The potential role of microfilaments in host cells for infection with infectious spleen and kidney necrosis virus infection.
Infectious spleen and kidney necrosis virus (ISKNV) belongs to the genus Megalocytivirus from the family Iridoviridae. Megalocytivirus causes severe economic losses to tropical freshwater and marine culture industry in Asian countries and is devastating to the mandarin fish farm industry in China particularly. We investigated the involvement of microfilaments in the early and late stages of ISKNV infection in MFF-1 cells by selectively perturbing their architecture using well-characterized inhibitors of actin dynamics. The effect of disruption of actin cytoskeleton on ISKNV infection was evaluated by indirect immunofluorescence analysis or real-time quantitative PCR. The depolymerization of the actin filaments with cytochalasin D, cytochalasin B, or latrunculin A reduced ISKNV infection. Furthermore, depolymerization of filamentous actin by inhibitors did not inhibit binding of the virus but affected virus internalization in the early stages of infection. In addition, the depolymerization of actin filaments reduced total ISKNV production in the late stages of ISKNV. This study demonstrated that ISKNV required an intact actin network during infection. The findings will help us to better understand how iridoviruses exploit the cytoskeleton to facilitate their infection and subsequent disease.


An update on lupus animal models.
The complexity and heterogeneity of the clinical presentation in systemic lupus of erythematosus (SLE), combined to the inherent limitations of clinical research, have made it difficult to investigate the cause of this disease directly in patients. Various mouse models have been developed to dissect the cellular and genetic mechanisms of SLE, as well as to identify therapeutic targets and to screen treatments. The purpose of this review is to summarize the major spontaneous and induced mouse models of SLE and to provide an update on the major advances they have contributed to the field. Mouse models of SLE have continued to contribute to understand the cellular, signaling and metabolic mechanisms contributing to the disease and how targeting these pathways can provide therapeutic targets. Whenever possible, we discuss the advantage of using one model over the others to test a specific hypothesis. Spontaneous and induced models of lupus models are useful tools for the study of the cause of the disease, identify therapeutic targets and screen treatments in preclinical studies. Each model shares specific subsets of attributes with the disease observed in humans, which provides investigators a tool to tailor to their specific needs.


The MgCO3-CaCO3-Li2CO3-Na2CO3-K2CO3 melts: Thermodynamics and transport properties by atomistic simulations.
Atomistic simulations provide a meaningful way to determine the physicochemical properties of liquids in a consistent theoretical framework. This approach takes on a particular usefulness for the study of molten carbonates, in a context where thermodynamic and transport data are crucially needed over a large domain of temperatures and pressures (to ascertain the role of these melts in geochemical processes) but are very scarce in the literature, especially for the calcomagnesian compositions prevailing in the Earth's mantle. Following our work on Li2CO3-Na2CO3-K2CO3 melts, we extend our force field to incorporate Ca and Mg components. The empirical interaction potentials are benchmarked on the density data available in the experimental literature [for the crystals and the K2Ca(CO3)2 melt] and on the liquid structure issued from ab initio molecular dynamics simulations. Molecular dynamics simulations are then performed to study the thermodynamics, the microscopic structure, the diffusion coefficients, the electrical conductivity, and the viscosity of molten Ca,Mg-bearing carbonates up to 2073 K and 15 GPa. Additionally, the equation of state of a Na-Ca-K mixture representative of the lavas emitted at Ol Doinyo Lengai (Tanzania) is evaluated. The overall agreement between the MD results and the existing experimental data is very satisfactory and provides evidence for the ability of the force field to accurately model any MgCO3-CaCO3-Li2CO3-Na2CO3-K2CO3 melt over a large T-P range. Moreover, it is the first report of a force field allowing us to study the transport properties of molten magnesite (MgCO3) and molten dolomite [CaMg(CO3)2].


Professional changes induced by a redesigned immunization supply chain in the Comé Health Zone, Benin.
At the end of 2013, the Government of Benin and Agence de Médecine Préventive (AMP) launched a demonstration project in Comé Health Zone (HZ) to optimize the vaccine supply chain. A key part of the demonstration project was the creation of an "informed push model" of vaccine distribution supported by a new logistician position at the health zone (district) level. At the conclusion of the demonstration project in 2015, the authors conducted an anthropological study consisting of semi-structured interviews with 62 participants to assess how the new model changed the professional identities, roles, responsibilities, and practices of personnel involved in vaccine management during and just after the demonstration project end in Comé HZ. The study found that health workers considered the logistician as a key player in enabling them to perform their public health mission, notably by improving knowledge and practices in vaccine management, providing supportive supervision, and improving the availability of vaccines and other supplies so that immunization sessions could occur more reliably and professionally within the communities they served. The demonstration project was widely accepted among study participants. The study was approved by the Cotonou Ethics Committee (CER-ISBA No. 56 dated 09/04/2015).


Clinical utility of the Duncan-Ely test for rectus femoris dysfunction during the swing phase of gait.
The Ely Test (or Duncan-Ely test) has been accepted as a clinical tool to assess rectus femoris spasticity by passively flexing the knee rapidly while the patient lies prone in a relaxed state. In this retrospective review, patients' dynamic knee range of motion (ROM) during gait and an electromyogram (EMG) were compared with the results of the Ely test. Data for 70 patients (44 males, 26 females; 104 limbs) were included. Mean age of patients was 13 years, SD 9 years, range 4 years 5 months to 54 years. All patients were diagnosed with cerebral palsy (spastic diplegia, n = 42; spastic quadriplegia, n = 15, and hemiplegia, n = 13). All patients were ambulatory (50 independent, 20 with assistive devices). A standard matrix was used to calculate sensitivity and specificity of the Ely test as well as its positive and negative predictive value. For the gait variables examined (decreased dynamic knee ROM, timing of peak knee flexion, and abnormal EMG in swing) the sensitivity of the Ely test ranged from 56 to 59% and the specificity ranged from 64 to 85%. For the same variables the positive predictive value ranged from 91 to 98% and the negative predictive value ranged from 4 to 19%. The Ely test was shown to have a good positive predictive value (i.e. the certainty about the presence of rectus spasticity in patients with a positive Ely test result) for rectus femoris dysfunction during gait.


Harvested human neurons engineered as live nervous tissue constructs: implications for transplantation. Laboratory investigation.
Although neuron transplantation to repair the nervous system has shown promise in animal models, there are few practical sources of viable neurons for clinical application and insufficient approaches to bridge extensive nerve damage in patients. Therefore, the authors sought a clinically relevant source of neurons that could be engineered into transplantable nervous tissue constructs. The authors chose to evaluate human dorsal root ganglion (DRG) neurons due to their robustness in culture. Cervical DRGs were harvested from 16 live patients following elective ganglionectomies, and thoracic DRGs were harvested from 4 organ donor patients. Following harvest, the DRGs were digested in a dispase-collagenase treatment to dissociate neurons for culture. In addition, dissociated human DRG neurons were placed in a specially designed axon expansion chamber that induces continuous mechanical tension on axon fascicles spanning 2 populations of neurons originally plated approximately 100 microm apart. The adult human DRG neurons, positively identified by neuronal markers, survived at least 3 months in culture while maintaining the ability to generate action potentials. Stretch-growth of axon fascicles in the expansion chamber occurred at the rate of 1 mm/day to a length of 1 cm, creating the first engineered living human nervous tissue constructs. These data demonstrate the promise of adult human DRG neurons as an alternative transplant material due to their availability, viability, and capacity to be engineered. Also, these data show the feasibility of harvesting DRGs from living patients as a source of neurons for autologous transplant as well as from organ donors to serve as an allograft source of neurons.


Tight binding models accurately predict band structures for copolymer semiconductors.
Conjugated polymers possess a wide range of desirable properties including accessible band gaps, plasticity, tunability, mechanical flexibility and synthetic versatility, making them attractive for use as active materials in organic photovoltaics (OPVs). In particular, push-pull copolymers, consisting of alternating electron-rich and electron-deficient moieties, offer broad optical absorption, tunable band gaps, and increased charge transfer between monomer units. However, the large number of possible monomer combinations to explore means screening OPV copolymers by first-principles quantum calculations is computationally intensive. If copolymer band structures could be rapidly computed from homopolymer data, potential materials could be screened more efficiently. In this work, we construct tight binding models of copolymer band structures with parameters determined by density functional theory (DFT) calculations on homopolymers. We use these models to predict copolymer valence and conduction bands, which compare well to direct DFT calculations of copolymer band structures.


Calcium losses resulting from an acute bout of moderate-intensity exercise.
The purpose of this study was to compare daily calcium (Ca) losses in sweat (S) and urine (U) on an exercise day (E) with losses on the preceding day (i.e., a rest day) during which no exercise (NE) was performed. Ten healthy male volunteers (23.9 +/- 3.2 years) performed a single bout of moderate exercise (running at 80% HRmax) for 45 min in a warm (32 degrees C, 58% relative humidity) environment on E. When E and NE were compared, neither Ca intake (1,232 +/- 714 and 1, 148 +/- 482 mg, respectively) nor urinary Ca excretion (206 +/- 128 and 189 +/- 130 mg, respectively) were different (p >.05). Sweat Ca losses during the exercise bout averaged 45 +/- 12 mg. The results indicate that, although a small amount of Ca is lost in sweat during 45 min of moderate-intensity exercise, measured (sweat and urine losses combined) Ca losses (251 +/- 128 and 189 +/- 130 mg) were not different (p >.05) between days (E and NE, respectively). These data suggest that moderate exercise for up to 45 min in a warm, humid environment does not markedly increase Ca intake requirements.


