
Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.


Differential impact of severe drought on infant mortality in two sympatric neotropical primates.
Extreme climate events can have important consequences for the dynamics of natural populations, and severe droughts are predicted to become more common and intense due to climate change. We analysed infant mortality in relation to drought in two primate species (white-faced capuchins, Cebus capucinus imitator, and Geoffroy's spider monkeys, Ateles geoffroyi) in a tropical dry forest in northwestern Costa Rica. Our survival analyses combine several rare and valuable long-term datasets, including long-term primate life-history, landscape-scale fruit abundance, food-tree mortality, and climate conditions. Infant capuchins showed a threshold mortality response to drought, with exceptionally high mortality during a period of intense drought, but not during periods of moderate water shortage. By contrast, spider monkey females stopped reproducing during severe drought, and the mortality of infant spider monkeys peaked later during a period of low fruit abundance and high food-tree mortality linked to the drought. These divergent patterns implicate differing physiology, behaviour or associated factors in shaping species-specific drought responses. Our findings link predictions about the Earth's changing climate to environmental influences on primate mortality risk and thereby improve our understanding of how the increasing severity and frequency of droughts will affect the dynamics and conservation of wild primates.


Noninvasive SpO2/FiO2 ratio as surrogate for PaO2/FiO2 ratio during simulated prolonged field care and ground and high-altitude evacuation.
Diagnosis of lung injury requires invasive blood draws to measure oxygen tension in blood. This capability is nonexistent in austere settings and during prolonged field care (PFC), that is, medical care characterized by inability to evacuate casualties from the point of injury for up to 72 hours. We analyzed pulse-oximeter-derived noninvasive SpO2 and assessed the SpO2/FiO2 ratio (SFR) as a surrogate for the PaO2/FiO2 ratio (PFR), an accepted marker of lung function. We hypothesized that SFR is a suitable surrogate for PFR in a data set from animal models of combat-relevant trauma, PFC, and aeromedical evacuation. Data from anesthetized swine (N = 30) subjected to combat relevant trauma, resuscitation, and critical care interventions were analyzed. Pairwise correlations and Bland-Altman and regression analyses were performed to compare PFR and SFR, based on averaged SpO2 values obtained from two monitoring devices. We performed 683 pairwise correlations. SpO2/FiO2 ratio was numerically higher than PFR with a 313 cutoff values for acute respiratory distress syndrome (ARDS) (PFR ≥300). Sensitivity/specificity for detection of mild ARDS was 75%/73% with a 200 to 300 PFR range corresponding to 252 to 312 SFR range. For moderate ARDS, sensitivity/specificity was 61%/93% with a 100 to 200 PFR range corresponding to 191 to 251 SFR range. For severe ARDS, sensitivity/specificity was 49%/97% with a 0 to 100 PFR range corresponding to 0 to 190 SFR range. For all groups, areas under the receiver operating characteristic curves ranged from 0.76 to 0.98. SpO2/FiO2 ratio is a useful surrogate for PFR when arterial blood gas testing is not available during dynamically changing physiologic conditions, for example, during austere conditions, PFC, or aeromedical evacuation, and may permit early detection of casualties in need of lung-specific life-saving interventions. Studies in critically ill humans are warranted.


Bisdemethoxycurcumin Inhibits Hepatocellular Carcinoma Proliferation Through Akt Inactivation via CYLD-Mediated Deubiquitination.
Bisdemethoxycurcumin (BDMC), a stable bioactive ingredient in curcuminoids, is associated with various antitumor functions, such as proliferation inhibition, metastasis suppression and apoptosis induction, in many cancer types. However, the mechanism of BDMC in hepatocellular carcinoma (HCC) remains unclear. We assessed the toxicity and the inhibitory effect of BDMC in the HepG2 cell line by using CCK-8 and colony formation assays. The regulatory effects of BDMC on Akt and MAPK signaling were investigated by Western blotting and immunoprecipitation. We found that the half-maximum inhibitory concentration (IC50) of BDMC after 48 hrs of treatment was 59.13 μM, and BDMC inhibited proliferation in a time- and dose-dependent manner in HepG2 cells. The inhibitory effect was caused by the inactivation of Akt signaling, but not Erk, Jnk or p38 signaling. In addition, the inactivation of Akt signaling was attributed to the inhibition of ubiquitination mediated by K63-Ub but not K48-Ub. Furthermore, we found that BDMC upregulated the expression of CYLD, leading to Akt deubiquitination and inactivation. BDMC inhibited HCC cell proliferation, and that this effect was induced by Akt inactivation via CYLD-mediated deubiquitination.


Early rehabilitation in older patients hospitalized with acute decompensated heart failure: A retrospective cohort study.
Although hospitalized patients with acute decompensated heart failure (ADHF) have severe physical dysfunction, little data are available on the comparative effectiveness of early versus late rehabilitation. This study examined the relationship between early compared to late rehabilitation and physical function among older patients hospitalized for ADHF. In a retrospective cohort study, independent patients aged ≥65 years at baseline who were hospitalized for ADHF from 2012 to 2014 and underwent inpatient rehabilitation were identified using Emergency Department visit data and electronic medical records at two hospitals. Patients were classified into those who underwent early rehabilitation (initiated within 72 hours of admission) and late rehabilitation (after 72 hours). Primary outcome was length of time from admission until the patient was able to walk independently. Multivariable competing-risk regression with death as the competing event was used to adjust for potential confounding factors, and multiple imputation (MI) analysis was performed. Of 259 individuals, 30 (11.6%) commenced rehabilitation within 72 hours after admission while 229 (88.4%) did so 72 hours after admission. Patients who received early rehabilitation had a higher rate of unassisted walking for at least 40 m by 30 days after admission (hazard ratio: 8.03; 95% confidence interval: 2.15 to 29.98; P = .002 in the multivariable adjusted model) than those who received late rehabilitation. Similar findings were observed on MI analysis. Early rehabilitation therapy commenced within 72 hours of admission was associated with a higher rate of recovery of an activity of daily living (independent walking on a level surface).


