Joint manifolds for data fusion.
The emergence of low-cost sensing architectures for diverse modalities has made it possible to deploy sensor networks that capture a single event from a large number of vantage points and using multiple modalities. In many scenarios, these networks acquire large amounts of very high-dimensional data. For example, even a relatively small network of cameras can generate massive amounts of high-dimensional image and video data. One way to cope with this data deluge is to exploit low-dimensional data models. Manifold models provide a particularly powerful theoretical and algorithmic framework for capturing the structure of data governed by a small number of parameters, as is often the case in a sensor network. However, these models do not typically take into account dependencies among multiple sensors. We thus propose a new joint manifold framework for data ensembles that exploits such dependencies. We show that joint manifold structure can lead to improved performance for a variety of signal processing algorithms for applications including classification and manifold learning. Additionally, recent results concerning random projections of manifolds enable us to formulate a scalable and universal dimensionality reduction scheme that efficiently fuses the data from all sensors.


[Chronic polypharmacy in one-third of the elderly in family practice].
Description of the extent and nature of polypharmacy in the elderly in general practice. Retrospective cross-sectional study. Medication and morbidity data were collected over July-December 1994 on all 2197 patients > or = 65 years registered in 3 family practices connected with the Medication and Morbidity Registration Network Groningen, the Netherlands. Special attention was paid to the simultaneous use of > or = 2 drugs during > or = 120 days in the study period ('chronic use'). Three categories of polypharmacy were distinguished: mild (2-3 drugs), moderate (4-5) and extensive (> 5). Forty per cent of the study group were males; 54% were 65-74 years, 34% were 75-84 years and 12% were > or = 85 years. The mean number of drugs used was 3.9 per person (SD: 3.6), of which 1.4 (SD: 1.8) chronically. Polypharmacy occurred in 35%: mild in 23%, moderate in 8% and extensive in 4%. All occurred mostly in the group between 75 and 84 years old. Cardiovascular drugs, in particular diuretics, and psycholeptics were mostly prescribed concomitantly with each other and with other drugs. The prevalence of concomitant use of drugs with potential interactions was low (< 3%). The indications for psycholeptic drugs were quite often not clear. Congestive heart failure, chronic obstructive pulmonary disease (COPD)/asthma and diabetes mellitus were mainly responsible for extensive polypharmacy.


Emerging partner violence among young adolescents in a low-income country: Perpetration, victimization and adversity.
Intimate partner violence (IPV) is prevalent in high- as well as low-income contexts. It results in a substantial public health burden and significant negative socioeconomic and health outcomes throughout the life-course. However, limited knowledge exists about IPV during early adolescence. This period is critical during the transition to adulthood for at least two reasons: it is when the majority of adolescents in low-income countries first encounter dating, sexuality and partnerships, often with older adolescents or adults, and it is also the period when lifelong patterns of violence and norms about acceptable IPV are formed. The current study is one of the first to measure IPV prevalence among young adolescents in a low-income setting, examine the potential etiology, and investigate relationships with gender ideology, poverty, mental health and childhood adversity. We surveyed 2,089 adolescents aged 10-16 in Malawi using standardized instruments. We estimated the prevalence of IPV, and use multivariate logistic regression to test potential correlates. More than a quarter (27%) of ever-partnered adolescents in Malawi report being victimized. A substantial proportion of both male and female adolescents (15%) report committing violence against their partner. Girls were more likely than boys to report being a victim of sexual IPV (24% versus 8%), and boys more likely to perpetrate such (9% versus 1%). Almost 10% of the sample had both committed and been a victim of IPV. Cumulative childhood adversity (e.g., physical abuse, witnessing domestic violence) was a consistent and strong correlate of IPV victimization (adjusted odds ratio (aOR) 1.30) and of perpetration (aOR 1.35). Depression and PTSD were likewise associated with IPV victimization in the overall sample. Notably, gender ideology was not predictive of either victimization or perpetration, even among boys. IPV is common for both male and female young Malawian adolescents, and includes both victimization and perpetration. IPV compounds other adversities experienced by adolescents in this low-income setting, and it is rarely alleviated through help from the health system or other formal support. These findings underscore the need to intervene early when interventions can still break destructive pathways and help foster healthier relationships. This focus on early adolescence is particularly critical in low-income countries given the early onset and rapid pace of the transition to adulthood, with sexual activity, dating and partnership thus being common already in young adolescence. Promising interventions would be those that reduce violence against or around children, as well as those that reduce the impacts of such trauma on mental health during adolescence.


Cerebral white matter involvement in children with mitochondrial encephalopathies.
In childhood mitochondrial encephalopathies the common MRI features are bilateral symmetric abnormalities in basal nuclei and brainstem. The presence of diffuse white matter abnormality has been described only in a few cases. Among a series of 110 children with mitochondrial encephalopathies, 8 patients with MR imaging consistent with a leukoencephalopathy were retrospectively evaluated. Diagnosis was based on the recognition of the biochemical defect in muscle homogenate. H-MR spectroscopic imaging was performed in six of them. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase deficiency was demonstrated in two patients. MRI showed severe involvement of the brain white matter without significant basal nuclei or brainstem abnormalities. Two patients developed large cystic areas since onset; in two others progressive vacuolisation of affected white matter was seen later in the course of the disease. One patient with pyruvate dehydrogenase deficiency also presented with a diffuse cortical polymicrogyria. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline and creatine with lactate accumulation in five patients, and was normal in one. These findings suggest that mitochondrial disorders should be included in the differential diagnosis of white matter disorders.


A xylosylphosphotransferase of Cryptococcus neoformans acts in protein O-glycan synthesis.
Cryptococcal meningoencephalitis is an AIDS-defining illness caused by the opportunistic pathogen Cryptococcus neoformans. This organism possesses an elaborate polysaccharide capsule that is unique among pathogenic fungi, and the glycobiology of C. neoformans has been a focus of research in the field. The capsule and other cellular glycans and glycoconjugates have been described, but the machinery responsible for their synthesis remains largely unexplored. We recently discovered Xpt1p, an enzyme with the unexpected activity of generating a xylose-phosphate-mannose linkage. We now demonstrate that this novel activity is conserved throughout the C. neoformans species complex, localized to the Golgi apparatus, and functions in the O-glycosylation of proteins. We also present the first survey of O-glycans from C. neoformans.


Causes of death in X chromatin positive males (Klinefelter's syndrome).
The causes of death in 466 X chromatin positive males (Klinefelter's syndrome) studied prospectively over the last 25 years have been analysed. We have previously reported the overall mortality to be increased by 50% and life expectancy reduced by about five years. A highly significant increase in mortality from cerebrovascular disease was observed in the sub group considered to be most representative of X chromatin positive males in general. In the age group up to 45 years this increase could be attributed to deaths from subarachnoid haemorrhage. An increase in mortality from respiratory diseases was observed in those ascertained in psychiatric hospitals. In the sample as a whole there were small but highly significant numbers of deaths from carcinoma of the breast and aortic valve disease. The deaths from carcinoma of the breast were comparable with those expected if female mortality rates were applied.


Cardiovascular risk factors in overweight and obese Chinese children: a comparison of weight-for-height index and BMI as the screening criterion.
Childhood obesity is a widespread and growing problem in the world. Body mass index (BMI) and weight-for-height criterion have been used to determine childhood obesity. No data was available to evaluate cardiovascular risk factors in overweight and obese Chinese children screened by weight-for-height index and Chinese newly developed BMI criterion. To evaluate cardiovascular risk factors in overweight and obese Chinese children by using Chinese BMI and weight-for-height index as screening criterion. A total of 215 children aged 7.5-13 years were recruited from 3 primary schools in Guangzhou, PR China. Measurements included body weight, height, waist and hip circumference, fasting serum glucose, insulin, total triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A (apo A), apolipoprotein B (apo B). Chinese BMI and weight-for- height criterion were used to classify overweight and obesity. According to Chinese BMI criterion, 65 from 108 obese children originally identified by weight-for-height were reclassified as obese and other 41 children were classified as overweight. Compared with non-obese children, obese children screened by Chinese BMI and weight-for-height index had increased levels of TG, LDL-C, apo B, insulin; decreased levels of HDL-C, apo A; and significantly higher prevalence of hypertriglyceridemia and high LDL-C. Children identified as overweight by Chinese BMI criterion had also shown high TG, LDL-C, apo B, insulin levels, low HDL-C, apo A levels, and significantly higher prevalence of hypertriglyceridemia than the normal weight children. Our study reveals that overweight and/or obesity screened by both Chinese new BMI and weight-for-height criterion are associated with increased levels of cardiovascular risk factors (e.g., elevated serum TG, LDL, apo B, and reduced HDL-C, apo A levels). Using Chinese BMI criterion may underestimate the prevalence of childhood obesity but it could be adopted as a unique tool for screening children's overweight in population-based screening programs.


Interactive effects of the GABABergic modulation of calcium channels and calcium-dependent potassium channels in lamprey.
The GABAB-mediated modulation of spinal neurons in the lamprey is investigated in this study. Activation of GABAB receptors reduces calcium currents through both low- (LVA) and high-voltage activated (HVA) calcium channels, which subsequently results in the reduction of the calcium-dependent potassium (KCa) current. This in turn will reduce the peak amplitude of the afterhyperpolarization (AHP). We used the modulatory effects of GABAB receptor activation on N-methyl-D-aspartate (NMDA)-induced, TTX-resistant membrane potential oscillations as an experimental model in which to separate the effects of GABAB receptor activation on LVA calcium channels from that on KCa channels. We show experimentally and by using simulations that a direct effect on LVA calcium channels can account for the effects of GABAB receptor activation on intrinsic membrane potential oscillations to a larger extent than indirect effects mediated via KCa channels. Furthermore, by conducting experiments and simulations on intrinsic membrane potential oscillations, we find that KCa channels may be activated by calcium entering through LVA calcium channels, providing that the decay kinetics of the calcium that enters through LVA calcium channels is not as slow as the calcium entering via NMDA receptors. A combined experimental and computational analysis revealed that the LVA calcium current also contributes to neuronal firing properties.