Intrinsic neuronal electroresponsiveness and its possible role in epileptogenesis.
An increased neuronal excitability is one of the most important factors involved in the physiopathology of epileptic states. It may occur via two major routes: an increase in cation inflow, a decreasing cation outflow. The recent discovery that Na+ and Ca2+ inflow may occur through channels that do not inactivate (close) rapidly and that can therefore produce plateau action potentials of great duration, make these conductances quite significant in the generation and maintenance of epilepsy. The presence of excitatory neurotransmitters released either by presynaptic terminal or by glial elements must also be considered. As for the mechanisms that operate by reducing outward cationic flow, a reduction in K+ conductance is mainly involved in membrane depolarization. Other ionic conductances of importance in epileptogenesis will relate most significantly to the reduction in synaptic inhibitory mechanisms, i.e. a reduction of GABAergic or glutaminergic synapses.


Topography of the human corpus callosum.
This study was undertaken to determine the topographical organization of fibers coursing through the human corpus callosum. We correlated the distribution of Wallerian degeneration in the corpus callosum with the anatomical sites of focal cortical lesions due to ischemic infarctions or circumscribed contusions. Fibers from the inferior frontal and anterior inferior parietal regions course through the rostrum and genu of the corpus callosum. Callosal connections from the temporo-parieto-occipital junctional region course through the splenium and caudal portion of the body of the corpus callosum. Both the superior parietal lobule and the occipital cortex give rise to interhemispheric fibers that course exclusively through the splenium of the corpus callosum. No callosal degeneration was associated with a cortical lesion in the anterior superior frontal region. The topographical organization of fibers in the human corpus callosum appears to be fairly similar to that found in the rhesus monkey (Macaca mulatta).


Exercise-based rehabilitation for coronary heart disease.
The burden of cardiovascular disease world-wide is one of great concern to patients and health care agencies alike. Circulatory diseases, including myocardial infarction (MI) and stroke, kill more people than any other disease. Cardiac rehabilitation aims to restore patients who have suffered myocardial infarction to optimal health through exercise only based rehabilitation or comprehensive cardiac rehabilitation (eg. smoking cessation advice, diet and counselling as well as exercise). Data from two published and widely cited meta-analyses (Oldridge 1988, O'Connor 1989) of over 4,000 patients each have demonstrated that patients randomised to exercise-based cardiac rehabilitation after MI have a statistically significant reduction in all-cause and cardiac mortality of about 20 to 25% compared to patients receiving conventional care. However, the trials included were small and often of poor methodological quality. Incomplete literature review methods may have resulted in publication bias thereby resulting in an over-estimate of the benefit of cardiac rehabilitation. The randomised controlled trials used in the reviews have focused almost exclusively on low-risk, middle-aged males post MI, thereby excluding women and the elderly. To determine the effectiveness of exercise only rehabilitation and exercise in addition to other rehabilitation interventions (termed comprehensive cardiac rehabilitation) compared with usual care on the mortality, morbidity, health-related quality of life (HRQoL) and modifiable cardiac risk factors of patients with coronary heart disease. Electronic databases were searched for randomised controlled trials, using standardised trial filters, from the earliest date available to December 31st 1998. Men and women of all ages, in both hospital-based and community-based settings, who have had myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, or who have angina pectoris or coronary artery disease defined by angiography have been included. Studies involving participants following heart transplant, heart valve surgery or heart failure have been excluded. Follow up periods of less than 6 months were excluded. Studies were selected independently by two reviewers, and data extracted independently. Authors were contacted where possible to obtain missing information. The current systematic review has allowed analysis of an increased number of patients from approximately 4500 in the earlier meta-analyses to 7683 (2582 in exercise only and 5101 in the comprehensive cardiac rehabilitation group). The quality of reporting overall was poor, with generally high losses to follow up. The pooled effect estimate for total mortality for the exercise only intervention shows a 27% reduction in all cause mortality (random effects model OR 0.73 (0.54, 0.98)). Similarly, comprehensive cardiac rehabilitation reduced all cause mortality compared to usual care, but to a lesser degree (OR 0.87 (0.71, 1.05)). Total cardiac mortality was reduced by 31% (random effects model OR 0.69 (0.51, 0.94)) and 26% (random effects model OR 0.74 (0.57, 0.96)) in the exercise only and comprehensive cardiac rehabilitation intervention groups respectively when compared to usual care. Neither intervention had any effect on the ocurrence of non-fatal myocardial infarction. There was a significant net reduction in total cholesterol in the comprehensive cardiac rehabilitation group (pooled WMD random effects model -0.57 mmol/l (-0.83, -0.31)), but not the exercise only rehabilitation group. Similarly, LDL was significantly reduced in the comprehensive cardiac rehabilitation group (pooled WMD random effects model -0.51 mmol/l (-0.82, -0.19). The effect of exercise only rehabilitation or comprehensive cardiac rehabilitation interventions on revascularisation rates, blood pressure or smoking behaviour could not be determined by this meta-analysis due to the small number of trials reporting these outcomes and heterogeneity between trials. It was not possible to combine the data from studies reporting HRQoL as an outcome. Eighteen different instruments were used to assess HRQoL in the 11 studies reporting it as an outcome. The data are presented qualitatively, only one trial reporting significant improvements with the intervention. Exercise-based cardiac rehabilitation appears to be effective in reducing cardiac deaths but the evidence base is weakened by poor quality trials. It is not clear from this review whether exercise only or a comprehensive cardiac rehabilitation intervention is more beneficial. The population studied in this review is still predominately male, middle aged and low risk. Identification of the ethnic origin of the participants was seldom reported. (ABSTRACT TRUNCATED)


Helping teenagers talk about guns and gun violence.
I recently had the opportunity to listen to teenagers talk about guns and gun violence when they attended a summer church camp. Two separate groups; one entering grade 7, 8, and 9 and one entering grade 10, 11, and 12 were asked to share their understandings, feelings, and opinions about guns in a small group setting. Relevant books, articles, and other media were reviewed as part of my preparation for this time. Ground rules were established prior to the conversations, including safety and confidentiality concerns. Each group was asked essentially the same two sets of questions, one related to their school life and one related to their home life. The shared stories generally confirmed the range of understandings, feelings, and opinions anticipated, and provided anecdotal evidence that teenagers today are faced with guns and gun violence as part of their daily lived realities, regardless of their individual, specific demographics. Only limited suggestions were offered to help teenagers cope with their realities. More importantly, this exercise gave the teenagers permission to voice their own thoughts and can serve as a model for future conversations among teenagers.


Transgenerational Consequences of Racial Discrimination for African American Health.
Disparities in African American health remain pervasive and persist transgenerationally. There is a growing consensus that both structural and interpersonal racial discrimination are key mechanisms affecting African American health. The Biopsychosocial Model of Racism as a Stressor posits that the persistent stress of experiencing discrimination take a physical toll on the health of African Americans and is ultimately manifested in the onset of illness. However, the degree to which the health consequences of racism and discrimination can be passed down from one generation to the next is an important avenue of exploration. In this review, we discuss and link literature across disciplines demonstrating the harmful impact of racism on African American physical health and the health of their offspring.


Central Airway Toxicity After High Dose Radiation: A Combined Analysis of Prospective Clinical Trials for Non-Small Cell Lung Cancer.
To study the dosimetric risk factors for radiation-induced proximal bronchial tree (PBT) toxicity in patients treated with radiation therapy for non-small cell lung cancer (NSCLC). Patients with medically inoperable or unresectable NSCLC treated with conventionally fractionated 3-dimensional conformal radiation therapy (3DCRT) in prospective clinical trials were eligible for this study. Proximal bronchial tree (PBT) and PBT wall were contoured consistently per RTOG 1106 OAR-Atlas. The dose-volume histograms (DVHs) of physical prescription dose (DVHp) and biological effective dose (α/β = 2.5; DVH2.5) were generated, respectively. The primary endpoint was PBT toxicities, defined by CTCAE 4.0 under the terminology of bronchial stricture/atelectasis. Of 100 patients enrolled, with a median follow-up of 64 months (95% confidence interval [CI], 50-78), 73% received 70 Gy or greater and 17% developed PBT toxicity (grade 1, 8%; grade 2, 6%; grade 3, 0%; and grade 4, 3%). The median time interval between RT initiation and onset of PBT toxicity was 8.4 months (95% CI, 4.7-44.1). The combined DVHs showed that no patient with a PBT maximum physical dose <65 Gy developed any PBT toxicity. Cox proportional hazards analysis and receiver operating characteristic analysis demonstrated that V75 of PBT was the most significant dosimetric parameter for both grade 1+ (P = .035) and grade 2+ (P = .037) PBT toxicities. The dosimetric thresholds for V75 of PBT were 6.8% and 11.9% for grade 1+ and grade 2+ PBT toxicity, respectively. V75 of PBT appeared be the most significant dosimetric parameter for PBT toxicity after conventionally fractionated thoracic 3DCRT. Constraining V75 of PBT can limit clinically significant PBT toxicity.


