[HIV and cancer : What's new in 2017?]
Since the era of combined antiretroviral therapy, life expectancy of people living with HIV has been improved and is associated with a change in causes of death. Cancer, both AIDS-defining or non-AIDS-defining cancers, has become the leading cause of death in people living with HIV associated with an increase in the incidence of some cancers compared to the general population. Epidemiology and the identification of risk factors is a crucial issue, particularly to determine the most appropriate prevention and screening strategies in this population. In the absence of dedicated clinical trials, the cancer management in these patients is based on general recommendations, with specific attention to comorbidities and drug interactions. In addition, the development of new innovative therapies such as immunotherapy with inhibitory antibodies of immune checkpoints receptor represents a hope for the patient care, both infected or not with HIV. In this context, the establishment of the national network CancerVIH makes sense, allowing the establishment of multi-disciplinary consultation meetings involving all the practitioners involved in the care of these patients with cancer, as well as the constitution of a national cohort and the promotion of dedicated trials, to improve and optimize the management for these patients.


Plasma concentration-effect relationships of intravenous and extended-release oral felodipine in hypertensive patients.
Felodipine, a dihydropyridine calcium antagonist, was given double-blind in a crossover design comparing once-daily doses of 20 mg felodipine extended-release (ER) tablets with placebo in 12 hypertensive patients. A 2-h intravenous infusion was given after a placebo washout. After oral felodipine, blood pressure (BP) was significantly lower than after placebo, both after the first dose and after 2 weeks of treatment. Supine BP 24 h after the first dose of placebo and felodipine was 159/97 and 153/92 mm Hg (p less than 0.01/0.05), respectively. Corresponding BPs at 2 weeks were 158/99 and 144/89 mm Hg (p less than 0.01/0.01). Approximately 75% of the maximal and 60% of the trough effect at steady state were obtained already after the first dose. The plasma concentration (CpF) vs. time curve after felodipine ER was relatively flat. After oral felodipine, a linear correlation was found between BP reduction and logarithmic CpF. After intravenous administration, CpF correlated well with a hyperbolic function. These data indicate that there is an almost linear relation between BP reduction and log CpF in the range from 2-20 nmol/L, and that little additional effect is to be expected above approximately 20 nmol/L. No hysteresis was found for the relationship between CpF and BP reduction. The absolute bioavailability of felodipine ER was 22%.


Gas chromatographic method for determination of chlorpyrifos and its metabolite 3,5,6-trichloro-2-pyridinol (TCP) in dates.
A method is described for the determination of the insecticide chlorpyrifos and its metabolite TCP in green, unprocessed, and processed dates with the seeds incorporated. After extraction, chloropyrifos is cleaned up using Florisil and analyzed using a gas chromatography (GC) equipped with a nitrogen/phosphorus detector. TCP is derivatized using bis-(trimethylsilyl)-acetamide (BSA) to form the TCP-derivative and analyzed by a gas chromatograph equipped with a Hall electrolytic conductivity detector. Recoveries of chlorpyrifos from all fortified dates (0.05 and 0.1 ppm) ranged from 86 to 110% with an average of 94.5%. Recoveries of TCP from all fortified dates (0.1 and 0.2 ppm) ranged from 79 to 99% with an average of 86%. Limits of detection for chlorpyrifos and TCP in green, unprocessed, and processed dates were 0.02 and 0.05 ppm, respectively.


[Association between IL-6 C-572G and susceptibility to spontaneous preterm birth].
To investigate the association between the genetic polymorphism of IL-6 C-572G and susceptibility to spontaneous preterm birth (SPTB). The subjects were from Beijing and the surrounding areas of Beijing. This case-control study enrolled 569 SPTB infants, including 56 extremely preterm (<28 weeks of gestation), 166 very preterm (28-31+6 weeks of gestation) and 347 moderate to late preterm infants (32 to 36+6 weeks of gestation). A total of 673 term infants were enrolled as the control group. The latest Sequenom MassARRAY®SNP detection technique was used for the typing of single nucleotide polymorphism of IL-6 C-572G. Compared with the CC genotypes, the IL-6 C-572G G-positive genotype (CG+GG genotype) was significantly associated with an increased susceptibility to moderate to late SPTB (OR=1.35, 95%CI: 1.01-1.80, P=0.04). Among the Chinese population, IL-6 C-572G polymorphism is associated with susceptibility to moderate to late SPTB.


Three-dimensional human bile duct formation from chemically induced human liver progenitor cells.
Background: The intrahepatic bile ducts (BDs) play an important role in the modification and transport of bile, and the integration between the BD and hepatocytes is the basis of the liver function. However, the lack of a source of cholangiocytes limits in vitro research. The aim of the present study was to establish three-dimensional BDs combined with human mature hepatocytes (hMHs) in vitro using chemically induced human liver progenitor cells (hCLiPs) derived from hMHs. Methods: In this study, we formed functional BDs from hCLiPs using hepatocyte growth factor and extracellular matrix. BDs expressed the typical biliary markers CK-7, GGT1, CFTR and EpCAM and were able to transport the bile-like substance rhodamine 123 into the lumen. The established three-dimensional BDs were cocultured with hMHs. These cells were able to bind to the BDs, and the bile acid analog CLF was transported from the culture medium through the hMHs and accumulated in the lumen of the BDs. The BDs generated from the hCLiPs showed a BD function and a physiological system (e.g., the transport of bile within the liver) when they were connected to the hMHs. Conclusion: We present a novel in vitro three-dimensional BD combined with hMHs for study, drug screening and the therapeutic modulation of the cholangiocyte function.


Robot evolutionary localization based on attentive visual short-term memory.
Cameras are one of the most relevant sensors in autonomous robots. However, two of their challenges are to extract useful information from captured images, and to manage the small field of view of regular cameras. This paper proposes implementing a dynamic visual memory to store the information gathered from a moving camera on board a robot, followed by an attention system to choose where to look with this mobile camera, and a visual localization algorithm that incorporates this visual memory. The visual memory is a collection of relevant task-oriented objects and 3D segments, and its scope is wider than the current camera field of view. The attention module takes into account the need to reobserve objects in the visual memory and the need to explore new areas. The visual memory is useful also in localization tasks, as it provides more information about robot surroundings than the current instantaneous image. This visual system is intended as underlying technology for service robot applications in real people's homes. Several experiments have been carried out, both with simulated and real Pioneer and Nao robots, to validate the system and each of its components in office scenarios.


Flowing through Gastrointestinal Barriers with Model Nanoparticles: From Complex Fluids to Model Human Intestinal Epithelium Permeation.
Most nanomaterial-based medicines are intravenously applied since oral administration comprises challenging-related biological obstacles, such as interactions with distinct digestive fluids and their transport through the intestinal barrier. Moreover, there is a lack of nanoparticle-based studies that faithfully consider the above-cited obstacles and boost oral-administered nanomedicines' rational design. In this study, the physicochemical stability of fluorescent model silica nanoparticles (f-SiO2NPs) passing through all simulated gastrointestinal fluids (salivary, gastric, and intestinal) and their absorption and transport across a model human intestinal epithelium barrier are investigated. An aggregation/disaggregation f-SiO2NPs process is identified, although these particles remain chemically and physically stable after exposure to digestive fluids. Further, fine imaging of f-SiO2NPs through the absorption and transport across the human intestinal epithelium indicates that nanoparticle transport is time-dependent. The above-presented protocol shows tremendous potential for deciphering fundamental gastrointestinal nanoparticles' evolution and can contribute to rational oral administration-based nanomedicine design.


Energy metabolism in infants with cystic fibrosis.
To determine whether a defect in energy metabolism exists in infants with cystic fibrosis (CF). Unselected, newly-diagnosed subjects with CF (n = 46) and 24 healthy infants aged <20 weeks had measurements of resting energy expenditure (REE), total energy expenditure (TEE) (n = 25), and body composition. Metabolizable energy intake (MEI) was calculated. Genotype, energy intake, and pancreatic status was determined in all subjects with CF, and 24 underwent bronchial lavage. At diagnosis, infants with CF detected by newborn screening had significant anthropometric deficits (mean [SD] z-weight = 0.5 [1.0], z-length = 0.7 [1.3]) associated with pancreatic insufficiency. Their REE, TEE, or MEI (absolute measurements, per unit body weight or fat-free mass) were not increased. No relationship between REE, TEE, or MEI and Delta F(508) genotype, and no proportional differences in individual components of MEI between subjects with CF and controls, or between subjects with CF who were homozygotes or compound heterozygotes for Delta F(508) were observed. REE and TEE were not correlated with bronchial infection or inflammation. Growth impairment during the first weeks of life in infants with CF is associated with pancreatic insufficiency. However, there is no evidence for a defect of energy metabolism related to Delta F(508), and in infants with CF, minimal lung disease is unaccompanied by increased energy expenditure.


Improvement of cardiac function after treatment with octreotide followed by trans-sphenoidal surgery in an acromegalic patient who presented with congestive heart failure.
Cardiovascular disease is a major cause of mortality and morbidity in patients with acromegaly. We describe the case of a 43-year-old man with acromegaly who presented with severe congestive heart failure. Treatment with the somatostatin analog octreotide improved cardiac function with an increase in left ventricular ejection fraction (LVEF) from 11% to 27%. LVEF further increased to 43% after trans-sphenoidal surgery. Recovery was uneventful. We emphasize the need for early diagnosis and effective treatment of acromegaly to prevent cardiovascular complications. Octreotide therapy or trans-sphenoidal surgery, if possible, should be considered to control cardiac function even in acromegalic patients with severe congestive heart failure.


Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors.
Different immunohistochemical sex cord-stromal markers have been previously studied in various types of ovarian sex cord-stromal tumors; however, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors compared with other tumors in this spectrum of neoplasms. The goals of this study were to determine which immunohistochemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor, and to establish whether there are substantial differences of expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers which have known variable specificity for sex cord-stromal lineage [inhibin, calretinin, MART-1/melan-A, CD99, steroidogenic factor 1 (SF-1, adrenal 4-binding protein), and WT1], were performed in 127 cases of 5 different types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). All cases in each type of sex cord-stromal tumor expressed SF-1. Inhibin and calretinin were expressed in all groups of tumors but with a lesser frequency (56% to 100% and 36% to 100% of cases, respectively). All types of tumors except steroid cell tumor expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. The only tumor groups that showed expression of MART-1 were Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor (94% and 96% of cases, respectively). The type of sex cord-stromal tumor that was least frequently positive for several of the different markers studied was fibroma/fibrothecoma. Among all tumor groups combined, inhibin and WT1 were the 2 markers showing the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (immunohistochemical composite score: possible range, 1 to 12) varied between tumors: adult granulosa cell tumor-inhibin (score 10.0); Sertoli cell tumor-WT1 (score 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)-WT1 (score 10.4); steroid cell tumor-inhibin (score 11.2); and fibroma/fibrothecoma-WT1 (score 8.9). We conclude that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each of the different types of sex cord-stromal tumors has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors with certain exceptions (eg, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma). SF-1 is the most sensitive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the findings relating to sensitivity and extent of expression in this study, and known specificity in the literature, the most informative sex cord-stromal markers to be used for the distinction from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1 (the exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist); however, the utility of immunohistochemistry for the diagnosis of fibroma/fibrothecoma is somewhat limited.


Tumor Infiltrating T Lymphocytes and Apoptosis in Colorectal Cancer.
Dysfunction of the immune system in colorectal cancer (CRC) can be due to a number of reasons including apoptosis of tumour infiltrating lymphocytes (TILs). The aims of this study was to investigate TILs in colorectal cancer and characterize apoptosis of TILs using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for detecting DNA fragments. We used monoclonal antibodies (mAbs) to T lymphocytes to detect TILs and double immunohistochemistry to assess apoptosis. T lymphocytes were detected in the immune infiltrate in CRC. TUNEL staining disclosed a high level of cell death among TILs. Apoptosis of T lymphocytes showed significant correlation with Dukes' stage (P = 0.02), lymphatic metastasis (P = 0.03), vascular metastasis (P = 0.01), lymph node metastasis (P = 0.02) and age of patient (P = 0.01). In conclusion, CRC may elude immunological surveillance by inducing apoptosis of TILs.


Psychodynamic variables as predictors of psychotherapy outcome.
Predicting the outcome of psychotherapy is a central concern in psychiatry. Twenty-one medical students seeking psychotherapy were evaluated on a number of psychodynamic and process variables using self-report scales and scales completed by the therapist before, during, and after psychotherapy. There were significant differences between patients and a comparison group on eight variables before therapy. Ten psychodynamic variables (six representing ego defense mechanisms) and four process variables were found to be highly correlated with outcome measures; the process variables were the best predictors of outcome. The data support the use of psychodynamic and process variables as predictors of outcome in psychoanalytically oriented psychotherapy.


Effects of xanthene dyes in cattle diets for insect control: diet digestibility and fecal excretion.
The effects of rose bengal, erythrosin B and fluorescein on ruminant digestion were evaluated by an in vitro rumen technique. Rose bengal reduced in vitro dry matter disappearance (IVDMD) values starting at .5 mM in the nutrient media and erythrosin B reduced IVDMD values starting at .05 mM in the nutrient media. Maximum reduction in IVDMD values was observed at 3.0 mM of rose bengal and erythrosin B. Fluorescein depressed digestion but not as severely as rose bengal or erythrosin B. Dry matter digestibility (DMD) values for steers given erythrosin B at a daily dosage of 6.5 mg/kg body weight were higher (P less than .05) than DMD values for control steers. DMD values were higher for steers given 16.3 or 26.1 mg erythrosin B/kg body weight daily than for the control steers, but the differences were not significant. There were no significant differences among animals given the different dosages in digestible energy. Recovery of erythrosin B from feces of treated steers varied with time, indicating that steers fed erythrosin B at a dosage of 6.5 mg/kg body weight might excrete feces during some periods of the day which would not control face fly development; however, administration of erythrosin B at a dosage of 16.3 mg/kg body weight would provide enough erythrosin B in feces to control face fly development throughout a 24-h period.


The role of the Lkb1/AMPK pathway in hematopoietic stem cells and Leukemia.
The liver kinase B1 (Lkb1)/AMP-activated protein kinase (AMPK) pathway maintains metabolic homeostasis of cells by promoting catabolism and inhibiting anabolism. Activation of this pathway induces tumor suppressors, including p53, and leads to inhibition of the mammalian target of rapamycin pathway, which often is overactivated in multiple cancers. Thus, the Lkb1/AMPK pathway suppresses cancer by negatively regulating cell proliferation. However, recent studies of mouse hematopoietic stem cells (HSCs) revealed that Lkb1 is critical for maintaining HSCs, rather than limiting their proliferation. Furthermore, the role of AMPK in cancer cells has remained elusive. Outstanding questions concern the role of the Lkb1/AMPK pathway in regulating the metabolism and proliferation of cancer cells within a physiological setting. This review focuses on the function of the Lkb1/AMPK pathway in HSCs and leukemia and provides an overview of the therapeutic strategies aimed at targeting this pathway in cancer.


Prognostic factors for perceived pain and function at one-year follow-up in primary care patients with neck pain.
To identify prognostic factors for perceived pain and function with focus at one-year follow-up in primary care patients treated for non-specific neck pain. A prospective study was performed including 193 neck pain patients. Before and after treatment period, and 12 months after the start date for treatment, patients completed a questionnaire including background data and aspects of pain, function and general health. Linear multiple regression analysis was used to identify prognostic factors with the dependent variables Oswestry score and pain intensity at 12-month follow-up. Response rate 81%. At 12-month follow-up, Oswestry score identified four prognostic factors: pain intensity; well-being; expectations of treatment; and duration of current episode. Adjusted R2 for the model was 0.32, and 20% of the patients had three of the four prognostic factors at entry, indicating risk of poor outcome. The dependent variable pain intensity revealed three prognostic factors: Oswestry score; duration of current episode; and similar problem during the previous five years. Adjusted R2 was 0.24, and 60% of the patients had two of the three prognostic factors at entry, indicating risk of poor outcome. Different prognostic factors (with the exception of duration of current episode) were identified by the two outcome variables. Thus the results suggest that it should be taken into account whether an impairment or disability outcome is used.


[Efficacy and safety of balloon valvuloplasty as a treatment of choice for pulmonary stenosis in children and adolescents].
Pulmonary artery stenosis (PS) is a congenital heart defect which occurs in 10% of all congenital heart defects. Pulmonary balloon valvuloplasty (BVP) has been the treatment of choice of PS over the last 30 years. The purpose of this study was to evaluate the effi- cacy of this method based on middle-term hospital follow-up, and safety of BVP based on our experience. The study included 88 patients diagnosed with PS.The patients were divided into three groups based on the severity of the disease. Also, they were divided into two age groups in order to analyze the frequency of complications. Hemodynamic measurements and echocardiography results were recorded before, 24-36 hours after BVP and at the end of follow-up. The studied group involved patients of average age 3.75 ± 4.3 years (20 days to 17 years). Immediately after BVP a significant decrease of pressure gradient across the pulmonary valve (PV) was recorded in all patients; this result was similar in all 3 groups of patients regardless of the severity of stenosis (p < 0.001). Complications of BVP occurred most commonly in children up to 12 months of age (ventricular tachycardia 4.5% and supraventricular tachycardia 6.8%). Pulmonary valve in- sufficiency after dilatation occurred in 6.6% of cases, and was most common in children aged up to 12 months. In 87 (98.9%) patients BVP was a definitive solution, and a significant residual stenosis was not recorded during follow-up. BVP is a safe and effective procedure in the treatment of isolated PS in children, regardless of the severity of stenosis but also regardless of patients' age.


Red cell or serum folate: what to do in clinical practice?
Folate deficiency has been linked to diverse clinical manifestations and despite the importance of accurate assessment of folate status, the best test for routine use is uncertain. Both serum and red cell folate assays are widely available in clinical laboratories; however, red cell folate is the more time-consuming and costly test. This review sought to evaluate whether the red cell assay demonstrated superior performance characteristics to justify these disadvantages. Red cell folate, but not serum folate, measurements demonstrated analytical variation due to sample pre-treatment parameters, oxygen saturation of haemoglobin and haematocrit. Neither marker was clearly superior in characterising deficiency but serum folate more frequently showed the higher correlation with homocysteine, a sensitive marker of deficiency. Similarly, both serum and red cell folate were shown to increase in response to folic acid supplementation. However, serum folate generally gave the greater response and was able to distinguish different supplementation doses. The C677T polymorphism of methylenetetrahydrofolate reductase alters the distribution of folate forms in red cells and may thereby cause further analytical variability in routine red cell folate assays. Overall, serum folate is cheaper and faster to perform than red cell folate, is influenced by fewer analytical variables and provides an assessment of folate status that may be superior to red cell folate.