Synchronization of clocks and metronomes: A perturbation analysis based on multiple timescales.
In 1665, Huygens observed that two pendulum clocks hanging from the same board became synchronized in antiphase after hundreds of swings. On the other hand, modern experiments with metronomes placed on a movable platform show that they often tend to synchronize in phase, not antiphase. Here, we study both in-phase and antiphase synchronization in a model of pendulum clocks and metronomes and analyze their long-term dynamics with the tools of perturbation theory. Specifically, we exploit the separation of timescales between the fast oscillations of the individual pendulums and the much slower adjustments of their amplitudes and phases. By scaling the equations appropriately and applying the method of multiple timescales, we derive explicit formulas for the regimes in the parameter space where either antiphase or in-phase synchronization is stable or where both are stable. Although this sort of perturbative analysis is standard in other parts of nonlinear science, surprisingly it has rarely been applied in the context of Huygens's clocks. Unusual features of our approach include its treatment of the escapement mechanism, a small-angle approximation up to cubic order, and both a two- and three-timescale asymptotic analysis.


Cross-generational response of a tropical sea urchin to global change and a selection event in a 43-month mesocosm study.
Long-term experimental investigations of transgenerational plasticity (TGP) and transgenerational acclimatization to global change are sparse in marine invertebrates. Here, we test the effect of ocean warming and acidification over a 25-month period of Echinometra sp. A sea urchins whose parents were acclimatized at ambient or one of two near-future (projected mid and end of the 21st century) climate scenarios for 18 months. Several parameters linked to performance exhibited strong effects of future ocean conditions at 9 months of age. The Ambient-Ambient group (A-A, both F0 and F1 at ambient conditions) was significantly larger (21%) and faster in righting response (31%) compared to other groups. A second set of contrasts revealed near-future scenarios caused significant negative parental carryover effects. Respiration at 9 months was depressed by 59% when parents were from near-future climate conditions, and righting response was slowed by 28%. At 10 months, a selective pathogenic mortality event led to significantly higher survival rates of A-A urchins. Differences in size and respiration measured prior to the mortality were absent after the event, while a negative parental effect on righting (29% reduction) remained. The capacity to spawn at the end of the experiment was higher in individuals with ambient parents (50%) compared to other groups (21%) suggesting persistent parental effects. Obtaining different results at different points in time illustrates the importance of longer term and multigeneration studies to investigate effects of climate change. Given some animals in all groups survived the pathogenic event and that effects on physiology (but not behavior) among groups were eliminated after the mortality, we suggest that similar events could constitute selective sweeps, allowing genetic adaptation. However, given the observed negative parental effects and reduced potential for population replenishment, it remains to be determined if selection would be sufficiently rapid to rescue this species from climate change effects.


Change in social support after retirement: longitudinal findings from the Normative Aging Study.
Although retirement is generally thought to lead to a decline in social support due to a loss of social contacts with coworkers, the evidence for this is at best contradictory. This longitudinal study examined change in social support among 1,311 men, participants in the Veterans Administration Normative Aging Study, over a 3-year period. In general, long-term retirees reported the least quantitative social support, and the continuing full-time workers the most; however, change in workforce status produced no apparent effect on quantitative support over the duration of this study. In general, qualitative support showed no retirement effects. We also examined more specific patterns of coworker friendship and again found a pattern similar to that of general quantitative support. The findings support our earlier suggestion of a distinction between retirement as a transition and retirement as a state, and also support the convoy model of social support in late life and the selectivity theory of developmental adaptation to aging.


Comparison of growth factors functionally related to epidermal growth factor in the urine of normal and human tumor-bearing athymic mice.
Urine from nude mice contains epidermal growth factor (EGF) and a minor acid-stable component with an apparent molecular weight of 20,000, which competes with EGF for binding to EGF membrane receptors and which promotes colony formation by normal rat kidney cells in soft agar. The levels of this Mr 20,000 urine-derived growth factor are increased approximately 4- to 10-fold in nude mice bearing tumors following s.c. injection of cultured human tumor cells. Following removal of the primary tumor, the concentration of this factor is reduced to basal levels, and thus, elevated levels of this growth factor appear to be dependent on tumor burden. The Mr 20,000 urinary component is separable into four EGF competing activities by high-performance liquid chromatography; the major species is immunologically related to mouse submaxillary gland EGF and therefore appears to be of host origin. However, in addition to elevated levels of host growth factor, urine from tumor-bearing mice also contains transforming growth factor activity in amounts comparable to that released by the tumor cells in culture. The tumor-derived urinary transforming growth factor activity is immunologically unrelated to EGF but is immunoreactive with an antiserum to transforming growth factor-alpha. We propose that the nude mouse may be a useful model to examine the role of both host- and tumor-derived growth factors in tumorigenesis and the usefulness of these factors as biological markers of response to therapy and tumor progression.


