The comparative effects of environmental enrichment with exercise and serotonin transporter blockade on serotonergic neurons in the dorsal raphe nucleus.
We have previously reported that inhibition of the serotonin transporter (SERT) by selective serotonin reuptake inhibitor (SSRI) fluoxetine significantly reduces the number of tryptophan hydroxylase (TPH)-positive cells in the dorsal raphe nucleus (DRN). We have been interested in exploring whether this SSRI-induced change in TPH might be modified by housing in an enriched environment. Like SSRI antidepressants, environmental enrichment (EE) and physical exercise have been found to have efficacy in the prevention and alleviation of depression. We postulated that EE with exercise and SERT inhibition would similarly affect TPH regulation and that EE with exercise might modify the effect of fluoxetine on TPH. Three week old male Sprague-Dawley rats were housed in either a standard cage (SE) or an enriched environment (EE). SE animals were singly housed with no access to enrichment objects. EE animals were group housed and were provided with various enrichment objects (e.g. running wheel) that were changed and rearranged regularly. Nine weeks after the experiment began, the rats were randomly assigned to one of four treatment groups: (1) SE control; (2) SE fluoxetine; (3) EE control; or (4) EE fluoxetine. Fluoxetine (5 mg/kg/day) was placed in the drinking water. Sections of DRN were processed for TPH immunohistochemistry. The number of TPH-positive cells was determined by blinded, manual counting. Results were analyzed by analysis of variance (ANOVA) followed by post-hoc Tukey tests. Significance was set at P < 0.05. For animals housed in a standard environment, fluoxetine induced a significant 29% reduction in the number of TPH-immunoreactive cells in the DRN. A similar reduction in TPH immunoreactivity was observed in animals that were housed in an enriched environment but not exposed to fluoxetine (39%). The number of TPH-positive cells in the DRN for animals housed in an enriched environment and exposed to fluoxetine was not significantly different than animals housed in an enriched environment and not exposed to fluoxetine. The reduction of TPH immunoreactivity in the DRN by EE with exercise suggests that a modified housing environment and voluntary exercise affects regulation of TPH, possibly via a mechanism similar to that of SERT inhibitors. This downregulation of serotonin biosynthesis by fluoxetine and EE with exercise may ultimately play a role in the therapeutic action of both interventions.


Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage.
In metazoans, target of rapamycin complex 1 (TORC1) plays the key role in nutrient- and hormone-dependent control of metabolism. However, the role of TORC1 in regulation of triglyceride storage and metabolism remains largely unknown. In this study, we analyzed the effect of activation and inhibition of the mammalian TORC1 (mTORC1) signaling pathway on the expression of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipolysis, lipogenesis, and lipid storage in different mammalian cells. Activation of mTORC1 signaling in 3T3-L1 adipocytes by ectopic expression of Rheb inhibits expression of ATGL and HSL at the level of transcription, suppresses lipolysis, increases de novo lipogenesis, and promotes intracellular accumulation of triglycerides. Inhibition of mTORC1 signaling by rapamycin or by knockdown of raptor stimulates lipolysis primarily via activation of ATGL expression. Analogous results have been obtained in C2C12 myoblasts and mouse embryonic fibroblasts with genetic ablation of tuberous sclerosis 2 (TSC2) gene. Overexpression of ATGL in these cells antagonized the lipogenic effect of TSC2 knockout. Our findings demonstrate that mTORC1 promotes fat storage in mammalian cells by suppression of lipolysis and stimulation of de novo lipogenesis.


Pathophysiology of bilateral hyperaldosteronism.
Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism. The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA. Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.


A 3D composite lithium metal anode with pre-fabricated LiZn via reactive wetting.
Lithium metal anodes (LMAs) have been suffering from challenging problems of solid electrolyte interface (SEI) formation and lithium morphological instability (LMI), which lead to a poor cycling life and notorious safety concerns. Herein, we prepared a 3D composite anode (Li@NFZO) by heat treatment and reactive wetting where nickel foam serves as the framework and LiZn/Li fills in the holes. Interestingly, it is found that such a nickel foam + LiZn combination can largely reinforce the electrode/electrolyte interface stability and thus slows down the electrolyte consumption. Furthermore, uniformly distributed and lithiophilic LiZn contributes to the homogenous Li plating so that dendrites can be geometrically disturbed. Therefore, stable cycling for 185 h at 5 mA h cm-2/5 mA cm-2 in symmetrical cells, 2.8× bare Li, was achieved. The cycling life of the LiFePO4//Li@NFZO full-cell at ≈6.6 g A h-1 electrolyte addition was prolonged to 120 cycles (80% capacity retention), compared to 66 cycles for the LiFePO4//Li full-cell.


Inhibition of T cell activation by the extracellular matrix protein tenascin.
Tenascin (TN) is an extracellular matrix protein that is expressed widely in the fetus and sparingly in the adult, but reappears at high levels in certain areas of tissue insult such as tumor matrices and sites of wound healing. We show here that soluble TN inhibits proliferation of human T cells in response to alpha CD3 Ab co-immobilized with the extracellular matrix protein fibronectin (FN). TN also inhibits proliferation driven by alpha CD3/IL-2 or by phorbol ester/IL-2, and it prevents high level induction of IL-2R. The presence of TN in culture medium does not detectably alter the pattern of tyrosine phosphorylation resulting from T cell triggering with alpha CD3, but at later time points prevents the appearance of functional NF-AT1 transcription factor complexes in T cell nuclear extracts. These findings are consistent with the postulated role for TN as a natural antagonist to FN action, and suggest that T cell responses occurring at tissue sites in which TN is expressed could be influenced by its presence.


Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients.
Risk of over-immunosuppression or immunization may mitigate the overall and long-term renal outcomes of kidney transplant recipients (KTR) admitted to the ICU in the modern era but remain poorly described. Thus, there is an unmet need to better characterize the survival of KTR admitted to the ICU, but also the renal and immunological outcomes of survivors. Retrospective observational study that included 200 KTR admitted between 2010 and 2016 to the ICU of a teaching hospital (median age 61 years [IQR 50.7-68]; time from transplantation 41 months [IQR 5-119]). Survival curves were compared using the Log-rank test. Mortality rates following admission to the ICU was low (26.5% at month-6), mainly related to early mortality (20% in-hospital), and predicted by the severity of the acute condition (SAPS2 score) but also by Epstein Barr Virus proliferation in the weeks preceding the admission to the ICU. Acute kidney injury (AKI) was highly prevalent (85.1%). Progression toward chronic kidney disease (CKD) was observed in 45.1% of survivors. 15.1% of survivors developed new anti-HLA antibodies (donor-specific antibodies 9.2% of cases) that may impact the long-term renal transplantation function. Notwithstanding the potential biases related to the retrospective and monocentric nature of this study, our findings obtained in a large cohort of KTR suggest that survival of KTR admitted in ICU is good but in-ICU management of these patients may alter both survival and AKI to CKD transition, as well as HLA immunization. Further interventional studies, including systematic characterization of the Epstein Barr virus proliferation at the admission (i.e., a potential surrogate marker of an underlying immune paralysis and frailty) will need to address the optimal management of immunosuppressive regimen in ICU to improve survival but also renal and immunological outcomes.


The ONCO-I2b2 project: integrating biobank information and clinical data to support translational research in oncology.
The University of Pavia and the IRCCS Fondazione Salvatore Maugeri of Pavia (FSM), has recently started an IT initiative to support clinical research in oncology, called ONCO-i2b2. ONCO-i2b2, funded by the Lombardia region, grounds on the software developed by the Informatics for Integrating Biology and the Bedside (i2b2) NIH project. Using i2b2 and new software modules purposely designed, data coming from multiple sources are integrated and jointly queried. The core of the integration process stands in retrieving and merging data from the biobank management software and from the FSM hospital information system. The integration process is based on a ontology of the problem domain and on open-source software integration modules. A Natural Language Processing module has been implemented, too. This module automatically extracts clinical information of oncology patients from unstructured medical records. The system currently manages more than two thousands patients and will be further implemented and improved in the next two years.


Decoupled Glucose and Lipid Metabolic Recovery after Viral Clearance in Direct-Acting Antiviral-Treated HCV Patients: A 3-Year Prospective Cohort Study.
The recovery pattern of hepatitis C virus (HCV)-associated metabolic alteration after sustained virological response (SVR) following direct-acting antivirals (DAAs) remains elusive. A prospective cohort study of chronic HCV-infected (CHC) patients (n = 415) receiving DAAs (n = 365) was conducted. Metabolic profiles were examined in SVR patients (n = 360) every 3-6 months after therapy and compared with those of sex- and age-matched controls (n = 470). At baseline, of 415, 168 (40.5%) had insulin resistance (IR). The following were associated: levels of high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), HCV RNA, fibrosis-4 score, and interferon-λ3-rs12979860 genotype with total cholesterol (TC) levels; and TG levels and BMI with HOMA-IR. Over a 3-year follow-up, in SVR patients, BMI and TC levels and TG/HDL-C ratios increased from baseline, while HOMA-IR trended downward by 72 weeks after therapy and then increased. The increased HDL-C levels began to decrease after 72 weeks after therapy. TC and HOMA-IR were negatively associated with each other until 24 weeks after therapy. Earlier increases in BMI and decreases in HOMA-IR were noted in SVR patients with than in those without baseline IR. Compared with controls, in the subgroup without baseline IR, SVR patients had increased BMI and HOMA-IR levels. Metabolic profiles were similar between SVR patients and controls in the subgroup with baseline IR. In SVR patients treated with DAAs, the recovery of altered lipid and glucose metabolism was not coupled until 72-week post-therapy, when HOMA-IR reached its nadir. SVR patients with baseline IR recovered from HCV-associated metabolic alterations earlier than those without baseline IR.