Dosage effects and individual responsivity to methylphenidate in attention deficit disorder.
Effects of three dosages of methylphenidate (0.15, 0.30 and 0.60 mg/kg) were assessed in 19 ADD-H children on a variety of cognitive, academic and behavioral measures in the laboratory and the classroom. A predominant linear pattern of improvement was found across almost all measures. A slight decrease between 0.3 and 0.6 mg/kg on one cognitive task leaves open the possibility that higher dosages reduce stimulant effectiveness or cause decrements on some kinds of "high-level/high load" tasks. Response patterns of individual children varied considerably across measures. All children improved on at least several measures. Results were interpreted as evidence for stimulant activation of self-regulatory processes.


Genetic predispositions of Parkinson's disease revealed in patient-derived brain cells.
Parkinson's disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson's genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson's patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson's disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson's patients may guide future personalized drug screens in preclinical research.


Pharmacokinetics of marbofloxacin after intravenous and intramuscular administration in Hanwoo, Korean native cattle.
Pharmacokinetic (PK) parameters of marbofloxacin (MRFX) in Korean cattle, Hanwoo, were determined following its intravenous (i.v.) or intramuscular (i.m.) administration at a dose of 2 mg/kg. Area under the curve (AUC0-24 hr), half-life (t1/2) and total body clearance (CLB) of i.v. MRFX were 6.87 hr∙µg/ml, 2.44 hr and 0.29 l/kg∙hr, respectively, and the corresponding values for i.m. administration of MRFX were 5.07 hr∙µg/ml, 2.44 hr and 0.39 l/kg∙hr. The suggested optimal doses of MRFX in Hanwoo cattle, calculated by integration of PK data obtained in the present study and previously reported minimum inhibitory concentration (MIC) for MRFX against susceptible (MIC ≤1 µg/ml) and intermediate (MIC ≤2 µg/ml) pathogenic bacteria, were 2.1 and 4.2 mg/kg/day by i.v. route and 3.9 and 7.8 mg/kg/day by i.m. route.


Idiopathic autoimmune thrombocytopenia purpura in a 12-year-old boy.
A 12 year old boy presented to the emergency room with chief complaints of nosebleed and petechiae on lower and upper extremities. The case was adopted for an assignment in a junior level Library Research and Case Studies Presentations course in a distance learning CLS curriculum. The study describes the patient's presentation and differential diagnosis based on laboratory results. The disease background is provided and treatment options are outlined.


Trichophagia and trichobezoar: case report.
Trichobezoar consists of a compact mass of hair occupying the gastric cavity to a various extent. When the trichobezoar extends past the duodenum it is better referred to as Rapunzel Syndrome. Although trichobezoars are well described in terms of surgical diagnostic and procedure, there are only but very scarce reports on psychiatric literature, usually associated with trichotillomania. The authors present a clinical case of trichobezoar and discuss the most relevant aspects concerning this entity. Presentation of psychiatric and surgical data concerning the case report. Previously reported cases are also mentioned. Report of a 27-year-old female patient with a trichobezoar submitted to surgical removal, with a prior intervention 4 years before also due to trichobezoar, and with unknown psychiatric antecedents or follow-up. A trichobezoar represents a serious surgical condition. It is important to consider such diagnosis in face of suggestive symptoms, even if signs of trichotillomania are not present. The discrepancies between the prevalence of trichotillomania and trichobezoars due to trichophagia may be due to issues related to self-selection of patients and symptom severity. Such issues may also be important in the study of impulsive-compulsive spectrum models and to their relevance to impulse control disorders.


Comprehensive imaging of C-2W plasmas: Instruments and applications.
The C-2W device ("Norman") [Gota et al., Nucl. Fusion 59, 112009 (2019)] has produced and sustained beam-driven field-reversed configuration (FRC) plasmas embedded in a magnetic mirror geometry using neutral beams and end-bias electrodes located in expander divertors. Several discrete vessels comprise this device, and many imaging instruments are required in order to view the plasma throughout. To meet this need, a suite of spatially and radiometrically calibrated, high-speed camera systems have been deployed. Besides global visualization of the plasma evolution and macro-stability, this imaging suite has been used in a variety of applications. One example application is a tomographic reconstruction of passive impurity emission. Calculation of the magnetic field in the equilibrium vessel is complicated by eddy currents in conducting structures and internal currents in the high-β FRC plasma. In addition, thus far non-perturbative measurements of internal field have not been available. The tomographic reconstruction of O4+ impurity emission enables an independent visualization of the plasma geometry, serving as a check on magnetic modeling and indirect evidence for field reversal within the FRC. A second application uses the cameras to view the Balmer-α emission throughout the plasma in order to estimate the ionization rate in each region. These rates can then be incorporated into particle balance calculations and a circuit model for currents from the end-bias electrodes. Finally, arcing on the electrode surfaces is identified through automated image processing of carefully selected spectral line emission.


Septic scarlet fever due to Streptococcus pyogenes cellulitis.
We report three cases of septic scarlet fever due to Streptococcus pyogenes Group A (serotype M1/T1/OF-) cellulitis in healthy young adults. Despite prompt treatment two of the patients died. Such cases of cellulitis associated with scarlet fever, severe toxaemia and septicaemia have not been reported in the post-antibiotic era.


Hepatic mixed function oxidase system and enzymatic glucose metabolism in rats.
Therapy with enzyme inducing drugs may improve glycemic control in patients with non-insulin-dependent diabetes mellitus. We evaluated the role of a mixed function oxidase system on glucose metabolism with an animal model. Rats were treated with an inducer (phenobarbital), an inhibitor (cimetidine) and a hepatotoxin (carbon tetrachloride) for a week to cause alterations in the liver. The mixed function oxidase system was assayed by determination of the cytochrome P-450 content and NADPH cytochrome c reductase in liver. Carbohydrate metabolism was evaluated by determining blood glucose, enzymes associated with glucose phosphorylation in the liver (glucokinase, hexokinase), glucose storage as glycogen and enzymatic delivery, glucose-6-phosphatase, and peripheral tissue by determining phosphorylating enzyme (hexokinase) and a key glycolytic enzyme (pyruvate kinase) and glycogen content in muscles. The therapy with the inducer enhanced glucose utilization in liver and storage in muscles. The inhibitor decreased the mixed function oxidase system, reduced glucose phosphorylating, but not gluconeogenetic enzymes, in the liver and increased glycolysis in muscles. Carbon tetrachloride, a hepatotoxin, impaired mixed function oxidase, glucose phosphorylating and delivering enzyme activity in liver, reduced blood glucose and caused glycogen accumulation in muscles. The function of liver microsomal enzyme system seems to be closely related to enzymatic glucose metabolism in the liver and muscles.


Association of Biochemical and Hematological Parameters With Enteric Fever Infection at the Dschang Regional Annex Hospital, Cameroon: A Cross-Sectional Study.
Background Enteric fever is a systemic infection in humans caused by the Gram-negative bacilliSalmonella enterica serovars Typhi and Paratyphi. Although the diagnosis typically involves the isolation of Salmonella enterica serovars, it is often determined based on laboratory findings and clinical observations. However, due to the wide variety and the non-specific character of clinical features, making a definitive diagnosis presents numerous challenges. Therefore, the aim of this study was to find the predictive hematological and biochemical parameters which would serve in the diagnosis, prognosis, and treatment of typhoid fever cases. Methodology A cross-sectional study was conducted from November 2020 to September 2021 on1076consented volunteerparticipants. Stool culture and identification tests enabled us to distinguish three groups including 423 Salmonella Typhi positive patients, 115 S. Paratyphi positive patients, and 538 Salmonella negative participants. Biochemical and hematological parameters were evaluated using standard methods from commercial kits and Sysmex KX-21N automated hematology analyzer, respectively. A multiple logistic regression analysis was performed to identify the validity of the hematological and biochemical characteristics for enteric fever diagnosis. Results Multiple logistic regression showed hyper creatininemia, hypoalbuminemia, hyper total proteinemia, hyper alkaline phosphatase (ALP), hyper alanine aminotransferase (ALT), hyper total bilirubinemia, hyper conjugated bilirubinemia, hyper triglyceridemia, hyper C-reactive protein (CRP), leukopenia, thrombocytopenia, lymphopenia, monocytopenia, low hemoglobin, low hematocrit, low mean corpuscular volume (MCV), low mean corpuscular hemoglobin (MCH), low platelet, low platelet crit level, high platelet distribution width (PDW) level, high erythrocyte sedimentation rate 1 (ESR1) level as significant biological abnormalities associated (odds ratio {OR} > 1; p < 0.05) with enteric fever infection. Similarly, hyper ESR2 was an independent predictor (OR > 1; p < 0.05) of S. Typhi infection. However, a negative and significant association (OR < 1; p < 0.05) was recorded between enteric fever infection and high mean platelet volume (MPV). Conclusion Overall the results of the biochemical and hematological profiles can serve as potential diagnostic markers for typhoid fever. These markers can also be useful in the appropriate management of those with enteric fever, preventing severity and limiting outcomes of mortality.


