High-Frequency Repetitive Transcranial Magnetic Stimulation Can Improve Depression in Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Study.
A recent evidence-based guideline demonstrated that bilateral repetitive transcranial magnetic stimulation (rTMS) over the motor cortex (M1) can improve motor symptoms of Parkinson's disease (PD). We conducted a randomized, double-blind, placebo-controlled study to evaluate the impact of bilateral M1 rTMS on depression in PD. Forty-six patients with PD and mild-to-moderate depression were randomly assigned to active (n = 23) and sham (n = 23) rTMS. Two patients in the sham group did not complete the protocol because of reasons unrelated to the study. High-frequency rTMS was applied over the primary motor cortex bilaterally for 10 days. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), and 1 day (short-term effect) and 30 days after the treatment session ended (long-term effect). The primary end point was the changes in depression, while secondary end points included health-related quality of life scales and Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). In the actively treated group, not only did the severity of depression improve (from 17 to 7 points, Montgomery-Åsberg Depression Rating Scale, median values, p < 0.001), but also the health-related quality of life (from 25.4 to 16.9 points, PDQ-39 summary index, median values, p < 0.001). Besides, we could also demonstrate an improvement in MDS-UPDRS Motor Examination (from 26 to 20 points, median values, p < 0.05). In the sham-treated group, none of the examined tests and scales improved significantly after treatment. Our results demonstrate the beneficial effects of high-frequency bilateral M1 rTMS on depression and health-related quality of life in PD. However, this effect of rTMS should also be confirmed in patients with severe depression by further clinical trials.


Treatment strategy in fibromyalgia syndrome: where are we now?
The treatment of the fibromyalgia syndrome (FMS) is not standardized and often ineffective, and the course of disease progression is unpredictable. To highlight the efficacy of the pharmacologic and nonpharmacologic treatments administered to FMS patients. Medline search for articles published between 1983 and 2007, using the keywords fibromyalgia, pharmacologic and nonpharmacologic treatment, and multidisciplinary modalities. Randomized controlled trials (RCTs) indicate that FMS has been treated by a wide range of drugs including antidepressants, opioids, nonsteroidal anti-inflammatory drugs, sedatives, muscle relaxants, and antiepileptic agents. Although the syndrome is now more widely recognized and understood, its treatment remains challenging and some physicians believe that no effective treatment exists. Only a few drugs have been shown to have clear-cut benefits in RCTs. FMS sufferers benefit from exercise and a number of the tested programs have involved more than 1 type of exercise. Two other major approaches are psychophysiologically based therapy, such as electromyography biofeedback, and interventions based on cognitive-behavioral therapy. Twelve controlled clinical studies have provided evidence supporting the efficacy of treatments administered to people with FMS by multidisciplinary teams using multicomponent strategies. It is difficult to draw definite conclusions concerning the most appropriate approach to managing FMS because of the methodological limitations of the available studies and the fact that the heterogeneity and nonstandardized nature of their therapeutic programs make them difficult to compare. An individually tailored multidisciplinary pharmacologic, rehabilitative, and cognitive-behavioral approach currently seems to be the most effective.


Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications.
Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness and 1 of the most common anxiety disorders with the prevalence of 3%. Although its pathogenesis remains unclear, the traditional model focused on alternations in the serotonin system. Selective serotonin reuptake inhibitors provide the most effective treatment; however, as much as 40-60% of patients do not respond to antidepressants therapy. Thus, attention has shifted towards other neurotransmitter systems and related neuroanatomical structures. Recently, there is extensive evidence showing a key role of glutamate pathways abnormalities within the cortico-striatal-thalamo-cortical circuitry and temporal lobes in OCD pathogenesis. In this review, we link together the existent neuroanatomical, neurophysiological, and neuropsychological evidence to argue for potential benefits of adjuvant treatment with glutamatergic agents, especially memantine. By a targeted de-excitation effect on the glutamatergic system in the temporal lobes and connected brain regions, memantine might further alleviate OCD symptoms. This effect should be even more pronounced in certain subtypes of patients with specific cognitive deficits and maladaptive compensatory memory processes (e.g., checkers).


Effects of protected fish oil in the diet of periparturient dairy goats on phenotypic variation in blood and milk leukocytes.
The goal of this study was to evaluate the effects of dietary protected fish oil (FO) on phenotypic variation in blood, milk leukocytes, and some productive and metabolic parameters in periparturient dairy goats. About 12 Alpine goats, selected from a larger group of second-parity animals, were fed from 15 days before kidding until the 15th day of lactation with the same basal diet that had been supplemented with either 47 g/head per day of FO or 47 g/head per day hydrogenated palm oil (PO). Dry matter intake, live body weight (LBW), body condition score (BCS), and productive performance were evaluated in 2 weeks after kidding. On days 15, 7, and 2 before kidding and days 2, 7, and 15 after kidding, plasma samples were collected for evaluation of alanine aminotransferase, aspartate aminotransferase, non-esterified fatty acids, glucose, beta-hydroxybutyrate, cholesterol, and urea levels. White blood cell and blood leukocyte subsets were counted in whole blood samples on the kidding day, as well as at 1, 4, and 15 days after kidding. In addition, milk somatic cell count, intramammary infection (IMI), and milk leukocyte subsets were evaluated on days 4 and 15 after kidding. No differences were observed in dry matter intake and BCS, while LBW was higher in FO-fed animals. Milk production and composition, plasma metabolites, and liver enzymes were similar in both experimental groups. Blood CD4 positive cells increased constantly (P = 0.05) in FO-fed group, while CD8 and CD14 cell counts significantly increased 4 days after kidding (P < 0.01). Milk leukocyte subsets showed a significant (P < 0.01) decrease in PO-fed group and a non-significant increase (P = 0.34) in FO-fed group, despite the presence of coagulase negative staphylococci IMI. The results of the productive performance evaluation agreed with those of many other studies, which did not find any significant differences between dairy goats fed diets enriched with FO or PO supplements. The administration of FO to dairy goats in transition appeared to affect the variation in blood leukocytes with a constant increase in CD4- and CD8-positive cells in comparison with a PO fat-supplemented diet.


Influence of sleep on anal sphincteric pressure in health and after ileal pouch-anal anastomosis.
Fecal incontinence at night may be a disturbing consequence of ileal pouch-anal anastomosis (IPAA). The hypothesis was that decreases in anal canal resting pressure occur as sleep deepens and that the decreases are more profound in pouch patients with incontinence than in controls. Using a sleeve catheter assembly for recording intraluminal and canal pressure and polysomnographic recordings of sleep stages, progressive decreases in anal canal resting pressure with deepening sleep occurred in 11 healthy controls (mean +/- SEM: 57 +/- 3 mm Hg to 43 +/- 3 mm Hg: P less than 0.05) and in 11 patients after IPAA (55 +/- 3 mm Hg to 42 +/- 4 mm Hg; P less than 0.05). Minute-to-minute variations in mean pressure were also found in both controls and IPAA patients, and they were greater at night in patients (P less than 0.05), except during rapid eye movement (REM) sleep. In three patients, resting pressure during REM sleep decreased markedly to 31 +/- 8 mm Hg. This decrease plus the variations in pressure during REM sleep led to incontinence. In conclusion, decreases in anal resting pressure coupled with marked minute-to-minute variations in pressure during sleep occurred in controls and in patients after IPAA and, when profound, led to nocturnal fecal incontinence in some patients.


Biogenic silver nanoparticles: In vitro and in vivo antitumor activity in bladder cancer.
Bladder cancer is the fifth most common disease in the United States, and the treatment and alternatives for patients have not changed in the last decades. Silver nanoparticles (AgNP) have been used in the treatment of various cancer, mainly because of the antineoplastic activity; however, their use and the molecular mechanisms towards bladder cancer still unexplored. Therefore, this work aims to evaluate the in vitro and in vivo antitumoral mechanisms of biogenic silver nanoparticles synthesized from Fusarium sp. First, AgNP showed cytotoxicity in a dose- and time-response relationship and detailed analysis demonstrated the induction of cell death via apoptosis, also inhibiting cell migration and proliferation in bladder carcinoma cell line 5637. Next, it was evaluated the antitumoral activity of AgNP against non-muscle invasive bladder cancer (NMIBC). Bladder cancer was chemically induced with N-methyl-N-nitrosourea (MNU) on C57BL/6JUnib female mice and treated by intravesical route with AgNP concentrations of 0.5, 0.2, and 0.05 mg/mL. Finally, treatment with AgNP (0.05 mg/mL) led to 57.13% of tumor regression, with 14.28% of the animals showing normal urothelium, and 42.85% showing flat hyperplasia, considered to be a benign lesion. Overall, these findings demonstrated that AgNP might be a cost-effective alternative and promising candidate for the treatment of bladder cancer.


Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): a stressor on the immune system.
Drug abuse is a global problem of considerable concern to health. One such health concern stems from the fact that many drugs of abuse have immunosuppressive actions and consequently have the potential to increase susceptibility to infectious disease. This article is focused on the impact of the amphetamine derivative, methylenedioxymethamphetamine (MDMA; 'Ecstasy') on immunity. Research conducted over the last 5 years, in both laboratory animals and humans, has demonstrated that MDMA has immunosuppressive actions. Specifically, MDMA suppresses neutrophil phagocytosis, suppresses production of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta, and increases production of the endogenous immunosuppressive cytokine (IL-10), thereby promoting an immunosuppressive cytokine phenotype. MDMA also suppresses circulating lymphocyte numbers, with CD4+ T cells being particularly affected, and alters T-cell function as indicated by reduced mitogen-stimulated T-cell proliferation, and a skewing of T-cell cytokine production in a T helper 2 (Th2) direction. For the most part, the aforementioned effects of MDMA are not the result of a direct action of the drug on immune cells, but rather caused by the release of endogenous immunomodulatory substances. Consequently, the physiological mechanisms that are thought to underlie the immunosuppressive effects of MDMA will be discussed. As many of the physiological changes elicited by MDMA closely resemble those induced by acute stress, it is suggested that exposure to MDMA could be regarded as a 'chemical stressor' on the immune system. Finally, the potential of MDMA-induced immunosuppression to translate into significant health risks for abusers of the drug will be discussed.


[The evolution of osmoregulation in vertebrates (on the centenary of the birth of E. M. Kreps)].
The paper substantiates the point of view that the first step in the evolution of osmoregulation in vertebrates involved development of water-impermeable epithelium which depended on specific distribution of aquaporins in plasma membranes, secretion of autacoids, formation of water-impermeable cell contacts with a high electrical resistance. Migration of vertebrates to the land was associated with appearance of the ability to regulate osmotic permeability of epithelium in a number of organs involving vasotocin and other pituitary hormones, insertion of aquaporins into the luminal plasma membrane. Enhancement of the renal role in the water-salt balance, intensification of the kidney function was due to a rise in renal circulation, glomerular filtration rate, and tubular reabsorption which, despite the increase in the energy expenditure, provided for an obvious enhancement of the renal work efficiency in maintaining the constancy of the internal medium. Colonisation of desert regions became possible in birds and mammals due to development of the system of urine osmotic concentration. Unlike the accepted point of view that this depended on the appearance of Henle's loops, the statement is substantiated that the leading role in this process is played by differentiation of the kidney into the cortex and medulla, as at our Laboratory nephron loops similar to Henle's loop have been revealed in the lamprey. In the vertebrates, the evolution shifted from the polyorgan to mono-organ type of osmotic homeostasis maintenance, with the leading role of the kidney in maintaining physico-chemical constants of the internal medium fluids.


The timing of liver transplantation after primary hepatectomy for hepatocellular carcinoma: a special reference to recurrence pattern and Milan criteria.
Hepatic resection (HR) is commonly applied as first-line treatment of hepatocellular carcinoma (HCC) even in the era of liver transplantation (LT). Outcomes and detailed recurrence pattern of 80 patients, who underwent curative HR for HCC were examined referring to Milan criteria. (I) After HR for HCCs exceeding Milan criteria (n=41), recurrence within the criteria was observed in 13 patients (group-A) and recurrence not-meeting the criteria was observed in 22 patients (group-B). group-A showed better 3-year recurrence-free survival rate than group-B (85.7% vs. 23.9%, P<0.05). Tumor size more than or equal to 6 cm was identified as the significant factor for having recurrence as in group-A pattern (P<0.05). Among the patients in group-A, re-recurrence after treating recurrent HCC was observed in eight patients (61.5%) with increased rate of extra-Milan criteria recurrence at 12 months from the initial recurrence. (II) After HR for HCCs meeting Milan criteria (n=39), recurrences within the criteria was observed in 15 patients (group-C) and recurrence not-meeting the criteria was observed in five patients (group-D). The 3-year recurrence-free survival rate was 62.8% in group-C and 40.0% in group-D (P<0.05). Increased rate of extra-Milan re-recurrence was observed later than 12 months from the recurrence in group-C. For HCCs not meeting Milan criteria, secondary LT after primary HR could be applied for a proportion of cases with less aggressiveness. For those meeting Milan criteria, primary LT should be the first therapeutic option. However, secondary LT could be offered for those with re-recurrence within criteria after primary HR.


Effect of Pneumoperitoneum and Lateral Position on Oropharyngeal Seal Pressures of Proseal LMA in Laparoscopic Urological Procedures.
A sustained and effective oropharyngeal sealing with supraglottic airway is required to maintain the ventilation during laparoscopic surgery. Previous studies have observed the Oropharyngeal Seal Pressure (OSP) for Proseal Laryngeal Mask Airway (PLMA) after pneumoperitoneum in supine and trendelenburg position, where PLMA was found to be an effective airway device. This study was conducted with ProSeal LMA, for laparoscopic Urologic procedures done in lateral position. To measure OSP in supine and lateral position and to observe the effect of pneumoperitoneum in lateral position on OSP. Secondary objectives were to assess adequacy of ventilation and incidence of adverse events. A total number of 25 patients of American Society of Anaesthesiologists (ASA) physical status II and I were enrolled. After induction of anaesthesia using a standardized protocol, PLMA was inserted. Ryle's tube was inserted through drain tube. The position of PLMA was confirmed with ease of insertion of Ryle's tube and fibreoptic grading of vocal cords. Patients were then put in lateral position. The OSP was measured in supine position. This value was baseline comparison for OSP in lateral position and that after pneumoperitoneum. We assessed the efficacy of PLMA for ventilation, after carboperitoneum in lateral position (peak airway pressure, End Tidal Carbon dioxide (EtCO2), SPO2). Incidence of adverse effects (displacement of device, gastric insufflation, regurgitation, coughing, sore throat, blood on device, trauma) was also noted. The OSP was above Peak Airway Pressure (PAP) in supine (22.1±5.4 and 15.4±4.49cm of H2O) and lateral position (22.6±5.3 and 16.1±4.6). After pneumoperitoneum, which was in lateral position, there was statistically significant (p-value <0.05) increase in both PAP (19.96±4.015) and OSP (24.32±4.98, p-value 0.03). There was no intraoperative displacement of PLMA. There was no event of suboptimal oxygenation. EtCO2 was always within normal limits. Gastric insufflation was present in one patient. One patient had coughing and blood was detected on device. Three patients had throat discomfort post-operatively. In this study, Oropharyngeal seal pressures with PLMA were found to increase after pneumoperitoneum in lateral position. PLMA forms an effective seal around airway and is an efficient and safe alternative for airway management in urological laparoscopic surgeries done in lateral position.


An inter-professional student-run medication review programme. Reducing adverse drug reactions in a memory outpatient clinic: a controlled clinical trial.
We investigated if the addition of an inter-professional student-led medication review team (ISP-team) to standard care can increase the number of detected ADRs and reduce the number of ADRs 3 months after an outpatient visit. In this controlled clinical trial, patients were allocated to standard care (control group) or standard care plus the ISP team (intervention group). The ISP team consisted of medical and pharmacy students and student nurse practitioners. The team performed a structured medication review and adjusted medication to reduce the number of ADRs. Three months after the outpatient visit, a clinical pharmacologist who was blinded for allocation performed a follow-up telephone interview to determine whether patients experienced ADRs. During the outpatient clinic visit, significantly more (p < 0.001) ADRs were detected in the intervention group (n = 48) than in the control group (n = 10). In both groups, 60-63% of all detected ADRs were managed. Three months after the outpatient visit, significantly fewer (predominantly mild and moderately severe) ADRs related to benzodiazepine derivatives and antihypertensive causing dizziness were detected in the patients of the intervention group. An ISP team in addition to standard care increases the detection and management of ADRs in elderly patients resulting in fewer mild and moderately severe ADRs.


Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy.
The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE). We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p<0.05. Patients with right and left MTLE showed a reduction in volume of the entorhinal (p<0.001) and perirhinal (p<0.01) cortices ipsilateral to the HA, compared with normal controls. Patients with right MTLE exhibited a significant asymmetry of all studied structures; the right hemisphere structures had smaller volume than their left side counterparts. We did not observe linear correlations between the volumes of different structures of the medial temporal lobe in patients with MTLE. Patients with refractory MTLE have damage in the temporal lobe that extends beyond the hippocampus, and affects the regions with close anatomical and functional connections to the hippocampus.


Modafinil elicits sympathomedullary activation.
The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.


[Impact beyond the objectives: a qualitative study of a faculty development program in medical education].
In medical education there has been increasing emphasis on faculty development programs aimed at the professionalization of teaching and increasing students' learning. However, these programs have been shown to have an impact beyond improvement in teaching skills. The medical school of the Pontificia Universidad Católica de Chile (EMUC) has been running a faculty development program (DEM) since 2000. To explore the perception of graduates on the effects of having participated in DEM on their development as teachers and clinicians. Using an exploratory, descriptive and qualitative design, the 79 teachers who graduated from DEM from 2004-2008 were sent a questionnaire containing three open questions. Their answers were analyzed using the Constant Comparative Method of Qualitative Analysis of Glaser and Strauss by four researchers. Faculty development, becoming a better clinician, personal development, appreciation of the value of teaching and strengthening of the academic community were the five categories that emerged from the answers. Graduates felt that, besides learning new educational skills, they changed their attitude towards teaching. DEM was perceived as facilitating self-awareness and reflection about the graduates' role as doctors and teachers. The graduates also valued meeting other faculty. Faculty development programs can have an impact far beyond the learning objectives. The planning and design of programs contributes to their wider impact. This should be taken into consideration in the design, planning, and evaluation of faculty development programs. Care should be taken to protect time for participation, reflection and for interaction with other academics.