Operative choledochoscopy in common bile duct surgery.
Surgical exploration of the common bile duct for gallstones is a common operation but carries a high residual stone rate. Conventional techniques for exploring the bile ducts are blind procedures. The surgeon cannot see what he is doing. Also there has been no reliable method for a postexploratory check of the bile ducts before closure, usually around a T-tube. Operative choledochoscopy allows the surgeon to see stones in the duct, may aid the removal of stones and provides visual postexploratory checks that the common bile duct and the hepatic ducts are clear, that papilla is patent and that no stone is left behind before closure. A personal series of 150 patients had operative choledochoscopy using a flexible fibreoptic choledochoscope. If there was a clear indication on preoperative investigations that the ducts should be explored, an operative cholangiogram was omitted and the choledochoscope used as the exploring instrument. In 127 patients with a diagnosis of gallstone disease, choledochoscopy was used at the primary operation. In 12 patients choledochoscopy was used at a secondary operation for recurrent gallstone disease, and 11 patients had malignant obstruction of the biliary tract. In 70 of the 127 patients, gallstones were found and extracted using the choledochoscope. In 53 patients the ducts were clear, and in 4, other lesions were found: 3 papillomas and one polycystic disease. One hundred and six of the patients had the common bile duct closed primarily with no T-tube drainage. There was no increase in complications and no deaths associated with choledochoscopy or primary closure of the common bile duct. There was one case of recurrent stone in the common bile duct presenting six years later. This is a failure rate of 1.4 omicron (O amongst the 70 patients in whom stones were found. Choledochoscopy reduces the incidence of residual common bile duct stone.


Differences in population structure of the anther smut fungus Microbotryum violaceum on two closely related host species, Silene latifolia and S. dioica.
We investigated the genetic population structure of the sexually transmitted plant pathogen, the fungus Microbotryum violaceum, on the two closely related host species Silene latifolia and S. dioica using microsatellite markers. We found strong deviations from Hardy-Weinberg expectations, with significant heterozygote deficiency in almost all populations. Fungal strains from the two host species were differentiated, and these host races differed in amount of variation within populations and differentiation among populations. Anther smut from S. latifolia harboured significantly less microsatellite diversity and were more genetically differentiated from each other than those from S. dioica. Small effective population sizes, rapid population turnover, and less gene flow among populations could lead to this higher population differentiation and lower within population genetic diversity for anther smut populations on S. latifolia than on S. dioica. These results are in concordance with host ecology because S. latifolia grows in more disturbed habitats than S. dioica and may provide a shorter-lived host environment.


Aquaporins in complex tissues: distribution of aquaporins 1-5 in human and rat eye.
Multiple physiological fluid movements are involved in vision. Here we define the cellular and subcellular sites of aquaporin (AQP) water transport proteins in human and rat eyes by immunoblotting, high-resolution immunocytochemistry, and immunoelectron microscopy. AQP3 is abundant in bulbar conjunctival epithelium and glands but is only weakly present in corneal epithelium. In contrast, AQP5 is prominent in corneal epithelium and apical membranes of lacrimal acini. AQP1 is heavily expressed in scleral fibroblasts, corneal endothelium and keratocytes, and endothelium covering the trabecular meshwork and Schlemm's canal. Although AQP1 is plentiful in ciliary nonpigmented epithelium, it is not present in ciliary pigmented epithelium. Posterior and anterior epithelium of the iris and anterior lens epithelium also contain significant amounts of AQP1, but AQP0 (major intrinsic protein of the lens) is expressed in lens fiber cells. Retinal Müller cells and astrocytes exhibit notable concentrations of AQP4, whereas neurons and retinal pigment epithelium do not display aquaporin immunolabeling. These studies demonstrate selective expression of AQP1, AQP3, AQP4, and AQP5 in distinct ocular epithelia, predicting specific roles for each in the complex network through which water movements occur in the eye.


Molecular detection methods of human papillomavirus (HPV).
Human papillomavirus (HPV) testing can identify women at risk of cervical cancer. Currently, molecular detection methods are the gold standard for identification of HPV. The three categories of molecular assays that are available are based on the detection of HPV DNA and include (1) non-amplified hybridization assays, such as Southern transfer hybridization (STH), dot blot hybridization (DB) and in situ hybridization (ISH); (2) signal amplified hybridization assays, such as hybrid capture assays (HC2); (3) target amplification assays, such as polymerase chain reaction (PCR) and in situ PCR. STH requires large amounts of DNA, is laborious and not reproducible, while ISH has only moderate sensitivity for HPV. The sensitivity of the HC2 assay is similar to that of PCR-based assays, with high sensitivity being achieved by signal rather than target amplification. PCR-based detection is both highly sensitive and specific. Since PCR can be performed on very small amounts of DNA, it is ideal for use on specimens with low DNA content. In the future, with the advance of technology, viral DNA extraction and amplification systems will become more rapid, more sensitive, and more automated.


A new wave of urologists? Graduating urology residents' practices of and attitudes toward social media.
Social media (SoMe) have revolutionized healthcare, but physicians remain hesitant to adopt SoMe in their practices. We sought to assess graduating urology residents' practices of and attitudes toward SoMe. A close-ended questionnaire, employing five-point Likert scales, was distributed to all final-year residents (n=100) in Canadian urology training programs in 2012, 2014, and 2016 to assess SoMe usage and perceived usefulness. All (100%) questionnaires were completed. Respondents frequently used online services for personal (100%) and professional (96%) purposes. Most (92%) used SoMe. Many (73%) frequently used SoMe for personal purposes, but few (12%) frequently used SoMe for professional purposes. While a majority (59%) opposed direct patient interaction online, most supported using SoMe to provide patients with static information (76%) and collaborate with colleagues (65%). Many (70-73%) were optimistic that novel solutions to privacy issues in online communications will arise, making SoMe and email contact with patients conceivable. Few (2-8%) were aware and had read guidelines and legislations regarding physician online practices; however, awareness of medical associations' and institutional SoMe policies significantly increased over time (p<0.05). Despite their active online use, graduating urology residents rarely used SoMe in professional settings and were wary of using it in patient care. Nevertheless, they were optimistic toward its integration in urology and supported its use in physician-physician communication. Considering SoMe's increased influence on urology and graduating residents' limited awareness of guidelines and legislations, postgraduate medical educators should encourage residents to become more familiar with current online communication recommendations.


Liver repopulation with bone marrow derived cells improves the metabolic disorder in the Gunn rat.
Reversible ischaemia/reperfusion (I/R) liver injury has been used to induce engraftment and hepatic parenchymal differentiation of exogenous beta2-microglubulin(-)/Thy1(+) bone marrow derived cells. To test the ability of this method of hepatic parenchymal repopulation, theoretically applicable to clinical practice, to correct the metabolic disorder in a rat model of congenital hyperbilirubinaemia. Analysis by confocal laser microscopy of fluorescence labelled cells and by immunohistochemistry for beta2-microglubulin, 72 hours after intraportal delivery, showed engraftment of infused cells in liver parenchyma of rats with I/R, but not in control animals with non-injured liver. Transplantation of bone marrow derived cells obtained from GFP-transgenic rats into Lewis rats resulted in the presence of up to 20% of GFP positive hepatocytes in I/R liver lobes after one month. The repopulation rate was proportional to the number of transplanted cells. Infusion of GFP negative bone marrow derived cells into GFP positive transgenic rats resulted in the appearance of GFP negative hepatocytes, suggesting that the main mechanism underlying parenchymal repopulation was differentiation rather than cell fusion. Transplantation of wild type bone marrow derived cells into hyperbilirubinaemic Gunn rats with deficient bilirubin conjugation after I/R damage resulted in 30% decrease in serum bilirubin, the appearance of bilirubin conjugates in bile, and the expression of normal UDP-glucuronyltransferase enzyme evaluated by polymerase chain reaction. I/R injury induced hepatic parenchymal engraftment and differentiation into hepatocyte-like cells of bone marrow derived cells. Transplantation of bone marrow derived cells from non-affected animals resulted in the partial correction of hyperbilirubinaemia in the Gunn rat.


The Chromatin Environment Around Interneuron Genes in Oligodendrocyte Precursor Cells and Their Potential for Interneuron Reprograming.
Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, arise from neural progenitor cells in the embryonic ganglionic eminences that also generate inhibitory neurons. They are ubiquitously distributed in the central nervous system, remain proliferative through life, and generate oligodendrocytes in both gray and white matter. OPCs exhibit some lineage plasticity, and attempts have been made to reprogram them into neurons, with varying degrees of success. However, little is known about how epigenetic mechanisms affect the ability of OPCs to undergo fate switch and whether OPCs have a unique chromatin environment around neuronal genes that might contribute to their lineage plasticity. Our bioinformatic analysis of histone posttranslational modifications at interneuron genes in OPCs revealed that OPCs had significantly fewer bivalent and repressive histone marks at interneuron genes compared to astrocytes or fibroblasts. Conversely, OPCs had a greater degree of deposition of active histone modifications at bivalently marked interneuron genes than other cell types, and this was correlated with higher expression levels of these genes in OPCs. Furthermore, a significantly higher proportion of interneuron genes in OPCs than in other cell types lacked the histone posttranslational modifications examined. These genes had a moderately high level of expression, suggesting that the "no mark" interneuron genes could be in a transcriptionally "poised" or "transitional" state. Thus, our findings suggest that OPCs have a unique histone code at their interneuron genes that may obviate the need for erasure of repressive marks during their fate switch to inhibitory neurons.