Patient-led follow-up reduces outpatient doctor visits and improves patient satisfaction. One-year analysis of secondary outcomes in the randomised trial Follow-Up after Rectal CAncer (FURCA).
FURCA (Follow-Up after Rectal Cancer) is a multi-centre randomised trial comparing patient-led follow-up with standard outpatient follow-up. This paper reports one-year follow-up data from the FURCA trial on selected secondary outcomes including type and number of contacts, patient-reported involvement and satisfaction with health care services during follow-up. Patients with rectal cancer (stage < IV) from four Danish surgical centres were randomised (1:1) into intervention (education and self-referral to project nurse) or standard follow-up (routine clinical doctor visits). The present analysis involved data on hospital contacts during the first year after surgery, patient involvement and satisfaction measured at one year, and baseline patient-reported and clinical variables. Of 512 eligible patients, 168 were allocated to patient-led follow-up (intervention) and 168 to standard follow-up (control). The total number of hospital contacts in the intervention arm did not differ significantly from the number of contacts in the control arm (p = 0.44). More patients had ≥15 contacts in the intervention arm than in the control arm (p = 0.004). The total number of outpatient doctor visits was significantly lower in the intervention arm (p < 0.001). Patients in both arms rated involvement and satisfaction high; yet patients in the intervention arm scored significantly higher on two of six items regarding involvement and all five items regarding satisfaction. Of the 168 patients in the intervention arm, 43% made direct contact (self-referral) to the project nurse, and 14 of these patients (8%) had ≥4 contacts. The primary reason for self-referral was bowel dysfunction. The findings indicate the value of a patient-led follow-up program in terms of direct access and more individually tailored intervention based on patients' needs, with most tasks being managed by nurses. Patient-led follow-up came with improved patient-perceived involvement and satisfaction; thus, it was both acceptable and favourable for the patients.


A review of the infectious diseases of African wild ruminants.
The important viral, protozoal and bacterial diseases of wild African ruminants are reviewed. Special attention is paid to the epidemiological factors that determine the role played by these animals in the transmission of diseases to domestic stock. Examples of the converse situation where livestock serve as a source of infection for wild ruminants are also given.


Role of a non-committed accessory cell in the in vivo suppression of a syngeneic tumour by immune lymphocytes.
CBA/J mice bearing a methylcholanthrene-induced sarcoma exhibited concomitant immunity to the tumour. The cellular basis for this immunity was investigated by local transfer of mixtures of lymphoid and tumour cells into the footpads of syngeneic mice. Peritoneal exudate cells obtained from tumour-bearing mice 1 day after intraperitoneal injection of saline had a marked tumour-suppressive effect, whereas normally resident peritoneal cells did not. Peritoneal exudate cells from which adherent cells had been removed ('lymphocytes') had a suppressive effect at high or low lymphocyte: tumour cell ratios in normal recipients. In irradiated (450 R) recipients the lymphocytes were suppressive at high ratios only. At low ratios the lymphocytes were suppressive only if the irradiated recipients had been partially shielded or if the lymphocytes were admixed with peritoneal exudate cells from normal mice. It is concluded that an amplifying mechanism, possibly involving macrophages, can operate in tumour cell suppression initiated by immune lymphocytes.


Characterization and Comparative Analysis of Complete Chloroplast Genomes of Three Species From the Genus Astragalus (Leguminosae).
Astragalus is the largest genus in Leguminosae. Several molecular studies have investigated the potential adulterants of the species within this genus; nonetheless, the evolutionary relationships among these species remain unclear. Herein, we sequenced and annotated the complete chloroplast genomes of three Astragalus species-Astragalus adsurgens, Astragalus mongholicus var. dahuricus, and Astragalus melilotoides using next-generation sequencing technology and plastid genome annotator (PGA) tool. All species belonged to the inverted repeat lacking clade (IRLC) and had similar sequences concerning gene contents and characteristics. Abundant simple sequence repeat (SSR) loci were detected, with single-nucleotide repeats accounting for the highest proportion of SSRs, most of which were A/T homopolymers. Using Astragalus membranaceus var. membranaceus as reference, the divergence was evident in most non-coding regions of the complete chloroplast genomes of these species. Seven genes (atpB, psbD, rpoB, rpoC1, trnV, rrn16, and rrn23) showed high nucleotide variability (Pi), and could be used as DNA barcodes for Astragalus sp. cemA and rpl33 were found undergoing positive selection by the section patterns in the coded protein. Phylogenetic analysis showed that Astragalus is a monophyletic group closely related to the genus Oxytropis within the tribe Galegeae. The newly sequenced chloroplast genomes provide insight into the unresolved evolutionary relationships within Astragalus spp. and are expected to contribute to species identification.


Occurrence of selected pharmaceuticals and caffeine in sewage treatment plants and receiving rivers in Beijing, China.
The occurrence of nine different types of pharmaceuticals and caffeine were analyzed in various units of three wastewater treatment plants (WWTPs) and their receiving rivers in Beijing, China. Analyte concentrations were determined using ultra performance liquid chromatograph-tandem quadruple mass spectrometers (UPLC-MS/MS) and multiple-reaction monitoring. The studied pharmaceuticals and caffeine were found in all the WWTPs and receiving rivers. Their concentrations in the WWTP influents varied from 38 ng/L of sulpiride to 89.5 microg/L of caffeine, and those in the effluents ranged from 27 ng/L of sulpiride to 2.7 microg/L of erythromycin. Typically, the biological treatment appeared more effective in the removal of pharmaceuticals and caffeine than primary treatment in a WWTP. For an individual compound, the overall removal efficiency varied from one WWTP to the next. Mean values ranged from no removal of carbamazepine to 99.8% removal of caffeine. Most of the compounds in the receiving rivers were present at similar or higher concentrations compared to those in the WWTP effluents. The data set for this study does not include variations in concentrations along receiving waters because there were other point and nonpoint sources discharging to these rivers. The preliminary aquatic environmental risk assessment showed that carbamazepine, erythromycin, and trimethoprim is a potential chronic environmental risk in water bodies in Beijing, China, and is worth further investigation.


3D feedback and observation for motor learning: Application to the roundoff movement in gymnastics.
In this paper, we assessed the efficacy of different types of visual information for improving the execution of the roundoff movement in gymnastics. Specifically, two types of 3D feedback were compared to a 3D visualization only displaying the movement of the expert (observation) as well as to a more 'traditional' video observation. The improvement in movement execution was measured using different methods, namely subjective evaluations performed by official judges, and more 'quantitative appraisals based on time series analyses. Video demonstration providing information about the expert and 3D feedback (i.e., using 3D representation of the movement in monoscopic vision) combining information about the movement of the expert and the movement of the learner were the two types of feedback giving rise to the best improvement of movement execution, as subjectively evaluated by judges. Much less conclusive results were obtained when assessing movement execution using quantification methods based on time series analysis. Correlation analyses showed that the subjective evaluation performed by the judges can hardly be predicted/ explained by the 'more objective' results of time series analyses.


[Epidemiology of prostate cancer from three centers and analysis of the first-line hormonal therapy for the advanced disease].
To analyze the epidemiology information of prostate cancer from three centers of Beijing, Shanghai, Guangzhou, and to reflect the current situation of prostate cancer in China, and to analyze the information of 272 patients with advanced prostate cancer who received hormonal therapy to find the prognostic factors of hormone therapy. Collect the information of 525 patients with prostate cancer from three centers. Two hundred and seventy-two cases of advanced prostate cancer with full information were selected from the 525 cases to analyze the prognostic factors of hormone therapy. Three hundred and fifty-seven cases (68.0%) had advanced disease at diagnosis and 80.2% patients received hormone therapy as the main therapy. Prognostic analysis indicated that Gleason score, bone metastasis and prostate specific antigen nadir were independent prognostic factors of progression-free survival time. In this report, most patients are advanced prostate cancer at diagnose, and hormonal therapy is the main therapy. Gleason score, bone metastasis, prostate specific antigen nadir are independent prognostic factors of advanced prostate cancer after hormone therapy.


Retroperitoneal or mesenteric primary liposarcoma: clinical and prognostic evaluations on five cases.
Retroperitoneal or mesenteric primary liposarcoma is a malignant neoplasia whose prognosis depends on the biological variants, the radical resection surgery and the histological subtypes, as well as on local and remote recurrences. Liposarcoma is the most common variant of this tumour among tumours of soft retroperitoneal tissue. The purpose of this study is to evaluate whether the treatment of this disease, carried out at the Ivrea Hospital for urgent reasons, may be considered in line with the experience of high-volume Centres. Between 1982 and 2016 five patients were hospitalized with a diagnosis of acute abdomen due to retroperitoneal or mesenteric primary liposarcoma: one myxoid of the mesentery, one well-differentiated of lesser epiploon, one well-differentiated of mesentery, and two dedifferentiates of the retroperitoneum. The five patients, all males, had a average age of 59 years (range 48-86) and were all subjected to general anaesthesia and open technique for total tumour removal. Only the patient with the myxoid liposarcoma had two recurrences. All are alive and healthy after a follow-up of 177 months (range 9-420). These tumours should be removed radically, if necessary in conjunction with contiguous organs. Rarity and therapeutic complexity require a treatment, sometimes even multimodal, in highvolume centres. Patients admitted in General Surgery Unit for unpostponable urgency should be operated by surgeons experienced in the treatment of abdominal disease to achieve survival results in line to those achievable in Hub Centres.