Electroacupuncture Attenuates Limb Ischemia-Reperfusion-Induced Lung Injury Via p38 Mitogen-Activated Protein Kinase-Nuclear Factor Erythroid-2-Related Factor-2/Heme Oxygenase Pathway.
Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.


Caloric restriction following early-life high fat-diet feeding represses skeletal muscle TNF in male rats.
Chronic metabolic diseases are on the rise worldwide and their etiology is multifactorial. Among them, inflammatory components like Tumor Necrosis Factor (TNF), contribute to whole-body metabolic impairment. Caloric Restriction (CR) combats metabolic diseases, but how it reduces inflammation remains understudied. We aimed to evaluate the impact of chronic CR on muscle inflammation, in particular TNF. In our study, 4-week old male Sprague-Dawley rats were fed a high-fat diet (HF, 45% Kcal of fat from lard) ad libitum for 3 months. After estimation of their energy requirement (1 month), they were then divided into three groups: HF ad libitum (OL), weight maintenance with AIN93M (9.5% Kcal from fat; ML, 100% of energy requirement), and caloric restriction (CR, AIN93M with 75% of energy requirement). This dietary intervention continued for six months. At this point, rats were sacrificed and gastrocnemius muscle was collected. CR induced a profound shift in fat and lean mass, and decreased growth factor IGF-1. Muscle qPCR analysis showed a marked decrease in inflammation and TNF (premRNA, mRNA, and protein) by CR, accompanied by Tnf promoter DNA hypermethylation. CR increased expression of histone deacetylase Sirt6 and decreased methyltransferase Suv39h1, together with decreased Tnf promoter and coding region binding of NF- κB and C/EBP-β. Following miRNA database mining, qPCR analysis revealed that CR downregulated the proinflammatory miR-19b and increased the anti-inflammatory miR-181a and its known targets. Chronic CR is able to regulate muscle-specific inflammation by targeting the NF-κB pathway as well as transcriptional and post-transcriptional regulation of Tnf gene.


The use of reliever medication in asthma: the role of negative mood and symptom reports.
The aim of this study was to investigate the relationships between negative mood, the reporting of asthma symptoms, and the use of short-acting bronchodilators (reliever medication). Forty-two adult asthma patients completed a daily questionnaire over 7 consecutive days. The questionnaire measured negative mood and the number of symptoms patients associated with their asthma. The symptoms included those typical of asthma, as well as nonspecific somatic and distress symptoms. Subjects were also asked to record their daily use of reliever medication and their peak flow values. Data analysis demonstrated that even when controlling for lung function, both asthma symptom labeling and negative mood were related to reliever use. A mediation model suggested that negative mood leads patients to associate a wide range of nonspecific symptoms with their asthma, thereby altering the perception of the severity of the asthma, which in turn influences their use of reliever medication. The results of this study are discussed in relation to asthma self-management strategies.


Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease.
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology. Recent genome-wide and locus-specific association studies identified RNF213 as an important MMD susceptibility gene. However, the exact mechanism by which an abnormality in RNF213 leads to MMD is unknown. To evaluate the role of RNF213 in the etiology of MMD, we generated RNF213-deficient mice (RNF213-/-) by deleting exon 32 of RNF213 by the Cre-lox system, and investigated whether they developed MMD. The temporal profile of cervical/intracranial arteries was evaluated by 9.4-T magnetic resonance angiography (MRA). The anatomy of the circle of Willis was analyzed by a trans-cardiac injection of carbon black dye. The common carotid arteries (CCA) were sectioned and the arterial wall thickness/thinness was evaluated by Elastica-Masson staining before and after CCA ligation, which selectively induced vascular hyperplasia. As a result, RNF213-/- grew normally, and no significant difference was observed in MRA findings, the anatomy of the circle of Willis, or vascular wall thickness/thinness between RNF-/- and wild-type littermates (Wt.) under normal conditions until 64 weeks of age. However, Elastica-Masson staining demonstrated that both the intima and medial layer were significantly thinner after CCA ligation in RNF213-/- than in Wt. after 14 days (P<0.01). In conclusion, mice lacking the RNF213 gene did not spontaneously develop MMD, indicating that a functional loss of RNF213 did not sufficiently induce MMD. Suppression of vascular remodeling in RNF213-/- requires further examination to clarify the role of RNF213.


Human immunodeficiency virus, sexually transmitted infections, and risk behaviors among clients of sex workers in Guatemala: are they a bridge in human immunodeficiency virus transmission?
Clients of female sex workers (FSWs) are an important target group for human immunodeficiency virus/sexually transmitted infection (HIV/STI) prevention. This study aimed to estimate their HIV and other STI prevalence, examine their risk behaviors, and evaluate their role as a bridge population in the spread of HIV/STIs. A cross-sectional study was performed among 553 clients recruited in commercial sex sites in the province of Escuintla, Guatemala. They were interviewed and tested for HIV and other STIs. Half of the clients who were approached refused participation. Median age was 28.9 years; 57.7% had a regular partner, of whom, 10.1% had concurrent noncommercial partnerships. Consistent condom use with FSWs and regular partners was 72.5% and 17.1%, respectively. Approximately 18% formed a bridge, and 40.0% a potential bridge. Among those who provided samples (70.5% provided a blood sample and 89.7%, urine sample), prevalence of HIV, syphilis, gonorrhea, chlamydia, and herpes simplex virus 2 was 1.5%, 1.0%, 0.8%, 5.5%, and 3.4%, respectively. Unprotected sex with FSWs and drug use just before sex were risk factors for having any STI (9.8% of participants). Bridge clients were significantly less educated, more employed, paid lower prices to the FSW just visited, and had a previous STI. There is a relatively high prevalence of HIV in clients compared to national estimates, and a substantial proportion of them act as a bridge for HIV/STI transmission between FSWs and the general population in Escuintla. Given that this is fuelling the current HIV epidemic, preventive interventions addressing this hard-to-reach group are urgently required.


An epidemic of bath water fever--endotoxin alveolitis?
In August, 1978, in Linnavuori industrial community an epidemic broke reaching nearly one half of the population. The acute disease was manifested by severe respiratory symptoms, fever, cough, and dyspnea. The symptoms were connected with the use of hot water. The symptoms of the disease resembled those of allergic alveolitis or humidifier fever. The tap water of the region was found to be heavily polluted. Besides an ample microbial growth a high endotoxin concentration was found. Specific antibodies to the microbes or radiographic lung changes referring to allergic alveolitis were not found. Leukocytosis and reduced diffusion capacities indicating an inflammatory reaction at the alveolar level were in the acute phase. It may be a toxic lung inflammation caused by endotoxins, at least partly at the bronchiolar-to-alveolar level. According to the follow-up, to date the disease has not caused lung damages.


A cross-sectional study of problem and pathological gambling in patients with schizophrenia/schizoaffective disorder.
Community data suggest frequent co-occurrence between schizophrenia/schizoaffective disorder and problem gambling. However, gambling behaviors in large samples of patients with schizophrenia/schizoaffective disorder have not been systematically examined to date. A sample of outpatient subjects (N = 337) diagnosed with either schizophrenia or schizoaffective disorder and who were treated in either the VA Connecticut Healthcare System or the Connecticut Mental Health Center was interviewed in order to examine the prevalence estimates and clinical correlates of problem and pathological gambling. Multinomial logistic regression models investigated clinically relevant measures in recreational or problem/pathological gamblers, as compared to nongamblers. Data were collected between June 2002 and November 2003. Sixty-five participants (19%) met criteria for past-year problem/pathological gambling, with 10% meeting criteria for pathological gambling. Significant correlates of problem and pathological gambling from multivariable models included greater alcohol use severity (P = .007), higher depression scores (P = .04), and more outpatient mental health care utilization (P = .03). Participants with problem/pathological gambling were more likely than recreational gamblers to gamble for excitement, gamble more frequently and heavily, and report either sports or card gambling as favorite. A substantial proportion of individuals in treatment for psychotic disorders report past-year gambling problems. Patients with co-occurring alcohol use problems and depression may be at particularly high risk. These findings suggest the need for improved prevention and treatment efforts related to problem/pathological gambling in individuals with psychotic disorders.