Nuclear export of the yeast hexokinase 2 protein requires the Xpo1 (Crm1)-dependent pathway.
Hexokinase 2 (Hxk2) from Saccharomyces cerevisiae was one of the first metabolic enzymes described as a multifunctional protein. Hxk2 has a double subcellular localization; it functions as a glycolytic enzyme in the cytoplasm and as a regulator of gene transcription of several Mig1-regulated genes in the nucleus. However, the mechanism by which Hxk2 enters and leaves the nucleus is still unknown. In low glucose conditions, Hxk2 is phosphorylated at serine 14, but how this phosphorylation may affect glucose signaling is also unknown at the moment. Here we report that the Hxk2 protein is an export substrate of the carrier protein Xpo1 (Crm1). We also show that the Hxk2 nuclear export and the binding of Hxk2 and Xpo1 involve two leucine-rich nuclear export signals (NES) located between leucine 23 and isoleucine 33 (NES1) and between leucine 310 and leucine 318 (NES2). We also show that the Hxk2 phosphorylation at serine 14 promotes Hxk2 export by facilitating the association of Hxk2 with Xpo1. Our study uncovers a new cargo for the Xpo1 yeast exportin and identifies Hxk2 phosphorylation at serine 14 as a regulatory mechanism that controls its nuclear exit in function of the glucose levels.


HOME VISIT QUALITY VARIATIONS IN TWO EARLY HEAD START PROGRAMS IN RELATION TO PARENTING AND CHILD VOCABULARY OUTCOMES.
Home-visiting programs aiming to improve early child development have demonstrated positive outcomes, but processes within home visits to individual families are rarely documented. We examined family-level variations in the home-visiting process (N = 71) from extant video recordings of home visits in two Early Head Start programs, using an observational measure of research-based quality indicators of home-visiting practices and family engagement, the Home Visit Rating Scales (HOVRS). HOVRS scores, showing good interrater agreement and internal consistency, were significantly associated with parent- and staff-reported positive characteristics of home visiting as well as with parenting and child language outcomes tested at program exit. When home-visiting processes were higher quality during the program, home visit content was more focused on child development, families were more involved in the overall program, and most important, scores on measures of the parenting environment and children's vocabulary were higher at the end of the program. Results showed that home visit quality was indirectly associated with child language outcomes through parenting outcomes. Observation ratings of home visit quality could be useful for guiding program improvement, supporting professional development, and increasing our understanding of the links between home-visiting processes and outcomes.


Combining fish and environmental PCR for diagnostics of diseased laboratory zebrafish in recirculating systems.
Precise knowledge of the health status of experimental fish is crucial to obtain high scientific and ethical standards in biomedical research. In addition to the use of sentinel fish, the examination of diseased fish is a fundamental part of all health monitoring concepts. PCR assays offer excellent sensitivity and the ability to test a broad variety of pathogenic agents in different sample types. Recently, it was shown that analysis of environmental samples such as water, sludge or detritus from static tanks can complement PCR analysis of fish and is actually more reliable for certain pathogens. In our study, we investigated whether the analysis of filtered water mixed with detritus of tanks including fish showing clinical signs of illness is suitable to complement health monitoring programs in recirculating systems. The obtained data indicate that pathogens such as Pseudoloma neurophilia or Myxidium streisingeri were exclusively or mainly found in fish, while mycobacteria were predominantly present in environmental samples. A combination of both sample types seems to be required for the detection of a broad range of infectious agents in zebrafish colonies using real-time PCR technology.


CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy.
Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I- (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8+ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4+ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4+ T cell-specific neoantigens for personalized cancer vaccine modalities.


Non-invasive diagnostic work-up of patients with clinically suspected pulmonary embolism; results of a management study.
Clinicians often deviate from the recommended algorithm for the diagnosis of pulmonary embolism consisting of ventilation-perfusion scintigraphy and pulmonary angiography. To assess the safety and feasibility of a diagnostic algorithm which reduces the need for lung scintigraphy and avoids the use of angiography. Consecutive patients with a clinical suspicion of pulmonary embolism were prospectively investigated according to an algorithm in which the diagnosis of pulmonary embolism was excluded after a low clinical probability estimate and a normal d-dimer test result, a normal perfusion scintigraphy result, or a non-high probability scintigraphy result in combination with normal serial ultrasonography of the legs. In these patients anticoagulant treatment was withheld and they were followed up for 3 months to record possible thromboembolic events. During the study period, 923 consecutive patients were seen, of whom 292 were excluded because of predefined criteria. Of the 631 included patients, the diagnosis was refuted on the basis of a low clinical probability estimate and a normal d-dimer test result (95 patients), normal perfusion scintigraphy (161 patients) and non-high probability lung scintigraphy followed by normal serial ultrasonography (210 patients). Of these 466 patients, venous thromboembolic complications during follow-up occurred in six (complication rate 1.3%, 95% confidence interval 0.5, 2.8). The diagnostic protocol was completed in 92% of all included patients. The diagnosis of pulmonary embolism can be safely ruled out by a non-invasive algorithm consisting of d-dimer testing combined with a clinical probability estimate, lung scintigraphy, or serial ultrasonography of the legs (in case of non-diagnostic lung scintigraphy).


The Asheville Project: participants' perceptions of factors contributing to the success of a patient self-management diabetes program.
To ascertain patients', providers', and managers' perceptions of the factors that contributed to the success of the Asheville Project. One-time focus groups of patients and diabetes care providers and individual interviews with managers involved in the project. The City of Asheville and Mission-St. Joseph's Health System (MSJ), Asheville, N.C. Twenty-one patients with diabetes who were employees of the two self-insured employers participating in the Asheville Project; four specially trained pharmacists who provided diabetes-related pharmaceutical care and one diabetes educator, all of whom received reimbursement for their services; six managers employed by the City of Asheville or MSJ who were involved in the project. A trained facilitator conducted four focus groups and six manager interviews in September 2001. Each session lasted 60 to 90 minutes, and the facilitator used a standard list of open-ended questions. The focus group sessions were recorded for subsequent analysis. Perceptions of focus group participants and managers of how the Asheville Project enabled patients with diabetes to become more responsible and successful in self-managing their condition. Focus group participants and managers were enthusiastic about their experiences with the project. Patients valued the relationships they established with their pharmacist or diabetes educator; as a result of these providers' support, patients felt more in control of their lives and were healthier. The waived co-payments for diabetes medications and related supplies was the decisive incentive for getting many patients to enroll in the project. For the providers, the project was a source of professional growth and satisfaction. Managers felt the project helped them fulfill their health care responsibilities to their employees, reduced overall costs, enhanced their organizations' reputations in health care delivery, and resulted in less absenteeism. Patients, providers, and managers in the Asheville Project believed that aligned incentives and community-based resources that provide health care services to patients with diabetes offer a practical, patient-empowering, and cost-effective solution to escalating health care costs.


Tracheostomy in COVID-19 acute respiratory distress syndrome patients and follow-up: A parisian bicentric retrospective cohort.
Tracheostomy has been proposed as an option to help organize the healthcare system to face the unprecedented number of patients hospitalized for a COVID-19-related acute respiratory distress syndrome (ARDS) in intensive care units (ICU). It is, however, considered a particularly high-risk procedure for contamination. This paper aims to provide our experience in performing tracheostomies on COVID-19 critically ill patients during the pandemic and its long-term local complications. We performed a retrospective analysis of prospectively collected data of patients tracheostomized for a COVID-19-related ARDS in two university hospitals in the Paris region between January 27th (date of first COVID-19 admission) and May 18th, 2020 (date of last tracheostomy performed). We focused on tracheostomy technique (percutaneous versus surgical), timing (early versus late) and late complications. Forty-eight tracheostomies were performed with an equal division between surgical and percutaneous techniques. There was no difference in patients' characteristics between surgical and percutaneous groups. Tracheostomy was performed after a median of 17 [12-22] days of mechanical ventilation (MV), with 10 patients in the "early" group (≤ day 10) and 38 patients in the "late" group (> day 10). Survivors required MV for a median of 32 [22-41] days and were ultimately decannulated with a median of 21 [15-34] days spent on cannula. Patients in the early group had shorter ICU and hospital stays (respectively 15 [12-19] versus 35 [25-47] days; p = 0.002, and 21 [16-28] versus 54 [35-72] days; p = 0.002) and spent less time on MV (respectively 17 [14-20] and 35 [27-43] days; p<0.001). Interestingly, patients in the percutaneous group had shorter hospital and rehabilitation center stays (respectively 44 [34-81] versus 92 [61-118] days; p = 0.012, and 24 [11-38] versus 45 [22-71] days; p = 0.045). Of the 30 (67%) patients examined by a head and neck surgeon, 17 (57%) had complications with unilateral laryngeal palsy (n = 5) being the most prevalent. Tracheostomy seems to be a safe procedure that could help ICU organization by delegating work to a separate team and favoring patient turnover by allowing faster transfer to step-down units. Following guidelines alone was found sufficient to prevent the risk of aerosolization and contamination of healthcare professionals.