Alkylphosphocholines as Promising Antitumor Agents: Exploring the Role of Structural Features on the Hemolytic Potential.
Alkylphosphocholines (APC) are promising antitumor agents, which have the cellular membrane as primary target; however, red blood cell damage limits their wide therapeutic use. A variety of APC analogs has been synthesized and tested showing less hemolytic effect than the class prototype, Miltefosine (HePC). In this work, chemometric methods were applied to a set of 34 APC derivatives to identify the most relevant structural and molecular features of hemolytic activity. The APC derivatives were divided into three groups: (i) N-methylpiperidine and N-methylmorpholine derivatives with a long alkyl chain or flexible cyclopentadecyl rings, displaying a hemolytic rate of 17 %; (ii) adamantyl and cyclopentadecyl derivatives, showing an average hemolysis of 39 %; and, N,N,N-trimethylammonium, trans-N,N,N-trimethylcyclohexanamine, and trans-N,N,N-trimethylcyclopentanamine derivatives, whose average hemolysis was 41 %. The findings suggested that the presence of either bulky cationic head groups, or rings such as adamantyl and cyclohexyl, primarily increases the hemolysis of compounds with eleven atoms in the alkyl chain. Moreover, the macrocyclic cyclopentadecyl seems to be important to the hemolytic potential especially of compounds with five carbon atoms in the alkyl chain. Regarding linear carbon chain derivatives with no ring substitution, less bulky cationic head groups seem to favor hemolysis. Thus, in order to design more potent and less toxic APC antitumors, the reported structural/molecular patterns should not be included in their structure.


Allodynia after lateral-medullary (Wallenberg) infarct. A PET study.
We used PET to study regional cerebral blood flow (rCBF) changes in nine patients with unilateral central pain after a lateral medullary infarct (Wallenberg's syndrome). All patients presented, on the abnormal side, a combination of hypaesthesia to noxious and thermal stimuli and allodynia to rubbing of the skin with a cold object (i.e. abnormal pain to innocuous stimulation). The rCBF responses during allodynia were compared with those obtained during stimulation of the normal side using (i) a cold non-noxious stimulus identical to that applied to the painful side, and (ii) an electrical high-frequency stimulus at painful ranges. Statistical analysis disclosed two abnormal patterns of rCBF change during allodynia. First, there is a quantitative change whereby the blood flow response was out of proportion with the actual intensity of the stimulus, i.e. the pattern of activation by innocuous rubbing of the skin was in our patients identical to that previously reported in response to painful stimuli in normal subjects. This pattern concerned primarily the contralateral thalamus in its lateral half and the primary and somatosensory areas, as well as inferior parietal [Brodmann area (BA) 39/40], anterior insular (BA 6) and medial prefrontal (BA 10) cortices. Thalamic over-activity may reflect abnormal transduction and amplification of sensory inputs after spinothalamic deafferentation. This might be responsible for both increased rCBF in multiple cortical targets and the perceived shift of stimulus intensity from innocuous to painful ranges. The second abnormality associated with allodynic sensation was qualitative. It concerned exclusively the contralateral cingulate gyrus, which did not exhibit the usual pain-related rCBF increase reported in normal subjects. This abnormal cingulate response may account for the peculiar response of lateral medullary infarct patients to allodynic pain, which is not simply perceived as an exaggerated pain sensation, but as a new, strange and extremely unpleasant feeling, not previously experienced by the patients.


Organ Sparing Surgery for Penile Cancer: A Systematic Review.
Although penile cancer represents only 1% of all male cancers, the traditional treatment, total or subtotal penectomy, carries devastating psychological and functional outcomes. Organ sparing surgery is an attractive option if it can provide satisfactory cancer control equivalent to or nearly equivalent to standard techniques. This approach is meeting increasing acceptance. We offer a timely comprehensive review to increase awareness of these procedures and their applicability, to evaluate the techniques objectively and to provide guidance to the practicing urologist. A PubMed® search was conducted using the key words "organ sparing/conserving" in "penile cancer" alone or in combination with "partial penectomy," "glansectomy," "glans resurfacing," "penile reconstruction," "laser," "Mohs," "outcomes" and "quality of life." Many techniques of organ sparing surgery in patients with penile cancer have been described through the years. To be practical and useful, a requirement of all these procedures is achievement of complete tumor excision confirmed by negative intraoperative frozen section and final pathological margins. Although organ sparing surgery carries a greater risk of local recurrence than penile amputation, overall patient survival is generally unaffected. Following strict indications and appropriate patient selection cancer specific survival after organ sparing surgery is equivalent to that of established techniques with the added benefits of improved quality of life and more acceptable morbidity. In properly selected patients with penile cancer organ sparing surgery provides comparable oncologic outcomes to conventional techniques, including total and subtotal amputations. Many patients are able to urinate while standing and a significant number are able to have intercourse.


The development of process-specific risk assessment and control in Germany.
After reading the series of articles on a new approach to controlling chemicals, an initiative targeted especially on small and medium-sized businesses, in the Annals of Occupational Hygiene (1998; 42: 355-411), German specialists for health and safety at work realized that problems in this area are very similar in the UK and Germany. Also, in Germany different institutions have developed an array of solutions to help small and medium-sized enterprises during recent years. In this paper, we present these activities and hope to promote an international discussion about practical support for work with chemical substances.


A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology.
The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.


[Genetics of congenital adrenal hyperplasia caused by steroid-21-hydroxylase deficiency: present-day aspects].
Congenital adrenal hyperplasia caused by a deficiency of 21-hydroxylase is an inherited disorder of adrenal steroidogenesis. In this study, the deficiency incidence is presented according to different author's and countries' results. Nowadays knowledge concerning its genetics are reviewed, especially HLA linkage. Allelic variants of deficiency and the "linkage disequilibrium" with HLA complete antigens are described. Finally, the main applications of that knowledge are presented: heterozygote detection and prenatal diagnosis.


Preexposure Prophylaxis in Latin America and the Caribbean-The Barbados Experience.
This study explored oral pre-exposure prophylaxis (PrEP) awareness, and sexual behavior of gay, bisexual, and other men who have sex with men (gbMSM) in Barbados. Factors associated with PrEP use were examined using Pearson chi-square and logistic regression. Of the 171 male participants who completed the survey, 22% were under 25 years old, 70% identified as gay/homosexual, and 59% were single. PrEP awareness was 77%, and of these 29% were current PrEP users. Users were more likely to have stable living arrangements (p < .05) and to identify as gay/homosexual (p=.03). Uptake by current PrEP users was attributed to non-judgmental and confidential PrEP services. Barriers identified by former PrEP users included cost and risks of STIs. Since the PrEP program is free, as is general health care for STIs, this suggests that there may be a knowledge gap. Further studies are needed to explore perceived barriers to the program.


Posterior Talar Shifting in Mobile-Bearing Total Ankle Replacement.
End-stage ankle osteoarthritis frequently involves multiplanar malalignment in both the coronal and the sagittal planes. Sagittal malalignment often includes anterior translation of the talus relative to the tibia. Restoration of the correct tibial and talar alignment is essential for the long-term survival of total ankle replacement. This study includes 66 consecutive patients who underwent total ankle arthroplasty with the Hintegra prosthesis from May 2011 to April 2014. There were 28 females (42.4%) and 38 males (57.6%) with a mean age of about 57 years (25-82 years). Patients were clinically and radiologically assessed preoperatively and at 2, 6, and 12 months postoperatively. At 12 months postoperatively, there was a statistically significant increase in American Orthopaedic Foot & Ankle Society scores from 31.9 to 72.3. Range of motion significantly increased from 9.5 to 25.4 degrees. In addition, there was a statistically significant decrease in visual analog scale (VAS) pain score from 8.9 to 2.2. Furthermore, there was a significant increase in the Tibio-Talar ratio from 2 to 6 months postoperatively (34.6%-37.2%). This study demonstrated significant improvements in clinical and radiologic outcomes after Hintegra total ankle arthroplasty. Significant movement of the talus occurs within the first 6 months postoperatively. This may be the result of rebalancing of muscle and ligament forces after surgery. Level IV, case series.


Cellular and molecular responses of Saudi chronic myeloid leukaemia patients to imatinib (STI-571): ten year experience.
The cyto-genetic hallmark of chronic myeloid leukaemia (CML), the Philadelphia chromosome (Ph), is the first consistent chromosomal abnormality that has been associated to a certain cancer type. In CML, Philadelphia chromosome is present leading to resistance to cell death and rapid proliferation. The aim of this study is to evaluate the different responses, toxicity and survival of Saudi CML patients to imatinib mesylate. All newly diagnosed CML patients who were treated with imatinib were included in this study. We investigated haematological, and molecular and cytogenetic responses by CBC, FISH and RT-PCR respectively. Cell proliferation and apoptosis were assayed using AUC and TUNEL respectively. Of the 12 cases, 9 (75%) were males and 3 (25%) were female. Four (33%) of the cases were diagnosed incidentally and 8 cases (67%) presented mainly with fatigue (75%), fever (58%), and splenomegaly (83%). Signs of bleeding and rashes were rare at presentation. The majority of patients had low risk (8, 67%), and 33% had intermediate risk; but none of them had high risk CML. At the last follow up, 11 (92%) were in remissions. One patient (8%) was in remission after 3 years, 4 (33%) were in remission after 6 years, one was in remission after 7 years and 5 (42%) were in remission after 10 years. Only one patient had incomplete major molecular response (MMR) to imatinib after 12 years. The majority of the patients (10, 83%) were in MMR after 6 years and 42% of them were in MMR after 10 years of therapy. Adverse effects of imatinib were not reported by the patients. Imatinib treatment resulted in the reduction of proliferation and induction of apoptosis of CML CFU-GM cells. Imatinib mesylate is capable of treating Philadelphia chromosome-positive CP-CML without any adverse effects.