Modeling the Influence of Ambient Temperature on the Interactions Between the Stable Fly (Diptera: Muscidae) and Its Natural Enemy Spalangia cameroni (Hymenoptera: Pteromalidae) to Assess Consequences of Climate Change.
A simulation model was used to predict how temperature influences biological control of stable flies (Stomoxys calcitrans (L.)) by the pupal parasitoid Spalangia cameroni. Temperature, which was either constant or fluctuated due to seasonal variation and/or environmental stochasticity, was modeled as a first order autocorrelation process. The simulations showed that stable flies could tolerate a wider temperature interval than expected from their thermal performance curve (TPC). This was attributed to the fact that immature flies develop in manure, which protects them against low air temperatures. In contrast, the parasitoids were found to have a narrower thermal tolerance range than expected from their TPC. This was attributed to the temperature-dependent functional response of S. cameroni, which was a limiting factor for the parasitoid's development and survival when host densities were low at suboptimal temperatures. The effects of seasonal variation on critical thermal limits were studied by means of thermal performance diagrams (TPDs). Fluctuating temperatures narrowed the thermal tolerance range of both species. At constant temperatures, the simulations showed that the optimal temperature for using S. cameroni in control of stable flies is ~20°C and that the parasitoid can persist in environments with yearly average temperatures between 18 and 29°C. However, if temperature variation was taken into consideration, it changed both the optimal temperature and the temperature interval at which biological control will be possible. This indicates that climate change causing increasing temperatures compounded with greater fluctuations may have serious consequences for biological control of pests.


Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector.
Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584).


3D QSAR and pharmacophore study of curcuminoids and curcumin analogs: interaction with thioredoxin reductase.
Curcumin is the yellow pigment of Curcuma longa that irreversibly inhibits the activity of thioredoxin reductase (TrxR) and forms adduct. TrxR, a homodimeric enzyme with E and F chains, is responsible for redox control of the cell and defense against oxidative stress. It is also well known that TrxR is over-expressed in tumor cells. Hence TrxR is a promising target for curcumin based therapy. Binding site of TrxR for curcumin is at the interface of homodimers. In the present study, naturally occurring curcuminoids and forty four synthetic analogs of curcumin were docked with SP/XP glide suite and E-pharmacophore was simulated. E-pharmacophore of both chains has shown three donor features and one acceptor feature. 3D atom based QSAR models have been proposed for the two series of curcumin analogues of known IC50values. The data obtained indicates that the training set model is quite efficient to predict the test set of data. Obtained models and ADMET prediction could be employed for design and synthesis of more potent inhibitors of TrxR.


Changes in catastrophizing and depressed mood during and after early cognitive behaviorally oriented interventions for pain.
Catastrophizing and depressed mood are risk factors for poor outcome in treatments for pain and appear to act as mediators for favorable outcome. However, little is known about how catastrophizing and depressed mood co-occur within individuals and how these patterns change during treatment, which is the focus of the current study. The study uses data from a randomized controlled trial about early cognitive behaviorally oriented interventions for patients with nonspecific spinal pain (N = 84). Cluster analyses were used to extract subgroups of individuals with similar scoring patterns on catastrophizing and depressed mood at pretreatment, mid-treatment, posttreatment, and at 6 months' follow-up. To track individual progress, the clusters were linked over time. The analyses revealed four clusters: "low depression and catastrophizing", "high depression and catastrophizing", "high depression", and "high catastrophizing". There was little individual transition from one scoring pattern to another across time, not at least for those scoring high on both depressed mood and catastrophizing. Moreover, high stability within this cluster was related to low levels of psychological flexibility at baseline. It is concluded that catastrophizing and depressed mood at the start of treatment were likely to remain high despite a cognitive behavioral intervention and that a lack of psychological flexibility may have a role.


Contact networks and the study of contagion.
The contact network among individuals in a patient group and in a control group is examined. The probability of knowing another person is modelled with parameters assigned to various factors, such as age, sex or disease, which may influence this probability. Standard likelihood techniques are used to estimate the parameters and to test the significance of the hypotheses, in particular the hypothesis of contagion, generated in the modelling process. The method is illustrated in a study of the Yale student body, in which infectious mononucleosis patients of the opposite sex are shown to know each other significantly more frequently than expected.


Grammaticality judgements in adolescents with and without language impairment.
Existing evidence suggests that young children with specific language impairment have unusual difficulty in detecting omissions of obligatory tense-marking morphemes, but little is known about adolescents' sensitivity to such violations. The study investigated whether limitations in receptive morphosyntax (as measured by grammaticality judgements) were present at age 16 years, and, if so, whether participants' profiles showed less sensitivity to omissions of tense and agreement morphemes than to (1) inappropriate uses (intrusions) of these same morphemes, and (2) omissions of morphemes that do not encode tense and agreement. The study also compared adolescents with language impairment and non-verbal IQ more than 1 standard deviation (SD) below the mean (nonspecific language impairment) to adolescents with specific language impairment. Adolescents with specific language impairment (n = 48), adolescents with non-specific language impairment (n = 25), and adolescents with normal language development (n = 108) performed speeded grammaticality judgements of sentences presented over headphones. Half the sentences were ungrammatical. They included omissions of non-tense morphemes (-ing and possessive -s), omissions of tense morphemes (-ed and third-person singular present -s), and intrusions of the same tense morphemes. The A' statistic was used as the dependent variable for comparisons across groups and item types. Overall, the normal language development group was more sensitive to grammatical violations than the specific language impairment and non-specific language impairment groups, and there was no significant interaction of group and item type. Post-hoc analyses showed that the specific language impairment group was less sensitive to violations than the normal language development group on each item type, and the specific language impairment and non-specific language impairment groups did not differ. Across groups, performance on omission of past tense -ed was lowest, and properties of the items that may have contributed to this difference were explored. The adolescents with language impairment in this study showed evidence of reduced sensitivity to morphological errors, including both tense-marking and non-tense-marking morphemes, but no evidence of any extraordinary difficulty in detecting the omission of tense-marking morphemes, in contrast to results from other research on younger children with specific language impairment. Participants whose non-verbal IQ score was too low to meet the criteria for specific language impairment performed similarly to their peers with specific language impairment. Grammatical competence is compromised in these adolescents with specific language impairment and non-specific language impairment. Neither researchers nor clinicians can assume that adolescents with language impairment have fully mastered grammatical morphology.


Accelerometer based measurement for the mapping of neck surface vibrations during vocalized speech.
This paper presents a detailed study of the vibrations on the surface of the neck during a vocalization of predefined fundamental frequency and intensity. This study was carried out as part of a wider investigation into the use of laryngeal vibrations as a channel of communication. Another potential application of this study is in identifying a suitable location for a hands-free electro-larynx for laryngectomees. An analog accelerometer, with dimensions 5x5x1.6mm and of mass 80mg, was used to perform the measurements. It was connected to a 12-bit analog to digital converter via single strands of insulated wire with a diameter of 100 microm. The resulting low inertia of the measuring device minimised the effect of the measuring device on the phenomenon under investigation. The analog to digital converter simultaneously sampled the accelerometer output and a pre-amplified audio signal from a microphone. This preliminary study was carried out on two able-bodied male subjects. Measurements were taken from forty-five preselected locations on the neck. Each subject made the vowel sound /i/ (long 'e') at three different fundamental frequencies, 150Hz, 200Hz and 250Hz. Once the vocal pitch and intensity matched pre-defined target values, a 200 ms recording was captured by a virtual instrument designed in LabVIEW. A detailed map of skin surface vibration amplitude during vocalization is presented and suitable locations for laryngeal vibration measurement are identified. Further more, detailed analysis of the time varying acceleration function at various measurement positions reveals a rich and complex source of information. Novel visualizations of these signals are presented.


Release of vasoactive hormones and circulatory changes in shock.
Circulatory shock mechanisms that may result in the acute renal failure (ARF) syndrome are summarized. Both circulatory and neurohumoral mechanisms leading to the shock state and ARF are emphasized. Release of vasoactive hormones, with a review of vasodilators and vasoconstrictors, is discussed in terms of release mechanisms, onset of release, magnitude and duration of plasma elevation, and the basal plasma level of each. Hemodynamic diagnoses in shock in both the classical low cardiac output and the early sepsis high cardiac output syndromes are commented upon with emphasis on the importance of early diagnosis and adequate measurements of the circulatory state for optimum therapy. The septic hyperdynamic syndrome is reviewed with particular regard to changes in the renal circulation and function. Mechanisms of lactic acidemia in the hyperdynamic syndrome in the presence of adequate nutrient tissue flow are discussed. Elevations of vasoactive hormones and their relationship to the early shock state are mentioned. Their elevations in late shock are reviewed with critical comments given as to the possible interactions and importance of the vasodilator and vasoconstrictor actions on organ function and survival. Blood pressure alone is not a good indicator of progress in the management of septic shock.


The position of mandibular and mental foramina in Kenyan African mandibles.
Analysis of 79 adult African mandibles indicated that 64.6% of the mandibular foramina were located below the level of the posterior extension of the occlusal plane while 30.7% were located along this plane. 56.1% of the mental foramina were located below the second premolar while 31.1% were between the second premolar and first molar. The remainder were located between the premolars. The mental foramen opened posterosuperiorly in 72.5% of the surfaces. Multiple mental foramina were found on 4.5% of the mandibles. While emphasising the importance of palpation prior to administration of mental nerve block, these observations suggest that in case of uneffective mandibular nerve block, for a significant proportion of Kenyan Bantus, attempts to place the anaesthetic solution slightly below the occlusal plane be considered.