Prevalence of Urogenital Mycoplasmas Among Men with NGU in Upper Silesia, Poland. Preliminary Study.
The prevalence of urogenital mycoplasmas in men with NGU in Upper Silesia (Poland) was studied. Mycoplasmas were detected in 36.7% men (Ureaplasma parvum and Mycoplasma genitalium were found in 30% and 16.7% respectively). Urealyticum urealyticum was not detected. We suggest including M. genitalium in the diagnostic scheme for nongonococcal urethritis (NGU).


The effects of exogenous surfactant treatment in a murine model of two-hit lung injury.
Because pulmonary endogenous surfactant is altered during acute respiratory distress syndrome, surfactant replacement may improve clinical outcomes. However, trials of surfactant use have had mixed results. We designed this animal model of unilateral (right) lung injury to explore the effect of exogenous surfactant administered to the injured lung on inflammation in the injured and noninjured lung. Mice underwent hydrochloric acid instillation (1.5 mL/kg) into the right bronchus and prolonged (7 hours) mechanical ventilation (25 mL/kg). After 3 hours, mice were treated with 1 mL/kg exogenous surfactant (Curosurf®) (surf group) or sterile saline (NaCl 0.9%) (vehicle group) in the injured (right) lung or did not receive any treatment (hydrochloric acid, ventilator-induced lung injury). Gas exchange, lung compliance, and bronchoalveolar inflammation (cells, albumin, and cytokines) were evaluated. After a significant analysis of variance (ANOVA) test, Tukey post hoc test was used for statistical analysis. At least 8 to 10 mice in each group were analyzed for each evaluated variable. Surfactant treatment significantly increased both the arterial oxygen tension to fraction of inspired oxygen ratio and respiratory system static compliance (P = 0.027 and P = 0.007, respectively, for surf group versus vehicle). Surfactant therapy increased indices of inflammation in the acid-injured lung compared with vehicle: inflammatory cells (685 [602-773] and 216 [125-305] × 1000/mL, respectively; P < 0.001) and albumin in bronchoalveolar lavage (BAL) (1442 ± 588 and 743 ± 647 μg/mL, respectively; P = 0.027). These differences were not found (P = 0.96 and P = 0.54) in the contralateral (uninjured) lung (inflammatory cells 131 [78-195] and 119 [87-149] × 1000/mL and albumin 135 ± 100 and 173 ± 115 μg/mL). Exogenous surfactant administration to an acid-injured right lung improved gas exchange and whole respiratory system compliance. However, markers of inflammation increased in the right (injured) lung, although this result was not found in the left (uninjured) lung. These data suggest that the mechanism by which surfactant improves lung function may involve both uninjured and injured alveoli.


Metabolic characterization of human non-Hodgkin's lymphomas in vivo with the use of proton-decoupled phosphorus magnetic resonance spectroscopy.
Development of biological and clinical uses of in vivo 31P magnetic resonance spectroscopy has been hampered by poor anatomic localization of spectra and poor resolution of overlapping signals within phosphomonoester and phosphodiester regions of the spectrum. We applied 1H-decoupling and nuclear Overhauser enhancement to improve resolution of 31P magnetic resonance spectra accurately localized to 21 non-Hodgkin's lymphomas (NHL) by using three-dimensional chemical shift imaging. All 21 spectra had large phosphomonoester signals (26% of total phosphorus) that contained high amounts of phosphoethanolamine relative to phosphocholine. There were no signals from glycerophosphoethanolamine or glycerophosphocholine but only a broad signal from membrane phospholipids in the phosphodiester region (20% of phosphorus). Prominent nucleoside triphosphates (47% of phosphorus) and low inorganic phosphate (7% of phosphorus) indicate well-perfused tissue with viable cells. Mean intracellular pH was 7.23. These characteristics were similar in all grades and stages of NHL. By analogy with recently reported studies in cell lines in vitro, we hypothesize that the pattern of phospholipid metabolites observed in NHL in vivo is partly a manifestation of sustained activation of phospholipase C or D. The techniques we implemented permitted us to obtain more information about in vivo metabolism of NHL than has heretofore been available. This information is important for the establishment of appropriate experimental models and provides a basis from which to examine potential clinical uses of 31P magnetic resonance spectroscopy.


Experiences of Suicide in Transgender Youth: A Qualitative, Community-Based Study.
Objective: The aim was to develop understanding around the experience of suicide in transgender youth. Method: Qualitative analysis with 85 interviews with transgender youth about their histories with suicidality was performed. Participants were recruited from community clinics in three counties (United States, Canada, and Ireland) between 2010 and 2014. Results: Factors that precipitated participants' suicide attempts included rejection based on gender identity and gender dysphoria. Participants demonstrated resilience by attempting to connect with loved ones for support and through self-awareness of mental states, including by regulating behaviors they perceived to adversely affect their mental health. Conclusions: Transgender youth may fear seeking health care due to health professionals' lack of understanding of transgender issues and fear of further victimization. Reframing suicidality as a rational decision-making process in response to stress may further understanding of why people attempt suicide and provide new avenues for intervention.


Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer.
The purpose of this study was to evaluate the role of BMPs on the formation of metastatic prostate cancer lesions to bone. Our results show that BMPs influence the development and progression of osteoblastic lesions and suggest that therapies that inhibit BMP activity may reduce the formation and progression of osteoblastic lesions. Prostate adenocarcinoma is the leading cause of cancer in North American men. The formation of skeletal metastases affects approximately 70% of patients with advanced disease, and a majority of these patients have osteoblastic lesions. Although BMPs have been found to be expressed in multiple oncogenic cell lines, their role in the formation of metastatic osteoblastic lesions remains uncharacterized. We hypothesized that BMPs influence the development of metastatic osteoblastic lesions associated with prostate cancer. Western blot analysis and RT-PCR was used to determine BMP receptor expression on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. Migration, invasion, and cellular proliferation assays were used to quantify the effects of BMP-2, -4, and -7 on LAPC-4 cells in vitro. LAPC-9 cells alone or transfected with a retrovirus overexpressing noggin were injected into the tibias of SCID mice, and the animals were followed for 8 weeks. Tumor size was determined by radiographs and direct measurement. Histology was performed at the time of death. We determined that BMP receptor mRNA and protein was expressed on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. In vitro studies showed that BMP-2 and -7 stimulated cellular migration and invasion of prostate cancer cells in a dose-dependent fashion, although BMP-4 had no effect. Noggin inhibited cellular migration and invasion of BMP-2- and -7-stimulated LAPC-4 cells. LAPC-9 cells implanted into immunodeficient mouse tibias formed an osteoblastic lesion with sclerotic bone at 8 weeks. Formation of osteoblastic lesions was inhibited by overexpression of noggin by prostate cancer cells transduced with a retrovirus containing the cDNA for noggin. BMPs are critical in the formation of the osteoblastic lesions associated with prostate cancer metastases, and future treatment strategies that inhibit local BMP activity may reduce the formation and progression of osteoblastic lesions.


Direct Chemical Imaging of Ligand-Functionalized Single Nanoparticles by Photoinduced Force Microscopy.
Chemical characterizations of biochemically functionalized single nanoparticles are necessary to optimize the nanoparticle surface functionality in recently advanced nanobiological applications but have not yet been fully explored because of technical difficulties. Exploiting the photoinduced force exerted on a light-illuminated nanoscale tip, nanoscale mid-infrared hyperspectral images with a 10 nm spatial resolution of a monolayer ligand-functionalized single gold nanoparticle under ambient and environmental conditions are presented. We extend our study to the diagnosis of nanoscale heterogeneous chemical contaminants which come from a particle functionalization process but are undetectable in conventional ensemble-averaged imaging technique. High sensitivity and high spatial resolution are achieved via the strongly localized tip-enhanced force at the junction between the gold-coated tip and the functionalized nanoparticle in photoinduced force microscopy, which far exceeds the capability of the conventional methods. The present study paves a new way to directly detect heterogeneous nanochemicals at the single-component level, which is necessary to evaluate nanomaterial safety in biomedical applications.


Neurospora Heterokaryons with Complementary Duplications and Deficiencies in Their Constituent Nuclei Provide an Approach to Identify Nucleus-Limited Genes.
Introgression is the transfer of genes or genomic regions from one species into another via hybridization and back-crosses. We have introgressed four translocations (EB4, IBj5, UK14-1, and B362i) from Neurospora crassa into N. tetrasperma. This enabled us to construct two general types of heterokaryons with mat-A and mat-a nuclei of different genotypes: one type is [T + N] (with one translocation nucleus and one normal sequence nucleus), and the other is [Dp + Df] (with one nucleus carrying a duplication of the translocation region and the other being deleted for the translocation region). Self-crossing these heterokaryons again produced [T + N] and [Dp + Df] progeny. From conidia (vegetative spores) produced by the heterokaryotic mycelia, we obtained self-fertile (heterokaryotic) and self-sterile (homokaryotic) derivative strains. [T + N] heterokaryons produced homokaryotic conidial derivatives of both mating types, but [Dp + Df] heterokaryons produced viable conidial homokaryons of only the mating type of the Dp nucleus. All four [T + N] heterokaryons and three [Dp + Df] heterokaryons produced both self-sterile and self-fertile conidial derivatives, but the [Dp(B362i) + Df(B362i)] heterokaryons produced only self-sterile ones. Conceivably, the Df(B362i) nuclei may be deleted for a nucleus-limited gene required for efficient mitosis or nuclear division, and whose deficit is not complemented by the neighboring Dp(B362i) nuclei. A cross involving Dp(EB4) showed repeat-induced point mutation (RIP). Because RIP can occur in self-crosses of [Dp + Df] but not [T + N] heterokaryons, RIP alteration of a translocated segment would depend on the relative numbers of [Dp + Df] vs. [T + N] ancestors.