[Optimizing surgical hand disinfection].
For more than 110 years hands of surgeons have been treated before a surgical procedure in order to reduce the bacterial density. The kind and duration of treatment, however, has changed significantly over time. Recent scientific evidence suggests a few changes with the aim to optimize both the efficacy and the dermal tolerance. Aim of this article is the presentation and discussion of new insights in surgical hand disinfection. A hand wash should be performed before the first disinfection of a day, ideally at least 10 min before the beginning of the disinfection as it has been shown that a 1 min hand wash significantly increases skin hydration for up to 10 min. The application time may be as short as 1.5 min depending on the type of hand rub. Hands and forearms should be kept wet with the hand rub for the recommended application time in any case. A specific rub-in procedure according to EN 12791 has been found to be suitable in order to avoid untreated skin areas. The alcohol-based hand rub should have a proven excellent dermal tolerance in order to ensure appropriate compliance. Considering these elements in clinical practice can have a significant impact to optimize the high quality of surgical hand disinfection for prevention of surgical site infections.


Digoxin reduces the incidence of prostate cancer but increases the cancer-specific mortality: A systematic review and pooled analysis.
Digoxin, a commonly used drug for congestive heart failure and cardiac arrhythmias, has been reported to exert cytotoxic and apoptosis-inducing effects on prostate cancer (PCa) cells. In this study, we aimed to perform a pooled analysis to summarise all the evidence related to the effects of digoxin on PCa development. Four electronic databases were systematically searched to filter the eligible studies. The hazard ratio (HR) with its 95% confidence interval (CI) was calculated. This study was registered on PROSPERO (ID: CRD42021226885). Ten clinical studies with a total of 108,444 participants (15,835 individuals were digoxin users) were included. The pooled result from 6 included studies demonstrated that digoxin usage was correlated with a significant decrease in PCa risk (adjusted RR = 0.892, 95% CI: 0.799-0.997, p = .044) when compared with the nonusers. Synthetic result of 4 eligible studies revealed that digoxin significantly correlated with higher prostate cancer-specific mortality than the controls (adjusted HR = 1.142, 95% CI: 1.005-1.297). No statistical heterogeneity was detected during this analysis (all I2 < 50%, p > .1). Our study confirmed a preventive effect of digoxin usage for the risk of PCa in men. However, digoxin use was associated with a significantly elevated risk of prostate cancer-specific mortality. This finding needs more well-designed studies to better interpret the causality.


Kinetics of ligand-receptor interaction reveals an induced-fit mode of binding in a cyclic nucleotide-activated protein.
Many receptors and ion channels are activated by ligands. One key question concerns the binding mechanism. Does the ligand induce conformational changes in the protein via the induced-fit mechanism? Or does the protein preexist as an ensemble of conformers and the ligand selects the most complementary one, via the conformational selection mechanism? Here, we study ligand binding of a tetrameric cyclic nucleotide-gated channel from Mesorhizobium loti and of its monomeric binding domain (CNBD) using rapid mixing, mutagenesis, and structure-based computational biology. Association rate constants of ∼10(7) M(-1) s(-1) are compatible with diffusion-limited binding. Ligand binding to the full-length CNG channel and the isolated CNBD differ, revealing allosteric control of the CNBD by the effector domain. Finally, mutagenesis of allosteric residues affects only the dissociation rate constant, suggesting that binding follows the induced-fit mechanism. This study illustrates the strength of combining mutational, kinetic, and computational approaches to unravel important mechanistic features of ligand binding.


Complications following carotid angioplasty and carotid stenting in patients with symptomatic carotid artery disease.
We review a single centre's experience of the endovascular treatment of carotid artery disease, present the 30-day and 1-year complication rates and assess whether changes in technique are associated with a change in clinical outcome. Patients who underwent carotid angioplasty with or without stenting for symptomatic > or = 70% carotid artery stenosis secondary to atherosclerosis were included. 333 procedures were performed, i.e. angioplasty alone (86), stent without cerebral protection (150) and stent with cerebral protection (97). At 30 days, the total major disabling stroke and all death rate was 3.0%. For angioplasty alone, this was 2.3%, for stent without cerebral protection 4.0% and for stent with cerebral protection 2.1%. If non-stroke-related deaths were excluded, it was 2.3, 3.3 and 0%, respectively. After 30 days, the 1-year ipsilateral stroke rate was 0.8%. Carotid artery stenting, in particular with a cerebral protection device, is a safe alternative to carotid endarterectomy for the treatment of symptomatic high-grade carotid artery disease.


Imaging of Ganglioneuroma: A Literature Review and a Rare Case of Cystic Presentation in an Adolescent Girl.
Retroperitoneal ganglioneuroma is a rare neuroectodermal tumor with a benign nature. We performed a literature review among 338 studies. We included 9 studies, whose patients underwent CT and/or MRI to characterize a retroperitoneal mass, which was confirmed to be a ganglioneuroma by histologic exam. The most common features of ganglioneuroma are considered to be a solid nature, oval/lobulated shape, and regular margins. The ganglioneuroma shows a progressive late enhancement on CT. On MRI it appears as a hypointense mass in T1W images and with a heterogeneous high-intensity in T2W. The MRI-"whorled sign" is described in the reviewed studies in about 80% of patients. The MRI characterization of a primitive retroperitoneal cystic mass should not exclude a cystic evolution from solid masses, and in the case of paravertebral location, the differential diagnosis algorithm should include the hypothesis of ganglioneuroma. In our case, the MRI features could have oriented towards a neurogenic nature, however, the predominantly cystic-fluid aspect and the considerable longitudinal non-invasive extension between retroperitoneal structures, misled us to a lymphatic malformation. In the literature, it is reported that the cystic presentation can be due to a degeneration of a well-known solid form while maintaining a benign character: the distinguishing malignity character is the revelation of immature cells on histological examination.


Binding of E. coli to human blood leukocytes.
The spontaneous binding of both piliated and non-piliated E. coli to human lymphocytes, monocytes, and polymorphonuclear leukocytes (PMN) was investigated. It was found that the piliated E. coli showed a higher binding percentage to lymphocytes than the nonpiliated bacteria. A specific antiserum raised in rabbit against E. coli strongly inhibited the binding of the homologous E. coli strain to lymphocytes and monocytes. On the other hand there was no difference in the binding of piliated and non-piliated E. coli to PMNs, and the specific E. coli antiserum did not inhibit the binding. The binding of E. coli to human lymphocytes obtained from healthy donors was investigated in a 3-week follow-up experiment. It was shown that there were significant differences between the binding of cells from different individuals, whereas there were no differences in the binding ability of the cells from the same individual in the 3-week follow up.


Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model.
Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.


Mood state at the beginning of the pregnancy and its influence on obstetric and perinatal outcomes.
Aim: We designed this study to ascertain the prevalence of depressive disorders and anxiety at the beginning of the pregnancy, studying possible associated factors and assessing the influence of mood disorders on perinatal outcomes. Methods: A representative sample of 191 pregnant women at first trimester of their pregnancies completed a questionnaire that included the Whooley´s questions, the Spanish version of the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory and a series of questions related to health status, general mood and sociodemographic variables. Later, we prospectively evaluated the influence of anxiety and depression on the perinatal and obstetric results in 145 of them. Results: More than 20% of pregnant women presented high levels of anxiety. The mean values of the state and trait anxiety scores were 38.7 (SD 9.8) and 34.5 (SD 9.5). The mean BDI score was 5.97 (SD 4.9), with 9.5% of participants achieving scores compatible with depression, (61% mild in, 22.2% moderate, and 16.6% severe). BDI scores were significantly lower in women who became pregnant after assisted reproductive techniques. We observed an association between depression and trait anxiety scores with an infant's low birth weight. The multivariate analysis showed that the feeling of happiness at the beginning of pregnancy was the best predictor of foetal weight. Conclusion: The prevalence of emotional disorders in the first trimester of pregnancy is high, with more than 20% of pregnant women presenting high levels of anxiety, and more than 9.5% presenting depression. During the first trimester, depression and anxiety were associated with low birth weight.


Three-Dimensional Heterostructured Reduced Graphene Oxide-Hexagonal Boron Nitride-Stacking Material for Silicone Thermal Grease with Enhanced Thermally Conductive Properties.
The thermally conductive properties of silicone thermal grease enhanced by hexagonal boron nitride (hBN) nanosheets as a filler are relevant to the field of lightweight polymer-based thermal interface materials. However, the enhancements are restricted by the amount of hBN nanosheets added, owing to a dramatic increase in the viscosity of silicone thermal grease. To this end, a rational structural design of the filler is needed to ensure the viable development of the composite material. Using reduced graphene oxide (RGO) as substrate, three-dimensional (3D) heterostructured reduced graphene oxide-hexagonal boron nitride (RGO-hBN)-stacking material was constructed by self-assembly of hBN nanosheets on the surface of RGO with the assistance of binder for silicone thermal grease. Compared with hBN nanosheets, 3D RGO-hBN more effectively improves the thermally conductive properties of silicone thermal grease, which is attributed to the introduction of graphene and its phonon-matching structural characteristics. RGO-hBN/silicone thermal grease with lower viscosity exhibits higher thermal conductivity, lower thermal resistance and better thermal management capability than those of hBN/silicone thermal grease at the same filler content. It is feasible to develop polymer-based thermal interface materials with good thermal transport performance for heat removal of modern electronics utilising graphene-supported hBN as the filler at low loading levels.