Study of GSK3b inhibitors SB415286 and SB216763 to improve osteoblastic differentiation on microstructured titanium.
Rough titanium surfaces enhance cell response to activation of Wnt canonical signalling, a pathway required for osteoblast differentiation. The present study investigated the effects of GSK3β-inhibitors SB216763 and SB415286 on osteoblastic differentiation on titanium surfaces with different topography and wettability. Osteoblastic MC3T3 cells were plated on smooth (Pickled), sand-blasted/acid-etched (SLA) or hyper hydrophilic SLA (modSLA) titanium discs and transfected with a reporter vector sys-tem for Wnt canonical signalling. Cells were also seeded in the presence or in the absence of GSK3b-inhibitors SB216763 or SB415286 and their viability, morphology and the expression of Wnt target and osteoblast specific genes was assessed by Real Time PCR. Inhibitors altered cell morphology and mostly reduced cell viability at high concentration. SB415286 markedly increased the expression of ALP in MC3T3 cells on rough surfaces at the concentration of 100 nM before decreasing its expression at higher concentrations. OCN expression was unaffected. Increasing concentrations of SB216763 increased the expression of ALP in MC3T3 cells on rough surfaces but OCN expression was not changed at any con-centration. SB216763 and SB415286 inhibitors should be further investigated as potential tools to improve cell differentiation on titanium surfaces for endosseous implants.


Preferential association of endophytic bradyrhizobia with different rice cultivars and its implications for rice endophyte evolution.
Plant colonization by bradyrhizobia is found not only in leguminous plants but also in nonleguminous species such as rice. To understand the evolution of the endophytic symbiosis of bradyrhizobia, the effect of the ecosystems of rice plantations on their associations was investigated. Samples were collected from various rice (Oryza sativa) tissues and crop rotational systems. The rice endophytic bradyrhizobia were isolated on the basis of oligotrophic properties, selective medium, and nodulation on siratro (Macroptilium atropurpureum). Six bradyrhizobial strains were obtained exclusively from rice grown in a crop rotational system. The isolates were separated into photosynthetic bradyrhizobia (PB) and nonphotosynthetic bradyrhizobia (non-PB). Thai bradyrhizobial strains promoted rice growth of Thai rice cultivars better than the Japanese bradyrhizobial strains. This implies that the rice cultivars possess characteristics that govern rice-bacterium associations. To examine whether leguminous plants in a rice plantation system support the persistence of rice endophytic bradyrhizobia, isolates were tested for legume nodulation. All PB strains formed symbioses with Aeschynomene indica and Aeschynomene evenia. On the other hand, non-PB strains were able to nodulate Aeschynomene americana, Vigna radiata, and M. atropurpureum but unable to nodulate either A. indica or A. evenia. Interestingly, the nodABC genes of all of these bradyrhizobial strains seem to exhibit low levels of similarity to those of Bradyrhizobium diazoefficiens USDA110 and Bradyrhizobium sp. strain ORS285. From these results, we discuss the evolution of the plant-bradyrhizobium association, including nonlegumes, in terms of photosynthetic lifestyle and nod-independent interactions.


Diverse polarization bi-stability in ferroelectric tunnel junctions due to the effects of the electrode and strain: an ab initio study.
Both electrodes and substrates are factors of great significance for the performance of ferroelectric tunnel junctions (FTJs) in designing functional nanodevices. To provide a comprehensive view on the polarization stability in FTJs due to the effects of an electrode and a substrate misfit strain, in this work we calculated more than 1000 FTJ structures by utilizing an ab initio density functional theory (DFT) method, via changing the symmetry of the FTJ structure (i.e., both asymmetric and symmetric FTJs), electrodes (including Au, Ag, Cu, Pt, Co, Fe, and SrRuO3), barrier thickness (ranging from 2 to 10 unit cells), polarization direction (both positive and negative polarizations) and epitaxial strain (i.e., -3%, -2.5%, -2%, -1.5% and -1%) as variables. This shows that the FTJs can exhibit quite diverse polarization bi-stability due to the combined effect of the electrode and strain control, which indicates diverse performance of the FTJs modulated by the electrode and strain. In particular, the polarization-mediated electrostatic potential in the barriers with different electrodes forecasts an electrode-tailored tunnel electroresistance effect. Our study provides guidance on the practical applications of FTJs with regard to the selection of electrodes and substrates.


Chemical IN04 Inhibits the Kinase Domain not the ROC Domain of LRRK1: Results from Homology Modeling and Molecular Docking.
Bone loss is the most common reason for broken bones among the elderly. An ideal agent for the treatment of bone loss should have both osteoclast inhibitory and osteoblast stimulatory functions. Leucine-rich repeat kinase 1 (LRRK1) is a novel target for alternative antiresorptive drugs to treat osteoporosis and osteoporotic fractures. Recently a chemical IN04, Methyl 3-[({([5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-thio}-acetyl)-amino]-benzoate, has been identified as a potential LRRK1 inhibitor. The aim of this work is to investigate how the chemical IN04 interacts with LRRK1 and inhibits its activity. A structural model of the LRRK1 kinase domain was constructed with SWISS-MODEL. The human protein kinase ROCO4 (PDB ID: 4YZN) was chosen as the template based on sequence homology, structural and phylogenetic analysis. In addition, a homology model of the LRRK1 ROC domain was also prepared based on the LRRK2 ROC domain structure (PDB ID: 2ZEJ). The interactions of IN04 with the active sites in the LRRK1 kinase domain and ROC domain were investigated by SwissDock. IN04 was docked into the active site of the LRRK1 kinase domain with similar interactions as ATP comparable to the ligand bound to homologous kinases. Many rational binding modes of IN04 to LRRK1 kinase domain were investigated and the most likely binding pose containing multiple hydrogen bonds and a salt bridge was discovered. However, IN04 cannot fit into the GDP-binding site of the ROC domain. Chemical IN04 inhibits LRRK1 by binding to the active site of the kinase domain but not the ROC domain.


SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma.
Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC). Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC. Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival. Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.


Intestinal polyps in the Nigerian African.
Intestinal polyps appear to be relatively rare in the African including Nigerians, South African Bantus, and Ugandans. Only 40 histologically confirmed cases were encountered over a period of ten years. Analysis of these cases reveals a preponderance (60%) of the non-neoplastic juvenile type of polyp. Neoplastic polyps were not encountered in any female patient. The mean ages of the patients are much lower than what has been observed in Caucasians inhabiting developed and industrialized countries. It is felt that there is probably a common or related aetiological agent for neoplastic intestinal polyps and carcinoma because the frequency of intestinal carcinoma appears to be relatively low in areas with a low frequency of neoplastic polyps.


Expression and function of tumour necrosis factor-alpha-converting enzyme in the central nervous system.
Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE/ADAM17) is a membrane protein belonging to the ADAM (a disintegrin and a metalloprotease) family able to cleave various membrane proteins, including the transmembrane form of TNF-alpha at its physiological processing site. Being an ADAM, TACE may mediate not only proteolysis but also adhesive interactions; however, the role of the disintegrin domain of TACE has not been studied. In the central nervous system (CNS), little is known about the physiological role of TACE, but some important pathophysiological functions have been reported recently, with both neurotoxic and neuroprotective repercussions. This article discusses and reviews the main contributions to this field of investigation addressing the expression and function of TACE in the CNS.


Sentinel node biopsy for head and neck melanoma: a systematic review.
This systematic review was conducted to examine the test performance of sentinel node biopsy in head and neck melanoma, including the identification rate and false-negative rate. PubMed, EMBASE, ASCO, and SSO database searches were conducted to identify studies fulfilling the following inclusion criteria: sentinel node biopsy was performed, lesions were located on the head and neck, and recurrence data for both metastatic and nonmetastatic patients were reported. Dual-blind data extraction was conducted. Primary outcomes included identification rate and test performance based on completion neck dissection or nodal recurrence. A total of 3442 patients from 32 studies published between 1990 and 2009 were reviewed. Seventy-eight percent of studies were retrospective and 22% were prospective. Trials varied from 9 to 755 patients (median 55). Mean Breslow depth was 2.53 mm. Median sentinel node biopsy identification rate was 95.2%. More than 1 basin was reported in 33.1% of patients. A median of 2.56 sentinel nodes per patient were excised. Sentinel node biopsy was positive in 15% of patients. Subsequent completion neck dissection was performed in almost all of these patients and revealed additional positive nodes in 13.67%. Median follow-up was 31 months. Across all studies, predictive value positive for nodal recurrence was 13.1% and posttest probability negative was 5%. Median false-negative rate for nodal recurrence was 20.4%. Sentinel node biopsy of head and neck melanoma is associated with an increased false-negative rate compared with studies of non-head and neck lesions. Positive sentinel node status is highly predictive of recurrence.