Technical Note: Procedure for the calibration and validation of kilo-voltage cone-beam CT models.
The aim of this work is to propose a general and simple procedure for the calibration and validation of kilo-voltage cone-beam CT (kV CBCT) models against experimental data. The calibration and validation of the CT model is a two-step procedure: the source model then the detector model. The source is described by the direction dependent photon energy spectrum at each voltage while the detector is described by the pixel intensity value as a function of the direction and the energy of incident photons. The measurements for the source consist of a series of dose measurements in air performed at each voltage with varying filter thicknesses and materials in front of the x-ray tube. The measurements for the detector are acquisitions of projection images using the same filters and several tube voltages. The proposed procedure has been applied to calibrate and assess the accuracy of simple models of the source and the detector of three commercial kV CBCT units. If the CBCT system models had been calibrated differently, the current procedure would have been exclusively used to validate the models. Several high-purity attenuation filters of aluminum, copper, and silver combined with a dosimeter which is sensitive to the range of voltages of interest were used. A sensitivity analysis of the model has also been conducted for each parameter of the source and the detector models. Average deviations between experimental and theoretical dose values are below 1.5% after calibration for the three x-ray sources. The predicted energy deposited in the detector agrees with experimental data within 4% for all imaging systems. The authors developed and applied an experimental procedure to calibrate and validate any model of the source and the detector of a CBCT unit. The present protocol has been successfully applied to three x-ray imaging systems. The minimum requirements in terms of material and equipment would make its implementation suitable in most clinical environments.


[Significance of parasitic blood supply in malignant retroperitoneal tumours (author's transl)].
Twenty-one neoplastic retroperitoneal tumours- in particular Wilm's tumours and neuroblastomas of the suprarenal glands in children - are analyzed angiographically and the significance of the parasitic blood supply evaluated. More than half of the tumours had penetrating or perforating vessels, but in only 50% there were operative and histologic signs of tumour spread into neighbouring structures. The remaining tumours had vascular adhesions. A hint may be the demarcation and the slight vascularity of the tumours. The value of the presence of penetrating or perforating vessels must not be overestimated regarding the spread of the tumour and inoperability.


Asymptomatic primary biliary cirrhosis is not associated with increased frequency of cardiovascular disease.
To estimate the prevalence of cardiovascular events in Primary biliary cirrhosis (PBC) and to determine whether this risk is higher within specific subgroups of patients with PBC. We included 180 patients with PBC (cases) and 151 patients seen for HCV infection (controls). Medical records were reviewed and statistical analyses were performed as appropriate. When compared to controls, PBC patients were older, leaner and had higher serum levels of total cholesterol, high density lipoprotein and low density cholesterol. There were more females in the PBC group (91.7% vs 43%, P < 0.001). More control subjects had smoked than the PBC patients (63.6% vs 35%, P < 0.001). The prevalence of hypertension, diabetes, coronary artery disease and stroke was similar between the two groups. Seven percent of controls and 10% of cases developed any type of cardiovascular disease (P = 0.3). Only 36.7% were asymptomatic at diagnosis. Three cardiovascular events were documented among asymptomatic patients (4.5%) and fifteen among symptomatic patients (13.2%; P = 0.06). Among PBC patients with fatigue, 10 (13.5%) had a cardiovascular event compared to 7 (6.7%) among patients without fatigue (P = 0.1). Asymptomatic PBC patients do not have a greater frequency of cardiovascular disease; nor do patients suffering with fatigue.


Patterns and trends in sources of information about sex among young people in Britain: evidence from three National Surveys of Sexual Attitudes and Lifestyles.
To assess progress in meeting young people's sex education needs in Britain by examining the current situation and changes over the past 20 years in sources of information about sexual matters and unmet information needs. Cross-sectional probability sample surveys. British general population. 3869 men and women aged 16-24 years, interviewed 2010-2012 for the third National Survey of Sexual Attitudes & Lifestyles (Natsal-3), compared with 16-24 year-olds in Natsal-1 (1990-1991; 792 men and women) and Natsal-2 (1999-2001; 2673 men and women). Reported source of information about sexual matters, unmet information needs and preferred source of additional information. Between 1990 and 2012, the proportion citing school lessons as their main source of information about sexual matters increased from 28.2% (95% CI 24.6 to 32.1) to 40.3% (95% CI 38.6 to 42.1). In 2010-2012, parents were reported as a main source by only 7.1% (95% CI 5.8 to 8.7) of men and 14.1% (95% CI 12.6 to 15.7) of women and, for women, were less commonly reported than in 1999-2001 (21.7%; 95% CI 19.6 to 24.0). Most young people reported not knowing enough when they first felt ready for sexual experience (68.1% men, 70.6% women), and this did not change substantially over time. They wanted more information about psychosexual matters (41.6% men, 46.8% women), as well as sexually transmitted infections (27.8% men, 29.8% women) and, for women, contraception (27.5%). Young people primarily wanted this information from school, parents or health professionals. Over the past 20 years, young people have increasingly identified school lessons as their main source of information about sex, although they continue to report needing more information on a broad range of topics. The findings support the expressed need for improved sex and relationships education in schools alongside greater involvement of parents and health professionals.


Listening to Relaxing Music Improves Physiological Responses in Premature Infants: A Randomized Controlled Trial.
Premature infants are exposed to high levels of noise in the neonatal intensive care unit (NICU). This study evaluated the effect of a relaxing music therapy intervention composed by artificial intelligence on respiratory rate, systolic and diastolic blood pressure, and heart rate. A double-blind, randomized, controlled trial was conducted in the NICUs of 2 general public hospitals in Andalusia, Spain. Participants were 17 healthy premature infants, randomly allocated to the intervention group or the control group (silence) at a 1:1 ratio. To be included in the study, the subjects were to be 32 to 36 weeks of gestation at birth (M= 32.33; SD = 1.79) and passed a hearing screening test satisfactorily. The intervention lasted 20 minutes, 3 times a day for 3 consecutive days, while infants were in the incubator. Infants' heart rate, respiratory rate, and blood pressure were assessed before and after each intervention session. After each session, the respiratory rate decreased in the experimental group (main between-groups effect (F1,13 = 6.73, P = .022, ηpartial = 0.34). Across the sessions, the heart rate increased in the control group (main between-groups effect, F1,11 = 5.09, P = .045, ηpartial = 0.32). Future studies can use this music intervention to assess its potential effects in premature infants. Nurses can apply the relaxing music intervention presented in this study to ameliorate the impact of the stressful environment on premature infants.


Cytokine production (IL-1 alpha, IL-1 beta, and TNF alpha) and endothelial cell activation (ELAM-1 and HLA-DR) in reactive lymphadenitis, Hodgkin's disease, and in non-Hodgkin's lymphomas. An immunocytochemical study.
Cryostat sections of 58 lymph nodes were immunostained with a polyclonal rabbit serum against IL-1 alpha, and with monoclonal antibodies directed to IL-1 alpha (Vmp18), IL-1 beta (Vhp20 and BRhC3), and tumor necrosis factor alpha (TNF alpha) (B154.7). Furthermore the presence of cytokine-containing cells was correlated with the expression of endothelial leukocyte adhesion molecule (ELAM-1; 29F2) and of human leukocyte antigen (HLA-DR) (OKIa-1) by endothelial cells. Cells containing IL-1 and/or TNF alpha were detected mainly in pathologic conditions characterized by reactive or neoplastic expansion of the lymph node paracortex. Cells positive for IL-1 were detected in 16 of 21 cases of Hodgkin's disease, in 4 of 4 cases of T-NHL, and in 5 cases of diffuse or mixed lymphadenitis. Interleukin-1 alpha was detected in macrophages, interdigitating reticulum cells (IDRCs), endothelial cells, and neoplastic Hodgkin's and Reed-Sternberg (H-RS) cells. Cells positive for IL-1 beta were much fewer and consisted mainly of macrophages. Hodgkin's Reed-Sternberg cells were negative for IL-1 beta even after in vitro stimulation with bacterial endotoxin. Tumor necrosis factor alpha (TNF alpha) was present in macrophages and H-RS cells. Endothelial leukocyte adhesion molecule-1 expression by endothelial venules was detected in 17 of 20 cases of Hodgkin's disease, in 2 of 4 cases of T-NHL, and in 5 of 5 cases of diffuse lymphadenitis. In these pathologic conditions, HLA-DR antigens also were expressed frequently by endothelial cells. Cytokine-containing cells and ELAM-1-positive high endothelial venules (HEV) were extremely rare in lymph nodes involved by follicular lymphadenitis (12 cases) or B-NHL (16 cases). In cases of reactive or neoplastic B-cell proliferations, HLA-DR-positive HEVs still were present often. Our results indicate that IL-1/TNF alpha production at tissue level is often associated with ELAM-1 expression by HEVs, but is less well correlated with expression of HLA-DR antigens by endothelial cells.


Achilles Tendon Adaptation During Transition to a Minimalist Running Style.
Achilles tendons (ATs) adapt to increased loading generated by long-term adoption of a minimalist shoe running style. There may be difference in the chronology and extent of adaptation between the sexes. To learn the chronology of AT adaptations in female and male runners who transitioned to a minimalist running style through a planned, progressive 12-wk transition program. Prospective cohort study of well-trained, traditionally shod runners who transitioned to minimalist shoe running. Repeated laboratory assessment at baseline and 3, 12, and 24 wk after initiating transition program. Fifteen women and 7 men (of 29 enrolled) completed the study. The authors used diagnostic ultrasound and isokinetic dynamometry to generate a force elongation curve and its derivatives at each time point. Greater adaptations were observed in men than in women, with men generating more force and having greater increases in CSA, stiffness, and Young's modulus and less elongation after 12 wk of training. Men demonstrated changes in AT properties that were consistent with increased loading of the triceps surae during exercise. The women demonstrated far smaller changes. Further investigation is warranted to understand when adaptations may occur in women and the implications of altered AT mechanical properties for performance and injury risk.