YY-1 and c-Jun transcription factors participate in the repression of the human involucrin promoter.
The human involucrin gene, which encodes a precursor of the keratinocyte cornified layer, is strongly expressed in response to differentiation stimuli. Earlier studies suggested that YY1 and components of the AP-1 family might participate in the silencing of involucrin in proliferating keratinocytes. This study shows that overexpression of either YY1 or c-Jun represses transcription of the human involucrin gene in multiplying keratinocytes. Transient overexpression and site-directed mutagenesis experiments of the involucrin 5'-non-coding region (5'-NCR) confirmed that YY1 and c-Jun repress involucrin transcription. This repression involves the distal zinc fingers of YY1 protein and the DNA binding and leucine zipper domains of c-Jun. The results with protein pull-down experiments are consistent with the hypothesis that interaction of YY1 with c-Jun is an important mechanism for involucrin repression. Cotransfection of YY1 modified the stimulatory function of mutant c-Jun proteins independently of their DNA binding capacity suggesting that interactions may be more complex in vivo. Additionally, c-Jun protein levels are affected by differentiation stimuli indicating the importance of c-Jun in the YY1 repression pathway. Thus YY1 and c-Jun have an important role in epidermal differentiation by negatively regulating the human involucrin gene.


Separated local field NMR experiments on oriented samples rotating at the magic angle.
Biophysical studies on membrane proteins by solid state NMR (SSNMR) can be carried out directly in a membrane environment. Samples are usually prepared in form of multi-lamellar dispersions for magic angle sample spinning or as aligned multi-layers for orientation dependent NMR experiments without sample rotation. A new development is the application of MAS NMR to aligned samples (MAOSS; Magic Angle Oriented Sample Spinning). In combination with separated local field (SLF) experiments, size and orientation of heteronuclear dipolar couplings may be extracted from two-dimensional experiments which correlate dipolar couplings with isotropic chemical shifts. The orientation of these (1)H-X dipolar couplings can be directly related to the orientation of molecular groups in the sample. Here, we demonstrate the feasibility of these experiments on highly ordered polyethylene fibers which serve as model compound. Based on these data, the experiment is also applied to ordered multi-layers of bacteriorhodopsin (purple membrane) which is used as a model for aligned membrane proteins. We present a detailed analysis of different experimental designs with respect to angular sensitivity and the influence of residual sample disorder ("mosaic spread"). The results of the MAOSS-SLF experiment are discussed within the context of established solid state NMR experiments which are usually performed without sample rotation and we compare the data to orientation information obtained from X-ray diffraction.


Adaptive Structure Discovery for Multimedia Analysis Using Multiple Features.
Multifeature learning has been a fundamental research problem in multimedia analysis. Most existing multifeature learning methods exploit graph, which must be computed beforehand, as input to uncover data distribution. These methods have two major problems confronted. First, graph construction requires calculating similarity based on nearby data pairs by a fixed function, e.g., the RBF kernel, but the intrinsic correlation among different data pairs varies constantly. Therefore, feature learning based on such predefined graphs may degrade, especially when there is dramatic correlation variation between nearby data pairs. Second, in most existing algorithms, each single-feature graph is computed independently and then combine them for learning, which ignores the correlation between multiple features. In this paper, a new unsupervised multifeature learning method is proposed to make the best utilization of the correlation among different features by jointly optimizing data correlation from multiple features in an adaptive way. As opposed to computing the affinity weight of data pairs by a fixed function, the weight of affinity graph is learned by a well-designed optimization problem. Additionally, the affinity graph of data pairs from different features is optimized in a global level to better leverage the correlation among different channels. In this way, the adaptive approach correlates the features of all features for a better learning process. Experimental results on real-world datasets demonstrate that our approach outperforms the state-of-the-art algorithms on leveraging multiple features for multimedia analysis.


Distribution patterns of variability for 18 immune system genes in Amerindians--relationship with history and epidemiology.
Native American populations generally have a higher prevalence of infectious diseases than non-Native populations and this fact can induce different pressures in their immune system. We investigated the patterns of population differentiation (FST ) of 32 polymorphisms related to adaptive immune response in four Native American populations (Aché, Guarani-Kaiowá, Guarani-Ñandeva and Kaingang), and the results were compared with the three major world population data [Yoruba of Ibadan, Nigeria (YRI), Utah residents with northern and Western Europe ancestry (CEU) and Han Chinese of Beijing, China (CHB)] available in the HapMap database. The Aché clearly differentiated from the other Amerindians, but when all Native Americans were compared with the samples of other ethnic groups the lowest difference (0.08) was found with CHB (Asians), the second lowest (0.15) with YRI (Africans) and the most marked with CEU (European-derived). The considerable intra and interethnic differences found can be explained both in terms of diverse evolutionary distances and more recent environmental pathogen exposures; and they should be appropriately considered prior to any specific public health action.


Structure of the green fluorescent protein NowGFP with an anionic tryptophan-based chromophore.
A green-emitting fluorescent variant, NowGFP, with a tryptophan-based chromophore (Thr65-Trp66-Gly67) was recently developed from the cyan mCerulean by introducing 18 point mutations. NowGFP is characterized by bright green fluorescence at physiological and higher pH and by weak cyan fluorescence at low pH. Illumination with blue light induces irreversible photoconversion of NowGFP from a green-emitting to a cyan-emitting form. Here, the X-ray structures of intact NowGFP at pH 9.0 and pH 4.8 and of its photoconverted variant, NowGFP_conv, are reported at 1.35, 1.18 and 2.5 Å resolution, respectively. The structure of NowGFP at pH 9.0 suggests the anionic state of Trp66 of the chromophore to be the primary cause of its green fluorescence. At both examined pH values Trp66 predominantly adopted a cis conformation; only ∼ 20% of the trans conformation was observed at pH 4.8. It was shown that Lys61, which adopts two distinct pH-dependent conformations, is a key residue playing a central role in chromophore ionization. At high pH the side chain of Lys61 forms two hydrogen bonds, one to the indole N atom of Trp66 and the other to the carboxyl group of the catalytic Glu222, enabling an indirect noncovalent connection between them that in turn promotes Trp66 deprotonation. At low pH, the side chain of Lys61 is directed away from Trp66 and forms a hydrogen bond to Gln207. It has been shown that photoconversion of NowGFP is accompanied by decomposition of Lys61, with a predominant cleavage of its side chain at the C(γ)-C(δ) bond. Lys61, Glu222, Thr203 and Ser205 form a local hydrogen-bond network connected to the indole ring of the chromophore Trp66; mutation of any of these residues dramatically affects the spectral properties of NowGFP. On the other hand, an Ala150Val replacement in the vicinity of the chromophore indole ring resulted in a new advanced variant with a 2.5-fold improved photostability.


Impact of conditioning on outcome of hematopoietic stem cell transplantation for wiskott-Aldrich syndrome.
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for Wiskott-Aldrich syndrome (WAS). The aim of this retrospective study is to report the effect of the conditioning regimen and donor source on disease-free survival (DFS) in children undergoing HSCT for WAS. Fourteen children who underwent HSCT at 4 Israeli centers from 1996 to 2011 were included in this study. Five children were transplanted from matched related donors (4/5 siblings, 1/5 fully matched uncle) and other donors were used in 9 children. Six patients were conditioned with full dose busulfan/cyclophosphamide (Bu/Cy) whereas 8 patients were conditioned with other regimens. Thirteen of 14 patients (92.8%) are alive with a median follow-up of 3.4 years (range, 5 mo to 12.5 y). Nine patients (64.3%) survive with complete clinical, immunologic, and hematologic recovery. Children conditioned with full dose Bu/Cy had a 100% DFS, compared with children conditioned with other regimens, 25%±19% (P=0.022). Donor source was not associated with DFS. Graft failure was related to the use of conditioning regimens other than full dose Bu/Cy and not to the donor source. Further studies are required to determine the best conditioning regimen and optimal donor source for children with WAS.


Should Depression Be Treated Before Lower Extremity Arthroplasty?
Patient optimization is becoming increasingly important before arthroplasty to ensure outcomes. It has been suggested that depression is a modifiable risk factor that should be corrected preoperatively. It remains to be determined whether psychological intervention before surgery will improve outcomes. We theorized that the use of preoperative depression scales to predict postoperative outcomes may be influenced by the pain and functional disability of arthritis. To determine whether depression is a modifiable risk factor that should be corrected preoperatively we asked the following questions: (1) What is the prevalence of depression in arthroplasty patients preoperatively? (2) Do depressive symptoms improve after surgery? (3) Is preoperative depression associated with outcome? Patients scheduled for surgery completed a patient health questionnaire (PHQ-9) to assess the presence and severity of depression pre-operatively and one year post-operatively. Sixty-five of the 282 patients had a PHQ-9 score >10 indicating moderate depression and 57 (88%) improved to <10 postoperatively (P = .0012). Ten patients had a PHQ-9 score >20 indicating severe depression and 9 (90%) improved to <10 postoperatively (P = .10). Of the 65 patients who had a PHQ-9 score >10 preoperatively, the median postoperative Hip Disability and Osteoarthritis Outcome Score (N = 40) was 92.3, while the median postoperative Knee Injury and Osteoarthritis Outcome Score (N = 25) was 84.6. The median postoperative Hip Disability and Osteoarthritis Outcome Score and Knee Injury and Osteoarthritis Outcome Score in nondepressed patients were 96.2 and 84.6, respectively (P = .9041). By diminishing pain and improving function through arthroplasty, depression symptoms improve significantly. Patients with depressive symptoms preoperatively had similar postoperative outcome scores compared to non-depressed patients. Patients should not be denied surgical intervention through optimization programs that include a depression scale threshold. III.