Choledocholithotripsy in a mare.
Obstructive choledocholithiasis in a 12-year-old mare was corrected surgically by choledocholithotripsy. The mare had a history of chronic weight loss, intermittent fever, partial anorexia, jaundice, recurrent abdominal pain, and an abdominal mass palpable per rectum. Values for alkaline phosphatase, bilirubin, gamma-glutamyl transferase, sorbitol dehydrogenase, and bromsulpthalein half-life were increased and bilirubinuria was evident before surgery. Two liver biopsies revealed periportal and portal fibrosis, bile duct proliferation, cholestasis, and variable amounts of hepatocellular necrosis, with infiltration by polymorphonuclear cells. Immediate clinical improvement was seen after surgery, and results of selected liver function tests gradually returned to normal. Since surgery, the mare has returned to her normal weight, has remained clinically normal for liver disease for 28 months, and has been useful as a broodmare.


Detection of oseltamivir-resistant pandemic influenza A(H1N1)pdm2009 in Brazil: can community transmission be ruled out?
Although surveillance efforts that monitor the emergence of drug-resistant strains of influenza are critical, systematic analysis is overlooked in most developing countries. We report on the occurrence of strains of pandemic influenza A(H1N1)pdm09 with resistance and decreased susceptibility to oseltamivir (OST) in Brazil in 2009, 2011 and 2012. We found 7 mutant viruses, 2 with the mutation S247N and other 5 with the mutation H275Y. Most of these viruses were from samples concentrated in the southern region of Brazil. Some of these resistant viruses were detected prior to the initiation of OST treatment, suggesting that community transmission of mutant viruses may exist. Moreover, we show that one of these OST-resistant (H275Y) strains of A(H1N1)pdm09 was discovered in the tri-border region between Brazil, Argentina and Paraguay, highlighting that this strain could also be found in other Latin American countries. Our findings reinforce the importance of enhanced antiviral resistance surveillance in Brazil and in other Latin American countries to confirm or rule out the community transmission of OST-resistant strains of A(H1N1)pdm09.


[Benign thyroid nodules: diagnostic and therapeutic approach].
In the last years an increase in thyroid nodules detection has been reported from several epidemiological studies. This trend is largely due to the routine use of diagnostic sonography procedures in clinical practice. Thyroid nodules, both palpable or not palpable, rarely turn out to be malignant. Fine-needle aspiration cytology (FNAc) plays a central role in establishing the nature of the nodule. Excluded the presence of malignant lesions, which are generally treated with surgery, physicians are faced with a variety of therapeutic options, and choosing the optimal approach can be a difficult task. These include a periodic follow-up alone without treatment, the iodine supplementation, the thyroid-hormone suppressive therapy, the radioiodine administration, the percutaneous ethanol injections, and the new technique of laser photocoagulation. In all cases, decisions on the management of benign thyroid nodules should always be based on clinical target and a careful analysis of benefits and risks to the patient.


Survey of Clinical Laboratory Practices for 2015 Middle East Respiratory Syndrome Coronavirus Outbreak in the Republic of Korea.
It is crucial to understand the current status of clinical laboratory practices for the largest outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infections in the Republic of Korea to be well prepared for future emerging infectious diseases. We conducted a survey of 49 clinical laboratories in medical institutions and referral medical laboratories. A short questionnaire to survey clinical laboratory practices relating to MERS-CoV diagnostic testing was sent by email to the directors and clinical pathologists in charge of the clinical laboratories performing MERS-CoV testing. The survey focused on testing volume, reporting of results, resources, and laboratory safety. A total of 40 clinical laboratories responded to the survey. A total of 27,009 MERS-CoV real-time reverse transcription PCR (rRT-PCR) tests were performed. Most of the specimens were sputum (73.5%). The median turnaround time (TAT) was 5.29 hr (first and third quartile, 4.11 and 7.48 hr) in 26 medical institutions. The median TAT of more than a half of the laboratories (57.7%) was less than 6 hr. Many laboratories were able to perform tests throughout the whole week. Laboratory biosafety preparedness included class II biosafety cabinets (100%); separated pre-PCR, PCR, and post-PCR rooms (88.6%); negative pressure pretreatment rooms (48.6%); and negative pressure sputum collection rooms (20.0%). Clinical laboratories were able to quickly expand their diagnostic capacity in response to the 2015 MERS-CoV outbreak. Our results show that clinical laboratories play an important role in the maintenance and enhancement of laboratory response in preparation for future emerging infections.


Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing.
Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.


YouTube and the single-rod contraceptive implant: a content analysis.
Since the internet has become an important source of contraceptive information with YouTube.com as the second most visited site, we analysed contraceptive implant YouTube videos for content and clinical accuracy. Using the terms 'contraceptive implant', 'Nexplanon' and 'Implanon', the top 20 results on YouTube by relevance and view count were identified. After excluding duplicates, single-rod implant videos in English were included. Videos were classified as providing a professional or patient perspective. Views, duration and comments were noted. Videos were rated for reliability, global quality scale and whether they were positive or negative about the implant. Inter-rater agreement was measured. A total of 120 videos were retrieved; 52 were eligible for review. Less than 23% were professional videos; the majority reported patient experience (46% testimonials, 27% real-time procedure videos, 4% other). Patient videos had been posted a significantly longer duration of time than professional videos (364 vs 188 days, p=0.02), were less reliable (p≤0.0001) and were of lower global quality (p<0.0001). Some 61% of implant testimonial videos were rated as 'positive experiences' and inter-rater agreement was very good (κ=0.81). All testimonials mentioned side effects, commonly irregular bleeding and discomfort with insertion. A minority (26%) reported misinformation. This study found that most of the information on YouTube pertaining to contraceptive implants is accurate, is presented from the patient's perspective, and promotes the method's use.


Identification of an internal cavity in the PhoQ sensor domain for PhoQ activity and SafA-mediated control.
The PhoQ/PhoP two-component signal transduction system is conserved in various Gram-negative bacteria and is often involved in the expression of virulence in pathogens. The small inner membrane protein SafA activates PhoQ in Escherichia coli independently from other known signals that control PhoQ activity. We have previously shown that SafA directly interacts with the sensor domain of the periplasmic region of PhoQ (PhoQ-SD) for activation, and that a D179R mutation in PhoQ-SD attenuates PhoQ activation by SafA. In this study, structural comparison of wild-type PhoQ-SD and D179R revealed a difference in the cavity (SD (sensory domain) pocket) found in the central core of this domain. This was the only structural difference between the two proteins. Site-directed mutagenesis of the residues surrounding the SD pocket has supported the SD pocket as a site involved in PhoQ activity. Furthermore, the SD pocket has also been shown to be involved in SafA-mediated PhoQ control.


The Clostridium cellulolyticum dockerin displays a dual binding mode for its cohesin partner.
The plant cell wall degrading apparatus of anaerobic bacteria includes a large multienzyme complex termed the "cellulosome." The complex assembles through the interaction of enzyme-derived dockerin modules with the multiple cohesin modules of the noncatalytic scaffolding protein. Here we report the crystal structure of the Clostridium cellulolyticum cohesin-dockerin complex in two distinct orientations. The data show that the dockerin displays structural symmetry reflected by the presence of two essentially identical cohesin binding surfaces. In one binding mode, visualized through the A16S/L17T dockerin mutant, the C-terminal helix makes extensive interactions with its cohesin partner. In the other binding mode observed through the A47S/F48T dockerin variant, the dockerin is reoriented by 180 degrees and interacts with the cohesin primarily through the N-terminal helix. Apolar interactions dominate cohesin-dockerin recognition that is centered around a hydrophobic pocket on the surface of the cohesin, formed by Leu-87 and Leu-89, which is occupied, in the two binding modes, by the dockerin residues Phe-19 and Leu-50, respectively. Despite the structural similarity between the C. cellulolyticum and Clostridium thermocellum cohesins and dockerins, there is no cross-specificity between the protein partners from the two organisms. The crystal structure of the C. cellulolyticum complex shows that organism-specific recognition between the protomers is dictated by apolar interactions primarily between only two residues, Leu-17 in the dockerin and the cohesin amino acid Ala-129. The biological significance of the plasticity in dockerin-cohesin recognition, observed here in C. cellulolyticum and reported previously in C. thermocellum, is discussed.


Value of inversion imaging to diagnosis in differentiating malignant from benign breast masses.
We aimed to evaluate the added value of inversion imaging in differentiating between benign and malignant breast masses when combined with the Breast Imaging Reporting and Data System (BI-RADS). A total of 364 patients with 367 breast masses (151 benign and 216 malignant) who underwent conventional ultrasound and inversion imaging prior to breast surgery were included. A 5-point inversion score (IS) scale was proposed based on the masses' internal echogenicity and distribution characteristics in the inversion images. The combination of IS and BI-RADS was compared with BI-RADS alone to evaluate the value of inversion imaging for breast mass diagnosis. The diagnostic performance of the BI-RADS and its combination with IS for breast masses were analyzed using area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The IS for malignant breast masses (3.96 ± 0.77) was significantly higher than benign masses (2.58 ± 0.98) (P < 0.001). The sensitivity, specificity, accuracy, PPV, and NPV of BI-RADS were 86.1%, 81.5%, 84.2%, 86.9%, and 80.4%, respectively, and an AUC was 0.909. By compared with BI-RADS, 72 breast masses were downgraded from suspected malignancy to benign, and 6 masses were upgraded from benign to suspected malignancy. Thus, the specificity was increased from 81.5 to 84.8%, it allows 72 benign masses avoid biopsy. The combination of inversion imaging with BI-RADS can effectively improve the diagnostic efficacy of breast masses, and inversion imaging could help benign masses avoid biopsy.