Improvement of 2'-hydroxybiphenyl-2-sulfinate desulfinase, an enzyme involved in the dibenzothiophene desulfurization pathway, from Rhodococcus erythropolis KA2-5-1 by site-directed mutagenesis.
In the microbial dibenzothiophene desulfurization pathway, 2'-hydroxybiphenyl-2-sulfinate is converted to 2-hydroxybiphenyl and sulfinate by desulfinase (DszB) at the last step, and this reaction is rate-limiting for the whole pathway. The catalytic activity and thermostability of DszB were enhanced by the two amino acid substitutions. Based on information on the 3-D structure of DszB and a comparison of amino acid sequences between DszB and reported thermophilic and thermostable homologs (TdsB and BdsB), two amino acid residues, Tyr63 and Gln65, were selected as targets to mutate and improve DszB. These two residues were replaced by several amino acids, and the promising mutant enzymes were purified and their properties were examined. Among the wild-type and mutant enzymes, Y63F had higher catalytic activity but similar thermostability, and Q65H showed higher thermostability but less catalytic activity and affinity for the substrate. To compensate for these drawbacks, the double mutant enzyme Y63F-Q65H was purified and its properties were investigated. This mutant enzyme showed higher thermostability without loss of catalytic activity or affinity for the substrate. These superior properties of the mutant enzyme have also been confirmed with resting cells harboring the mutant gene.


Time course of inhibition and facilitation in patients with schizophrenia.
Negative priming (NP) paradigms have been used extensively to understand the nature and time course of inhibitory deficits in patient populations. A majority of these studies have reported abnormal NP effects, with patients showing faster reaction times on NP sequences compared to the slowing displayed by controls. A Stroop NP task was employed to measure immediate (within-trial) attentional processing as well as the sustainment (between-trial) of these processes in 12 medicated schizophrenia inpatients and 13 matched controls. Two response stimulus intervals (RSIs) were presented (500 ms and 2000 ms). Within-trial Stroop effects (interference and facilitation) and between-trial priming effects (negative and positive priming) were measured. Clinical symptomatology and duration of illness were also examined. At short RSIs of 500 ms, chronically ill state hospital schizophrenia patients failed to exhibit NP. In contrast, the control subjects exhibited normal NP at the short RSI but this priming faded at the long 2000 ms RSI and was no longer significant. The facilitatory priming effects remained stable across time in both groups. These results suggest that schizophrenia patients are better able to inhibit irrelevant stimuli that are immediate, but the sustainment of inhibition across very short time intervals (500 ms) may fade compared to controls.


Eribulin in metastatic breast cancer: Real world data.
Metastatic breast cancer (MBC) is incurable. Systemic therapy is the standard treatment; however, an optimal sequence of chemotherapy has not been established. Evaluating effectiveness and safety of eribulin in MBC treatment and comparing the results obtained with published literature. Observational, descriptive and retrospective study of patients with MBC treated with eribulin from 01/12/2015 to 30/10/2021. Effectiveness was analysed using Kaplan-Meier-survival-curves, for the overall number of patients treated and stratified by treatment line. Safety was measured according to adverse events (AE) based on CTCAE v5.0. Data analysis was performed using R v4.0.1. They were included in this study 53 women who received eribulin (median age 58 years). Comparison of median survival from this study versus published data were: progression-free-survival (PFS) 3 (IC95%: 3-4) versus 3.7 months and overall-survival (OS) 8 (IC95%: 3-4) versus 13.2 months for the overall number of patients. For the 1-3 line treatment group, PFS was 6 (IC95%: 3-NA) and OS was 15 (IC95%: 6-NA). There were 322 AEs, the most frequent being blood disorders 16% (52), general disorders 12% (38), and gastrointestinal disorders 12% (38). The median PFS was similar to that reported previously, with lower OS. There was a tendency to achieve better results when eribulin was used earlier. Eribulin is a less well-tolerated drug than published literature.


The molecular basis for distinct pathways for protein import into Arabidopsis chloroplasts.
The translocons at the outer envelope membrane of chloroplasts (TOCs) initiate the import of thousands of nucleus-encoded proteins into the organelle. The identification of structurally and functionally distinct TOC complexes has led to the hypothesis that the translocons constitute different import pathways that are required to coordinate the import of sets of proteins whose expression varies in response to organelle biogenesis and physiological adaptation. To test this hypothesis, we examined the molecular basis for distinct TOC pathways by analyzing the functional diversification among the Toc159 family of TOC receptors. We demonstrate that the N-terminal A-domains of the Toc159 receptors regulate their selectivity for preprotein binding. Furthermore, the in vivo function of the two major Toc159 family members (atToc159 and atToc132) can be largely switched by swapping their A-domains in transgenic Arabidopsis thaliana. On the basis of these results, we propose that the A-domains of the Toc159 receptors are major determinants of distinct pathways for protein import into chloroplasts.


Technology, medicine & health, Part 2. The dilemmas of diagnostic certainty.
In Part 1 of this series we discussed how it is that our new understandings of biology at the molecular level are revealing to us unexpected complexities in those processes labeled as diseases. Here in Part 2 we examine some remarkable ultra-sensitive tools with which it is becoming feasible to clarify these complexities with degrees of certainty heretofore regarded as impossible.


A Comparative Assessment of Postoperative Analgesic Efficacy of Lornoxicam versus Tramadol after Open Reduction and Internal Fixation of Mandibular Fractures.
Pain after any surgical procedure is inevitable but can be controlled by administration of analgesics in most cases. Postoperative pain after surgical treatment of mandibular fractures can be treated by nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics. The purpose of this study is to critically compare the postoperative analgesic efficacy of small doses of intravenous TRAMADOL (opioid analgesic) versus LORNOXICAM (NSAID) in patients with mandibular trauma undergoing open reduction and internal fixation (ORIF) and to assess the presence of any adverse effects due to NSAID or opioid use. Forty adult ASA grade I-II patients with mandibular trauma, scheduled for ORIF under general anesthesia in the Department of Oral and Maxillofacial Surgery, College of Dental Sciences, Davangere, were selected for the study. The patients were randomly assigned into a tramadol group (Group T) and a lornoxicam group (Group L) and were administered intravenous tramadol 50 mg and intravenous lornoxicam 8 mg, respectively, at specific postoperative intervals. Pain intensity was quantitatively assessed at the 2nd, 4th, 6th, 12th, and 24th postoperative hours using a visual analog scale of 10 cm. Adverse effects of the analgesics were also recorded and compared. Both the drugs resulted in a significant decrease in pain intensity from 2nd to 24th postoperative hours, but better pain control was observed in Group L at 24th postoperative hour. Only two patients experienced nausea and vomiting in Group T and one patient experienced gastric acidity in Group L. The comparative results clearly demonstrate that pain control by intravenous lornoxicam is significantly better than by intravenous tramadol at 24th postoperative hour after ORIF of mandibular trauma. Side effects produced by both the drugs were minor and had no apparent effect on the study results.


Prolactin regulation in 14 cases of galactorrhea and hypogonadism with minimal modifications of the sella turcica (author's transl).
In this study we report 13 cases of amenorrhea-galactorrhea and one of a male patient complaining of gynecomastia, galactorrhea, sexual impotence and sterility with oligoasthénospermy. In these cases, the size of the sella turcica was normal but we found a localized depression of the bottom of the sella turcica; these modifications were situated at the antero-inferior part of the sella in 12 cases and posteriorly in the 2 others. Basal prolactin level was higher than normal values in 13 cases (12 female and 1 male patients): individual values varied between 45 and 367 ng/ml. Nycthermeral rhythm disappeared in the 9 cases studied. Administration of L-Dopa (500 mg orally) significantly suppressed the prolactin values in the 11 cases studied. Oral water loading (20 ml/kg) left prolactin values unchanged (10 cases). After oral glucose tolerance test (1 g/kg) no significant systematic variation occurred. The increase of prolactin values after stimulation by 200 microg. TRH IV as a bolus (4 cases) was not significant. We have found similar prolactin variations in cases of hyperprolactinemia with either normal pituitary fossa (7 cases) or macro-adenoma (6 cases).


An integrated phenol 'sensoremoval' microfluidic nanostructured platform.
Phenol is a widely used chemical that for several reasons may be released into the environment and, consequently, its detection and subsequent destruction into the ground and surface waters are of special importance. Herein, a simple lab-on-a-chip (LOC) device based on biocompatible and biodegradable CaCO3- poly(ethyleneimine) (PEI) nanostructured microparticles (MPs) to detect and remove phenolic wastes is proposed. The detection of phenol using a hybrid polydimethylsiloxane (PDMS)/glass chronoimpedimetric microchip and its removal in the same LOC system through the use of an extra CaCO3-PEI MPs microcolumn is achieved. For the first time, the chronoimpedance technique is applied in a LOC system for phenol sensing in a range of 0.01-10 µM achieving the limit of detection (LOD) of 4.64 nM. Moreover, this device shows a high repeatability with a relative standard deviation of 3% which is almost 4 times lower than that for the chronoamperometry technique. This LOC system represents an integrated platform for phenol sensing and removal (sensoremoval) that can be easily fabricated and is of a low cost, disposable and amenable to mass production.