Oxytocin receptor-mediated activation of phosphoinositidase C and elevation of cytosolic calcium in the gonadotrope-derived alphaT3-1 cell line.
Gonadotropes synthesize and secrete LH and FSH under the control of GnRH, which acts via phosphoinositidase C (PIC)-linked G protein coupled receptors. Additionally, gonadotropin released from the pituitary is influenced by oxytocin, a peptide that has been shown to play a role in generation of the preovulatory LH surge. Although oxytocin receptors are present in the pituitary, studies have identified their presence on lactotropes but not on gonadotropes, raising the question of which cells act as the direct target of oxytocin in gonadotrope regulation. In this study, we examined effects of oxytocin on alphaT3-1 cells, a gonadotrope-derived cell line. Oxytocin, vasopressin, and vasotocin each stimulated accumulation of [3H]inositol phosphates in cells prelabeled with [3H]inositol, indicating activation of PIC. The rank order of potency (oxytocin > vasotocin > vasopressin) and sensitivity to inhibition by oxytocin and vasopressin receptor antagonists, revealed the effect to be mediated by oxytocin-selective receptors. Like other PIC activators, these nonapeptides caused biphasic (spike-plateau) increases in the cytosolic Ca2+. The spike response to oxytocin and GnRH were both retained in Ca2+-free medium, reflecting mobilization of intracellular Ca2+, and were comparably reduced by thapsigargin, implying mobilization of Ca2+ from a shared thapsigargin-sensitive intracellular pool. Brief stimulation with oxytocin, vasopressin, or vasotocin prevented subsequent Ca2+ responses to oxytocin, but not to GnRH, suggesting that the oxytocin receptor undergoes rapid homologous desensitization and reinforcing the interpretation that the nonapeptides act via the same receptor type. Oxytocin did not increase Ca2+ in cells stimulated with GnRH, whereas GnRH caused a spike Ca2+ increase even in the presence of oxytocin, implying that different mechanisms of desensitization (Ca2+ pool depletion and receptor uncoupling) are operating for two distinct PIC-coupled receptors in these cells. The demonstration that oxytocin acts directly via PIC-linked, oxytocin-selective receptors to increase cytosolic Ca2+ in a gonadotrope-derived cell line is consistent with the possibility that oxytocin has a comparable effect on nonimmortalized gonadotropes.


Agent-based simulation for weekend-extension strategies to mitigate influenza outbreaks.
Non-pharmaceutical strategies are vital in curtailing impacts of influenza and have been intensively studied in public health. However, few strategies have explicitly utilized the weekend effect, which has been widely reported to be capable of reducing influenza infections. This study aims to explore six weekend-extension strategies against seasonal and pandemic flu outbreaks. The weekend-extension strategies were designed to extend regular two-day weekend by one, two and three days, respectively, and in combination with either a continuous or discontinuous pattern. Their effectiveness was evaluated using an established agent-based spatially explicit simulation model in the urbanized area of Buffalo, NY, US. If the extensions last more than two days, the weekend-extension strategies can remarkably reduce the overall disease attack rate of seasonal flu. Particularly, a three-day continuous extension is sufficient to suppress the epidemic and confine the spread of disease. For the pandemic flu, the weekend-extension strategies only produce a few mitigation effects until the extensions exceed three days. Sensitivity analysis indicated that a compliance level above 75% is necessary for the weekend-extension strategies to take effects. This research is the first attempt to incorporate the weekend effect into influenza mitigation strategies. The results suggest that appropriate extensions of the regular two-day weekend can be a potential measure to fight against influenza outbreaks, while minimizing interruptions on normal rhythms of socio-economy. The concept of weekend extension would be particularly useful if there were a lack of vaccine stockpiles, e.g., in countries with limited health resources, or in the case of unknown emerging infectious diseases.


Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat.
Nerve growth factor (NGF) has a well characterized role in the development of the nervous system and there is evidence that it interacts with nociceptive primary afferent fibres. Here we applied a synthetic tyrosine kinase A IgG (trkA-IgG) fusion molecule for 10-12 days to the innervation territory of the purely cutaneous saphenous nerve in order to bind, and thereby neutralize endogenous NGF in adult rats. Using neurophysiological analysis of 152 nociceptors we now show that sequestration of NGF results in specific changes of their receptive field properties. The percentage of nociceptors responding to heat dropped significantly from a normal 57% to 32%. This was accompanied by a rightward shift and a reduced slope of the stimulus response function relating the intracutaneous temperature to the neural response. The number of nociceptors responding to application of bradykinin was also significantly reduced from a normal of 28% to 8%. In contrast, the threshold for mechanical stimuli and the response to suprathreshold stimuli remained unaltered, as did the percentage of nociceptors responding to noxious cold. The reduced sensitivity of primary afferent nociceptors was accompanied by a reduction in the innervation density of the epidermis by 44% as assessed with quantitative immunocytochemical analysis of the panaxonal marker PGP 9.5. This demonstrates that endogenous NGF in the adult specifically modulates the terminal arborization of unmyelinated fibres and the sensitivity of primary afferent nociceptors to thermal and chemical stimuli in vivo.


Tuberculosis during Pregnancy in Northern Israel, 2002-2012: Epidemiology and Clinical Practices.
Atypical presentation of tuberculosis (TB) during pregnancy may cause diagnostic delay and adversely influence pregnancy outcome. To examine the incidence and clinical and epidemiological features of TB during pregnancy and investigate infection control measures at delivery and during the postpartum period. We retrospectively evaluated all reported cases of TB diagnosed during pregnancy to 6 months postpartum in Israel's Northern Health District (2002-2012). Active TB was detected in six patients; all were negative for human immunodeficiency virus (HIV). Two patients were diagnosed in the postpartum period, and four had pulmonary involvement. The average incidence during this period (3.9 per 100,000 pregnancies) was similar to that in the general population. Five patients were at high risk of contracting TB due to either recent immigration from a high-burden country or being in contact with another individual with active TB. Patients with pleuropulmonary involvement had prolonged cough and abnormal chest X-rays, without fever. Diagnosis was delayed for 3 to 7 months from symptom onset. Investigation of the newborn to rule out intrauterine infection was conducted in only one of four relevant cases. All patients were infected with organisms susceptible to all first-line drugs, and all were cured with standard therapy. There was a considerable delay in the diagnosis of TB among pregnant women, and investigation of the newborn upon delivery to rule out TB infection was routinely omitted. Effective management of TB during pregnancy and the postpartum period requires a multidisciplinary approach including an obstetrician, pediatrician, TB specialist, and public health physician.


Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region.
Calcium-sensing receptor gene (CaSR) is a candidate to explain susceptibility to calcium kidney stones. Thus, we studied CaSR gene single-nucleotide polymorphisms (SNPs) and haplotypes associated with stones. Four hundred and sixty-three calcium stone formers and 213 healthy controls were genotyped for 21 SNPs mapping the whole CaSR gene. CaSR gene structure was studied. SNPs and haplotypes were analysed for association with stones. Three haplotype blocks were identified in the CaSR gene. The first block was characterized by six SNPs and included gene promoters. The rs7652589 and rs1501899 SNPs and the CATTCA haplotype of the first block were significantly more frequent in normocitraturic calcium kidney stone formers than controls. The risk of stones was increased in normocitraturic homozygous patients and heterozygotes for the CATTCA haplotype. The rate of stones was higher in stone formers with the CATTCA haplotype. In a three-generation family, calcium stones were associated with the CATTCA haplotype. The bioinformatic analysis identified a new site for the octamer-binding transcription factor 1 in the presence of the variant alleles at the rs7652589 and rs1501899 SNPs. This transcription factor may downregulate the transcription of vitamin D-dependent genes and the CaSR expression. Conclusion. SNPs and CATTCA haplotype of the CaSR gene first block is associated with kidney stones in normocitraturic patients.


Exposure to Violence, Posttraumatic Stress Symptoms, and Borderline Personality Pathology Among Adolescents in Residential Psychiatric Treatment: The Influence of Emotion Dysregulation.
Exposure to violence during adolescence is a highly prevalent phenomenon associated with a range of deleterious outcomes. Theoretical literature suggests that emotion dysregulation is one consequence of exposure to violence associated with the manifestation of posttraumatic stress symptoms (PTSS) and borderline personality (BP) pathology. Thus, the goal of the present study was to examine the mediating role of emotion dysregulation in the relation between exposure to violence and both PTSS and BP pathology in a sample of 144 adolescents (age 10- to 17-years; 51% male; 55% African American) admitted to a psychiatric residential treatment center. Exposure to violence was associated with greater emotion dysregulation, which, in turn, was associated with greater PTSS and BP pathology. Furthermore, emotion dysregulation mediated the associations between exposure to violence and both PTSS and BP pathology. Findings suggest the importance of assessing and treating emotion dysregulation among violence-exposed adolescents in psychiatric residential treatment.


An exploratory study with an adaptive continuous intravenous furosemide regimen in neonates treated with extracorporeal membrane oxygenation.
The objective of the present study was to explore a continuous intravenous furosemide regimen that adapts to urine output in neonates treated with extracorporeal membrane oxygenation (ECMO). Seven neonates admitted to a paediatric surgical intensive care unit for ECMO therapy were treated with a furosemide regimen consisting of a loading bolus (1-2 mg/kg) followed by a continuous infusion at 0.2 mg/kg per hour, which was adjusted according to the target urine production of 6 ml/kg per hour. Therapeutic drug monitoring for furosemide concentrations in blood was performed. The mean +/- standard deviation furosemide dose was 0.17 +/- 0.06 mg/kg per hour, 0.08 +/- 0.04 mg/kg per hour and 0.12 +/- 0.07 mg/kg per hour, respectively, on the first day, second day and third day of the study. The median (range of the urine production of the study subjects) urine production over the consecutive study days was 6.8 (0.8-8.4) mg/kg per hour, 6.0 (4.7-8.9) mg/kg per hour and 5.4 (3.4-10.1) ml/kg per hour. The target urine production was reached after a median time of 7 (3-37) hours. The regimen was haemodynamically well tolerated and the median furosemide serum concentration was 3.1 (0.4-12.9) mug/ml, well below the toxic level. The evaluated furosemide infusion appears an effective means to reduce volume overload in neonates treated with ECMO. The data of this preliminary study suggest that the starting dose of furosemide was too high, however, because the urine output was excessive and required frequent adaptations. The results of this study therefore indicate that a novel pharmacokinetic/pharmacodynamic model needs to be developed for neonates treated with ECMO.


[Functional state of the adrenal cortex in patients with Parkinsonism before and after surgical treatment].
The results of biochemical examinations of the hormonal function of the adrenal cortex in 22 patients with Parkinson's disease are presented as seen prior and following stereotaxic operations on the ventro-lateral nucleus of the thalamus. It was found that parkinsonics have a decreased androgenic, glucocorticoid and mineralocorticoid function of the adrenal cortex. Long history and growing severity of the disease manifest themselves in a distinct inhibition of the adrenal cortex function. The importance of the changes in the functional state of the hypothalamo-hypophyseal system in the revealed disorders in the hormonal activity is emphasized. Along with a beneficial clinical effect surgery brings about an improvement of the functional state of the adrenal cortex.