Translation is actively regulated during the differentiation of CD8+ effector T cells.
Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8+ effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal-expansion phase, followed by inhibition of the translation of those transcripts when the CD8+ Teff cells stopped dividing just before the contraction phase. That translational suppression was more pronounced in terminal effector cells than in memory precursor cells and was regulated by antigenic stimulation and signals from the kinase mTOR. Our studies show that translation of transcripts encoding ribosomal proteins is regulated during the differentiation of CD8+ Teff cells and might have a role in fate 'decisions' involved in the formation of memory cells.


[Production of a new monoclonal anti-AB reagent].
Techniques of monoclonal antibodies production have well progressed in the developed countries. But, they are still absent in the third world. In this report, the murine hybridoma technology was performed to produce anti-ABH monoclonal antibodies. The anti-AB specificity of several hybridomas was determined by agglutination techniques using phenotyped red cells panels. An anti-AB monoclonal antibody was selected and compared to other reagents for its use as a blood grouping reagent. Its characteristics were in accordance with the international standards. Hybridoma establishment to produce a good monoclonal reagent is henceforth possible in Morocco.


Beyond xMOOCs in healthcare education: study of the feasibility in integrating virtual patient systems and MOOC platforms.
Background. Massive Open Online Courses (MOOCs) are an emerging trend in online learning. However, their technology is not yet completely adjusted to the needs of healthcare education. Integration of Virtual Patients within MOOCs to increase interactivity and foster clinical reasoning skills training, has been discussed in the past, but not verified by a practical implementation. Objective. To investigate the technical feasibility of integrating MOOCs with Virtual Patients for the purpose of enabling further research into the potential pedagogical benefits of this approach. Methods. We selected OpenEdx and Open Labyrinth as representative constituents of a MOOC platform and Virtual Patient system integration. Based upon our prior experience we selected the most fundamental technical requirement to address. Grounded in the available literature we identified an e-learning standard to guide the integration. We attempted to demonstrate the feasibility of the integration by designing a "proof-of-concept" prototype. The resulting pilot implementation was subject of verification by two test cases. Results. A Single Sign-On mechanism connecting Open Labyrinth with OpenEdx and based on the IMS LTI standard was successfully implemented and verified. Conclusion. We investigated the technical perspective of integrating Virtual Patients with MOOCs. By addressing this crucial technical requirement we set a base for future research on the educational benefits of using virtual patients in MOOCs. This provides new opportunities for integrating specialized software in healthcare education at massive scale.


Complete genome sequence of phototrophic betaproteobacterium Rubrivivax gelatinosus IL144.
Rubrivivax gelatinosus is a facultative photoheterotrophic betaproteobacterium living in freshwater ponds, sewage ditches, activated sludge, and food processing wastewater. There have not been many studies on photosynthetic betaproteobacteria. Here we announce the complete genome sequence of the best-studied phototrophic betaproteobacterium, R. gelatinosus IL-144 (NBRC 100245).


Acute Changes in Right Ventricular Function in Pediatric Patients with Pulmonary Valve Stenosis Undergoing Percutaneous Valvuloplasty: A Speckle-Tracking Study.
Pulmonary valve stenosis determines multiple effects on the right ventricular dimension and function. Percutaneous balloon valvuloplasty is the treatment of choice in severe pulmonary valve stenosis in patients of all ages. However, little is known regarding right ventricular function immediate changes after percutaneous balloon dilation. Pediatric patients with isolated pulmonary valve stenosis represent a pure clinical model of chronic RV pressure overload not affected by other confounders or comorbidities. This study seeks to explore right ventricle (RV) mechanics in pediatric patients early after percutaneous balloon pulmonary valvuloplasty (BPV) for valvar pulmonary stenosis (PS). Forty-three pediatric patients (19 males), mean age 3.2 ± 4.9 years old, with severe pulmonary valve stenosis and indication for percutaneous balloon valvuloplasty were recruited. All patients underwent standard transthoracic echocardiography (TTE), and speckle-tracking echocardiography (STE) with an analysis of right ventricle free-wall longitudinal strain (RVFWLS) one day before and one day after the procedure. For each patient, we collected invasive parameters during the interventional procedure before and after BPV. After the procedure, there was an immediate significant reduction in both peak-to-peak transpulmonary gradient (peak-to-peak PG) and ratio between the right ventricle and aortic systolic pressure (RV/AoP) with a drop of ∆29.3 ± 14.67 mmHg and ∆0.43 ± 0.03, respectively. Post-procedural echocardiography showed peak and mean transvalvar pressure gradient drop (∆50 ± 32.23 and ∆31 ± 17.97, respectively). The degree of pulmonary valve regurgitation was mild in 8% of patients before the procedure, affecting 29% of our patients post-BPV (p = 0.007). The analysis of right ventricular mechanics showed a significant improvement of fractional area change (FAC) immediately after BPV (40.11% vs. 44.42%, p = 0.01). On the other hand, right ventricular longitudinal systolic function parameters, TAPSE and global RVFWLS, did not improve significantly after intervention. The segmental analysis of the RVFWLS showed a significant regional increase in the myocardial deformation of the apical segments. Percutaneous BPV represents an efficient and safe procedure to relieve severe pulmonary valve stenosis. The analysis of the right ventricular function on echocardiography demonstrated an immediate global systolic function improvement, while longitudinal systolic function was persistently impaired 24 h after intervention, possibly due to the necessity of a longer recovery time.


Genome Resource for Neocamarosporium betae (syn. Pleospora betae), the Cause of Phoma Leaf Spot and Root Rot on Beta vulgaris.
Neocamarosporium betae (syn. Phoma betae, Pleospora betae) is the cause of Phoma leaf spot and root decay on Beta vulgaris worldwide. Despite the economic importance of the pathogen, many aspects of its life cycle and population biology remain unknown. The first genome assembly of N. betae was constructed to facilitate identification of mating-type loci and development of microsatellite markers for population genetics studies. The de novo assembled genome is provided as a resource for future genetic studies to understand the genetic mechanisms underlying disease development and host-pathogen interactions.


Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects.
A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9-36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability.


Plasma somatostatin and cholecystokinin levels in preterm infants during their first two years of life.
Plasma somatostatin and cholecystokinin are two gut peptides with opposite functions which are regulated by two different parts of the autonomic nervous system. Previously we have shown that plasma somatostatin and cholecystokinin levels are higher in preterm infants during the 1st d of life than in adults or in their mothers, and that plasma somatostatin is negatively correlated to gestational age. We have longitudinally studied these two peptides in 28 preterm infants, 17 boys and 11 girls, up until the age of 2 y. The mean (SD) gestational age was 32.3 (2.8) wk, the mean birth weight was 1877 (515) g, and the mean birth length was 42.8 (3.8) cm. Blood samples were taken on the 1st d of life, at 6 wk, and at 3, 6, 12, and 24 mo of age. Plasma was analyzed by specific somatostatin and cholecystokinin RIAs. The median plasma somatostatin and cholecystokinin levels were lowest at 3 mo (somatostatin = 17.4/cholecystokinin = 10.5 pmol/L) and highest at 6 mo (somatostatin = 37.3/cholecystokinin = 27.1 pmol/L). At 24 mo plasma somatostatin remained at the same level, and cholecystokinin had decreased to half that level. After the 1st d of life plasma somatostatin and cholecystokinin levels were not correlated to gestational age or attained weight or length. The plasma somatostatin level at 3 mo of age was negatively correlated to the increment in knee-heel distance between 3 and 6 mo of age.


A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders.
Metal-ion misregulation and oxidative stress have been linked to the progressive neurological decline associated with multiple neurodegenerative disorders. Transition metal-mediated oxidation of biomolecules via Fenton chemical reactions plays a role in disease progression. Herein we report the synthesis, characterization and antioxidant activity of 2; a pyclen derivative with enhanced antioxidant character.


Immunity and Inflammation in Atherosclerosis.
There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease. Lessons from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice, and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb atherosclerosis. Here, we summarize and discuss the pathogenesis of atherosclerosis with a focus on adaptive immunity. We discuss some limitations of animal models and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment.