The effect of Mg(2+) incorporation on the structure of calcium carbonate clusters: investigation by the anharmonic downward distortion following method.
Mg(2+) is considered to play an important role in the formation of calcium carbonate polymorphs; however, how it affects polymorph selection during the early stages of CaCO3 formation is not yet well understood. In the present study, in order to clarify the effect of Mg(2+) on the nucleation of calcium carbonate polymorphs, the stable structures of anhydrous additive-free and Mg-containing calcium carbonate clusters are derived using the anharmonic downward distortion following method, based on quantum chemical calculations. Optimization is performed at the B3LYP/6-31+G(d) level and the solvent effect is induced by the self-consistent reaction field method using the conductor-like polarized continuum calculation model. Calculation results show that incorporating Mg(2+) into clusters can change the clusters' stable configuration. In the case of dimers and trimers, a Mg ion strongly prefers to locate at the centre of the clusters, which suggests that Mg is easy to incorporate into the clusters once it is released from its tight hydration shell. Notably, structures similar to the crystalline phase appear when only four CaCO3 units aggregate into the cluster: in the stable structure of the additive-free CaCO3 tetramer, the arrangement of Ca and CO3 ions is almost the same as that of the calcite structure, while the structure of the Mg-containing CaCO3 tetramer resembles the aragonite structure in the way that CO3 ions are stacked. These results indicate that Mg can play a key role in aragonite formation not only by inhibiting calcite growth but also by directly promoting aragonite nucleation in the early stages of CaCO3 formation.


Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice.
Airway macrophages provide a first line of host defense against a range of airborne pathogens, including influenza virus. In this study, we show that influenza viruses differ markedly in their abilities to infect murine macrophages in vitro and that infection of macrophages is nonproductive and no infectious virus is released. Virus strain BJx109 (H3N2) infected macrophages with high efficiency and was associated with mild disease following intranasal infection of mice. In contrast, virus strain PR8 (H1N1) was poor in its ability to infect macrophages and highly virulent for mice. Depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in BJx109-infected mice but did not modulate disease severity in PR8-infected mice. The severe disease observed in macrophage-depleted mice infected with BJx109 was associated with exacerbated virus replication in the airways, leading to severe airway inflammation, pulmonary edema, and vascular leakage, indicative of lung injury. Thymic atrophy, lymphopenia, and dysregulated cytokine and chemokine production were additional systemic manifestations associated with severe disease. Thus, airway macrophages play a critical role in limiting lung injury and associated disease caused by BJx109. Furthermore, the inability of PR8 to infect airway macrophages may be a critical factor contributing to its virulence for mice.


Graphene Strained by Defects.
Using graphene nanomechanical resonators we demonstrate the extent to which the mechanical properties of multilayer graphene films are controllable, in real time, through introduction and rearrangement of defects. We show both static and re-entrant (cyclical) changes in the tensile stress using a combination of ion implantation, chemical functionalization, and thermal treatment. While the dramatic increase in static tensile stress achievable through laser annealing can be of importance for various MEMS applications, we view the direct observation of a time-variable stress as even more significant. We find that defect-rich films exhibit a slow relaxation component of the tensile stress that remains in the resonator long after the laser exposure is finished (trelax ≈ 100 s ≫ tcooling), analogous to a wind-up toy. We attribute this persistent component of the time-variable stress to a set of metastable, multivacancy structures formed during the laser anneal. Our results indicate that significant stress fields generated by multivacancies, in combination with their finite lifetime, could make them a powerful and flexible tool in nanomechanics.


[Lyme borreliosis--incidence of serum anti-myelin antibodies].
The method of enzyme immunoassay (ELISA) was used for detection of antibodies against the basic protein myelin (antimyelin antibodies) for a group of serum samples (n 36) with positive anti-borrelia immunoglobulins IgG and IgM (ELISA-Borrelia afzelii) and their immune complexes (ELISA-PEG). Antimyelin antibodies (ELISA-Doxa Kit-Myelin Basic Protein Antibodies) were assessed in 31% (n 11) of examined serum samples of patients with the working diagnosis of Lyme borreliosis. Statistical analysis (p 0.07) confirmed a more frequent incidence of antimyelin antibodies in younger female subjects (age 31 years) as compared with a group of sera (n 25) where the authors did not record the formation of immunoglobulins against the basic myelin protein (age 51 years). Neither the value of titres nor the frequency of detected anti-borrelia IgG and IgM and immune complexes did not differ significantly in the two groups. From the assembled results ensues that in the course of Lyme borreliosis, in chronic affection of organs an autoimmune reaction may develop where the basic myelin protein is damaged (demyelinizatio) and subsequently antimyelin antibodies are formed.


Invertebrates may not be so different after all.
Sex determination is widespread, but uses highly varied molecular mechanisms. A possible case of conservation between phyla is that of doublesex (dsx) from Drosophila and mab-3 (male abnormal 3) from Caenorhabditis elegans, genes related in sequence and some elements of function. mab-3 controls multiple aspects of male development, including sense organ formation in the tail and yolk transcription in the intestine, both similar to functions of dsx. Indeed, the male isoform of DSX can replace MAB-3 in C. elegans. Do related genes control sexual development in vertebrates, despite great differences in the biology of sex determination? We have identified several dsx-related genes in mouse and human. One, Dmrt1, appears to play a conserved role in vertebrate male gonad development. In humans, DMRT1 maps to a short interval required for testis differentiation. In all vertebrates examined, including mammals, birds, fish, and reptiles, Dmrt1 is expressed early in the genital ridge, in most cases with higher expression in future male gonads. A null mutation in murine Dmrt1 causes severe defects in testis differentiation, resembling those associated with human deletions removing the gene. Mutant females are unaffected. Other DM domain genes are expressed in embryonic gonad and are currently under study.


Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids.
1. The aim of this study was to describe the time course of the response of human muscle protein synthesis (MPS) to a square wave increase in availability of amino acids (AAs) in plasma. We investigated the responses of quadriceps MPS to a approximately 1.7-fold increase in plasma AA concentrations using an intravenous infusion of 162 mg (kg body weight)(-1) h(-1) of mixed AAs. MPS was estimated from D3-leucine labelling in protein after a primed, constant intravenous infusion of D3-ketoisocaproate, increased appropriately during AA infusion. 2. Muscle was separated into myofibrillar, sarcoplasmic and mitochondrial fractions. MPS, both of mixed muscle and of fractions, was estimated during a basal period (2.5 h) and at 0.5-4 h intervals for 6 h of AA infusion. 3. Rates of mixed MPS were not significantly different from basal (0.076 +/- 0.008 % h(-1)) in the first 0.5 h of AA infusion but then rose rapidly to a peak after 2 h of approximately 2.8 times the basal value. Thereafter, rates declined rapidly to the basal value. All muscle fractions showed a similar pattern. 4. The results suggest that MPS responds rapidly to increased availability of AAs but is then inhibited, despite continued AA availability. These results suggest that the fed state accretion of muscle protein may be limited by a metabolic mechanism whenever the requirement for substrate for protein synthesis is exceeded.


Lymphomas and lymphoproliferative disorders clinically presenting as renal carcinoma: a clinicopathological study of 14 cases.
Although uncommon, lymphomas and lymphoproliferative disorders (LPDs) that manifest as renal or perirenal masses can mimic primary renal cancers upon clinical and radiological evaluations. However, such distinction is critical as the management of these diseases are drastically different. This study reports the clinical, radiological and pathological features of 14 lymphomas/LPDs that were initially managed as primary renal carcinomas. The surgical pathology file was queried for kidney resections or biopsies with a diagnosis of lymphoma or LPD. The clinical symptomatology, imaging results, pathology data, treatment regimens and outcome data were obtained by electronic patient data search and/or chart review. Lymphomas/LPDs accounted for only 29 of 5490 (0.5%) of renal neoplasms diagnosed by pathology over a 27 year period. Of these 29 cases, 14 had a presumptive clinical diagnosis of renal carcinoma prior to nephrectomy or biopsy. Eleven of 14 (78.6%) had concurrent retroperitoneal, periaortic or distant adenopathy. Only two cases had inferior vena caval invasion. On pathological examination, the majority of these cases were mature B-cell neoplasms; however, three of 14 cases were initially interpreted as poorly differentiated carcinoma on routine histological sections. Upon staging, all 14 cases had nodal and/or additional extranodal involvement while only two of 14 cases demonstrated vascular invasion. Lymphomas/LPDs should always be kept in the differential diagnosis for unusual renal or perirenal masses. Extensive regional or distant adenopathy without vascular invasion favours a clinical diagnosis of LPD, while the presence of both regional adenopathy and vascular invasion should raise clinical suspicion for renal carcinoma.