Extracellular Vesicles Reflect the Efficacy of Wheatgrass Juice Supplement in Colon Cancer Patients During Adjuvant Chemotherapy.
Colorectal cancer (CC) is the third most common type of cancer, accounting for 10% of all cancer cases. Adjuvant chemotherapy is recommended in stages II-III CC. Wheatgrass juice (WGJ) from wheat seeds has high nutritional values, may induce synergistic benefits to chemotherapy and may attenuate chemotherapy-related side effects. Extracellular vesicles (EVs) are subcellular membrane blebs. EVs include exosomes (generated in the endosome, in size <150 nm) and microvesicles (shed from the plasma cell membrane) provide information on their parental cells and play a role in intercellular communication. We aimed to elucidate the effects of chemotherapy administration with supportive treatment of WGJ on CC patients' EVs characteristics. EVs were isolated from the blood samples of 15 healthy controls (HCs) and 50 CC patients post-surgery, treated by chemotherapy, with or without additional daily WGJ. Blood samples were taken before, during, and at the end of chemotherapy. EVs were characterized by size, concentration, membrane antigens and cytokine content using nanoparticle-tracking analysis, western blot, flow cytometry, and protein array methods. EVs were found to be similar by size and concentration with reduced levels of exosome markers (CD81) on samples at the end of combined treatment (chemotherapy and WGJ). Higher levels of endothelial EVs, which may indicate impairment of the vascular endothelial cells during treatment, were found in CC patients treated by chemotherapy only compared to those with chemotherapy and daily WGJ. Also, EVs thrombogenicity was lower in patients added WGJ compared to patients who had only chemotherapy (levels of tissue factor p = 0.029 and endothelial protein C receptor p = 0.005). Following treatments, levels of vascular endothelial growth factor receptors (VEGFR-1) and the majority of growth-factors/pro-inflammatory cytokines were higher in EVs of patients treated by chemotherapy only than in EVs obtained from patients with the combined treatment. Daily consumption of WGJ during chemotherapy may reduce vascular damage and chemotherapy-related thrombogenicity, growth factors and cytokines, as reflected by the characteristics of patient's EVs.


Sonohysterography: the next step in the evaluation of the abnormal endometrium.
Sonohysterography is a simple ultrasound (US) procedure that may be used to evaluate the endometrium. The technique involves placement of a 5-F catheter into the endometrial canal with subsequent instillation of sterile saline solution under US guidance. Fifty patients successfully underwent sonohysterography because of apparent abnormal endometrial thickening at transvaginal US, a nonspecific finding. Patients tolerated this procedure well, and no complications were encountered. In the 39 patients who proved to have endometrial pathologic conditions, sonohysterography demonstrated focal processes (polyps, carcinoma, hamartoma) in 15, diffuse processes (hyperplasia, secretory endometrium) in 21, and both focal and diffuse pathologic conditions in three. If a focal process can be delineated, a visually directed biopsy may be necessary. However, if the process is diffuse, a blind aspiration biopsy may be performed on an outpatient basis. In the majority of patients, the diffuse or focal nature of the disease could not be predicted on the basis of initial transvaginal US. Because sonohysterography allows distinction between diffuse and focal abnormalities, it provides physicians with a cost-effective way to plan the next step in case management.


The patient as the pivot point for quality in health care delivery.
Health care enterprises make comprehensive and durable changes in people. This human-centered purpose defines the fundamental nature of quality in health care settings. Traditional perspectives of quality and familiar views of customer satisfaction are inadequate to manage the complex relationships between the health care delivery firm and its patients. Patients play four roles in health care systems that must be reflected when defining and measuring quality in these settings: patient as supplier, patient as product, patient as participant, and patient as recipient. This article presents a conceptual model of quality that incorporates these diverse patient roles. The strategic and managerial implications of the model are also discussed.


Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT).
To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.


Uncovering therapeutic targets for glioblastoma: a systems biology approach.
Even though glioblastoma, WHO grade IV (GBM) is one of the most devastating adult cancers, current treatment regimens have not led to any improvements in patient life expectancy or quality of life. The constitutively active EGFRvIII receptor is one of the most commonly mutated proteins in GBM and has been linked to radiation and chemotherapeutic resistance. To define the mechanisms by which this protein alters cell physiology, we have recently performed a phosphoproteomic analysis of EGFRvIII signaling networks in GBM cells. The results of this study provided important insights into the biology of this mutated receptor, including oncogene dose effects and differential utilization of signaling pathways. Moreover, clustering of the phosphoproteomic data set revealed a previously undescribed crosstalk between EGFRvIII and the c-Met receptor. Treatment of the cells with a combination employing both EGFR and c-Met kinase inhibitors dramatically decreased cell viability in vitro. In this perspective, we highlight the use of systems biology as a tool to better understand the molecular basis of GBM tumor biology as well as to uncover non-intuitive candidates for therapeutic target validation.


Purpura fulminans skin loss: surgical management protocols at a regional burns centre.
People with significant skin loss after sepsis frequently require skin grafting; as such, they are often referred to regional burns units for definitive soft-tissue cover. Such individuals have complex requirements after severe sepsis, and usually have complicated wounds. We have developed a protocol for managing these patients and their wounds within a high dependency, intensive-care unit, using allograft as an adjunct in preparing the tissue bed before autografting. This protocol includes optimisation of nutritional needs, microbiological surveillance and definitive soft tissue cover. We retrospectively reviewed all children referred over 18 months for management of skin and soft tissue loss after meningitis purpura fulminans. We reviewed the initial management of the septicaemia, associated co-morbidities, site and size of soft tissue defect, time to presentation for definitive skin cover, surgical procedure performed, timing of surgical intervention, and recovery of the patient's wounds. A total of six people (all children), with a mean age of 7 months (age range 4-21 years) were admitted to our unit between March 2004 and September 2005. Total percentage skin loss was 12% (6-20%). All of the children underwent debridement, received allograft to areas of skin loss and necrosis as a primary procedure, and subsequently underwent autograft. Two children required amputation of one or more limbs, and the stumps were covered with allograft followed by skin autograft. All patients had excellent autograft skin taken using this protocol.


Integrated approach to prevent functional decline in hospitalized elderly: the Prevention and Reactivation Care Program (PReCaP).
Hospital related functional decline in older patients is an underestimated problem. Thirty-five procent of 70-year old patients experience functional decline during hospital admission in comparison with pre-illness baseline. This percentage increases considerably with age. To address this issue, the Vlietland Ziekenhuis in The Netherlands has implemented an innovative program (PReCaP), aimed at reducing hospital related functional decline among elderly patients by offering interventions that are multidisciplinary, integrated and goal-oriented at the physical, social, and psychological domains of functional decline. This paper presents a detailed description of the intervention, which incorporates five distinctive elements: (1) Early identification of elderly patients with a high risk of functional decline, and if necessary followed by the start of the reactivation treatment within 48 h after hospital admission; (2) Intensive follow-up treatment for a selected patient group at the Prevention and Reactivation Centre (PRC); (3) Availability of multidisciplinary geriatric expertise; (4) Provision of support and consultation of relevant professionals to informal caregivers; (5) Intensive follow-up throughout the entire chain of care by a casemanager with geriatric expertise. Outcome and process evaluations are ongoing and results will be published in a series of future papers. The Netherlands National Trial Register: NTR2317.


Evolutionary rates of mitochondrial genomes correspond to diversification rates and to contemporary species richness in birds and reptiles.
Rates of biological diversification should ultimately correspond to rates of genome evolution. Recent studies have compared diversification rates with phylogenetic branch lengths, but incomplete phylogenies hamper such analyses for many taxa. Herein, we use pairwise comparisons of confamilial sauropsid (bird and reptile) mitochondrial DNA (mtDNA) genome sequences to estimate substitution rates. These molecular evolutionary rates are considered in light of the age and species richness of each taxonomic family, using a random-walk speciation-extinction process to estimate rates of diversification. We find the molecular clock ticks at disparate rates in different families and at different genes. For example, evolutionary rates are relatively fast in snakes and lizards, intermediate in crocodilians and slow in turtles and birds. There was also rate variation across genes, where non-synonymous substitution rates were fastest at ATP8 and slowest at CO3. Family-by-gene interactions were significant, indicating that local clocks vary substantially among sauropsids. Most importantly, we find evidence that mitochondrial genome evolutionary rates are positively correlated with speciation rates and with contemporary species richness. Nuclear sequences are poorly represented among reptiles, but the correlation between rates of molecular evolution and species diversification also extends to 18 avian nuclear genes we tested. Thus, the nuclear data buttress our mtDNA findings.


Anxiety among College Students Who Self-Isolated During the Omicron Variant of SARS-CoV-2 in China.
We investigated the prevalence of anxiety and its associated risk factors among college students who self-isolated for 30 days during the emergence of the Omicron variant in China. We sampled college students specializing in four academic majors by cluster sampling and conducted questionnaires separately on days 1, 10, 20, and 30 after self-isolation. Anxiety was assessed using the 7-item Generalized Anxiety Disorder Scale (GAD-7) and Self-Rating Anxiety Scale (SAS). An odds ratio (OR) with a 95% confidence interval (CI) was used to estimate the strength of associations. A total of 10231 college students responded to the questionnaire 4 times. More students reported experiencing anxiety as the period of self-isolation approached 30 days. Among the students from four different major disciplines, medical students reported the highest rate of anxiety after 30 days of self-isolation, whereas humanities students exhibited the lowest rate of anxiety. Factor analysis indicated that the main reason for anxiety among all participating students was a delay in course completion. For engineering and medical students, there was an association between anxiety and research project delay. This study reveals the level of anxiety associated with COVID-19 pandemic-related self-isolation in college students and finds that it was aggravated by long-term isolation.