IGF-I downregulates resistin gene expression and protein secretion.
Resistin (Rstn) is known as an adipocyte-specific secretory factor that can cause insulin resistance and decrease adipocyte differentiation. Conversely, based on various studies, insulin-like growth factors (IGFs) can improve insulin resistance and stimulate adipocyte adipogenesis. Whether IGFs exert their effects through the control of Rstn's production or modulation of Rstn's action is unknown. This study was designed to examine the influence and the signaling of IGF-I on Rstn gene expression and protein secretion by 3T3-L1 adipocytes. We found that IGF-I suppressed Rstn mRNA expression and protein release in dose- and time-dependent manners. The IC50 of IGF-I was approximately 1 nM for a range of 6-10 h of treatment. Treatment with cycloheximide, but not with actinomycin D, prevented IGF-I-suppressed Rstn mRNA expression, suggesting that IGF-I destabilizes Rstn mRNA and that IGF-I's effect requires new protein, but not mRNA, synthesis. Pretreatment with IGF-I receptor (IGF-IR) antibody blocked IGF-I-altered IGF-IR activity and Rstn mRNA levels. Neither PD-98059, SB-203580, nor LY-294002 changed the IGF-I-decreased levels of Rstn mRNA, but they inhibited IGF-I-stimulated activities of MEK1, p38 MAPK, and phosphoinositide 3-kinase, respectively. However, SB-203580 antagonized the IGF-I-decreased Rstn protein release. These data demonstrate that IGF-I downregulates Rstn gene expression via IGF-IR-dependent and MEK1-, p38 MAPK-, and phosphoinositide 3-kinase-independent pathways and likely modifies the distribution of Rstn protein between the intracellular and extracellular compartments via a p38 MAPK-dependent pathway. Decreases in Rstn production and secretion induced by IGF-I may be related to the mechanism by which IGF-I modulates body weight and diabetes in animals.


Periventricular lesions and MS diagnostic criteria in young adults with typical clinically isolated syndromes.
In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria.


Does occupational lifting and carrying among female health care workers contribute to an escalation of pain-day frequency?
The aim of the study was to investigate if different frequencies, loads and trunk postures of occupational lifting and carrying increases the risk of sub-chronic (1-30 days last 12 months) low back pain (LBP) to become persistent (>30 days last 12 months) among female health care workers. Female health care workers answered a questionnaire about occupational lifting or carrying frequency (rarely, occasionally and frequently), load (low: 1-7 kg, moderate: 8-30 kg and heavy: >30 kg) and trunk posture (upright or forward bent back), and days with LBP in 2005 and 2006. The odds ratio (OR) for developing persistent LBP in 2006 from these characteristics of occupational lifting and carrying was investigated with multi-adjusted logistic regressions among female health care workers with sub-chronic LBP (n = 2381) in 2005. Among health care workers with sub-chronic LBP, increased risk of persistent LBP was found from frequently lifting or carrying with forward bent back of moderate loads (OR: 1.63; 95% CI: 1.15-2.33) and heavy loads (OR: 1.56; 95% CI: 1.04-2.34). No increased risk for LBP to develop into a persistent condition was found for frequent lifting with upright back, frequent lifting or carrying of light loads, or occasionally lifting or carrying of any loads. Preventive initiatives for sub-chronic LBP to develop into a persistent condition ought to focus on reducing frequent lifting and carrying of moderate and heavy loads with forward bent back.


CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase-producing modulators of Ca2+ signaling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD+ levels were also fully restored, while the levels of the two main products of CD38, nicotinamide and ADP-ribose, were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38-/- mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with isatuximab (SARCLISA® ) a monoclonal anti-CD38 antibody. Finally, treatment of mdx and utrophin-dystrophin-deficient (mdx/utr-/- ) mice with CD38 inhibitors resulted in improved skeletal muscle performances. Thus, we demonstrate that CD38 actively contributes to DMD physiopathology. We propose that a selective anti-CD38 therapeutic intervention could be highly relevant to develop for DMD patients.


Immortalization of human umbilical vein endothelial cells with telomerase reverse transcriptase and simian virus 40 large T antigen.
To establish normally conditionally-immortalized human umbilical vein endothelial cells (HUVECs) by ectopic expression of the human telomerase catalytic enzyme (hTERT) and simian virus 40 large T (SV40 LT) antigen. Primary HUVECs were transfected with recombinant retrovirus containing hTERT or SV40 LT respectively. Subsequently drug resistant cell clones were screened and expanded for further studies. Endothelial cell biomarkers were confirmed by examination. The morphological phenotype of the transfected cells was similar to the non-transfected cells. Von Willebrand factor, hTERT and SV40 LT could be detected in transfected HUVECs. Moreover, higher telomerase activity in transfected cells was maintained for over 50 population doublings compared with only low level of endogenous telomerase transiently at early population doublings in primary HUVECs. When exposed to TNF-alpha (tumor necrosis factor-alpha), the expression of E-selectin in transfected cells was significantly up-regulated, but no alteration of endothelial lipase was found. Ectopic coexpression of hTERT and SV40 LT can effectively immortalize HUVECs without tumorigenicity in vitro. Immortalized HUVECs may be an ideal target of further molecular function studies.


Genetic influences on osteoarthritis in women: a twin study.
To assess the relative contribution of genetic and environmental factors to common forms of osteoarthritis of the hands and knees. Classic twin study with unselected twins who were screened radiologically for osteoarthritis. 130 identical and 120 non-identical female twins aged 48-70 recruited from a London based twin register and through a national media campaign. Similarity in identical compared with non-identical twin pairs for radiographic changes at the interphalangeal and first carpometacarpal joints of the hands and the tibiofemoral joint and patellofemoral joint of the knee expressed as intraclass correlations. The intraclass correlations of radiographic osteophytes and narrowing at most sites and the presence of Heberden's nodes and knee pain were higher in the identical pairs. The intraclass correlation of the total radiographic osteoarthritis score in identical pairs (rMZ) was 0.64 (SE 0.05) compared with 0.38 (0.08) in non-identical pairs. The proportion of genetic variance of total osteoarthritis score (osteophytes and narrowing) with modelling techniques was estimated at 0.54 (95% confidence interval 0.43 to 0.65) and ranged from 0.39 to 0.65 for different sites and features (p < 0.001) after adjustment for age and weight. These results demonstrate for the first time a clear genetic effect for radiographic osteoarthritis of the hand and knee in women, with a genetic influence ranging from 39-65%, independent of known environmental or demographic confounders. The results of this study should lead to further work on isolating the gene or genes involved in the pathogenesis of the common disabling disease.


Recent trends in the number of laboratory animals used in Japan.
Surveys on the numbers of laboratory animals used in Japan have been conducted by both the Japanese Association for Laboratory Animal Science (JALAS) and the Japanese Association for Laboratory Animals in National Universities (JALAN). According to the JALAS, in 1998, 5,626,116 animals were used in experiments. Rodents, such as mice and rats, made up 87% of that total, while the total number of dogs, cats and monkeys used was less than 1%. The JALAS reported that the total number of animals used in experiments in 1990 was 8,737,770, a peak of 10,013,584 was reached in 1995, and thereafter the number gradually decreased to 5,626,116 in 1998. During this period, the number of all the species used, except non-human primates and farm animals, decreased. The number of dogs and cats used decreased by over 65%. This decrease was attributed to the activities of animal welfare groups. On the other hand, the JALAN reported that the total number of animals used in experiments doubled from 1991 to 1999. The increase could be attributed to use of genetically modified mice, such as transgenic and knockout mice. Noting problems with the methods used, we concluded that the number of the laboratory animals used in Japan, other than rodents, has been gradually decreasing since 1991.


Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype.
KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.


Echocardiographic epicardial fat thickness and coronary artery disease.
The association between epicardial fat and coronary artery disease has not been evaluated. The objective of the present study was to evaluate the relationship of echocardiographic epicardial fat to the presence and severity of coronary artery disease in a clinical setting. Two hundred and three consecutive patients who underwent echocardiography and diagnostic coronary angiography were studied. The epicardial fat thickness on the free wall of the right ventricle was measured at end-diastole from the parasternal long-axis views of 3 cardiac cycles. Coronary angiograms were analyzed for the extent and severity of coronary artery disease using Gensini's score. The patients were divided into 2 groups according to the fourth quartile of epicardial fat thickness (Group I <7.6 mm; Group II > or =7.6 mm). There were no significant differences in the baseline characteristics except for waist circumference (p=0.023). Significant correlations were demonstrated between epicardial fat thickness and age (r=0.332, p<0.001), C-reactive protein (r=0.182, p=0.009), body mass index (r=0.142, p=0.044) and waist circumference (r=0.229, p=0.001). The patients with a higher epicardial fat thickness were associated with a high Gensini's score (p=0.014). Multivariate analysis showed that age (odds ratio (OR) 5.29, p=0.003), epicardial fat thickness (OR 10.53, p=0.004), diabetes (OR 8.06, p=0.006) and smoking (OR 14.65, p=0.015) were independent factors affecting significant coronary artery stenosis. Epicardial fat thickness was significantly correlated with the severity of coronary artery disease in patients with known coronary artery disease.


Ewing's sarcoma / primitive neuroectodermal tumor of the kidney.
A 42-year-old female presented with right back pain. The CT scan revealed a 72-mm space-occupying lesion in the middle portion of the right kidney. No metastasis was proven. She underwent laparoscopic radical nephrectomy and lymph node disection. The histopathological examination revealed a high-grade primitive small round tumor the cells of which were strongly positive for CD99 and vimentin. Fluorescence in situ hybridization analysis using a DNA probe for the Ewing sarcoma breakpoint region 1 (EWSR 1) on chromosome 22g12 revealed a rearrangement of the EWSR 1 locus. The diagnosis was Ewing's sarcoma / primitive neuroectodermal tumor of the kidney. She underwent 13 cycles of chemotherapy, and has no evidence of recurrence 19 months after surgery.


[Coagulase-negative Staphylococcus bacteraemia: prognosis factors and influence of antibiotic treatment].
Coagulase-negative staphylococci (CNS) are the most frequent isolated microorganism in blood cultures; mortality has been associated to severity and to adequacy of empirical treatment but the relevance of the latter is not clearly recognised. The aims of the study were to analyze clinical and microbiological factors related to mortality in patients with CNS bacteraemia and the influence of empirical treatment in prognosis. A prospective cohort study of patients with CNS bacteraemia was performed (January to June 2010) at a university-affiliated hospital; a determination of clinical significance was made and true bacteraemia was defined according to CDC criteria. We analysed epidemiological, clinical and microbiological variables related to mortality. A total of 269 cases were included (97 were considered true bacteraemia); 92% survived and mortality was 8% (1.6% CNS bacteraemia related mortality). Staphylococcus epidermidis was the most frequent isolated species; 93 patients were included in the related mortality study of patients with true bacteraemia. Factors associated to mortality in the bivariate analysis (p<0.05) were: Winton score I-III, presence of pacemakers, sepsis or infective endocarditis and persistent bacteraemia. Adequate empirical treatment was not associated to survival. Severity at onset, the development of septic complications and having a pacemaker are associated to mortality in patients with CNS bacteraemia; in our cohort, inadequate empirical treatment is not related to mortality.