A large patient study confirming that facioscapulohumeral muscular dystrophy (FSHD) disease expression is almost exclusively associated with an FSHD locus located on a 4qA-defined 4qter subtelomere.
Facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disorder, represents the third most common human muscular dystrophy. The FSHD disease locus, at chromosome 4q35, is associated with large contractions of the polymorphic repeat sequence array D4Z4. In addition to FSHD disease association with large D4Z4 deletions, a biased interaction with a specific 4qter subtelomeric sequence has been described in patients. Two distinct 4qter subtelomeres, defined as types 4qA and 4qB, have been identified and shown to be equally prevalent in the Caucasian population. In almost all 4q35-linked patients with FSHD, however, disease expression only occurs when large D4Z4 deletions are located on 4qA-defined 4qter subtelomeres. Conversely, large D4Z4 repeat contractions situated on 4qB-defined subtelomeres either are not disease-causing or exhibit a greatly reduced disease penetrance. This study was initiated to confirm this direct FSHD disease association data by measuring the frequency of type 4qA-defined and 4qB-defined subtelomeric sequences in a large cohort of 164 unrelated patients with FSHD from Turkey and the UK, all known to have large D4Z4 deletions. An almost complete association was found between large D4Z4 repeat array deletions located on 4qA-defined 4qter subtelomeres and disease expression in our large FSHD patient cohort. The observed failure of probes 4qA and 4qB to hybridise to two patient-derived DNA samples confirms the presence of an additional rare type of 4qter subtelomeric sequence in humans.


Follicular-cell derived thyroid cancer in children.
Thyroid carcinoma is a rare disease in children, and is mostly of the papillary histological type. It is often extended at presentation with frequent lymph node metastases. Treatment includes surgery (total thyroidectomy and lymph node dissection) and radioiodine therapy in case of extensive disease. Life long thyroxine treatment is given to all patients and when carefully controlled is devoided of adverse effects. Long term prognosis is favorable, but a few deaths have been reported some decades after initial treatment. Adverse prognostic indicators are younger age at discovery and presence of distant metastases.


Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.
The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.


Long-term results of aggressive management of diabetic foot ulcers suggest significant cost effectiveness.
This study was undertaken to examine the hypothesis that the initial high limb salvage rate in patients with diabetes who are treated aggressively with a multidisciplinary approach to management of severe, chronic lower extremity wounds is durable and cost effective. In 1991 a cohort of 41 patients with diabetes with severe, chronic foot wounds was selected by a neutral, blinded observer who had no knowledge of the outcomes from a group of 101 consecutive such patients who had been treated at our wound center from 1983 to 1990. All had limb-threatening lesions, scoring 3 to 4 on the Wagner scale, were treated for at least 7 days with adjunctive hyperbaric oxygen, and had photographic and medical documentation. Durability of wound repair was examined in 1991 and 1993. Initial limb salvage was 85%. Mean hospital charges were $31,264, including average hyperbaric charges of $15,000. At the initial review, 28 of the patients with previously salvaged limbs (80%) were contacted. Of the 28 patients, 27 remained intact (96%). The mean durability of repair was 2.6 years. At the second review, the mean duration of repair in surviving patients was 4.6 years with no further expenditures relative to the salvaged limb. In patients who died, average durability was 3.4 years, also without additional expenditure referable to the salvaged extremity. Most complex lower extremity lesions were healed by a comprehensive wound care program which included vascular surgery and hyperbaric oxygen. The results were durable, and the treatment was cost effective and humane compared with early amputation.


Carbon Quantum Dots/TiOx Electron Transport Layer Boosts Efficiency of Planar Heterojunction Perovskite Solar Cells to 19.
In planar n-i-p heterojunction perovskite solar cells, the electron transport layer (ETL) plays important roles in charge extraction and determine the morphology of the perovskite film. Here, we report a solution-processed carbon quantum dots (CQDs)/TiO2 composite that has negligible absorption in the visible spectral range, a very attractive feature for perovskite solar cells. Using this novel CQDs/TiO2 ETL in conjunction with a planar n-i-p heterojunction, we achieved an unprecedented efficiency of ∼19% under standard illumination test conditions. It was found that a CQDs/TiO2 combination increases both the open circuit voltage and short-circuits current density as compared to using TiO2 alone. Various advanced spectroscopic characterizations including ultrafast spectroscopy, ultraviolet photoelectron spectroscopy, and electronic impedance spectroscopy elucidate that the CQDs increases the electronic coupling between the CH3NH3PbI3-xClx and TiO2 ETL interface as well as energy levers that contribute to electron extraction.


Association of microRNA-34a overexpression with proliferation is cell type-dependent.
Recently Welch et al. reported that microRNA (miRNA)-34a functions as a potential tumor suppressor in neuroblastoma cells (Oncogene 26: 5017-22, 2007). Here, we conversely show that miRNA-34a supports cell proliferation in rat oxidative stress-induced renal carcinogenesis and is overexpressed in various types of human cancers. While searching for genetically unstable chromosomal areas in rat renal carcinogenesis, we found the miRNA-34 family reciprocally overexpressed in chromosomal areas with frequent allelic loss. By in situ hybridization and reverse transcription-polymerase chain reaction, cerebral neurons and Purkinje cells showed the highest expression of a major type, miRNA-34a, followed by a variety of endocrine cells and proliferating cells including germinal center lymphocytes and mouse embryonic fibroblasts and stem cells. In contrast, normal renal tubules, hepatocytes and myocardial cells showed faint expression. After 3 weeks of ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, regenerating renal proximal tubular cells showed high miRNA-34a expression. All of the Fe-NTA-induced rat renal carcinomas and an array of human cancers (151 positive cases of 177) showed high expression of miRNA-34a. Furthermore, knockdown of miRNA-34a with small interfering RNA significantly suppressed proliferation not only of renal carcinoma cells but also of HeLa and MCF7 cells. These results indicate that miRNA-34a overexpression, an acquired trait during carcinogenesis, supports cell proliferation in the majority of cancers suggesting an unexpected link in the cellular metabolism between cancer and neuronal and/or endocrine cells, which warrants further investigation.


Update for astrocytomas: medical and surgical management considerations.
Astrocytomas include a wide range of tumors with unique mutations and varying grades of malignancy. These tumors all originate from the astrocyte, a star-shaped glial cell that plays a major role in supporting functions of the central nervous system (CNS), including blood-brain barrier (BBB) development and maintenance, water and ion regulation, influencing neuronal synaptogenesis, and stimulating the immunological response. In terms of epidemiology, glioblastoma (GB), the most common and malignant astrocytoma, generally occur with higher rates in Australia, Western Europe, and Canada, with the lowest rates in Southeast Asia. Additionally, significantly higher rates of GB are observed in males and non-Hispanic whites. It has been suggested that higher levels of testosterone observed in biological males may account for the increased rates of GB. Hereditary syndromes such as Cowden, Lynch, Turcot, Li-Fraumeni, and neurofibromatosis type 1 have been linked to increased rates of astrocytoma development. While there are a number of specific gene mutations that may influence malignancy or be targeted in astrocytoma treatment, O 6-methylguanine-DNA methyltransferase (MGMT) gene function is an important predictor of astrocytoma response to chemotherapeutic agent temozolomide (TMZ). TMZ for primary and bevacizumab in the setting of recurrent tumor formation are two of the main chemotherapeutic agents currently approved in the treatment of astrocytomas. While stereotactic radiosurgery (SRS) has debatable implications for increased survival in comparison to whole-brain radiotherapy (WBRT), SRS demonstrates increased precision with reduced radiation toxicity. When considering surgical resection of astrocytoma, the extent of resection (EoR) is taken into consideration. Subtotal resection (STR) spares the margins of the T1 enhanced magnetic resonance imaging (MRI) region, gross total resection (GTR) includes the margins, and supramaximal resection (SMR) extends beyond the margin of the T1 and into the T2 region. Surgical resection, radiation, and chemotherapy are integral components of astrocytoma treatment.


Transient species involved in catalytic dioxygen/peroxide activation by hemoproteins: possible involvement of protonated Compound I species.
Interaction of hemoproteins with peroxide leads in several cases to transient formation of ferric peroxo, ferric hydroperoxo, and "high-valent", formally Fev, oxo or hydroxo Compound species. Here, density functional calculations on ferric peroxo, ferric hydroperoxo, Compound and protonated Compound heme active site models are reported. The theoretical results, including calculated isotropic Fermi contact couplings and anisotropic spin dipole couplings, are found to generally correlate well with experimental EPR/ENDOR data. Hydrogen bonding and solvation affect the ferric-peroxo/ferrous-superoxo electromerism. The transition between the two electromers appears smooth, but neither hydrogen bonding to up to two water molecules, nor solvation appear able to dramatically alter the redox state of the superoxo ligand or of the iron. The presence of almost one full unpaired electron on the iron and of one full unpaired electron on the dioxygenic ligand in the "ferric-peroxo" state suggests a possible description of non-protonated "ferric-peroxo" as {ferric-superoxo+porphyrin radical}. Emerging from the DFT data is the possibility that a protonated Compound has already been detected in ENDOR experiments on cytochrome P450. The general feasibility of a protonated Compound in P450 monooxygenases is probed in light of these findings. To encompass the multiple mechanisms available in P450 for substrate oxidation, we define "mechanistic promiscuity" as the feature allowing an enzyme to perform the same reaction, with the same product, using more than one mechanism.


Acute kidney injury in the critical care setting.
Acute kidney injury is a sudden reduction in renal function which impairs the kidneys' ability to maintain fluid, electrolyte and acid-base balance. The syndrome often develops secondary to severe illness and is associated with a significant increase in morbidity and mortality rate in critically ill patients. This article gives an overview of the pathophysiology and aetiology of acute kidney injury, as well as the associated complications and clinical diagnostic signs. The authors also describe some common causes of the syndrome in critically ill patients, specifically sepsis, liver failure and cardiac failure, and discuss patient management in the critical care setting, with a focus on haemodynamic support and continuous renal replacement therapy.