Determination of r-7,t-8,9,c-10-tetrahydroxy-7,8,9, 10-tetrahydrobenzo[a]pyrene in human urine by gas chromatography/negative ion chemical ionization/mass spectrometry.
r-7,t-8,9,c-10-Tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (trans-anti-BaP-tetraol) is the major hydrolysis product of r-7, t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), the principal ultimate carcinogen of the environmental pollutant benzo[a]pyrene (BaP). As part of a program to establish activation/detoxification profiles of urinary metabolites of BaP in humans, we developed a method for quantifying trans-anti-BaP-tetraol. Urine was collected from three groups of individuals exposed to BaP: psoriasis patients treated with a coal tar-containing ointment, steel workers, and smokers. [(2)H(12)]-trans-anti-BaP-tetraol was added to the urine as an internal standard. The urine was treated with beta-glucuronidase and sulfatase, and then the BaP-tetraols were enriched by reverse-phase and phenylboronic acid solid-phase extraction. The resulting fraction was treated with sodium hydride and methylmethane sulfonate to convert BaP-tetraols to the corresponding tetramethyl ethers (BaP-TME). The mixture was purified by normal-phase HPLC and analyzed by gas chromatography/negative ion chemical ionization/mass spectrometry with selected ion monitoring. [(13)CH(3)](4)-trans-anti-BaP-TME was used as an external standard. Ions at m/z 376, 380, and 388 were monitored for quantitation of trans-anti-BaP-TME, [(13)CH(3)](4)-trans-anti-BaP-TME, and [(2)H(12)]-trans-anti-BaP-TME, respectively. The instrumental detection limit was approximately 1 fmol of trans-anti-BaP-TME. trans-anti-BaP-tetraol (as trans-anti-BaP-TME) was detected in 20 of 20 individuals receiving coal tar therapy (mean, 16 fmol/mL of urine), 13 of 13 exposed steel workers (mean, 4.1 fmol/mL of urine), and nine of 21 cigarette smokers (mean, 0.5 fmol/mL of urine). The means in these groups were significantly different (P < 0.0001). The urine of steel workers was also analyzed for cis-anti-BaP-tetraol and cys-syn-BaP-tetraol, but neither was found. The results of this study provide a quantitative method for determination of parts per trillion levels of trans-anti-BaP-tetraol in human urine. Ultimately, this method can be employed as part of a phenotyping approach for assessing BaP metabolites in human urine.


Regioselective Protection and Deprotection of Nanocellulose Molecular Design Architecture: Robust Platform for Multifunctional Applications.
Regioselectively substituted nanocellulose was synthesized by protecting the primary hydroxyl group. Herein, we took advantage of the different reactivities of primary and secondary hydroxyl groups to graft large capping structures. This study mainly focuses on regioselective installation of trityl protecting groups on nanocellulose chains. The elemental analysis and nuclear magnetic resonance spectroscopy of regioselectively substituted nanofibrillated cellulose (NFC) suggested that the trityl group was successfully grafted in the primary hydroxyl group with a degree of substitution of nearly 1. Hansen solubility parameters were employed, and the binary system composed of an ionic liquid and pyridine as a base was revealed to be the optimum condition for regioselective functionalization of nanocellulose. Interestingly, the dissolution of NFC in the ionic liquid and the subsequent deprotection process of NFC substrates hardly affected the crystalline structure of NFC (3.6% decrease in crystallinity). This method may provide endless possibilities for the design of advanced engineered nanomaterials with multiple functionalities. We envisage that this protection/deprotection approach may lead to a bright future for the fabrication of multifunctional devices based on nanocellulose.


Sol-gel-coated mid-infrared fiber-optic sensors.
Application of organically modified sol-gels as novel recognition membranes for mid-infrared fiber-optic sensors is demonstrated for the first time by in situ detection of nitro-based aromatic compounds in aqueous media. Sol-gels were prepared by acid- and base-catalyzed copolymerization of alkyltrimethoxysiloxanes and applied onto the surface of silver halide (AgCl(0.3)Br(0.7)) fibers by drip coating. The coating process was monitored in situ using Fourier transform infrared (FT-IR) spectroscopy. Homogeneity of the layers was analyzed by scanning electron microscopy. Sol-gel-coated evanescent held sensors were investigated with respect to their capacity to suppress interfering water background absorptions, repeatability of dissolved analyte enrichment, and sensor response time. Nitrobenzene and parathion are the investigated analytes; figures of merit are derived from calibration curves determined to assess sensitivity and reproducibility of the developed sensor system. It can be concluded that sol-gel-coated infrared fiber-optic sensors enable reproducible detection of nitro-based aromatic compounds in the low ppm concentration range. Due to wide flexibility in tuning chemical properties of sol-gel films along with superior mechanical and chemical stability, organically modified sol-gels represent highly interesting coating materials for mid-infrared sensing applications.


Asystole associated with cluster headache.
A 43-year-old man with asystole and syncope occurring during cluster headache attacks is reported. The asystole and syncope attacks disappeared completely following prophylactic therapy with methysergide maleate. To the authors' knowledge, the present case is unique in associating asystole with cluster headache attacks and may be due to hyperactivity of the parasympathetic system.


The Activity of Escherichia coli Chaperone SurA Is Regulated by Conformational Changes Involving a Parvulin Domain.
The periplasmic chaperone SurA is critical for the biogenesis of outer membrane proteins (OMPs) and, thus, the maintenance of membrane integrity in Escherichia coli. The activity of this modular chaperone has been attributed to a core chaperone module, with only minor importance assigned to the two SurA peptidyl-prolyl isomerase (PPIase) domains. In this work, we used synthetic phenotypes and covalent tethering to demonstrate that the activity of SurA is regulated by its PPIase domains and, furthermore, that its activity is correlated with the conformational state of the chaperone. When combined with mutations in the β-barrel assembly machine (BAM), SurA mutations resulting in deletion of the second parvulin domain (P2) inhibit OMP assembly, suggesting that P2 is involved in the regulation of SurA. The first parvulin domain (P1) potentiates this autoinhibition, as mutations that covalently tether the P1 domain to the core chaperone module severely impair OMP assembly. Furthermore, these inhibitory mutations negate the suppression of and biochemically stabilize the protein specified by a well-characterized gain-of-function mutation in P1, demonstrating that SurA cycles between distinct conformational and functional states during the OMP assembly process. This work reveals the reversible autoinhibition of the SurA chaperone imposed by a heretofore underappreciated parvulin domain. Many β-barrel-associated outer membrane (OM) virulence factors, including the P-pilus and type I fimbriae, rely on SurA for proper assembly; thus, a mechanistic understanding of SurA function and inhibition may facilitate antibiotic intervention against Gram-negative pathogens, such as uropathogenic Escherichia coli, E. coli O157:H7, Shigella, and Salmonella. In addition, SurA is important for the assembly of critical OM biogenesis factors, such as the lipopolysaccharide (LPS) transport machine, suggesting that specific targeting of SurA may provide a useful means to subvert the OM barrier.


Iron acquisition and regulation in Campylobacter jejuni.
Iron affects the physiology of bacteria in two different ways: as a micronutrient for bacterial growth and as a catalyst for the formation of hydroxyl radicals. In this study, we used DNA microarrays to identify the C. jejuni genes that have their transcript abundance affected by iron availability. The transcript levels of 647 genes were affected after the addition of iron to iron-limited C. jejuni cells. Several classes of affected genes were revealed within 15 min, including immediate-early response genes as well as those specific to iron acquisition and metabolism. In contrast, only 208 genes were differentially expressed during steady-state experiments comparing iron-rich and iron-limited growth conditions. As expected, genes annotated as being involved in either iron acquisition or oxidative stress defense were downregulated during both time course and steady-state experiments, while genes encoding proteins involved in energy metabolism were upregulated. Because the level of protein glycosylation increased with iron limitation, iron may modulate the level of C. jejuni virulence by affecting the degree of protein glycosylation. Since iron homeostasis has been shown to be Fur regulated in C. jejuni, an isogenic fur mutant was used to define the Fur regulon by transcriptome profiling. A total of 53 genes were Fur regulated, including many genes not previously associated with Fur regulation. A putative Fur binding consensus sequence was identified in the promoter region of most iron-repressed and Fur-regulated genes. Interestingly, a fur mutant was found to be significantly affected in its ability to colonize the gastrointestinal tract of chicks, highlighting the importance of iron homeostasis in vivo. Directed mutagenesis of other genes identified by the microarray analyses allowed the characterization of the ferric enterobactin receptor, previously named CfrA. Chick colonization assays indicated that mutants defective in enterobactin-mediated iron acquisition were unable to colonize the gastrointestinal tract. In addition, a mutation in a receptor (Cj0178) for an uncharacterized iron source also resulted in reduced colonization potential. Overall, this work documents the complex response of C. jejuni to iron availability, describes the genetic network between the Fur and iron regulons, and provides insight regarding the role of iron in C. jejuni colonization in vivo.


Hydrodynamics of diamond-shaped gradient nanopillar arrays for effective DNA translocation into nanochannels.
Effective DNA translocation into nanochannels is critical for advancing genome mapping and future single-molecule DNA sequencing technologies. We present the design and hydrodynamic study of a diamond-shaped gradient pillar array connected to nanochannels for enhancing the success of DNA translocation events. Single-molecule fluorescence imaging is utilized to interrogate the hydrodynamic interactions of the DNA with this unique structure, evaluate key DNA translocation parameters, including speed, extension, and translocation time, and provide a detailed mapping of the translocation events in nanopillar arrays coupled with 10 and 50 μm long channels. Our analysis reveals the important roles of diamond-shaped nanopillars in guiding DNA into as small as 30 nm channels with minimized clogging, stretching DNA to nearly 100% of their dyed contour length, inducing location-specific straddling of DNA at nanopillar interfaces, and modulating DNA speeds by pillar geometries. Importantly, all critical features down to 30 nm wide nanochannels are defined using standard photolithography and fabrication processes, a feat aligned with the requirement of high-volume, low-cost production.


Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa).
Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.


Epidemiology of leptospirosis in dairy farm workers in the Manawatu. Part II. A case-control study of high and low risk farms.
Subsequent to a cross-sectional serological survey of Manawatu dairy farm workers, a case-control study was carried out to investigate the correlation between titres to leptospiral serovars in workers and those in cattle in their herds. A total of 52 herds was investigated, 25 of which were high risk where milkers had titres of 1:96 or greater, and 27 were case-controls where milkers had no detectable agglutinin titres at a minimum serum dilution of 1:24. The serological prevalence of titres to hardjo in cattle on high risk farms (76.5%) was significantly higher (P<0.05) than on the case-control farms (60.0%). The geometric mean titres of seropositive cattle on high risk farms were also significantly higher (P<0.01) than in the cattle from the case-control farms, especially in the younger cohorts. These findings suggest that there was active endemic hardjo infection in the two- to three-year-old cattle on the high risk farms. Titres to pomona were demonstrated in only 5.2% of the cattle from both types of farm. Workers with titres to pomona tended to be from farms on which stock, especially calves, were bought-in and pigs were kept. Conventional measures for protecting milkers from contact with infected urine appeared to be ineffective and it is concluded that prevention of leptospirosis in dairy farm workers can only be achieved by elimination of infection in the herd by vaccination of cattle.


Diagnosis and treatment of effort-induced thrombosis of the axillary subclavian vein due to venous thoracic outlet syndrome.
Venous thoracic outlet syndrome (VTOS) is uncommon but most frequently occurs in young, active, healthy patients. This condition typically presents as subclavian vein (SCV) effort thrombosis, also known as Paget-Schroetter syndrome. The pathophysiology underlying VTOS is chronic repetitive compression injury of the SCV in the costoclavicular space, resulting in progressive venous scarring, focal stenosis, and eventual thrombosis. Clinical evaluation includes a history and physical examination followed by catheter-based venography, for definitive confirmation of the diagnosis and initial treatment with pharmacomechanical thrombolysis. After restoration of SCV patency, patients are maintained with anticoagulation and surgical therapy is usually planned within 4 to 6 weeks. Surgical management of VTOS can be accomplished via different protocols involving either the transaxillary, infraclavicular or paraclavicular approaches to thoracic outlet decompression. The paraclavicular approach is emphasized in this review, because it affords the surgeon the ability to safely perform complete thoracic outlet decompression (complete anterior and middle scalenectomy, removal of the entire first rib, and resection of the subclavius muscle and costoclavicular ligament), along with definitive management of the damaged SCV (external venolysis, intraoperative venography, and direct vein reconstruction, if needed, using patch angioplasty or bypass grafting), in one operative setting. After surgical therapy, interval anticoagulation and a comprehensive physical therapy and rehabilitation program are important in achieving a return to full function. Current protocols on the basis of the paraclavicular surgical approach have thereby routinely provided patients with lasting symptomatic relief, freedom from indefinite anticoagulation, and the ability to return to unrestricted upper extremity activity.


Visual orientation and spatial frequency discrimination: a comparison of single neurons and behavior.
Neurons in the visual cortex respond selectively to stimulus orientation and spatial frequency. Changes in response amplitudes of these neurons could be the neurophysiological basis of orientation and spatial frequency discrimination. We have estimated the minimum differences in stimulus orientation and spatial frequency that can produce reliable changes in the responses of individual neurons in cat visual cortex. We compare these values with orientation and spatial frequency discrimination thresholds determined behaviorally. Slopes of the tuning functions and response variability determine the minimum orientation and spatial frequency differences that can elicit a reliable response change. These minimum values were obtained from single cells using receiver operating characteristic (ROC) analysis. The average minimum orientation and spatial frequency differences that could be signaled reliably by cells from our sample were 6.4 degrees (n = 22) and 21.3% (n = 18), respectively. These values are approximately 0.20 of the average full tuning width at one-half height of the cells. Although these average values are well above the behaviorally determined thresholds, the most selective cells signaled orientation and frequency differences of 1.84 degrees and 5.25%, respectively. These values are of the same order of magnitude as the behavioral thresholds. We show that, because of slow fluctuations in a cell's responsivity, ROC analysis overestimates response variability. We estimate that these slow response fluctuations elevated our estimates of single cell "thresholds" by, on average, 30%. Our data point to an approximate correspondence between orientation and spatial frequency discrimination "thresholds" determined behaviorally and those estimated from the most selective single cortical cells. Interpretation of this quantitative correspondence is considered in the discussion.


Retroperitoneal leiomyoma with periorbital and peripheral edema.
Removal of a large retroperitoneal leiomyoma from a 51-year-old woman resulted in complete resolution of periorbital edema and pitting edema of the hands and feet from which she had suffered for 8 months. Cardiac, renal and dietary studies gave normal results. The diagnosis of leiomyoma, which is uncommon in the retroperitoneal region, was supported by the findings on light and electron microscopy. The patient remains asymptomatic after 3 years. The association of such widespread edema with a retroperitoneal tumour is rare; the cause is unknown.


Response to phenelzine and amitriptyline in subtypes of outpatient depression.
Outpatients with depression and mixed anxiety-depression were treated for six weeks with phenelzine sulfate, amitriptyline hydrochloride, or placebo in a controlled trial. Both active drugs were superior to placebo and were closely comparable in efficacy. Interactions were examined between drug response and classifications based on three different usages of the term atypical depression: additional anxiety or phobic symptoms, atypical functional shift, and nonendogenous depression. Some additional related classifications were also included. There was a tendency for phenelzine to have stronger effects in patients with additional anxiety and without evidence of chronic characterological depression. However, interactions were relatively few. These findings suggest that the two classes of antidepressant affect similar clinical subgroups within the outpatient depressive spectrum, with only relatively weak differences.


Identifying Rewards Over Difficulties Buffers the Impact of Time in COVID-19 Lockdown for Parents in Australia.
Physical isolation measures, known as lockdown or shelter-in-place, experienced during coronavirus disease 2019 (COVID-19) have the potential to cause psychological distress. This study was conducted to examine parents' perceived stress and whether reports of rewards and challenges during lockdown impact stress. Data were collected using a cross-sectional online survey in New South Wales, Australia, across the 4-week lockdown. The survey was completed by 158 parents of children aged under 6 years. Stress was measured using the short form of the Perceived Stress Scale (PSS-4). Rewards and challenges were reported in response to two open-ended questions. There was a weak negative correlation between PSS-4 scores and days in isolation (r = -0.167, p = 0.022), with parents who had spent longer in isolation reporting fewer stress symptoms. The relationship between time in isolation and stress was moderated by the degree to which parents described more rewards than challenges: parents who perceived high rewards and low challenges reported lower PSS-4 scores with more days in lockdown, whereas parents who perceived low rewards and high challenges reported higher PSS-4 scores with more days in lockdown. The moderation model examining associations between time in isolation and rewards ratio explained 13% of the variance in PSS-4 scores. Lockdowns are not uniformly or consistently negative experiences for parents. Identifying positive aspects of the experience may serve to buffer negative mental health risks across time. Understanding resilience strategies is critical for supporting current psychological wellbeing and to adequately prepare for future pandemic experiences.


Photosynthesis and growth responses of pea Pisum sativum L. under heavy metals stress.
The present work aimed to study the physiological effects of cadmium (Cd) and copper (Cu) in pea (Pisum sativum). Pea plants were exposed to increasing doses of cadmium chloride (CdCl2) and copper chloride (CuCl2) for 20 d. The examined parameters, namely root and shoot lengths, the concentration of photosynthetic pigments and the rate of photosynthesis were affected by the treatments especially with high metals concentrations. The analysis of heavy metals accumulation shows that leaves significantly accumulate cadmium for all the tested concentrations. However, copper was significantly accumulated only with the highest tested dose. This may explain the higher inhibitory effects of cadmium on photosynthesis and growth in pea plants. These results are valuable for understanding the biological consequences of heavy metals contamination particularly in soils devoted to organic agriculture.


Serum albumin inhibits echovirus 7 uncoating.
Echoviruses induce a wide spectrum of diseases in man, the most severe being meningitis. In neonates, however, a severe systemic infection can be observed, leading to death. Serum albumin is the most abundant protein in plasma and most interstitial fluids, and its functions include osmoregulation and transport and delivery of hydrophobic molecules such as fatty acids and steroids. The results of cold-synchronized one-step growth analysis of echovirus 7 infection and sucrose-gradient analysis of A-particles suggest that physiological concentrations of albumin block echovirus 7 infection by inhibiting uncoating. The blockage was reversible and was still effective when albumin was added 30 min after virus adsorption. Inhibition of uncoating was confirmed by using rhodanine, a known specific inhibitor of echovirus uncoating. After removal of the albumin blockage, addition of rhodanine perpetuated the inhibition. Serum and interstitial albumin concentrations may limit echovirus infection in vivo and thereby act as an extracellular determinant for echovirus tropism.