The DULK (Dutch leakage) and modified DULK score compared: actively seek the leak.
A standardized postoperative score, the DULK (Dutch leakage) score, has been demonstrated to be a useful clinical tool in the diagnosis of anastomotic leakage. It is complicated, however, and a simplification (the modified DULK score) based on fewer parameters derived from multiple logistic regression analyses has been developed. These include clinical condition, abdominal pain not localized at the wound, C-reactive protein level and respiratory rate. The accuracy of each was compared. Data of all patients from five Dutch centres operated on between 16 October 2007 and 1 November 2009 with an anastomosis in the colon or rectum were entered into a prospectively maintained database. In total, 782 patients were included of whom 81 (10.4%) had a clinically relevant anastomotic leakage. The DULK score gave an overall sensitivity of 97% for anastomotic leakage, overall specificity of 53%, a positive predictive value (PPV) of 16% and a negative predictive value (NPV) of 99%. The modified DULK score used clinical condition, abdominal pain not localized at the wound, C-reactive protein level and respiratory rate. With at least one parameter present, overall sensitivity was 97%, overall specificity 57%, PPV 17% and NPV 99.5%. With at least two points PPV was 41% and with three points 57%. Both the original and modified DULK scores are useful for the early diagnosis of clinically relevant anastomotic leakage. The modified DULK score offers the benefit of fewer parameters and so can easily be used in a clinical environment to estimate the likelihood of anastomotic leakage. However, the early diagnosis of anastomotic leakage remains difficult.


Unexplained CD4+ T-lymphocytopenia without evidence of HIV infection.
The human immunodeficiency virus, HIV has long been known to be associated with CD4+ T-lymphocytopenia. In clinical practice, a low CD4 count usually implies an underlying HIV infection until proven otherwise. Non-HIV related CD4 depletion is a rare phenomenon, but has caused much public concern. A Chinese lady with unexplained CD4+ T-lymphocytopenia is presented, followed by a review of the condition as well as its practical implications.


Interactions between risk assessors and risk managers during three major food incidents in Europe.
Risk analysis consists of risk assessment (RA), risk management (RM), and risk communication (RC). In most countries, RA and RM of food safety are separated to achieve a high scientific integrity, and typically occur in sequential order. However, in case of a food safety incident, even though being separate processes, RA and RM are performed simultaneously due to great time pressure and expected high impacts. The aim of this study was to analyze and evaluate the observed interactions between RA and RM processes, during three major food incidents in Europe, and to provide suggestions for possible improvement. Based on the differences observed between the three cases, strengths and weaknesses of each system have been identified. The enterohemorrhagic Escherichia coli (EHEC) crisis in 2011 in Germany, the horsemeat scandal in 2013 in Ireland, and the fipronil incident in 2017 in the Netherlands were used as case studies. Timelines of these incidents and crisis management procedures in place in each of the three countries provided the basis for further analysis. First, results showed that details of the communication processes between RA and RM bodies were frequently lacking in crisis management protocols. Second, RA, RM, and RC processes differed for each incident, due to differences in estimated risk for public health, but also due to differences in the organization within a country. Based on our results, we recommend that crisis management protocols should contain a section on communication between RA, RM, and on communication between member states in the EU.


Oligoprogression of Solid Tumors on Immune Checkpoint Inhibitors: The Impact of Local Ablative Radiation Therapy.
The breakthrough of a limited number of clones while on immune checkpoint inhibitors (ICIs), known as oligoprogression, has been previously described. The benefit of ablative radiation therapy (RT) directed at these clones, as opposed to changing systemic therapy, is unclear. We analyzed 30 patients with advanced solid tumors, the majority of whom (23/30, 86.7%) had either hepatocellular or urothelial carcinoma, who experienced oligoprogression on ICIs and were referred for RT. In this study, oligoprogression was defined as having experienced progression at three or fewer metastatic sites outside of the brain after achieving at least stable disease on ICIs for a minimum of three months. The median time to oligoprogression was 11.1 months from the initiation of immunotherapy. 24 patients had one oligoprogressive lesion and six had two. The median radiation dose delivered was 4650 cGy in a median of five fractions. The median progression-free survival (PFS) after RT was 7.1 months, and the time to oligoprogression was not a significant predictor of PFS2. 26 patients continued on ICIs after RT. While 17 patients subsequently progressed, 15 did so at three or fewer metastatic sites and could have theoretically stood to benefit from an additional course of salvage RT to further extend the lifespan of their ICIs. Overall survival at 6, 12, and 24 months was 100.0%, 96.3%, and 82.8%, respectively. These results suggest that RT may provide a PFS benefit and extend the lifespan of ICIs in patients who experience oligoprogression. Regardless of PFS, however, overall survival in this population appears to be excellent.


Can public sector community health workers deliver a nurturing care intervention in South Africa? The Amagugu Asakhula feasibility study.
Nurturing care interventions have the potential to promote health and development in early childhood. Amagugu Asakhula was designed to promote developmentally important dietary and movement behaviours among children of preschool age (3-5 years) in South Africa. An initial formative study in Cape Town found the intervention to be feasible and acceptable when delivered by community health workers (CHWs) linked to a community-based organisation. This study evaluated the delivery of the Amagugu Asakhula intervention by CHWs linked to a public sector primary health care facility in Soweto, as this mode of delivery could have more potential for sustainability and scalability. A qualitative design was utilised to assess feasibility, acceptability, adoption, appropriateness, implementation, fidelity and context. CHWs (n = 14) delivered the intervention to caregivers (n = 23) of preschool-age children in Soweto over 6 weeks. Following the completion of the intervention, focus group discussions were held with CHWs and caregivers. Further data were obtained through observations, study records and key informant interviews (n = 5). Data were analysed using deductive thematic analysis guided by a process evaluation framework. The delivery of the Amagugu Asakhula intervention through CHWs linked to a primary health care facility in Soweto was not found to be feasible due to contextual challenges such as late payment of salaries influencing CHW performance and willingness to deliver the intervention. CHWs expressed dissatisfaction with their general working conditions and were thus reluctant to take on new tasks. Despite barriers to successful delivery, the intervention was well received by both CHWs and caregivers and was considered a good fit with the CHWs' scope of work. Based on these findings, delivery of the Amagugu Asakhula intervention is not recommended through public sector CHWs in South Africa. This feasibility study informs the optimisation of implementation and supports further testing of the intervention's effectiveness when delivered by CHWs linked to community-based organisations. The present study further demonstrates how implementation challenges can be identified through qualitative feasibility studies and subsequently addressed prior to large-scale trials, avoiding the wasting of research and resources.


Antigenic and structural features of goblet-cell mucin of human small intestine.
With the use of a newly developed solid-phase radioimmunoassay method, the major antigenic determinants of human small-intestinal goblet-cell mucin were investigated and related to the overall tertiary structure of the mucin. Preliminary hapten inhibition studies with various oligosaccharides of known sequence and structure suggested that the determinants did not reside in carbohydrate. Exhaustive thiol reduction, however, almost abolished antigenicity, caused breakdown of the mucin into small heterogeneous glycopeptides, and liberated a 'link' peptide of Mr 118000. Western 'blots' of reduced mucin from polyacrylamide gels on to nitrocellulose sheets showed that a small amount of residual antigenicity remained in large-Mr glycopeptides (Mr greater than 200000). The 'link' peptide was not antigenic. Timed Pronase digestion of native mucin resulted in a progressive loss of antigenic determinants. Gel electrophoresis revealed that after 8h of digestion the 118000-Mr peptide had disappeared, whereas antigenicity, which was confined to large-Mr glycopeptides, was destroyed much more slowly with time (70% by 24h, 100% by 72h). Despite the loss of antigenicity, 72h-Pronase-digested glycopeptides retained all of the carbohydrate of the native mucin. Therefore the antibody to human small-intestinal mucin appears to recognize a 'naked' (non-glycosylated and Pronase-susceptible) peptide region(s) of mucin glycopeptides. For full antigenicity, however, disulphide bonds are required to stabilize a specific three-dimensional configuration of the 'naked' region.


The Corticosterone-Glucocorticoid Receptor-AP1/CREB Axis Inhibits the Luteinizing Hormone Receptor Expression in Mouse Granulosa Cells.
Under stress conditions, luteinizing hormone (LH)-mediated ovulation is inhibited, resulting in insufficient oocyte production and excretion during follicular development. When the body is stressed, a large amount of corticosterone (CORT) is generated, which will lead to a disorder of the body's endocrine system and damage to the body. Our previous work showed that CORT can block follicular development in mice. Since LH acts through binding with the luteinizing hormone receptor (Lhcgr), the present study aimed to investigate whether and how corticosterone (CORT) influences Lhcgr expression in mouse ovarian granulosa cells (GCs). For this purpose, three-week-old ICR female mice were injected intraperitoneally with pregnant mare serum gonadotropin (PMSG). In addition, the treatment group was injected with CORT (1 mg/mouse) at intervals of 8 h and the control group was injected with the same volume of methyl sulfoxide (DMSO). GCs were collected at 24 h, 48 h, and 55 h after PMSG injection. For in vitro experiments, the mouse GCs obtained from healthy follicles were treated with CORT alone, or together with inhibitors against the glucocorticoid receptor (Nr3c1). The results showed that the CORT caused a downregulation of Lhcgr expression in GCs, which was accompanied by impaired cell viability. Moreover, the effect of the CORT was mediated by binding to its receptor (Nr3c1) in GCs. Further investigation revealed that Nr3c1 might regulate the transcription of Lhcgr through inhibiting the expression of Lhcgr transcription factors, including AP1 and Creb. Taken together, our findings suggested a possible mechanism of CORT-induced anovulation involving the inhibition of Lhcgr expression in GCs by the CORT-Nr3c1-AP1/Creb axis.