Arthroscopic intervention in early hip disease.
Advancement in diagnostic and therapeutic applications for hip arthroscopy have dispelled previous myths about early hip disease. Arthroscopic findings have established the following facts: Acetabular labral tears do occur; acetabular chondral lesions do exist; tears are most frequently anterior and often associated with sudden twisting or pivoting motions; and labral tears often occur in association with articular cartilage lesions of the adjacent acetabulum or femoral head, and if present for years, contribute to the progression of delamination process of the chondral cartilage. Magnetic resonance arthrography represents an improvement over conventional magnetic resonance imaging, it does have limitations when compared with direct observation. Although indications for hip arthroscopy are constantly expanding, the most common indications include: labral tears, loose bodies, chondral flap lesions of the acetabular or femoral head, synovial chondromatosis, foreign body removal, and crystalline hip arthropathy (gout, pseudogout, and others). Contraindications include conditions that limit the potential for hip distraction such as joint ankylosis, dense heterotopic bone formation, considerable protrusio, or morbid obesity. Complication rates have been reported between 0.5 and 5%, most often related to distraction and include sciatic or femoral nerve palsy, avascular necrosis, and compartment syndrome. Transient peroneal or pudendal nerve effects and chondral scuffing have been associated with difficult or prolonged distraction. Meticulous consideration to patient positioning, distraction time and portal placement are essential. Judicious patient selection and diagnostic expertise are critical to successful outcomes. Candidates for hip arthroscopy should include only those patients with mechanical symptoms (catching, locking, or buckling) that have failed to respond to conservative therapy. The extent of articular cartilage involvement has the most direct relationship to surgical outcomes. Improvements in technique and instrumentation have made hip arthroscopy an efficacious way to diagnose and treat a variety of intra-articular problems.


SARS-CoV-2 neutralizing antibody bebtelovimab - a systematic scoping review and meta-analysis.
The COVID-19 pandemic is a major global public health crisis. More than 2 years into the pandemic, effective therapeutic options remain limited due to rapid viral evolution. Stemming from the emergence of multiple variants, several monoclonal antibodies are no longer suitable for clinical use. This scoping review aimed to summarize the preclinical and clinical evidence for bebtelovimab in treating newly emerging SARS-CoV-2 variants. We systematically searched five electronic databases (PubMed, CENTRAL, Embase, Global Health, and PsycINFO) from date of inception to September 30, 2022, for studies reporting on the effect of bebtelovimab in SARS-CoV-2 infection, using a combination of search terms around -bebtelovimab‖, -LY-CoV1404‖, -LY3853113‖, and -coronavirus infection‖. All citations were screened independently by two researchers. Data were extracted and thematically analyzed based on study design by adhering to the stipulated scoping review approaches. Thirty-nine studies were included, thirty-four non-clinical studies were narratively synthesized, and five clinical studies were meta-analyzed. The non-clinical studies revealed bebtelovimab not only potently neutralized wide-type SARS-CoV-2 and existing variants of concern such as B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but also retained appreciable activity against Omicron lineages, including BA.2.75, BA.4, BA.4.6, and BA.5. Unlike other monoclonal antibodies, bebtelovimab was able to bind to epitope of the SARS-CoV-2 S protein by exploiting loop mobility or by minimizing side-chain interactions. Pooled analysis from clinical studies depicted that the rates of hospitalization, ICU admission, and death were similar between bebtelovimab and other COVID-19 therapies. Bebtelovimab was associated with a low incidence of treatment-emergent adverse events. Preclinical evidence suggests bebtelovimab be a potential treatment for COVID-19 amidst viral evolution. Bebtelovimab has comparable efficacy to other COVID-19 therapies without evident safety concerns.


[Non-traumatic rupture of the spleen].
A non-traumatic rupture of the spleen is a rare, serious condition with a high mortality rate. This sort of rupture can occur in a healthy patient or in patients with an underlying disease such as an infection or a haematological disorder. Here we describe a 52-year-old man who had Legionella pneumonia and suffered a spontaneous rupture of the spleen. He had to undergo a splenectomy following an unsuccessful embolisation of the lienal artery. He recovered. In the second patient, a 73-year-old man with monoclonal gammopathy, rupture of the spleen was caused by amyloidosis of the spleen. Rupture of the spleen can cause life threatening haemorrhage, so early recognition is important.


Photosynthetic parameters of leaves of wild type and Cyt b6/f deficient transgenic tobacco studied by CO2 uptake and transmittance at 800 nm.
Parallel measurements of CO2 assimilation and 800 nm transmission were carried out on intact leaves of wild type and cytochrome b6/f deficient transgenic tobacco grown at different light intensities and temperatures, with the aim to diagnose rate-limiting processes in photosynthesis and investigate their adaptations to growth conditions. Maximum CO2- and light-saturated photosynthetic rate, mesophyll conductance, assimilatory charge and specific carboxylation efficiency were determined from CO2 fixation measurements and postillumination P700 rereduction time constant was measured from the transient of the 800 nm signal. Results show that growth conditions continue to modulate the expression of genes in transgenic plants, interfering with the antisense modulation, but under all environmental conditions the antisense treatment to decrease Cyt b6/f complexes ensured that the control of electron/proton transport rate by proton backpressure on the PSI donor side was stronger than the control by electron backpressure on the PSI acceptor side. Coordinated control of gene expression and enzyme activation ensures that different parts of the photosynthetic machinery--components of the electron transport chain, ribulose-1,5-bisphosphate carboxylase/oxygenase, enzymes of the sucrose and starch synthesis chains-are synthesized more or less proportionally under different environmental conditions and in case of mild genetic interference.


Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation.
While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-kappaB, a key regulator of inflammation and the immune response. NF-kappaB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-kappaB. Interestingly, NF-kappaB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-kappaB enhances SXR activity. This SXR/PXR-NF-kappaB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.


Decreased high-density lipoprotein cholesterol levels in polyarticular juvenile idiopathic arthritis.
To investigate the prevalence of dyslipoproteinemia in a homogeneous cohort of polyarticular juvenile idiopathic arthritis patients. Based on the National Cholesterol Education Program, fasting lipoprotein levels and risk levels for coronary artery disease were determined in 28 patients with polyarticular juvenile idiopathic arthritis. The exclusion criteria included diabetes, thyroid dysfunction, smoking, proteinuria, lipid-lowering drugs, and hormone/diuretic therapy. Disease activity, disease duration, and therapy with corticosteroids and/or chloroquine were defined at the time of lipid measurements. Dyslipoproteinemia was identified in 20 of the 28 (71%) patients with polyarticular juvenile idiopathic arthritis. The primary lipoprotein risk factor was decreased high-density lipoprotein cholesterol (57%), followed by elevated levels of low-density lipoprotein cholesterol (18%), triglycerides (14%), and total cholesterol (7%). The male patients had decreased high-density lipoprotein cholesterol levels than the female patients (p<0.05). The incidence of decreased high-density lipoprotein cholesterol levels did not seem to be affected by disease activity or therapy because the incidence was similar in patients with active or inactive disease, with or without corticosteroid use and with or without chloroquine use. In addition, the frequency of decreased high-density lipoprotein cholesterol levels was similar in patients with short (≤5 years) vs. long (>5 years) disease duration. Dyslipoproteinemia is highly prevalent in patients with polyarticular juvenile idiopathic arthritis and is primarily related to decreased high-density lipoprotein cholesterol levels; therefore, early intervention is essential.


Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice.
Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.


Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany.
The use of pesticides exposes humans to numerous harmful molecules. Exposure in early-life may be responsible for adverse effects in later life. This study aimed to assess the metabolic modifications induced in pregnant rats and their offspring by a pesticide mixture representative of human exposure. Ten pregnant rats were exposed to a mixture of eight pesticides: acetochlor (246 μg/kg bw/d) + bromoxynil (12 μg/kg bw/d) + carbofuran (22.5 μg/kg bw/d) + chlormequat (35 μg/kg bw/d) + ethephon (22.5 μg/kg bw/d) + fenpropimorph (15.5 μg/kg bw/d) + glyphosate (12 μg/kg bw/d) + imidacloprid (12.5 μg/kg bw/d) representing the main environmental pesticide exposure in Brittany (France) in 2004. Another group of 10 pregnant rats served as controls. Females were fed ad libitum from early pregnancy, which is from gestational day (GD) 4 to GD 21. Urine samples were collected at GD 15. At the end of the exposure, mothers and pups were euthanized and blood, liver, and brain samples collected. 1H NMR-based metabolomics and GC-FID analyses were performed and PCA and PLS-DA used to discriminate between control and exposed groups. Metabolites for which the levels were significantly modified were then identified using the Kruskal-Wallis test, and p-values were adjusted for multiple testing correction using the False Discovery Rate. The metabolomics analysis revealed many differences between dams of the two groups, especially in the plasma, liver and brain. The modified metabolites are involved in TCA cycle, energy production and storage, lipid and carbohydrate metabolism, and amino-acid metabolism. These modifications suggest that the pesticide mixture may induce oxidative stress associated with mitochondrial dysfunction and the impairment of glucose and lipid metabolism. These observations may reflect liver dysfunction with increased relative liver weight and total lipid content. Similar findings were observed for glucose and energy metabolism in the liver of the offspring, and oxidative stress was also suggested in the brains of male offspring.