Kefir: a multifaceted fermented dairy product.
Kefir is a fermented dairy beverage produced by the actions of the microflora encased in the "kefir grain" on the carbohydrates in the milk. Containing many bacterial species already known for their probiotic properties, it has long been popular in Eastern Europe for its purported health benefits, where it is routinely administered to patients in hospitals and recommended for infants and the infirm. It is beginning to gain a foothold in the USA as a healthy probiotic beverage, mostly as an artisanal beverage, home fermented from shared grains, but also recently as a commercial product commanding shelf space in retail establishments. This is similar to the status of yogurts in the 1970s when yogurt was the new healthy product. Scientific studies into these reported benefits are being conducted into these health benefits, many with promising results, though not all of the studies have been conclusive. Our review provides an overview of kefir's structure, microbial profile, production, and probiotic properties. Our review also discusses alternative uses of kefir, kefir grains, and kefiran (the soluble polysaccharide produced by the organisms in kefir grains). Their utility in wound therapy, food additives, leavening agents, and other non-beverage uses is being studied with promising results.


Time-resolved double-slit interference pattern measurement with entangled photons.
The double-slit experiment strikingly demonstrates the wave-particle duality of quantum objects. In this famous experiment, particles pass one-by-one through a pair of slits and are detected on a distant screen. A distinct wave-like pattern emerges after many discrete particle impacts as if each particle is passing through both slits and interfering with itself. Here we present a temporally- and spatially-resolved measurement of the double-slit interference pattern using single photons. We send single photons through a birefringent double-slit apparatus and use a linear array of single-photon detectors to observe the developing interference pattern. The analysis of the buildup allows us to compare quantum mechanics and the corpuscular model, which aims to explain the mystery of single-particle interference. Finally, we send one photon from an entangled pair through our double-slit setup and show the dependence of the resulting interference pattern on the twin photon's measured state. Our results provide new insight into the dynamics of the buildup process in the double-slit experiment, and can be used as a valuable resource in quantum information applications.


Biliverdin therapy protects rat livers from ischemia and reperfusion injury.
Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1beta, tumor necrosis factor alpha, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs.


A novel negative Fe-deficiency-responsive element and a TGGCA-type-like FeRE control the expression of FTR1 in Chlamydomonas reinhardtii.
We have reported three Fe-deficiency-responsive elements (FEREs), FOX1, ATX1, and FEA1, all of which are positive regulatory elements in response to iron deficiency in Chlamydomonas reinhardtii. Here we describe FTR1, another iron regulated gene and mutational analysis of its promoter. Our results reveal that the FeREs of FTR1 distinguish itself from other iron response elements by containing both negative and positive regulatory regions. In FTR1, the -291/-236 region from the transcriptional start site is necessary and sufficient for Fe-deficiency-inducible expression. This region contains two positive FeREs with a TGGCA-like core sequence: the FtrFeRE1 (ATGCAGGCT) at -287/-279 and the FtrFeRE2 (AAGCGATTGCCAGAGCGC) at -253/-236. Furthermore, we identified a novel FERE, FtrFeRE3 (AGTAACTGTTAAGCC) localized at -319/-292, which negatively influences the expression of FTR1.


New and recurrent ulcerations after percutaneous achilles tendon lengthening in transmetatarsal amputation.
The purpose of the study was to review the incidence rate of new and recurrent ulcerations in transmetatarsal amputations after original ulcers healed with percutaneous Achilles' tendon lengthening as an isolated procedure. We reviewed 35 charts from period of January 1995 to March 2007, and 28 were included for the final review. Twenty-four ulcers were grade 1A, 2 were 0A and 1B, and 1 was 1C using the University of Texas Grading System. Time to heal of ulceration post-TAL was 9.4 weeks (range 3-72 weeks). For statistical analysis, we used binomial distribution for dichotomous variables. Results demonstrated 4 limbs did not heal, 10 patients had an ulcer recurrence (p<0.001), and 6 developed new ulcers. Of the 28 patients in which TAL was performed, 16 developed new neuropathic ulcers (including recurrent ulcers; p=0.0099). High recurrence and new ulcers formation exist after TAL in patients with an unbalanced metatarsal amputation, and extrinsic/ intrinsic factors may need to be addressed to prevent recurrence. 4.


Gastroenterologists' attitudes and self-reported practices regarding inflammatory bowel disease.
The purpose was to assess organization-, physician-, and patient-based aspects of inflammatory bowel disease (IBD) practice variation within an integrated care delivery system and the extent to which physicians are interested in adopting a chronic care model and/or nurse assistance to manage IBD patients. As part of an observational cohort study to understand variation in IBD care and outcomes, we conducted semistructured, open-ended interviews with 17 gastroenterologists and 1 gastroenterology registered nurse at 6 clinics in an integrated care delivery system. Interviews were taperecorded and transcribed. We coded and analyzed transcripts using standard qualitative methods. Physicians reported a range of attitudes and practices regarding IBD. Analysis showed differences in 3 domains and 8 subdomains: 1) patient education and choices, including health education and patient use of complementary and alternative medicine; 2) decisions about diagnosis and treatment, including practice guidelines, conferring with colleagues, using infliximab, and medical hospitalization; and 3) organizational aspects of care, including primary care involvement with IBD and MD attitudes toward ancillary support. Standardized algorithms on care for IBD patients do not exist, but opportunities may exist to improve IBD care by: having initial work-ups and management of patients in remission in primary care; creating and maintaining opportunities for gastroenterologists to confer with colleagues and acknowledged local experts; and having nurse coordination for medications and labs and/or some type of specialty IBD clinic for high-need patients. This research highlights the need for more directed comparative efficacy and effectiveness trials that will serve to define preferred treatment strategies.


Role of exocellular polymer in the design of activated sludge.
This research is aimed at understanding the reactor-settler interaction. The reactor operating conditions affect the sludge-settling properties due to (a) production of exocellular polymer that serves as a flocculant in the settler and (b) population shift from flocculating bacteria to filamentous microorganisms that do not settle. A structured kinetic model that accounts for stored substrate and production of polymers, biomass, and inerts was constructed and applied to various open and closed reactor configurations. It is based on our observation that, in a batch reactor, the polymer is produced during endogenous respiration. The model describes well the observed temporal variation in substrate, biomass, and polymer concentration. Application of the model to continuous operation predicts increasing polymer concentration with sludge age, which is in good agreement with one study in the literature. Our study in a once-through reactor, as well as others, suggests an inverse dependence. The difference is probably due to different operating modes. Our study confirmed the role of the polymer in the sedimentation process. Under some conditions, however, a slow population shift to filamentous growth becomes the dominant factor.


Virological evidence of the impact of non-pharmaceutical interventions against COVID-19 in Ecuador, a resource-limited setting.
Ecuador had substantial COVID-19-mortality during 2020 despite early implementation of non-pharmaceutical interventions (NPIs). Resource-limited settings like Ecuador have high proportions of informal labour which entail high human mobility, questioning efficacy of NPIs. We performed a retrospective observational study in Ecuador's national reference laboratory for viral respiratory infections during March 2020-February 2021 using stored respiratory specimens from 1950 patients, corresponding to 2.3% of all samples analysed within the Ecuadorian national surveillance system per week. During 2020, detection of SARS-CoV-2 (Pearson correlation; r = -0.74; p = 0.01) and other respiratory viruses (Pearson correlation; r = -0.68; p = 0.02) by real-time RT-PCR correlated negatively with NPIs stringency. Among respiratory viruses, adenoviruses (Fisher's exact-test; p = 0.026), parainfluenzaviruses (p = 0.04), enteroviruses (p < 0.0001) and metapneumoviruses (p < 0.0001) occurred significantly more frequently during months of absent or non-stringent NPIs (characterized by <55% stringency according to the Oxford stringency index data for Ecuador). Phylogenomic analyses of 632 newly characterized SARS-CoV-2 genomes revealed 100 near-parallel SARS-CoV-2 introductions during early 2020 in the absence of NPIs. NPI stringency correlated negatively with the number of circulating SARS-CoV-2 lineages during 2020 (r = -0.69; p = 0.02). Phylogeographic reconstructions showed differential SARS-CoV-2 dispersion patterns during 2020, with more short-distance transitions potentially associated with recreational activity during non-stringent NPIs. There were also fewer geographic transitions during strict NPIs (n = 450) than during non-stringent or absent NPIs (n = 580). Virological evidence supports that NPIs had an effect on virus spread and distribution in Ecuador, providing a template for future epidemics in resource-limited settings and contributing to a balanced assessment of societal costs entailed by strict NPIs.


Auricular leishmaniasis mimicking squamous cell carcinoma of the pinna.
Cutaneous leishmaniasis can occur on any exposed area of the body; however, the pinna is an exceptionally rare site for the disease. Caused by the parasite Leishmania, cutaneous leishmaniasis has a wide range of presentations and thus is very easy to misdiagnose or mistake for a neoplastic lesion. Here, we report the case of a middle-aged male patient presenting with a painful, ulcerated lesion on the left auricle initially suspected to be a malignancy with histopathology eventually revealing a diagnosis of auricular leishmaniasis. The patient received appropriate therapy and was found to be disease free at follow-up. These isolated lesions of the pinna often resemble neoplastic lesions and thus may escape diagnosis for months at a time, increasing patient stress as well as expenditure. In addition, prompt recognition may also help mitigate recurrence of the disease, making it worthwhile to include cutaneous leishmaniasis as part of the differential, especially in endemic areas.