Optimization of ultrafast all-optical resonator switching.
We present general optimization arguments for resonator-based all-optical switching. Several generic resonator geometries, namely Fabry-Perot resonators, circular gratings as well as micro-ring resonators, are discussed and their particular features highlighted. We establish analytical models which allow a direct comparison of the different all-optical switch geometries. For the parameter range investigated, we find a clear advantage of photonic band-gap resonators (based on Bragg-type reflection) over micro-ring resonators (based on total internal reflection).


Kawasaki disease seasonality in Venezuela supports an arbovirus infection trigger.
Kawasaki disease (KD) is an inflammatory disease primarily affecting infants and young children, whose etiology remains uncertain. Observational studies of the overlap between KD outbreaks and seasonal peaks of arboviral infections, suggest the possible role of these pathogens as triggers of KD. In Venezuela, regions with the highest reported arboviral infections simultaneously have the highest incidence of KD. One proposed explanation for this association involves the role of proinflammatory mediators, interleukin-1 (IL-1), IL-6, tumor necrosis factor, and vascular endothelial growth factor as mediators of coronary endothelial damage. The promotion of inflammation and tissue destruction by these cytokines is thought to contribute to the coronary endothelial damage experienced in KD. The utilization of overlapping KD and arboviral infection trends contribute to the comprehension of KD etiology, with improvements in diagnosis, prognosis and treatment.


SARS-CoV-2 Antibody Prevalence among Industrial Livestock Operation Workers and Nearby Community Residents, North Carolina, 2021 to 2022.
Industrial livestock operations (ILOs), particularly processing facilities, emerged as centers of coronavirus disease 2019 (COVID-19) outbreaks in spring 2020. Confirmed cases of COVID-19 underestimate true prevalence. To investigate the prevalence of antibodies against SARS-CoV-2, we enrolled 279 participants in North Carolina from February 2021 to July 2022: 90 from households with at least one ILO worker (ILO), 97 from high-ILO intensity areas (ILO neighbors [ILON]), and 92 from metropolitan areas (metro). More metro (55.4%) compared to ILO (51.6%) and ILON participants (48.4%) completed the COVID-19 primary vaccination series; the median completion date was more than 4 months later for ILO compared to ILON and metro participants, although neither difference was statistically significant. Participants provided a saliva swab we analyzed for SARS-CoV-2 IgG using a multiplex immunoassay. The prevalence of infection-induced IgG (positive for nucleocapsid and receptor binding domain) was higher among ILO (63%) than ILON (42.9%) and metro (48.7%) participants (prevalence ratio [PR], 1.38; 95% confidence interval [CI], 1.06 to 1.80; reference category ILON and metro combined). The prevalence of infection-induced IgG was also higher among ILO participants than among an Atlanta health care worker cohort (PR, 2.45; 95% CI, 1.80 to 3.33) and a general population cohort in North Carolina (PRs, 6.37 to 10.67). The infection-induced IgG prevalence increased over the study period. Participants reporting not masking in public in the past 2 weeks had higher infection-induced IgG prevalence (78.6%) than participants reporting masking (49.3%) (PR, 1.59; 95% CI, 1.19 to 2.13). Lower education, more people per bedroom, Hispanic/Latino ethnicity, and more contact with people outside the home were also associated with higher infection-induced IgG prevalence. IMPORTANCE Few studies have measured COVID-19 seroprevalence in North Carolina, especially among rural, Black, and Hispanic/Latino communities that have been heavily affected. Antibody results show high rates of COVID-19 among industrial livestock operation workers and their household members. Antibody results add to evidence of health disparities related to COVID-19 by socioeconomic status and ethnicity. Associations between masking and physical distancing with antibody results also add to evidence of the effectiveness of these prevention strategies. Delays in the timing of receipt of COVID-19 vaccination reinforce the importance of dismantling vaccination barriers, especially for industrial livestock operation workers and their household members.


Medroxyprogesterone acetate induces c6 glioma chemosensitization via antidepressant-like lysosomal phospholipidosis/myelinosis in vitro.
The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lysosomal-phospholipidosis. Exact patterns of myelinosis accompanying to MPA chemo-sensitization is important, because uncoupling of nuclear versus mitochondrial toxicity of anti-neoplastics by MPA would lead to safer employment of glioma chemotherapy with reduced neurotoxicity. By monitoring and comparing cell kinetics with fine structural features of cell death, the authors estimated subcellular effects accompanying growth-inhibitory drug actions in C6 glioma. The analysis revealed that MPA induced mainly lysosomal phospholipidosis, while inhibiting clonogenicity alone and augmenting procarbazine efficacy. It induced apoptosis in combination with cisplatin. It reduced mitochondrial-damage-based early cytotoxicity of methotrexate, yet it did not hinder its anti-clonogenic efficacy. Progesterone analogues - similar to antidepressants - inhibit cholesterol esterification, and this efficacy relates with their P-glycoprotein inhibition. Reducing esterification and plasma-membrane localization of cholesterol may lead MPA induction of lysosomal phospholipidosis, growth indolency, and drug sensitization in glioma.


Evolving Concepts in Helicobacter pylori Management.
Helicobacter pylori is the most common chronic bacterial infection worldwide and the most significant risk factor for gastric cancer, which remains a leading cause of cancer-related death globally. H pylori and gastric cancer continue to disproportionately impact racial and ethnic minority and immigrant groups in the United States. The approach to H pylori case-finding thus far has relied on opportunistic testing based on symptoms or high-risk indicators, such as racial or ethnic background and family history. However, this approach misses a substantial proportion of individuals infected with H pylori who remain at risk for gastric cancer because most infections remain clinically silent. Moreover, individuals with chronic H pylori infection are at risk for gastric preneoplastic lesions, which are also asymptomatic and only reliably diagnosed using endoscopy and biopsy. Thus, to make a significant impact in gastric cancer prevention, a systematic approach is needed to better identify individuals at highest risk of both H pylori infection and its complications, including gastric preneoplasia and cancer. The approach to H pylori eradication must also be optimized given sharply decreasing rates of successful eradication with commonly used therapies and increasing antimicrobial resistance. With growing acceptance that H pylori should be managed as an infectious disease and the increasing availability of susceptibility testing, we now have the momentum to abandon empirical therapies demonstrated to have inadequate eradication rates. Molecular-based susceptibility profiling facilitates selection of a personalized eradication regimen without necessitating an invasive procedure. An improved approach to H pylori eradication coupled with population-level programs for screening and treatment could be an effective and efficient strategy to prevent gastric cancer, especially in minority and potentially marginalized populations that bear the heaviest burden of H pylori infection and its complications.


Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors.
Kinin B1 and B2 receptors (kB1R and kB2R) play important roles in many physiological and pathological processes. In some cases, kB1R or kB2R activation can have overlapping or complementary beneficial effects, thus an activator of both receptors might be advantageous. We found that replacement of the C-terminal Arg in the natural kB2R activators bradykinin (BK) or kallidin (KD) with Lys (K(9)-BK or K(10)-KD) resulted in agonists that effectively stimulate the downstream signaling of both the kB1R and kB2R as measured by increased inositol turnover, intracellular calcium, ERK1/2 phosphorylation, arachidonic acid release and NO production. However, K(9)-BK and K(10)-KD displayed some characteristics of biased agonism for kB2Rs as indicated by the rapid kinetics of ERK1/2 phosphorylation induced by K(9)-BK or K(10)-KD compared with the prolonged response mediated by BK or KD. In contrast, kinetics of ERK phosphorylation stimulated by K(10)-KD activation of the kB1R was the same as that induced by known kB1R agonist des-Arg(10)-KD. Furthermore, the endocytosis of kB2Rs mediated by K(9)-BK and K(10)-KD was remarkably less than that induced by BK and KD respectively. K(10)-KD stimulated kB1R and kB2R-dependent calcium responses and ERK1/2 phosphorylation in bovine endothelial cells. In cytokine-treated human endothelial cells, K(10)-KD stimulated ERK1/2 phosphorylation and a transient peak of NO production that was primarily kB2R-dependent. K(10)-KD also stimulated prolonged NO production that was both kB1R and kB2R-dependent. These data provide the first examples of dual agonists of kB1R and kB2R, and a biased agonist of kB2R and may provide useful clues for developing dual modulators of kB1Rs and kB2Rs for potential therapeutic use.


Kidney transplantation using elderly non-heart-beating donors: a single-center experience.
Although acceptable outcomes have been reported in both non-heart-beating (NHB) and elderly donors individually, the large pool of elderly NHB donors has not yet been fully utilized. In 1994, we expanded our transplant protocol to include NHB donors aged over 65 years and this study compares the clinical outcomes with regular NHB transplantations. Up to June 2005, 24 patients were transplanted at our center with kidneys from NHB donors aged 65 years or more, whereas 176 patients received grafts from conventional NHB donors during the same period. Grafts from older donors were associated with inferior glomerular filtration rates (29 vs. 44 mL/min after 1 year, p=0.01) and graft survival (52% vs. 68% after 5 years, p=0.19) compared to younger NHB donor grafts, although the difference in graft survival was not statistically significant. Exclusion of older NHB donor kidneys with severe vascular pathology resulted in similar graft survival of older and younger NHB donor kidneys. We conclude that the use of elderly NHB donors in order to expand the donor pool was associated with unacceptable clinical outcomes and cannot be justified without further refinement in their selection, for example, by histological assessment of pretransplant biopsies.