A General Protocol for the Polycondensation of Thienyl N-Methyliminodiacetic Acid Boronate Esters To Form High Molecular Weight Copolymers.
Thienyl di-N-methyliminodiacetic acid (MIDA) boronate esters are readily synthesized by electrophilic C-H borylation producing bench stable crystalline solids in good yield and excellent purity. Optimal conditions for the slow release of the boronic acid using KOH as the base in biphasic THF/water mixtures enables the thienyl MIDA boronate esters to be extremely effective homo-bifunctionalized (AA-type) monomers in Suzuki-Miyaura copolymerizations with dibromo-heteroarenes (BB-type monomers). A single polymerization protocol is applicable for the formation of five alternating thienyl copolymers that are (or are close analogues of) state of the art materials used in organic electronics. The five polymers were produced in excellent yields and with high molecular weights comparable to those produced using Stille copolymerization protocols. Therefore, thienyl di-MIDA boronate esters represent bench stable and low toxicity alternatives to highly toxic di-trimethylstannyl AA-type monomers that are currently ubiquitous in the synthesis of these important alternating copolymers.


Color signaling in conspicuous red sticklebacks: do ultraviolet signals surpass others?
The use of ultraviolet (UV) signals for communication tasks is widespread in vertebrates. For instance, there is a UV component to mate choice in several species. Nevertheless, it remains unclear how the signal value of the UV wave band compares to that of other regions of the animal's visible spectrum. We investigated the relative importance of UV signals compared with signals of longer wavelengths in the threespine stickleback (Gasterosteus aculeatus), a species using UV wavelengths in female and male mate choice as well as in shoaling behavior. In a choice experiment, female sticklebacks were simultaneously presented with four male visual appearances manipulated by optical filters. Each male lacked one wavelength range of the stickleback's visible spectrum corresponding to the spectral sensitivities of the four cone types. The resulting male appearances thus had no UV (UV-), no short-wave (SW-), no medium-wave (MW-) or no long-wave (LW-) body reflectance. Males without UV wavelengths and long wavelengths ("red") were least preferred. In contrast, the removal of medium and most notably short wavelengths left male attractiveness to females rather unaffected. Using color metrics, the effects of the four optical filters on stickleback perception of three male body regions were illustrated as quantal catches calculated for the four single cones. The removal of UV light (UV-) considerably reduced visual attractiveness of courting males to female three-spined sticklebacks particularly in comparison to the removal of short-wave light (SW-). We thus report first experimental evidence that the UV wave band clearly outranks at least one other part of an animal's visible spectrum (SW-) in the context of communication. In addition, females were also less attracted to males presented without long wavelengths (LW-) which supports the traditionally considered strong influence of the red color component on stickleback mate choice. Overall, the removal of medium wavelengths (MW-) and especially short (SW-) left male attractiveness for females rather unaffected. Our work suggests that, in addition to long wavelengths ("red"), the UV wave band contains important information for visual mate choice in sticklebacks. Hence, the previously suggested exclusive role of the characteristic red nuptial coloration in visual interactions between reproductively active stickleback conspecifics may be overestimated with UV wavelengths playing a more important role than previously suggested.


Functional significance of MMP-9 in tumor necrosis factor-induced proliferation and branching morphogenesis of mammary epithelial cells.
Tissue remodeling is a key process involved in normal mammary gland development, with matrix metalloproteinases (MMPs) playing an important role in this process. Our laboratory has demonstrated that tumor necrosis factor (TNF) stimulates branching morphogenesis of mammary epithelial cells (MEC) within a reconstituted basement membrane. Studies were therefore undertaken to determine whether MMPs might mediate the effects of TNF. Using a primary culture model in which rat MEC grow three-dimensionally within a reconstituted basement membrane, we found that TNF stimulated secretion of MMP-9 but not MMP-2. To determine whether MMP-9 was involved in TNF-induced proliferation and branching morphogenesis, we used a peptide containing the prodomain sequence of MMPs and two MMP inhibitors. Both the prodomain peptide (5 x 10(-4)-10(-3) M), as well as BB-94 (10(-8)-10(-5) M) and CGS 27023A (10(-6)-10(-5) M), inhibited TNF-induced proliferation and branching morphogenesis in a concentration-dependent manner. Finally, to verify the specific requirement for MMP-9, we demonstrated that an MMP-9 neutralizing antibody blocked TNF-induced proliferation and branching morphogenesis. Together, these data suggest that TNF-regulated MMP-9 may play a role in the controlled invasion of the fad pad that occurs during normal mammary gland development and that misregulation of MMP-9 may contribute to the invasiveness of breast cancer.


Psychological interventions for cystic fibrosis.
As survival estimates for cystic fibrosis (CF) steadily increase long-term management has become an important focus for intervention. Psychological interventions are largely concerned with emotional and social adjustments, adherence to treatment and quality of life, however no systematic review of such interventions has been undertaken for this disease. To describe the extent and quality of effectiveness studies utilising psychological interventions for CF and whether these interventions provide significant psychosocial and physical benefits in addition to standard care. Relevant trials were identified from searches of Ovid MEDLINE, the Cochrane trial registers for CF and Depression, Anxiety and Neurosis Groups and PsychINFO; unpublished trials were located through professional networks and Listserves. Most recent search: April 2003. This review included RCTs and quasi-randomised trials. Study participants were children and adults diagnosed with CF, and their immediate family members. Psychological interventions were from a broad range of modalities and outcomes were primarily psychosocial, although physical outcomes and cost effectiveness were also considered. Two reviewers independently selected relevant trials and assessed their methodological quality. For binary and continuous outcomes a pooled estimate of treatment effect was calculated for each outcome. This review is based on the findings of eight studies, representing data from a total of 358 participants. Studies fell into four conceptually similar groups: (1) gene pre-test education counselling for relatives of those with CF (one study); (2) biofeedback, massage and music therapy to assist physiotherapy (three studies); (3) behavioural intervention to improve dietary intake in children up to 12 years (three studies); and (4) self-administration of treatments to improve quality of life in adults (one study). Interventions were largely educational or behavioural, targeted at specific treatment concerns during the chronic phase. No completed studies concentrating on complex treatment approaches were found. There is some evidence that behavioural interventions can improve emotional outcomes in people with CF and their carers. There was no consistent effect on lung function although one small study showed that biofeedback assisted breathing re-training was associated with improvement in some measures of spirometric lung function. Insufficient evidence is available at this point for interventions aimed at other aspects of the disease process. Multicentre approaches are required to increase the sample sizes of studies in the psychosocial field and to enhance the power and precision of the findings. This has consequent implications for funding.


Surveillance for traumatic brain injury-related deaths--United States, 1997-2007.
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Approximately 53,000 persons die from TBI-related injuries annually. During 1989-1998, TBI-related death rates decreased 11.4%, from 21.9 to 19.4 per 100,000 population. This report describes the epidemiology and annual rates of TBI-related deaths during 1997-2007. January 1, 1997-December 31, 2007. Data were analyzed from the CDC multiple-cause-of-death public-use data files, which contain death certificate data from all 50 states and the District of Columbia. During 1997-2007, an annual average of 53,014 deaths (18.4 per 100,000 population; range: 17.8-19.3) among U.S. residents were associated with TBIs. During this period, death rates decreased 8.2%, from 19.3 to 17.8 per 100,000 population (p = 0.001). TBI-related death rates decreased significantly among persons aged 0-44 years and increased significantly among those aged ≥75 years. The rate of TBI deaths was three times higher among males (28.8 per 100,000 population) than among females (9.1). Among males, rates were highest among non-Hispanic American Indian/Alaska Natives (41.3 per 100,000 population) and lowest among Hispanics (22.7). Firearm- (34.8%), motor-vehicle- (31.4%), and fall-related TBIs (16.7%) were the leading causes of TBI-related death. Firearm-related death rates were highest among persons aged 15-34 years (8.5 per 100,000 population) and ≥75 years (10.5). Motor vehicle-related death rates were highest among those aged 15-24 years (11.9 per 100,000 population). Fall-related death rates were highest among adults aged ≥75 years (29.8 per 100,000 population). Overall, the rates for all causes except falls decreased. Although the overall rate of TBI-related deaths decreased during 1997-2007, TBI remains a public health problem; approximately 580,000 persons died with TBI-related diagnoses during this reporting period in the United States. Rates of TBI-related deaths were higher among young and older adults and certain minority populations. The leading external causes of this condition were incidents related to firearms, motor vehicle traffic, and falls. Accurate, timely, and comprehensive surveillance data are necessary to better understand and prevent TBI-related deaths in the United States. CDC multiple-cause-of-death public-use data files can be used to monitor the incidence of TBI-related deaths and assist public health practitioners and partners in the development, implementation, and evaluation of programs and policies to reduce and prevent TBI-related deaths in the United States. Rates of TBI-related deaths are higher in certain population groups and are primarily related to specific external causes. Better enforcement of existing seat belt laws, implementation and increased coverage of more stringent helmet laws, and the implementation of existing evidence-based fall-related prevention interventions are examples of interventions that can reduce the incidence of TBI in the United States.


The polycomb protein Ezh2 impacts on induced pluripotent stem cell generation.
Reprogramming of somatic cells toward pluripotency involves extensive chromatin reorganization and changes in gene expression. Polycomb group (PcG) proteins are key regulators of chromatin structure, cell identity, and development. In this study, we investigated the impact of Ezh2, a core subunit of Polycomb repressive complex 2 (PRC2), on the generation of induced pluripotent stem (iPS) cells. We found that Ezh2 expression is induced during iPS cell generation and iPS cells contain high levels of Ezh2 mRNA and protein. Importantly, shRNA knockdown of Ezh2 during reprogramming severely impairs iPS cell generation. Mechanistically, Ezh2 acts during reprogramming at least in part through repressing the Ink4a/Arf locus, which represents a major roadblock for iPS cell generation. Interestingly, knockdown of Ezh2 in established pluripotent cells leaves pluripotency and self-renewal of embryonic stem cells and iPS cells unaffected. Altogether, our results demonstrate that Ezh2 is critical for efficient iPS cell generation, whereas it is dispensable for maintaining the reprogrammed iPS cell state.