[Incidence of decubitus ulcers in an intensive care unit].
Decubitus ulcers are an important problem which must be known by health professionals in general and by nurses in particular. Its prevention is one of the basic care in Nursing. This care becomes especially relevant in patients who are admitted into Intensive Care Units. The objectives of the study are to know the incidence rate of patients who develop decubitus ulcers during their stay in the Unit and the proposal to introduce measures aiming to decrease its incidence. In general, the study proves that 17% of patients develop decubitus ulcers during their hospitalization and that 31.8% of patients who are catalogued as risk patients develop ulcers. The preventive measures introduced are the reassessment and application of prevention and treatment of decubitus ulcers protocols, the creation of improvement groups where these problems are approached, perfecting courses about decubitus ulcers, clinical sessions where strategies are unified, graphic divulging measures (notices, etc.) and antiscaric materials such as heelers, small cushions for head support, pillows, etc.


Enhanced rutin accumulation in tobacco leaves by overexpressing the NtFLS2 gene.
Rutin, one of the metabolites of the flavonoid pathway, shows great potential in industrial applications as a key component in pharmaceutical medicines and biological pesticides. Although the genetic manipulation of transcription factors (TFs) could increase rutin levels in plants, the accompanying accumulation of structurally similar chemicals complicates industrial rutin extraction. In this study, we demonstrated remarkably elevated rutin content (3.5-4.4-fold relative to controls) in transgenic tobacco plants by overexpressing NtFLS2. The levels of other intermediates in the branch pathway did not change much except for a moderate increase of kaempferol-3-O-rutinoside. Furthermore, the transcript levels of pathway genes in transgenic lines were comparable with controls, indicating genetic engineering did not significantly alter the branch pathway. Additionally, the transgenic tobacco plants appeared normal except for a flower color change from light red to white suggesting that it could be a valuable material for industrial extraction of rutin.


[Aggregation of normal and transformed cells attached to a substrate].
On the surface of the nirtocellulose membrane filter (pore size 0.3--0.5 mem), normal mouse or hamster embryo fibroblasts formed discrete cell aggregates. Behaviour of transformed fibroblast-like cells of 9 different lines was compared with that of normal cells. Cells of 3 transformed lines grew on this substratum as a uniform monolayer displaying no tendency to aggregation. The following 3 cell lines exposed a slightly "patchy" cell distribution on the 3rd--4th day of cultivation but were unable to form discrete aggregates. The remaining 3 lines did form aggregates but the dynamics of aggregation and the final aggregation pattern for two of them were abnormal. Only one of the 9 investigated transformed lines had the normal aggregation behaviour. Hence, in the course of the neoplastic evolution, cells lose their ability fo form aggregates on the filter surface. Mechanisms of cell aggregation and possible reasons of differencies in the aggregation behaviour between normal and transformed cells, are discussed.


Isolation and unambiguous synthesis of cryptolepinone: An oxidation artifact of cryptolepine
Cryptolepinone (3) was isolated as an artifact of extraction from Cryptolepis sanguinolenta. Previously, this compound had been identified as the natural products hydroxycryptolepine (2) and 3. Synthesis via an unambiguous pathway has confirmed the structure of cryptolepinone. Spectroscopic studies in various solvents have shown that the natural product artifact or its synthetic equivalent can exist in the keto (cryptolepinone) or enol (hydroxycryptolepine) form.


Symptom pattern and pathophysiological correlates of weight loss in tertiary-referred functional dyspepsia.
In patients with gastrointestinal symptoms, weight loss is an alarm symptom, indicative of organic disease. Recent studies reported weight loss in subsets of functional dyspepsia (FD) patients. The aim of this study was to analyse symptom patterns associated with weight loss in tertiary care FD. Six hundred and thirty-six FD patients (67% female, mean age 43 years) completed a dyspepsia questionnaire, and underwent gastric emptying and gastric barostat studies. After identifying independent symptom domains through orthogonal factor analysis, patients were clustered on the basis of symptom profile. Clusters were compared in terms of their association with weight loss and gastric emptying or sensorimotor function. Weight loss (4.2 kg on average) correlated most strongly with early satiety followed by nausea and vomiting (rho respectively 0.38, 0.28 and 0.23, all P < 0.0001). Factor analysis revealed three factors: Factor 1 characterized by nausea, vomiting and early satiety; factor 2 by early satiety, postprandial fullness and bloating; and factor 3 by pain, epigastric burning and belching. Subsequent cluster analysis revealed six patient clusters. The most severe cluster, which loaded high on all three factors, and a cluster dominated factor 2 were associated with the highest average weight loss (6.8 and 8.0 kg, respectively). The former cluster was also characterized by visceral hypersensitivity and delayed gastric emptying. The lowest weight loss occurred in the two clusters that had depressed scores for both early satiety associated factors (2.4 and 2.5 kg, respectively). In tertiary care FD, weight loss is strongly associated with two early satiety associated symptom clusters.


Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012.
Initial treatments for patients with differentiated thyroid cancer are supported primarily by single-institution, retrospective studies, with limited follow-up and low event rates. We report updated analyses of long-term outcomes after treatment in patients with differentiated thyroid cancer. The objective was to examine effects of initial therapies on outcomes. This was a prospective multi-institutional registry. A total of 4941 patients, median follow-up, 6 years, participated. Interventions included total/near-total thyroidectomy (T/NTT), postoperative radioiodine (RAI), and thyroid hormone suppression therapy (THST). Main outcome measures were overall survival (OS) and disease-free survival using product limit and proportional hazards analyses. Improved OS was noted in NTCTCS stage III patients who received RAI (risk ratio [RR], 0.66; P = .04) and stage IV patients who received both T/NTT and RAI (RR, 0.66 and 0.70; combined P = .049). In all stages, moderate THST (TSH maintained subnormal-normal) was associated with significantly improved OS (RR stages I-IV: 0.13, 0.09, 0.13, 0.33) and disease-free survival (RR stages I-III: 0.52, 0.40, 0.18); no additional survival benefit was achieved with more aggressive THST (TSH maintained undetectable-subnormal). This remained true, even when distant metastatic disease was diagnosed during follow-up. Lower initial stage and moderate THST were independent predictors of improved OS during follow-up years 1-3. We confirm previous findings that T/NTT followed by RAI is associated with benefit in high-risk patients, but not in low-risk patients. In contrast with earlier reports, moderate THST is associated with better outcomes across all stages, and aggressive THST may not be warranted even in patients diagnosed with distant metastatic disease during follow-up. Moderate THST continued at least 3 years after diagnosis may be indicated in high-risk patients.


Electron spin resonance studies on normal human uterus and cervix and on benign and malignant uterine tumors.
Electron spin resonance (ESR) studies at -130 degrees have been made on frozen samples of normal human cervix and uterus and on frozen samples of various pathological conditions of the cervix and uterus including fibroleiomyoma and carcinoma. Fifty-five samples of normal cervix and endometrium, 40 samples of nonmalignant disturbances, 15 benign tumor samples, and 20 malignant samples were studied. Very strong ESR signals were seen in frozen powders and frozen intact samples of normal cervix and endometrium and in nonmalignant gynecological conditions. In many cases, the ESR signal was greatly decreased or even undetectable in cancer samples. The substance(s) responsible for the ESR signal in frozen intact tissue (g = 2.11 to 2.15) is decreased in concentration when the sample is ground to powder under liquid nitrogen, and an anisotropic signal (g = 2.002 to 2.035) then becomes much more evident. The ESR signals in intact and in powder samples are sensitive to temperature variations; the signals disappear around 0 degrees, and only the intact samples show significant recovery of signal on recooling. The anisotropic g values and temperature sensitivity in the powders may result from an organic peroxy radical that is more strongly associated with a metal ion in intact samples.


[Measurement of carotenoids by high pressure liquid chromatography: from difficulties to solutions].
The measurement of serum carotenoids by HPLC has been largely improved during the last 10 years. However these techniques still require much time and skills, and direct application of published methods is rarely satisfying. We report here the difficulties that we met to transfer some HPLC methods described in the literature to our laboratories. We propose some solution to overcome the problems that we have encountered, our experience will perhaps help out other biologists. We reported also some results obtained in healthy populations.


Identification and characterization of Sox genes in the silkworm, Bombyx mori.
Sox genes encode a family of transcription factors with important roles in metazoan development, including sex-determination, embryogenesis, neurogenesis, and skeletogenesis. We identified Sox genes in the Bombyx mori genome and characterized their evolution and expression patterns. Nine Sox genes were annotated, and could be classified into five groups, B-F. Four Sox genes in the B group were tandemly clustered on one chromosome, a characteristic common to their orthologs in other insects. The intron number in the high-mobility group (HMG) box of Sox genes exhibited low diversity across surveyed insects. Based on 40 different silkworm variety genomes, we found a similar number of single nucleotide polymorphisms (SNPs) in the coding sequences of each Sox gene, for domesticated and wild groups. However, a gene-based examination showed that SoxB3 and SoxD might be evolving under positive selection during silkworm domestication. Phylogenetic analysis showed that SoxC, SoxD, and SoxF originated before the radiation of insects, and groups B and E evolved through gene duplication after the radiation of insects. Furthermore, BmSox21a, BmSoxB3, BmSoxD, and BmSoxE reveal stage, tissue, or sex-dependent expression patterns. These results provide a foundation for further surveying the functions of Sox genes during silkworm development and domestication.