Pharmacological evidence that serotonergic stimulation of prolactin secretion is mediated via the dorsal raphe nucleus.
Administration of the serotonin-releasing drug DL-p-chloroamphetamine (PCA) to rats caused a dose-dependent increase in plasma prolactin levels. The effect was maximal 2 h after administration. The effect of PCA was prevented by prior administration of the serotonin synthesis inhibitor p-chlorophenylalanine-methyl ester (PCPA). PCPA pretreatment did not prevent the increase in plasma prolactin levels after administration of the serotonin agonist quipazine which is consistent with a postsynaptic receptor interaction of quipazine. To determine which serotonergic neurons are involved, the prolactin responses to PCA were determined in rats sustaining lesions of the dorsal or median raphe nuclei. The lesions were produced in desmethylimipramine-pretreated rats by local injections of 5,7-dihydroxytryptamine (5,7-DHT) 2 weeks prior to the PCA challenge. In rats with dorsal raphe lesions, the effect of PCA on prolactin secretion was significantly attenuated. In contrast, median raphe lesions did not prevent the effect of PCA on plasma prolactin levels. In summary, these data support the hypothesis that release of serotonin increases prolactin secretion. In addition, these data suggest that serotonergic neurons in the dorsal raphe nucleus are part of a neural pathway which can mediate increases in prolactin secretion.


Antigenic studies of Candida. II. Antigenic relation of Candida albicans group A and group B to Candida stellatoidea and Candida tropicalis.
Hasenclever, H. F. (U. S. Public Health Service, Bethesda, Md.), William O. Mitchell, and Joseph Loewe. Antigenic studies of Candida. II. Antigenic relation of Candida albicans group A and group B to Candida stellatoidea and Candida tropicalis. J. Bacteriol. 82:574-577. 1961.-Previous work in our laboratory has shown the presence of two antigenic groups within the species Candida albicans. These groups have been designated as groups A and B. Subsequent studies have been conducted to show the antigenic relationship of these groups with Candida stellatoidea and Candida tropicalis. Antisera to two strains each of C. albicans group A, C. albicans group B, C. stellatoidea, and C. tropicalis were used in this investigation. Individual suspensions from each of nine strains of C. stellatoidea and from ten strains each of the other groups and species were used to test the agglutinative properties of unadsorbed and adsorbed antisera. Separate samples of antisera to each immunizing strain were reciprocally cross adsorbed with the other immunizing strains and tested for agglutination. The results indicated that C. albicans group A and C. tropicalis were antigenically identical and C. albicans group B and C. stellatoidea were antigenically indistinguishable.


Further experiments on the action of antithymocyte serum in experimental Junín virus infection.
Rabbit anti-mouse thymocyte serum (ATS) administrated as late as 7 days after infection suppressed host cell-mediated responsiveness to intracerebrally injected Junín virus, thereby diminishing the morbility and mortality of this infection. It did not affect either the humoral antibody response or the virus titer in brain. This findings suggest that: a) in mouse brain cells, Junín virus infection is basically non-cytopathic: b) cell-mediated immunity is responsible for morbility and mortality and does not clear up virus from brain as in other viral encephalitides; and c) ATS may be of therapeutic interest by suppressing or diminishing the cell-mediated response to Junín virus.


Antigenic differences between the major glycoproteins of bovine herpesvirus type 1.1 and bovine encephalitis herpesvirus type 1.3.
Differences in the antigenic structure of the major glycoproteins, gI, gIII and gIV, of bovine herpesvirus type 1.1 (BHV1.1) and the neurovirulent BHV1.3 were demonstrated with a panel of monoclonal antibodies (MAbs) prepared against the BHV1.1 glycoproteins. Glycoprotein gIII of BHV1.3 was the most dissimilar, reacting with only four of 15 gIII-specific MAbs. Glycoproteins gI and gIV of BHV1.3 reacted with eight of 11 and eight of 12 specific MAbs, respectively. Monospecific bovine antisera to the two viruses supported findings from the MAb analysis in that gI and gIV glycoproteins were cross-recognized, but gIII was not. Virus-neutralizing MAbs reactive to each glycoprotein and which reacted with both viruses also neutralized both viruses. Previously undescribed glycoproteins which were antigenically related to the intact gIII glycoproteins, but of reduced sizes and lacking at least one gIII epitope, were found for both viruses. Tunicamycin inhibition experiments and immunoprecipitation data suggested that these proteins were intracellular degradation products. Comparisons of the peptide footprints of the glycoproteins from the two viruses using protease V8 digestion after immunoprecipitation with cross-reactive MAbs revealed distinctive footprint patterns for the respective glycoproteins.


Perceptions and satisfaction of a mandatory continuing professional development programme amongst Aotearoa New Zealand podiatrists.
Aotearoa New Zealand (NZ) registered podiatrists are required to participate in a mandatory continuing professional development (CPD) programme. This study investigated podiatrist's perceptions and satisfaction surrounding mandatory CPD requirements following the implementation of a new 2-year CPD programme. A cross-sectional study of NZ registered podiatrists was conducted between October 9th and December 9th, 2020. Data was collected using a web-based survey. The 39-item survey included questions to elicit participant characteristics, perceptions of CPD, difficulties undertaking CPD, and satisfaction with the new CPD programme. The survey findings were reported using descriptive statistics and conventional content analysis. One hundred and thirty-four podiatrists completed the survey. Most respondents worked in private practice (n = 107, 80 %), were in full-time employment (n = 83, 62 %), and had greater than 16 years of work experience (n = 73, 54 %). Respondents agreed it was important to engage in CPD (n = 126, 94 %) and reported that knowledge gained from CPD contributed to their daily work (n = 78, 58 %). 44 % (n = 58) reported difficulties keeping up to date with CPD. The main barriers to CPD participation reported were workload (n = 90, 67 %) and lack of time (n = 84, 63 %). Three categories (understanding the CPD programme; access to CPD; and time to complete CPD) were identified from the qualitative analysis to describe why it was difficult to meet CPD requirements. NZ podiatrists value CPD and are satisfied with most aspects of the mandatory CPD programme apart from the hours attributed to compulsory activities. The current approach to cultural safety CPD requires revision, with a move away from a time-based approach to a system that promotes an understanding and relevance to practice. Lack of time, practice workload, financial barriers, geographical location, and employment context were factors that influenced a practitioner's ability to engage in CPD. Facilitation of CPD activities that are flexible to ensure relevance to the practitioner's specific work within their scope of practice, and that can occur in the workplace environment, may address barriers and increase engagement with to CPD activities.


A new approach of drawing airport noise contours on computer based on Surfer.
Noise contours are used to describe the extent of airport noise pollution and to plan land use around airports. The L(WECPN) (weighted equivalent continuous perceive noise level) recommended by ICAO(International Civil Aviation Organization) is adopted as airport noise rating parameter in this paper. With the help of various mathematical models in the software Surfer, noise contours can be drawn automatically by the completed program in Visual C++ Code. Corrections for thrust, velocity, atmospheric temperature, humidity and lateral ground attenuation are also considered in the new method, which can improve the efficiency of drawing contours. An example of its use for drawing noise contours of an airport in Zhejiang Province of China is proposed and the predictions and the measurements show agreements well.


Mothers' attitudes to and experience of breast feeding: a primary care study.
This study investigated the attitudes to breast feeding of women registered with 24 general practitioners in Nottingham. A total of 514 women were interviewed in the antenatal period and then followed up at six weeks and six months after the birth of their child. Seventy per cent of the women planned to breast feed their baby, 23% planned to bottle feed and 7% were undecided. Only 26 women changed their plans. Although 73% of the women interviewed began breast feeding, this had fallen to 49% by six weeks and 26% by six months. Logistic regression analysis showed that multiparae who had bottle fed or stopped breast feeding their previous child during the first six weeks were 5.15 times more likely to stop breast feeding in the first six weeks, than those who had breast fed their previous child for six weeks or more. Primiparae in social classes 3M, 4 or 5 or who were unemployed were 3.68 times more likely to stop than women in higher social classes, while those who said they had considered bottle feeding were 2.40 times more likely to stop. Most women gave an inadequate milk supply as a reason for stopping, but sore nipples were also a problem in the first six weeks. Of all the women who had started breast feeding 46% felt they did not have enough milk at some stage and despite the finding that 49% of those who sought advice from a health professional were advised to feed more often, 42% said they had been advised to give bottle feeds.(ABSTRACT TRUNCATED AT 250 WORDS)


Preparedness and response to terrorism: a framework for public health action.
Political group violence in the form of terrorist actions has become a reality worldwide, affecting the health and economies of populations. As a consequence, preparedness and response are becoming an integral part of public health action. Risk appraisal, preservation of human and civil rights and communications within and between countries are all issues to be considered in the process. The combination of the natural history of terrorist actions and the epidemiological triangle model has been adapted in this paper and suggested as a comprehensive approach for preparedness and action. It covers preparedness (pre-event), response (event) and the consequences (post-event) of a terrorist attack. It takes into account the human factor, vectors and environment involved in each one of the phases. Terrorism is a global reality with varying underlying causes, manifestations and impact on the health of the public. Preparedness, response and rehabilitation are an integral part of public health action. Consideration of the pre-event, event and post-event phases in terrorist actions, together with the human factor, vector/agent and environment in each of these phases, offers a framework for public health preparedness, response and rehabilitation. Planning should consider risk assessment, risk communication, inter-sectorial cooperation, enactment of laws and regulations which consider protection of the public's health and civil liberties. Allocation of resources would need to make allowance for maintenance and development of ongoing public health activities.


How much do patients' preferences contribute to resource use?
Regional variation in health care use may stem, in part, from the fact that patients in high-utilization regions demand and receive more-intensive care. We examine the association between patients' care-seeking preferences and use of services, using a national survey of Medicare patients. Patients' preferences, in addition to health and sociodemographic characteristics, are associated with differences in individuals' use of office visits. However, we find that patients' preferences for seeking primary and specialty medical care do not play a significant role in explaining regional variation in health care use.