Operator dependent choice of prostate cancer biopsy has limited impact on a gene signature analysis for the highly expressed genes IGFBP3 and F3 in prostate cancer epithelial cells.
Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE) core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated. Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed. The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell-containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels. The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low.


Metabolism of pantethine in cystinosis.
D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 microM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 microM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.


Role of nitric oxide and reactive oxygen species in platelet-activating factor-induced microvascular leakage.
Platelet-activating factor (PAF), released during inflammatory responses, increases microvascular permeability to fluid and macromolecules. Previous studies in the hamster cheek pouch microcirculation have shown that PAF-induced increases in permeability can be diminished by pretreatment with a nitric oxide synthase inhibitor indicating that nitric oxide is required for PAF to cause leakage, although nitric oxide itself does not cause leakage. We evaluated the hypothesis that PAF stimulates the production of reactive oxygen species (ROS) that then react with nitric oxide to form a new species that signals the increase in vascular permeability. The hamster cheek pouch microcirculation was used to quantify the leakage of FITC-dextran following topical application of PAF. PAF-induced leakage was markedly inhibited (70%) by prior superfusion of the cheek pouch with superoxide dismutase and catalase. Superfusing the cheek pouch with ROS generated by xanthine oxidase and hypoxanthine produced leakage similar to that observed with PAF. Pretreating the cheek pouch with a nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine, L-NA) inhibited ROS-induced leakage by 59% and PAF-induced leakage by 64%. The effects of L-NA and superoxide dismutase plus catalase on PAF-induced leakage were not additive. Systemic administration of mercaptoethylguanidine, a peroxynitrite scavenger, inhibited PAF-induced leakage by 60%. These results suggest that PAF-induced leakage may be mediated by an interaction between ROS and NO, perhaps through the formation of peroxynitrite or one of its products.


The impact of correction methods on rare-event meta-analysis.
Meta-analyses have become the gold standard for synthesizing evidence from multiple clinical trials, and they are especially useful when outcomes are rare or adverse since individual trials often lack sufficient power to detect a treatment effect. However, when zero events are observed in one or both treatment arms in a trial, commonly used meta-analysis methods can perform poorly. Continuity corrections (CCs), and numerical adjustments to the data to make computations feasible, have been proposed to ameliorate this issue. While the impact of various CCs on meta-analyses with rare events has been explored, how this impact varies based on the choice of pooling method and heterogeneity variance estimator is not widely understood. We compare several correction methods via a simulation study with a variety of commonly used meta-analysis methods. We consider how these method combinations impact important meta-analysis results, such as the estimated overall treatment effect, 95% confidence interval coverage, and Type I error rate. We also provide a website application of these results to aid researchers in selecting meta-analysis methods for rare-event data sets. Overall, no one-method combination can be consistently recommended, but some general trends are evident. For example, when there is no heterogeneity variance, we find that all pooling methods can perform well when paired with a specific correction method. Additionally, removing studies with zero events can work very well when there is no heterogeneity variance, while excluding single-zero studies results in poorer method performance when there is non-negligible heterogeneity variance and is not recommended.


A randomized study to assess the efficacy of herbal product to prevent cisplatin-induced nephrotoxicity in a rat model.
This study aimed to investigate the protective effect and antioxidant activity of an herbal product that made from multiple plants in a rat model of kidney dysfunction induced by intraperitoneal cisplatin. Twenty-four rats were divided into four different groups namely: Group 1 - control healthy animals without any specific medication, Group 2 - Herbal product only 5 mg/kg, Group 3 - cisplatin only and Group 4 - Herbal product 5 mg/kg + cisplatin. Evaluation of our findings demonstrated a significant (p = 0.017) reduction in Catalase activities and a significant increase (p = 0.001) in renal tissue Malondialdehyde levels in cisplatin- treated rats when compared with the control group. Also, Glutathion and Glutathione peroxidase content revealed significant (p = 0.031) reduction in renal tissues of cisplatintreated rats compared with the control group. Pre-treatment of rats with the herbal product ameliorated these cisplatininduced changes of the antioxidant enzymes. No statistically significant changes were demonstrated in Superoxide dismutase activities in the tissue specimens of any group. This potent antioxidant herbal medicine was found to have potential antioxidant activity, which may in turn to be effective in the protection of kidney tissue resulting from cisplatin application. Therefore, much attention should be given to the possible role of natural dietary antioxidants for protecting the kidney.


Discrete dipole moment method for calculation of the T matrix for nonspherical particles.
A computational method, based on a moment solution to the discrete dipole approximation (DDA) interaction equations, is proposed for calculation of the T matrix of arbitrary-shaped particles. It is shown that the method will automatically provide the conservation-of-energy and origin-invariance properties required of the T matrix. Furthermore, the method is significantly faster than a T-matrix calculation by direct inversion of the DDA equations. Because the method retains the dipole lattice representation of the particle, it can be applied with relative ease to particles with irregular shapes-although in the same respect it will not automatically simplify for axisymmetric particles. Calculations of scattering matrix distributions, in fixed and random orientations, are made for tetrahedron, cylindrical, and prolate spheroid particle shapes and compared with DDA and extended boundary condition method results.


Investigation of functional brain network reconfiguration during vocal emotional processing using graph-theoretical analysis.
Vocal expression is essential for conveying the emotion during social interaction. Although vocal emotion has been explored in previous studies, little is known about how perception of different vocal emotional expressions modulates the functional brain network topology. In this study, we aimed to investigate the functional brain networks under different attributes of vocal emotion by graph-theoretical network analysis. Functional magnetic resonance imaging (fMRI) experiments were performed on 36 healthy participants. We utilized the Power-264 functional brain atlas to calculate the interregional functional connectivity (FC) from fMRI data under resting state and vocal stimuli at different arousal and valence levels. The orthogonal minimal spanning trees method was used for topological filtering. The paired-sample t-test with Bonferroni correction across all regions and arousal-valence levels were used for statistical comparisons. Our results show that brain network exhibits significantly altered network attributes at FC, nodal and global levels, especially under high-arousal or negative-valence vocal emotional stimuli. The alterations within/between well-known large-scale functional networks were also investigated. Through the present study, we have gained more insights into how comprehending emotional speech modulates brain networks. These findings may shed light on how the human brain processes emotional speech and how it distinguishes different emotional conditions.


Use of human papillomavirus type 11 virions in an ELISA to detect specific antibodies in humans with condylomata acuminata.
Human papillomavirus types 6 and 11 (HPV-6 and HPV-11) are the major aetiological agents of condylomata acuminata. Serological studies of this disease have been difficult to perform and interpret because native, type-specific antigens have not been available. In particular, since these viruses have not been propagated in vitro and sufficient quantities of virions are not present in lesions, virus particles have been difficult to obtain. In the present study, we used HPV-11 particles, obtained from human tumours produced in athymic mice, as antigen in an ELISA to compare antibody responses between 46 patients with biopsyproven condylomata acuminata and 44 controls. The median [interquartile range] of the absorbance values for the condylomata acuminata and the control groups were respectively 0.324 [0.183, 1.029] and 0.118 [0.047, 0.286] (P = 0.0001). Thirty-three per cent of the absorbance values in the condylomata acuminata group were higher than any of those of the control group. Sera from patients whose biopsies contained the papillomavirus common antigen were more reactive than sera from patients whose biopsies did not contain it (P = 0.0014). This study demonstrates the presence of specific antibodies directed at native HPV-11 viral particles in the sera of patients with condylomata acuminata, and describes a test which can be used in future serological studies of this common sexually transmitted disease.


Involvement of CXC chemokines (CXCL1-CXCL17) in gastric cancer: Prognosis and therapeutic molecules.
Gastric cancer (GC) is the fifth-most prevalent and second-most deadly cancer worldwide. Due to the late onset of symptoms, GC is frequently treated at a mature stage. In order to improve the diagnostic and clinical decision-making processes, it is necessary to establish more specific and sensitive indicators valuable in the early detection of the disease whenever a cancer is asymptomatic. In this work, we gathered information about CXC chemokines and GC by using scientific search engines including Google Scholar, PubMed, SciFinder, and Web of Science. Researchers believe that GC chemokines, small proteins, class CXC chemokines, and chemokine receptors promote GC inflammation, initiation, and progression by facilitating angiogenesis, tumor transformation, invasion, survival, metastatic spread, host response safeguards, and inter-cell interaction. With our absolute best professionalism, the role of CXC chemokines and their respective receptors in GC diagnosis and prognosis has not been fully explained. This review article updates the general characteristics of CXC chemokines, their unique receptors, their function in the pathological process of GC, and their potential application as possible indicators for GC. Although there have only recently been a few studies focusing on the therapeutic efficacy of CXC chemokine inhibitors in GC, growing experimental evidence points to the inhibition of CXC chemokines as a promising targeted therapy. Therefore, further translational studies are warranted to determine whether specific antagonists or antibodies designed to target CXC chemokines alone or in combination with chemotherapy are useful for diagnosing advanced GC.