Auxin activity: Past, present, and future.
Long before its chemical identity was known, the phytohormone auxin was postulated to regulate plant growth. In the late 1800s, Sachs hypothesized that plant growth regulators, present in small amounts, move differentially throughout the plant to regulate growth. Concurrently, Charles Darwin and Francis Darwin were discovering that light and gravity were perceived by the tips of shoots and roots and that the stimulus was transmitted to other tissues, which underwent a growth response. These ideas were improved upon by Boysen-Jensen and Paál and were later developed into the Cholodny-Went hypothesis that tropisms were caused by the asymmetric distribution of a growth-promoting substance. These observations led to many efforts to identify this elusive growth-promoting substance, which we now know as auxin. In this review of auxin field advances over the past century, we start with a seminal paper by Kenneth Thimann and Charles Schneider titled "The relative activities of different auxins" from the American Journal of Botany, in which they compare the growth altering properties of several auxinic compounds. From this point, we explore the modern molecular understanding of auxin-including its biosynthesis, transport, and perception. Finally, we end this review with a discussion of outstanding questions and future directions in the auxin field. Over the past 100 yr, much of our progress in understanding auxin biology has relied on the steady and collective advance of the field of auxin researchers; we expect that the next 100 yr of auxin research will likewise make many exciting advances.


Carotid blood flow response to Conray-60: diagnostic implications.
The vasoactive effect of the angiographic contrast medium Conray-60 (iothalamate meglumine 60%) on carotid blood flow was studied by the video dilution technique in 26 subjects during routine neuroangiography. After a test series of 1 ml injections of contrast material into the carotid arteries at designated time intervals, an increase in carotid blood flow was found in normal controls at 30 sec, while a significant decrease in flow was observed in patients with atheromatous disease and avascular intracranial masses (p less than 0.01). Test responses in patients with intracranial aneurysm, neoplasm, and granulomatous vasculitis are also reported. The differential effect of contrast material on the cerebral circulation correlates well with several pathologic states of the central nervous system and may be used as a simple test to diagnose and evaluate a variety of vascular disorders.


The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis.
Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.


Determinants of malaria program expenditures during elimination: case study evidence from select provinces in the Philippines.
...Even though eliminating malaria from the endemic margins is a part of the Global Malaria Action Plan, little guidance exists on what resources are needed to transition from controlling malaria to eliminating it. Using Philippines as an example, this study aimed to (1) estimate the financial resources used by sub-national malaria programs in different phases during elimination and (2) understand how different environmental and organizational factors may influence expenditure levels and spending proportions. The Philippines provides an opportunity to study variations in sub-national programs because its epidemiological and ecological diversity, devolved health system, and progressive elimination strategy all allow greater flexibility for lower-level governments to direct activities, but also create challenges for coordination and resource mobilization. Through key informant interviews and archival record retrieval in four selected provinces chosen based on eco-epidemiological variation, expenditures associated with provincial malaria programs were collected for selected years (mid-1990s to 2010). Results show that expenditures per person at risk per year decrease as programs progress from a state of controlled low-endemic malaria to elimination to prevention of reintroduction regardless of whether elimination was deliberately planned. However, wide variation across provinces were found: expenditures were generally higher if mainly financed with donor grants, but were moderated by the level of economic development, the level of malaria transmission and receptivity, and the capacity of program staff. Across all provinces, strong leadership appears to be a necessary condition for maintaining progress and is vital in controlling outbreaks. While sampled provinces and years may not be representative of other sub-national malaria programs, these findings suggest that the marginal yearly cost declines with each phase during elimination.


Neurologic complications of immune checkpoint inhibitors.
Introduction: Immune checkpoint inhibitors (ICI) are associated with a wide spectrum of neurologic immune-related adverse events (irAEs) including meningo-encephalitis, myasthenia gravis and various neuropathies. Although relatively rare, they often present significant diagnostic complexity and may be under-recognized. Permanent neurologic deficits and/or fatality have been described but improvement is noted in most cases with ICI discontinuation and immunosuppressive therapy.Areas covered: This review highlights the most frequently reported ICI-associated neurologic toxicities with a particular focus on those that may be more severe and/or fatal. Data from case series and pharmacovigilance studies is leveraged to provide an overview of associated clinical features, expected outcomes and appropriate management. Various immunobiologic triggers have been proposed to explain why certain patients might develop neurologic irAEs and are also briefly discussed.Expert opinion: All providers who care for patients with cancer should be made aware of common neurologic irAEs and able to recognize when prompt evaluation and consultation with appropriate specialists are indicated. Symptoms suggestive of encephalitis, myasthenia-gravis or an acute polyradiculopathy such as Guillain-Barre Syndrome (GBS) in patients exposed to these agents warrant immediate attention with a low threshold for hospitalization to expedite work-up and monitor for severe and/or life-threatening manifestations.


Longitudinal surveillance of outpatient quinolone antimicrobial use in Canada.
Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is important. To assess the use of quinolone antimicrobials within Canadian provinces over time. ANTIMICROBIAL PRESCRIBING DATA COLLECTED BY IMS HEALTH CANADA WERE ACQUIRED FROM THE CANADIAN INTEGRATED PROGRAM FOR ANTIMICROBIAL RESISTANCE SURVEILLANCE AND THE CANADIAN COMMITTEE FOR ANTIMICROBIAL RESISTANCE, AND WERE USED TO CALCULATE TWO YEARLY METRICS: prescriptions per 1000 inhabitant-days and the mean defined daily doses (DDDs) per prescription. These measures were used to produce linear mixed models to assess differences among provinces and over time, while accounting for repeated measurements. The quinolone class of antimicrobials is used similarly among Canadian provinces. Year-to-year increases in quinolone prescribing occurred from 1995 to 2010, with a levelling off in the latter years. Year-to-year decreases in the DDDs per prescription were found to be significant from 2000 to 2010. Although the overall use of antimicrobials differs significantly among Canadian provinces, the use of the quinolone class does not vary at the provincial level. Results suggest that prescribing of ciprofloxacin may be a potential target for antimicrobial stewardship programs; however, decreases in the average DDDs per prescription suggest continued uptake of appropriate treatment guidelines.


[Calcium lithiasis II. Idiopathic or hypophosphatemic hypercalciuria? Vitamin D - metabolism and othophosphate therapy].
Hypophosphateamia in patients with Ca lithiasis leads to the activation of the vitamin D endocrine system: the plasma 1.25(OH)2-D3 concentration is raised. The raised 1,25(OH)2-D3 biosynthesis causes an increase in intestinal Ca absorption, which in its turn explains the hypercalciuria. The syndrome originally presented by Albright and his pupils as "idiopathic hypercalciuria" in fact corresponds to a secondary, reactive D hypervitaminosis. According to the present findings the often wrongly used term "so-called idiopathic calciuria" should be replaced by the pathogenetically correcter term "hypophosphataemic calciuria". Efficient treatment of this syndrome consists in sufficient oral orthophosphate substitution. In the interests of a better understanding as a requirement for suitable treatment of this metabolic disorder, the vitamin D metabolites and their renal key enzymes, 25-OH-Vitamin-D3-1-Hydroxylase and 25-OH-Vitamin -D3-24-Hydroxylase, are described. The hormonal control add the activation and inactivation of the vitamin D endocrine system are explained independently of the individual Ca and phosphate requirement of the organism. The dependence of renal Ca excretion on the rate of glomerular filtration is pointed out once again. The clinical-diagnostic term hypercalciuria must not be applied globally but individually. Indications, counter-indications, dosage, duration and side-effects of the orthophosphate therapy are discussed.


Plasmids in the genus Bifidobacterium.
A total of 1461 bacterial isolates, representing 24 different species of the genus Bifidobacterium, were examined for the presence of plasmid DNA. Approximately 20% of the isolates contained detectable plasmids, but only four species were presented: B. longum, the predominant bifid species in the human intestine; B. globosum, the most common in animals; and B. asteroides and B. indicum, species found exclusively in the intestines of western and asiatic honey bees, respectively. Multiple plasmids were common among isolates of B. longum and B. asteroides, while all plasmid-bearing isolates of B. globosum and 60% of B. indicum isolates contained only one plasmid each. Certain multiple plasma profiles were predominant among the B. longum and B. asteroides isolates.


Could application of epinephrine improve hemostatic efficacy of hemoclips for bleeding peptic ulcers? A prospective randomized study.
Bleeding from peptic ulcers can be effectively and safely treated with endoscopic hemoclips therapy. However, due to certain limiting factors of hemoclips, application of combination with another endoscopic method may give better results. The aim of this study was to examine the efficacy and safety of endoscopic hemoclips therapy and to evaluate potential benefits of this therapy combined with epinephrine in the treatment of bleeding peptic ulcers. This prospective randomized study included 70 patients with bleeding gastric or duodenal ulcer. In 34 of the patients endoscopic hemoclips therapy was applied (group I), and in 36 of them a combined therapy of hemoclips and epinephrine (group II). Initial hemostasis was achieved in most patients treated with endoscopic hemoclips therapy (94.1%) as well as in the patients treated with combination therapy (97.2%). After initial hemostasis achieved rebleeding occurred in 3 (9.3%) patients treated with hemoclips and in 2 (5.7%) patients treated with combination therapy, but this difference was not statistically significant (p > 0.05). The difference in the achieved final hemostasis between the group I (91.1%) and the group II (94.4%) was not statistically significant. Also, the differences between the two groups of patients in the need for blood transfusions, length of hospital stay, need for surgery and mortality were not statistically significant (p > 0.05). Endoscopic hemoclips therapy is effective and safe in treatment of bleeding peptic ulcers. Combination therapy of hemoclips and epinephrine has no advantage over hemoclips monotherapy.