Recent advances of novel ultrathin two-dimensional silicon carbides from a theoretical perspective.
Compared to graphene with semimetallic features, two-dimensional (2D) silicon carbide (Si-C) materials constitute another highly promising family for opto-electronic applications owing to their intrinsic electronic gaps. Recent theoretical studies of 2D Si-C materials thoroughly investigated their structure and properties. Herein, we overview these high-throughput approaches aiming to theoretically design 2D Si-C crystals. Graphene-like siligraphene and non-siligraphene are described in terms of morphology, physicochemical properties and potential applications based on the insights provided by simulations. In addition, the current progress of experimental exploration of 2D Si-C materials and underlying challenges are assessed as well.


The Anatomy of the SARS-CoV-2 Biomedical Literature: Introducing the CovidX Network Algorithm for Drug Repurposing Recommendation.
Driven by the COVID-19 pandemic and the dire need to discover an antiviral drug, we explored the landscape of the SARS-CoV-2 biomedical publications to identify potential treatments. The aims of this study are to identify off-label drugs that may have benefits for the coronavirus disease pandemic, present a novel ranking algorithm called CovidX to recommend existing drugs for potential repurposing, and validate the literature-based outcome with drug knowledge available in clinical trials. To achieve such objectives, we applied natural language processing techniques to identify drugs and linked entities (eg, disease, gene, protein, chemical compounds). When such entities are linked, they form a map that can be further explored using network science tools. The CovidX algorithm was based upon a notion that we called "diversity." A diversity score for a given drug was calculated by measuring how "diverse" a drug is calculated using various biological entities (regardless of the cardinality of actual instances in each category). The algorithm validates the ranking and awards those drugs that are currently being investigated in open clinical trials. The rationale behind the open clinical trial is to provide a validating mechanism of the PubMed results. This ensures providing up to date evidence of the fast development of this disease. From the analyzed biomedical literature, the algorithm identified 30 possible drug candidates for repurposing, ranked them accordingly, and validated the ranking outcomes against evidence from clinical trials. The top 10 candidates according to our algorithm are hydroxychloroquine, azithromycin, chloroquine, ritonavir, losartan, remdesivir, favipiravir, methylprednisolone, rapamycin, and tilorone dihydrochloride. The ranking shows both consistency and promise in identifying drugs that can be repurposed. We believe, however, the full treatment to be a multifaceted, adjuvant approach where multiple drugs may need to be taken at the same time.


Theoretical and experimental analysis of scatter from inhomogeneous slabs in a 60Co beam: the differential tissue-air ratio method (DTAR).
A theoretical and experimental analysis of scatter from inhomogeneous slabs in a 60Co beam has been developed. This analysis has been used to examine the differential scatter-air ratio method (DSAR). It has been found that a simplification of this method gives more accurate results than the original one. Thus, a method which takes advantage of this simplification has been developed, called the 'differential tissue-air ratio method (DTAR)'. It is compared with experimental results. The accuracy is satisfactory for a wide range of applications (usually approaching the limits of the precision of the measurements, about 2%) and leads to calculation times not significantly longer than any conventional method (e.g. Batho).


Patient Reported Experiences at a Swedish National Burn Centre.
Previous studies have shown that burn patients were satisfied with the received care. Satisfaction was not strongly associated to burns or to psycho-social characteristics, suggesting that other factors, related to burn care specific aspects, may be important. The aim of this study was to analyze the independent effect of provided workload on the general satisfaction in adult patients at a Swedish national Burn Centre. The study population (n = 122) included patients ≥18 years, treated at the Linköping Burn Centre between 2016 and 2017. Experienced burn care was evaluated with the PS-RESKA survey (score range: 0-4), and provided workload was scored with the Burn Scoring System (BSC). Groups were compared with χ 2 test, MW test, or Fisher´s exact test. Multivariable logistic regression analyzed the independent effect of BSC on the outcome High Satisfaction (= score ≥3 to the survey-question: "How would you score your global experience at the Burn Centre?"). In-patients (n = 60) had more often larger burns and required more workload than out-patients (median[IQR]: TBSA% = 6.3 [3-12.3] % vs. 0.7 [0.3-2] %, p < .001; BSC = 65 [25.5-135.5] vs. 6 [4-9], p < .001). Both groups were highly satisfied with the experienced care (mean score [SD] = 3.68 [0.57] vs. 3.41 [0.77], p = .03). Neither characteristics of the patients (age, sex), nor TBSA% nor provided workload (BSC) were independently associated with High Satisfaction. Regardless of burn severity, demographics and provided workload, adult patients with burns were highly satisfied with the experienced burn care. This finding suggested that the reason of the satisfaction was multifactorial.


Inhibition of beta-lactamase synthesis in Staphylococcus aureus by minocycline.
The effect of minocycline on beta-lactamase synthesis in Staphylococcus aureus was examined. Some inhibition of synthesis was detectable in organisms exposed to 0.015 mg minocycline/litre (0.15 of the single cell MIC) and complete inhibition was observed at 0.05 mg drug/litre (0.5 MIC). In contrast, total cell protein synthesis was less susceptible to inhibition by minocycline. Although synthesis of beta-lactamase was inhibited by low concentrations of minocycline, benzylpenicillin and minocycline failed to show synergy when tested in a variety of combinations against penicillinase producing staphylococci. In fact, benzyl-penicillin did not influence the minocycline MIC, and in the majority of cases the same pattern was exhibited by minocycline i.e. it did not generally alter the penicillin MIC. This is an example of true indifference whereby each antibiotic behaves as if the other were not present. The results presented here are discussed in relation to the possibility of therapeutic control of beta-lactamase producing organisms by suppressing the level of enzyme produced.