Exercise Regulates MicroRNAs to Preserve Coronary and Cardiac Function in the Diabetic Heart.
Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the effectiveness of exercise in preventing or reversing the progression of DHD remains controversial. Cardiac function is critically dependent on the preservation of coronary vascular function. We aimed to elucidate the effectiveness and mechanisms by which exercise facilitates coronary and cardiac-protection during the onset and progression of DHD. Diabetic db/db and nondiabetic mice, with or without underlying cardiac dysfunction (16 and 8 weeks old, respectively) were subjected to either moderate-intensity exercise or high-intensity exercise for 8 weeks. Subsequently, synchrotron microangiography, immunohistochemistry, Western blot, and real-time polymerase chain reaction were used to assess time-dependent changes in cardiac and coronary structure and function associated with diabetes mellitus and exercise and determine whether these changes reflect the observed changes in cardiac-enriched and vascular-enriched microRNAs (miRNAs). We show that, if exercise is initiated from 8 weeks of age, both moderate-intensity exercise and high-intensity exercise prevented the onset of coronary and cardiac dysfunction, apoptosis, fibrosis, microvascular rarefaction, and disruption of miRNA signaling, as seen in the nonexercised diabetic mice. Conversely, the cardiovascular benefits of moderate-intensity exercise were absent if the exercise was initiated after the diabetic mice had already established cardiac dysfunction (ie, from 16 weeks of age). The experimental silencing or upregulation of miRNA-126 activity suggests the mechanism underpinning the cardiovascular benefits of exercise were mediated, at least in part, through tissue-specific miRNAs. Our findings provide the first experimental evidence for the critical importance of early exercise intervention in ameliorating the onset and progression of DHD. Our results also suggest that the beneficial effects of exercise are mediated through the normalization of cardiovascular-enriched miRNAs, which are dysregulated in DHD.


Lipopolysaccharide profile typing as a technique for comparative typing of gram-negative bacteria.
We have applied the technique of lipopolysaccharide (LPS) profiling in sodium dodecyl sulfate-polyacrylamide gel electrophoresis to the typing of 124 isolates of 12 gram-negative species from suspected outbreaks of infection. LPS was prepared by proteinase K digestion or micro-phenol-water extraction. A total of 11 of the 12 species gave clear ladder band profiles, the exception being Acinetobacter baumannii. When compared with conventional typing for Enterobacter cloacae, Pseudomonas aeruginosa, and Serratia marcescens, LPS profile type alone was sufficient to allow relatedness or distinguishability of isolates to be established, and this was corroborated by serotype and phage type data. Serologically nontypeable isolates invariably lacked O repeating units and thus could not be classified by their silver stain profile. We conclude that LPS profiling is useful for the epidemiological investigation of small clusters of isolates in order to determine whether or not cross-infection between patients has occurred.


Expression of Cell Competition Markers at the Interface between p53 Signature and Normal Epithelium in the Human Fallopian Tube.
There is a growing body of evidence regarding cell competition between normal and mutant mammalian cells, which suggest that it may play a defensive role in the early phase of carcinogenesis. In vitro study in the past has shown that overexpression of vimentin in normal epithelial cells at the contact surface with transformed cells is essential for the cell competition involved in epithelial defense against cancer. In this study, we attempted to examine cell competition in human tissue in vivo by investigating surgically resected human fallopian tubes that contain p53 signatures and serous tubal intraepithelial lesions (STILs), a linear expansion of p53-immunopositive/TP53 mutant tubal epithelial cells that are considered as precursors of pelvic high grade serous carcinoma. Immunofluorescence double staining for p53 and the cell competition marker vimentin was performed in 21 sections of human fallopian tube tissue containing 17 p53 signatures and 4 STILs. The intensities of vimentin expression at the interface between p53-positive cells at the end of the p53 signature/STIL and adjacent p53-negative normal tubal epithelial cells were compared with the background tubal epithelium. As a result, the average vimentin intensity at the interfaces relative to the background intensity was 1.076 (95% CI, 0.9412 - 1.211 for p53 signature and 0.9790 (95% CI, 0.7206 - 1.237) for STIL. Thus, it can be concluded that overexpression of the cell competition marker vimentin are not observed in human tissue with TP53 alterations.


Benefits on public health from transport-related greenhouse gas mitigation policies in Southeastern European cities.
Climate change is a major environmental threat of our time. Cities have a significant impact on greenhouse gas emissions as most of the traffic, industry, commerce and more than 50% of world population is situated in urban areas. Southern Europe is a region that faces financial turmoil, enhanced migratory fluxes and climate change pressure. The case study of Thessaloniki is presented, one of the only two cities in Greece with established climate change action plans. The effects of feasible traffic policies in year 2020 are assessed and their potential health impact is compared to a business as usual scenario. Two types of measures are investigated: operation of underground rail in the city centre and changes in fleet composition. Potential co-benefits from reduced greenhouse gas emissions on public health by the year 2020 are computed utilizing state-of-the-art concentration response functions for PMx, NO2 and C6H6. Results show significant environmental health and monetary co-benefits when the city metro is coupled with appropriate changes in the traffic composition. Monetary savings due to avoided mortality or leukaemia incidence corresponding to the reduction in PM10, PM2.5, NO2 and C6H6 exposure will be 56.6, 45, 37.7 and 1.0 million Euros respectively. Promotion of 'green' transportation in the city (i.e. the wide use of electric vehicles), will provide monetary savings from the reduction in PM10, PM2.5, NO2 and C6H6 exposure up to 60.4, 49.1, 41.2 and 1.08 million Euros. Overall, it was shown that the respective GHG emission reduction policies resulted in clear co-benefits in terms of air quality improvement, public health protection and monetary loss mitigation.


Physiologic and biochemical measurements and response to noxious stimulation at various concentrations of MS-222 in koi (Cyprinus carpio).
To evaluate the physiological effect and response to noxious stimulation at five concentrations of MS-222 in koi (Cyprinus carpio). Prospective experimental study. Twenty-one healthy adult unknown sex koi fish weighing mean 450±SD 120 g. Each fish was exposed to five different concentrations of MS-222 (50, 70, 110, 150 and 190 mg L(-1) ) in a random sequence during the same anaesthetic event. For each concentration of MS-222, vital functions such as heart rate (HR) (via Doppler) and opercular rate (OpR) were recorded after a standardized induction period. Response to two noxious stimuli in the form of haemostat clamp pressure applied on the tail and the lip was evaluated, and blood was drawn to measure biochemical and blood gas values. Decrease in response to noxious stimulation with an increase of MS-222 concentration both for the lip (p=0.0027) and the tail (p<0.0001) stimulus was observed. Biochemical values were unaffected by the concentration of MS-222 with the exception of lactate concentration which was weakly correlated with the duration of anaesthesia (r=0.31, p<0.001) and the number of times the fish was clamped or bled prior to sampling (r=0.23, p<0.001). Opercular rate decreased with the increase in anaesthetic concentration, and HR was not affected. Our results indicated a decrease in response to stimulus and a decrease in OpR that were associated with increased concentrations of MS-222. This may assist in establishing anaesthetic protocols using MS-222 in fish and supports the use of supramaximal pressure stimuli to teleost fish under variable MS-222 concentrations as a model for future studies.


Towards a unified classification of the ectodermal dysplasias: opportunities outweigh challenges.
The ectodermal dysplasias include a complex and highly diverse group of heritable disorders that share in common developmental abnormalities of ectodermal derivatives. The broader definition of ectodermal dysplasias (as heritable disorders involving at least two of the ectodermal derivatives nails, teeth, hair, and eccrine sweat glands) encompasses 170-200 conditions. Some conditions included by this definition are relatively common; others are rare and, in some cases, family-specific. Classification of the ectodermal dysplasias has largely been approached by categorizing patterns of clinical findings (phenotypic grouping). In the last 2 decades great progress has been made in understanding the molecular pathogenesis and inter-relatedness of some of these conditions and a new consensus approach to classification that incorporates this new information is needed. A comprehensive and definitive classification of these disorders would be highly valuable for the many stakeholders in ED. As disease-specific molecular treatments are developed, accurate classification will assume greater importance in designing registries to enable rapid identification of those with rare disorders who may wish to participate in clinical trials. Ideally a working classification of such a disparate collection of conditions would have a design and architecture that would facilitate easy accessibility by each of the key stakeholder groups and would encourage enhanced interaction between these parties. Attaining this objective is a major challenge but is achievable. This article reviews the historical-clinical perspective and the impact of recent developments in molecular biology in the field. Reflections are offered as to the future direction of classification systems in these disorders.


Population pharmacokinetic model for adherence evaluation using lamivudine concentration monitoring.
Interpretation of antiretroviral drug concentration measurements could be aided by information about adherence to recent doses. We developed a population pharmacokinetic model of lamivudine in young children to propose reference lamivudine concentrations for evaluation of adherence to recent treatment doses. The steady state pharmacokinetics of lamivudine were evaluated in 68 young HIV-infected children receiving antiretroviral treatment twice daily. A population pharmacokinetic analysis was conducted using NONMEM 7. A 2-compartment model with transit absorption best described lamivudine pharmacokinetics. After adjustment for maturation and body weight (using allometric scaling), the variability of clearance was small, hence simulations could accurately predict lamivudine concentrations. Higher lamivudine trough concentrations were detected before the morning dose, possibly owing to slower overnight clearance. Reference values for lamivudine concentrations that can be used to evaluate adherence to recent doses are proposed. Lamivudine concentration measurement can be used to assess recent treatment adherence.


Algal docosahexaenoic acid affects plasma lipoprotein particle size distribution in overweight and obese adults.
Fish oils containing both EPA and DHA have been shown to have beneficial cardiovascular effects, but less is known about the independent effects of DHA. This study was designed to examine the effects of DHA on plasma lipid and lipoprotein concentrations and other biomarkers of cardiovascular risk in the absence of weight loss. In this randomized, controlled, double-blind trial, 36 overweight or obese adults were treated with 2 g/d of algal DHA or placebo for 4.5 mo. Markers of cardiovascular risk were assessed before and after treatment. In the DHA-supplemented group, the decrease in mean VLDL particle size (P ≤ 0.001) and increases in mean LDL (P ≤ 0.001) and HDL (P ≤ 0.001) particle sizes were significantly greater than changes in the placebo group. DHA supplementation also increased the concentrations of large LDL (P ≤ 0.001) and large HDL particles (P = 0.001) and decreased the concentrations of small LDL (P = 0.009) and medium HDL particles (P = 0.001). As calculated using NMR-derived data, DHA supplementation reduced VLDL TG (P = 0.009) and total TG concentrations (P = 0.006). Plasma IL-10 increased with DHA supplementation to a greater extent than placebo (P = 0.021), but no other significant changes were observed in glucose metabolism, insulin sensitivity, blood pressure, or markers of inflammation with DHA. In summary, DHA supplementation resulted in potentially beneficial changes in some markers of cardiometabolic risk, whereas other markers were unchanged.