Complications of semiflexible, closed-loop anterior chamber intraocular lenses.
Anterior chamber intraocular lenses (IOLs) provided good visual rehabilitation of aphakia in a majority of patients. An increasing number of eyes with closed-loop, semiflexible anterior chamber implants are now being seen with decreased vision due to corneal edema and persistent cystoid macular edema. We evaluated 53 such eyes in 52 patients who presented with decreased vision one to 51 months (average, 15 months) after lens implantation. The most frequent lens implanted was the Surgidev Style 10 Leiske IOL. Surgery for IOL removal or exchange with or without penetrating keratoplasty was performed in 34 (64%) of 53 eyes; visual acuity recovery ranged from 20/20 to hand motions (average, 20/80). Despite clear corneal grafts in 24 (92%) of the 26 eyes that underwent corneal transplantation, visual acuity of 20/40 or better was obtained in only nine eyes (26%). Based on the intractable inflammatory sequelae associated with anterior chamber closed-loop IOLs, we strongly urge discontinuation of their use.


Single photon emission computed tomography myocardial imaging: clinical applications and future directions.
Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) has proven to be an invaluable tool in the non-invasive assessment of patients with cardiovascular diseases. Exercise and pharmacologic stress SPECT MPI has been extensively studied and validated in the diagnosis and prognosis of patients with known and suspected coronary artery disease. In addition to the assessment of perfusion, electrocardiography-gated SPECT offers additional functional and volumetric information that can have significant implications on patient care. SPECT also has well-developed applications in systolic heart failure for identifying viable myocardium and predicting response to revascularization. Emerging applications of SPECT imaging include: l) phase analysis for quantitative assessment of LV dyssynchrony that may serve to improve patient selection for CRT; 2) application of heart-to-mediastinal ratio via 123I meta-iodobenzylguanidine (I-MIBG) imaging for the prediction of sudden death in patients with reduced left ventricular function, that may serve to improve patient selection for ICD therapy, and 3) use of metabolic tracers to identify the changes of ''ischemic memory'', which may help with rapid and appropriate triage of patients in the emergency room setting. SPECT MPI remains a cornerstone of clinical care that is evolving with emerging and novel applications that will continue to improve the care of patients with cardiovascular disease in the future.


Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS.
This report describes a new human B7-like gene designated B7-H2. Cell surface expression of B7-H2 protein is detected in monocyte-derived immature dendritic cells. Soluble B7-H2 and immunoglobulin (Ig) fusion protein, B7-H2Ig, binds activated but not resting T cells and the binding is abrogated by inducible costimulator Ig (ICOSIg), but not CTLA4Ig. In addition, ICOSIg stains Chinese hamster ovary cells transfected with B7-H2 gene. By suboptimal cross-linking of CD3, costimulation of T-cell proliferation by B7-H2Ig is dose-dependent and correlates with secretion of interleukin (IL)-2, whereas optimal CD3 ligation preferentially stimulates IL-10 production. The results indicate that B7-H2 is a putative ligand for the ICOS T-cell molecule. (Blood. 2000;96:2808-2813)


Chemical composition analysis of Angelica sinensis (Oliv.) Diels and its four processed products by ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry combining with nontargeted metabolomics.
Angelica sinensis (Oliv.) Diels. has been used for women to enrich the blood, prevent and treat blood deficiency syndrome in Traditional Chinese Medicine for thousands of years. Wine-processed Angelica sinensis, soil-processed Angelica sinensis, oil-processed Angelica sinensis, and charred-processed Angelica sinensis are the most significant four processed products used in Chinese clinic. However, there have been few studies aimed at comparing their chemical differences. Ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry combining with nontargeted metabolomics was applied to investigate the diversity of processed products of Angelica sinensis. A total of 74 compounds with the variable importance in the projection value more than 1.5 and P less than 0.05 in ANOVA were highlighted as the compounds that contribute most to the discrimination of Angelica sinensis and four processed products. The results showed the metabolic changes between Angelica sinensis and its four processed products, there were 19 metabolites, 3 metabolites, 6 metabolites, and 45 metabolites were tentatively assigned in soil-processed Angelica sinensis, wine-processed Angelica sinensis, oil-processed Angelica sinensis, and charred-processed Angelica sinensis, respectively. These results suggested that the proposed metabolomics approach was useful for the quality evaluation and control of processed products of Angelica sinensis.


Acute respiratory failure and intravascular coagulation.
The possible association between acute respiratory failure and disseminated intravascular coagulation was examined in eight patients with severe acute respiratory failure--a condition characterized by tachypnea, right to left intrapulmonary shunting of blood greater than 30 per cent of cardiac output, increased pulmonary artery pressure with low or normal pulmonary artery wedge pressure and roentgenologic interstitial pulmonary edema. Treatment consisted of mechanical ventilation with positive end expiratory pressure sufficient to minimize intrapulmonary shunting. There was no abnormality in platelet concentration fibrin split product concentration, fibrinogen concentration, prothrombin time or activated partial thromboplastin time during the period of most severe respiratory failure in any patient. However, mean platelet concentration fell to 90,000+/-9,000 per cubic millimeter, less than 0.001, and mean fibrin split product levels rose to 60+/-10 micrograms per milliliter, p less than 0.05, the fourth day after the onset of acute respiratory failure. No significant change occurred in other coagulation parameters. Disseminated intravascular coagulation developed in none of the patients nor was there any correlation between coagulation abnormalities and severity of acute respiratory failure that would suggest a cause and effect relationship.


Two putative parallel pathways for naringenin biosynthesis in Epimedium wushanense.
Flavonoids that exhibit various biological activities such as antioxidant, antitumor, antiviral, antibacterial and anti-inflammatory properties are found in a wide range of medicinal plants. Among the flavonoid-producing plants identified so far, the genus Epimedium is recognised as a group of prolific prenyl-flavonoid glycoside producers with high economic value in the global dietary supplement market. To date, the biosynthetic genes for prenyl-flavonoid glycosides still remain elusive in Epimedium. Here, we identified five genes in Epimedium wushanense responsible for the biosynthesis of naringenin, the common precursor for flavonoid natural products. We successfully set up the biosynthetic pathway of naringenin using l-tyrosine as the precursor through enzymatic assays of these genes' encoding products, including phenylalanine ammonia-lyase (EwPAL), 4-coumarate-CoA ligase (Ew4CL1), chalcone synthase (EwCHS1), chalcone isomerase (EwCHI1) and CHI-like protein (EwCHIL3). Intriguingly, in vitro characterisation of the above catalytic enzymes' substrate specificity indicated a route parallel to naringenin biosynthesis, which starts from l-phenylalanine and ends in pinocembrin. The fact that there is no pinocembrin or pinocembrin-derived flavonoid accumulated in E. wushanense prompted us to propose that pinocembrin is likely converted into naringenin in vivo, constituting two parallel biosynthetic pathways for naringenin. Therefore, our study provides a basis for the full elucidation of the biosynthetic logic of prenyl-flavonoid glycoside in Epimedium, paving the way for future metabolite engineering and molecular breeding of E. wushanense to acquire a higher titre of desired, bioactive flavonoid compounds.


Lidar-signal compression by photomultiplier gain modulation: influence of detector nonlinearity.
The application of photomultiplier gain modulation to the compression of wide-dynamic-range lidar signals is investigated in relation to the effect of the gain level on anode-signal linearity. Gain reduction is achieved by the coupling of modulation signals through either multidynode or focus-grid gating networks. This technique facilitates signal recovery and prevents detector nonlinearity and dynode damage caused by high near-field lidar signals. The measurements were performed in the current mode primarily on a 50-mm-diameter, 12-stage photomultiplier (EMI 9214) with a bialkali photocathode. With 3- or 4-dynode-based modulation made at a photomultiplier voltage of 1300 V and a gain of 1 x 10(7), signals of ~6 mA can be maintained at the 1% linearity limit from 100% to 0.2% modulation, corresponding to a 500-fold reduction in the lidar-signal dynamic range. A significant advantage to dynode modulation is that it preserves the shot-signal-to-noise ratio of the incoming signal, which is not true for focus-grid modulation or external predetection schemes such as controlled obscuration or Pockels-cell modulation that attenuate the as-yet unamplified signal.


Potential role for IL-23 in hepatic ischemia/reperfusion injury.
IL-12 and IL-23 are related cytokines that share a p40 subunit. Our previous studies identified IL-12 as a primary initiator of the cytokine cascade induced after hepatic ischemia/reperfusion. Because those studies were conducted prior to the discovery of IL-23, it is not clear whether IL-12 or IL-23 is the relevant cytokine in this response. The current studies show that the antibodies used in our original study cross-react with IL-23. We also found that both IL-12 p35 and IL-23 p19 mRNA are expressed rapidly in the liver after ischemia/reperfusion. Finally, isolated Kupffer cells produced TNFalpha in response to IL-23, but not IL-12, suggesting that IL-23 may be the relevant initiator of the hepatic inflammatory response to ischemia/reperfusion.


MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus.
Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+), located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.


Engaging nurses to achieve a culture of excellence: a children's hospital journey towards Pathway to Excellence accreditation.
High-quality nursing care is linked to improved patient experience and patient outcomes, so having work environments that nurture a culture of nursing excellence is fundamental to delivering high-quality patient care. The American Nurses Credentialing Center (ANCC) runs the Pathway to Excellence programme, an international accreditation recognising healthcare organisations that provide nurses with a positive and safe practice environment in which they can excel. In 2020, Nottingham Children's Hospital became the first children's hospital in Europe to gain Pathway to Excellence accreditation, demonstrating that it has developed a culture of nursing excellence and a positive environment for nurses to work in. This article describes the hospital's journey towards accreditation. Crucial to its success were strategic planning, transformational leadership and using a change management approach, as well as effective staff engagement guided by the ADKAR model for change, an acronym representing five individual outcomes in terms of awareness, desire, knowledge, ability and reinforcement.