Genomic organization and polymorphism of human angiotensin II type 2 receptor: no evidence for its gene mutation in two families of human premature ovarian failure syndrome.
Angiotensin II type 2 (AT(2)) receptor is highly expressed in the fetal tissues and decreases rapidly after birth. AT(2) receptor is re-expressed in the adult atretic ovarian follicles. Recently, it has been reported that AT(2) receptor mediates apoptosis. Primarily, we have cloned human AT(2) receptor cDNA and mapped it to the X-chromosome. To further analyze the organization and function of the AT(2) receptor gene, in this study we cloned the human AT(2) receptor genomic DNA. Human AT(2) receptor gene is composed of three exons and two introns. Primer extension analysis revealed a putative transcription initiation site at 24 bp downstream from TATA box. Furthermore, we identified a polymorphism (C-A) in 3' untranslated region of exon 3, which may be a useful genetic marker for genetic analysis of human X-linked inherited disease. In this study, we postulated that the patients with premature ovarian failure, which has been reported to be linked with X-chromosome abnormality, have AT(2) receptor mutation that may contribute to the early onset of atresia. We examined the entire coding sequence of this receptor in two different families of sisters with premature ovarian failure (POF) but found no changes in nucleotide sequences.


Nurses' perceptions of transfusion training: an evaluation.
Within Scottish hospitals transfusion education is mandatory for all staff involved in the process of transfusion. Currently two modes of delivery exist, face-to-face and e-learning. The researcher,a transfusion practitioner, wished to evaluate the perceptions of registered nurses within her local children's hospital to the transfusion education available. The aim of the evaluation was to ascertain whether there were perceived benefits, whether expectations were met and whether nurses perceived that there were any barriers to undertaking the education. Both quantitative and qualitative data were obtained by means of a questionnaire; all registered nurses in the hospital were invited to participate. The study indicates a high level of compliance with mandatory transfusion education and suggests both satisfaction and perceived benefits with transfusion education among those who responded. Some barriers were highlighted, but it was noted that these were not exclusive to transfusion education and in the current challenging environment with conflicting priorities on time, resolution may be complex.


Systematic review and meta-analysis of the effectiveness of commercially available vaccines against bovine herpesvirus, bovine viral diarrhea virus, bovine respiratory syncytial virus, and parainfluenza type 3 virus for mitigation of bovine respiratory disease complex in cattle.
To evaluate and analyze data from controlled studies on the effectiveness of vaccinating cattle with commercially available viral antigen vaccines for mitigation of the effects of bovine respiratory disease complex (BRDC). Systematic review and meta-analysis. 31 studies comprising 88 trials. Studies that reported the effectiveness of commercially available bovine herpesvirus-1 (BHV-1), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and parainfluenza type 3 virus (PI3) vaccines for protection of cattle against BRDC or its components were included in the analysis. Studies or trials were categorized as natural exposure or experimental challenge and were further divided by the viral antigen evaluated and vaccine type (modified-live virus [MLV] or inactivated vaccine). Meta-analysis was performed; summary Mantel-Haenszel risk ratios were determined, and Forest plots were generated. In natural exposure trials, beef calves vaccinated with various antigen combinations had a significantly lower BRDC morbidity risk than did nonvaccinated control calves. In trials evaluating BHV-1 and MLV BVDV vaccines in experimental challenge models, vaccinated calves had a lower BRDC morbidity risk than did control calves; however, in experimental challenge trials evaluating MLV BRSV and PI3 vaccines, no significant difference in morbidity or mortality risk was found between vaccinated and control calves. Estimating clinical efficacy from results of experimental challenge studies requires caution because these models differ substantially from those involving natural exposure. The literature provides data but does not provide sufficiently strong evidence to guide definitive recommendations for determining which virus components are necessary to include in a vaccination program for prevention or mitigation of BRDC in cattle.


Laboratory diagnosis of leptospirosis: a challenge.
Leptospirosis is caused by pathogenic bacteria called leptospires that are transmitted directly or indirectly from animals to humans. It occurs worldwide but is most common in tropical and subtropical areas. It is a potentially serious but treatable disease. Its symptoms may mimic those of a number of other unrelated infections such as influenza, meningitis, hepatitis, dengue, or other viral hemorrhagic fevers. The spectrum of the disease is extremely wide, ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality. Laboratory diagnosis tests are not always available, especially in developing countries. Numerous tests have been developed, but availability of appropriate laboratory support is still a problem. Direct observation of leptospires by darkfield microscopy is unreliable and not recommended. Isolation of leptospires can take up to months and does not contribute to early diagnosis. Diagnosis is usually performed by serology; enzyme-linked immunosorbent assay and the microscopic agglutination tests are the laboratory methods generally used, rapid tests are also available. Limitation of serology is that antibodies are lacking at the acute phase of the disease. In recent years, several real-time polymerase chain reaction assays have been described. These can confirm the diagnosis in the early phase of the disease prior to antibody titers are at detectable levels, but molecular testing is not available in restricted resources areas.