Early psychotic experiences: Interventions, problems and perspectives.
Psychotic or psychotic-like experiences and symptoms may precede and be indicative of later psychosis emergence. DSM-5 has introduced Attenuated Psychosis Syndrome (APS) as a condition for further study, arguing for its clinical validity and the need for identifying sub- threshold psychotic states. Early psychosis intervention has an already established role in reducing the Duration of Untreated Psychosis (DUP), delaying psychosis onset and relieving Ultra High Risk (UHR) individuals from their presenting symptoms. Pharmacological and mainly psycho-therapeutical approaches are suggested for this purpose. Cognitive Behavior Therapy (CBT) seems to have clear evidence of favorable outcome concerning transition to psychosis rates, omega-3 fatty acids lower but promising evidence, while low-dose antipsychotic medication or antidepressant treatment may seem beneficial, but it remains unclear if the reported favorable effects persist in the long term and how long intervention in UHR subjects should be given for. Case management and close monitoring based on principles of social psychiatry are considered key elements for the management of UHR individuals. However, the blazing case about early psychosis concerns the accurate specification of the prodromal stage of psychosis, which may set the basis for meaningful and effective early intervention. Although psychometric tools have been developed and provide a common criteria-based recognition method, debate is alive and well regarding "false positive" cases, since most UHR subjects will not finally develop psychosis. Moreover, transition rates to psychosis have been declining over the years, leading to fierce criticism over the validity of the UHR/ APS state and legitimacy of its treatment. On this framework, ethical issues of stigmatizing through unnecessary diagnosing and antipsychotics' prescribing are matters of serious questioning. Clinical heterogeneity and high comorbidity are further implications of the UHR state. Current research emphasizes on improving validity of inclusion criteria and formulating personalised and clinical stage- based intervention strategies. In order to do that, early psychosis recognition and intervention services are established throughout the world, trying to contribute in research by applying clinical, cognitive or neuropsychological criteria. Nevertheless, in the majority of so far conducted studies, samples sizes are considered small and duration of follow-up short, which are limitations yet to overcome. Other scientific voices argue that the UHR state might represent a non-specific risk factor for psychiatric disorders in general and not necessarily for psychosis and tend to examine the UHR and early intervention idea under the prism of subthreshold or early mental distress state. Either way, recognizing and intervening early in emerging psychiatric states, especially in those with psychotic or psychotic-like symptomatology, share indisputable benefits under the broader concept of prevention, setting a strong scientific-clinical rationale for service provision to help-seeking people and the possibility of changing the course for those with vulnerability to psychotic illnesses.


[Identification of human gender by hand x-ray].
A planimetric analysis of hand bones x-ray images is proposed for gender identification. The gender is determined by two methods: by interval estimation of bones size and calculation of the discriminant function and its comparison with group centroid values.


Removing electroencephalographic artifacts by blind source separation.
Eye movements, eye blinks, cardiac signals, muscle noise, and line noise present serious problems for electroencephalographic (EEG) interpretation and analysis when rejecting contaminated EEG segments results in an unacceptable data loss. Many methods have been proposed to remove artifacts from EEG recordings, especially those arising from eye movements and blinks. Often regression in the time or frequency domain is performed on parallel EEG and electrooculographic (EOG) recordings to derive parameters characterizing the appearance and spread of EOG artifacts in the EEG channels. Because EEG and ocular activity mix bidirectionally, regressing out eye artifacts inevitably involves subtracting relevant EEG signals from each record as well. Regression methods become even more problematic when a good regressing channel is not available for each artifact source, as in the case of muscle artifacts. Use of principal component analysis (PCA) has been proposed to remove eye artifacts from multichannel EEG. However, PCA cannot completely separate eye artifacts from brain signals, especially when they have comparable amplitudes. Here, we propose a new and generally applicable method for removing a wide variety of artifacts from EEG records based on blind source separation by independent component analysis (ICA). Our results on EEG data collected from normal and autistic subjects show that ICA can effectively detect, separate, and remove contamination from a wide variety of artifactual sources in EEG records with results comparing favorably with those obtained using regression and PCA methods. ICA can also be used to analyze blink-related brain activity.


New Alkaloids from Green Vegetable Soybeans and Their Inhibitory Activities on the Proliferation of Concanavalin A-Activated Lymphocytes.
A comprehensive phytochemical study of the chemical constituents of green vegetable soybeans resulted in the isolation of two new alkaloids, soyalkaloid A, 1, and isoginsenine, 2, together with four known ones, ginsenine, 3, (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, 4, (1R,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, 5, and indole-3-carboxylic acid, 6. The structures of compounds 1-6 were elucidated on the basis of spectroscopic and chemical analyses. All of the alkaloids were isolated from soybeans for the first time, and compound 1 was a new indole-type alkaloid with a novel carbocyclic skeleton. Their inhibitory activities on the proliferation of concanalin A-activated lymphocytes were assessed by CCK8 assay.


Exploration of the neck for hyperparathyroidism.
A step-by-step plan for exploration of the neck for hyperparathyroidism has evolved during a 15-year experience with 148 patients at the Toronto General Hospital. Selective catheterization of the veins of the neck with parathormone immunoassay has been a valuable aid in preoperative localization and is particularly helpful in those patients who have had a previous neck dissection. The success of the exploration is based on a practical knowledge of the embryology and anatomy of the parathyroid glands, meticulous dissection and the identification of all glands. The "angle of identification", as described, has been helpful in operative localization. The parathyroid gland or glands that are grossly abnormal are excised, and the remaining glands biopsied and examined by an experienced pathologist, expert in quick-section techniques.


Aortic Thickness: A Forgotten Paradigm in Risk Stratification of Aortic Disease.
This study aimed at risk-stratifying aortic dilatation using aortic wall thickness (AWT) and comparing methods of AWT assessment. Demographic, epidemiological, and perioperative data on 72 consecutive aortic surgeries (age = 62 years[standard deviation (SD) = 12] years) performed by a single surgeon were collected from hospital database. Aortic thickness was measured on computed tomography scans, as well as intraoperatively in four quadrants, at the level of aortic sinuses, as well as midascending aorta, using calipers. Aortic wall stress was calculated using standard mathematical formulae. The ascending aorta was 48.2 (SD = 8) mm and the mean thickness at ascending aorta level was 1.9 (SD = 0.3) mm. There was congruence between imaging and intraoperative measurements of thickness, as well as between the radiologist and surgeon. Preoperatively, 16 patients had multiple imaging studies showing an average rate of growth of 1.2 mm per year without significant difference in thickness. The wider the aorta, the thinner was the lateral or convex wall. Aortic stenosis (p = 0.01), lateral to medial wall thickness ratio (p = 0.04), and history of hypertension (p = 0.00), all had protective effect on aortic root stress. The ascending aortic stress was directly affected by age (p = 0.03) and inversely related to lateral to medial wall thickness ratio (p = 0.03). Aortic thickness can be measured preoperatively and easily confirmed intraoperatively. Risk stratification based on both aortic thickness and diameter (stress calculations) would better predict acute aortic events in dilated aortas and define aortic resection criteria more objectively.


Clinical experience with transdermal and orally administered opioids in palliative care patients--a retrospective study.
Transdermal fentanyl is a widely used opioid for the treatment of cancer pain. Simplicity of use and high patient compliance are the main advantages of this opioid. However, based on our clinical experience, transdermal fentanyl is often not efficacious in terminally ill palliative care patients. We thus retrospectively examined the pain management and need for opioid switching in cancer patients admitted to our palliative care unit. Of 354 patients admitted to our palliative care unit from 2004 through 2005, 81 patients were pre-treated with transdermal fentanyl. Demographic and cancer-related data (diagnosis, symptoms, pain score on a numeric rating scale (NRS)), analgesic dose at admission and discharge were compared. mean +/- SD, ANOVA, Wilcoxon's test was used for inter-group comparisons, significance P < 0.05, adjusted for multiple testing. Pain scores are given in median (range). Mean transdermal fentanyl dose at admission was 81.0 +/- 55.8 microg/h. In 79 patients transdermal fentanyl treatment was discontinued. In two patients, analgesic treatment according to WHO I provided sufficient pain relief. The other 77 patients were switched to other opioids: 33 patients to oral morphine and 44 to oral hydromorphone. In patients switched to morphine the dose at discharge (104.7 +/- 89.0 mg) was lower than at admission (165.5 mg morphine equivalence). In patients switched to hydromorphone the dose of 277.8 +/- 255.0 mg morphine equivalent was higher at discharge than at admission (218.2 +/- 131.4 mg morphine equivalence--considering an equianalgesic conversion ratio morphine: hydromorphone = 7.5: 1). Pain scores decreased significantly after opioid rotation (NRS at rest/on exertion: 4 (0-10)/7 (2-10) versus 1 (0-3)/2 (0-5); P < 0.001). In the patient group switched to morphine, sufficient pain relief was achieved by lower equianalgesic morphine doses, compared with the doses at admission. In the patient group switched to hydromorphone, higher equianalgesic morphine doses were needed at discharge, considering an equianalgesic conversion ratio of morphine: hydromorphone = 7.5: 1. Patients with far advanced cancer often suffer from sweating and cachexia, which may have negative effects on the absorption of transdermal fentanyl. Opioid switching to oral morphine or hydromorphone was well tolerated and proved to be an efficacious option for cancer pain treatment.