A link between hepatic glucose production and peripheral energy metabolism via hepatokines.
Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.


Root planing and curettage.
Root planing and curettage are at least as satisfactory as other surgical techniques for the gain and maintenance of attachment in most periodontal pockets. Reduction of pocket depth and root exposure are less following subgingival curettage than after other modalities of surgery. It is not known if soft tissue curettage adds anything to the results of scaling and root planing. Curettage is demanding with regards to technical skill and time, and may be impractical in many instances compared to flap surgery.


Expression of the Epstein-Barr virus nuclear protein 2 in rodent cells.
A 3.0-kilobase-pair Epstein-Barr virus (EBV) DNA segment necessary for lymphocyte immortalization encodes at least part of a nuclear protein (EBNA2) which is characteristically expressed in latently infected, immortalized cells. A 1.5-kilobase open reading frame within this DNA segment has now been inserted into a murine leukemia virus (MuLV)-derived expression vector (pZIP-NEO-SV(X)1) which provides for transcription of heterologous DNA but not for translational start. Transfection of the recombinant DNA into NIH 3T3 cells resulted in expression of a full-sized EBNA2 which localized to the cell nucleus. Significant new evidence is thereby provided that this 1.5 kilobase open reading frame includes a translational start site and encodes the entire EBNA2 protein. Transfection of the recombinant DNA into a helper cell line (psi am22b) providing amphotropic MuLV-packaging functions resulted in the release of a recombinant MuLV carrying the EBNA2 gene. This recombinant virus can infect rodent cells and convert them to stable EBNA2 expression. Rat-1 cells infected with the MuLV EBNA2 recombinant expressed EBNA2 and grew more rapidly in medium supplemented with 1 or 0.5% fetal calf serum than did Rat-1 cells infected with MuLV vector lacking EBNA2. The Rat-1 cells expressing EBNA2 remained contact inhibited, anchorage dependent, and nontumorigenic in nude mice. Different EBV isolates have one of at least two EBNA2 alleles. Despite divergence between the two alleles, a human serum recognized the prototype EBNA2 allele (EBNA2A) as well as the variant EBNA2B allele characteristic of some Burkitt tumor EBV isolates. The EBNA2B allele was also expressed from the MuLV-derived vector. The reproducible expression of EBNA2A or EBNA2B from these recombinant vectors will facilitate analysis of the EBNA2A and EBNA2B phenotypes.


Elastin-like polypeptide and γ-zein fusions significantly increase recombinant protein accumulation in soybean seeds.
Soybean seeds are an ideal host for the production of recombinant proteins because of their high content of proteins, long-term stability of seed proteins under ambient conditions, and easy establishment of efficient purification protocols. In this study, a polypeptide fusion strategy was applied to explore the capacity of elastin-like polypeptide (ELP) and γ-zein fusions in increasing the accumulation of the recombinant protein in soybean seeds. Transgenic soybean plants were generated to express the γ-zein- or ELP-fused green fluorescent protein (GFP) under the control of the soybean seed-specific promoter of β-conglycinin alpha subunit (BCSP). Significant differences were observed in the accumulation of zein-GFP and GFP-ELP from that of the unfused GFP in transgenic soybean seeds based on the total soluble protein (TSP), despite the low-copy of T-DNA insertions and similar expression at the mRNA levels in selected transgenic lines. The average levels of zein-GFP and GFP-ELP accumulated in immature seeds of these transgenic lines were 0.99% and 0.29% TSP, respectively, compared with 0.07% TSP of the unfused GFP. In mature soybean seeds, the accumulation of zein-GFP and GFP-ELP proteins was 1.8% and 0.84% TSP, an increase of 3.91- and 1.82-fold, respectively, in comparison with that of the unfused GFP (0.46% TSP). Confocal laser scanning analysis showed that both zein-GFP and GFP-ELP were abundantly deposited in many small spherical particles of transgenic seeds, while there were fewer such florescence signals in the same cellular compartments of the unfused GFP-expressing seeds. Despite increased recombinant protein accumulation, there were no significant changes in the total protein and oil content in seeds between the transgenic and non-transformed plants, suggesting the possible presence of threshold limits of total protein accumulation in transgenic soybean seeds. Overall, our results indicate that γ-zein and ELP fusions significantly increased the accumulation of the recombinant protein, but exhibited no significant influence on the total protein and oil content in soybean seeds.


How Not to Be Misled by Disorders Mimicking Angioedema: A Review of Pseudoangioedema.
Angioedema is a vascular reaction involving the lower dermis, subcutis and/or submucosal tissue and causing a temporary localized swelling in any part of the body. For many health care professionals, the diagnosis presents an ongoing challenge; several disorders may manifest with subcutaneous or submucosal swelling and falsely be assumed to be angioedema. The clinicians at the emergency department and in the immunology/allergy clinics must be skilled at recognizing the features of angioedema and its differential diagnosis. The review is based on a literature search with specific indexing terms in PubMed, a review of bibliographies and the authors' clinical experience. The most essential diseases that mimic angioedema, the so-called pseudoangioedemas, will each be discussed and illustrated by clinical photos, pointing out key features that help clarify the diagnoses and differentiate these from classic angioedema. A variety of dermatologic conditions can cause swelling that resembles angioedema, some with a potentially fatal outcome if misdiagnosed. Knowledge of pseudoangioedema is fundamental in the emergency setting when handling patients with edema and should be kept in mind when assessing an atypical angioedema case.


SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain.
The SynGAP protein is a major regulator of synapse biology and neural circuit function. Genetic variants linked to epilepsy and intellectual disability disrupt synaptic function and neural excitability. SynGAP has been involved in multiple signaling pathways and can regulate small GTPases with very different roles. Yet, the molecular bases behind this pleiotropy are poorly understood. We hypothesize that different SynGAP isoforms will mediate different sets of functions and that deciphering their spatio-temporal expression and subcellular localization will accelerate understanding their multiple functions. Using isoform-specific antibodies recognizing SynGAP in mouse and human samples we found distinctive developmental expression patterns for all SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP-α1 isoforms, which directly bind to postsynaptic density-95, in cortex and hippocampus during the first 2 weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non-synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non-synaptic to a mostly postsynaptic density localization with age and β isoforms were always found enriched in non-synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy.


Long-term functional speech and swallowing outcomes following pharyngolaryngectomy with free jejunal flap reconstruction.
Surgery for advanced cancer of the hypopharynx is a complex issue. Surgical intervention needs to take into consideration the resultant quality of life, in particular fundamental functional outcomes such as speech and swallowing. The aim of this study is to look at these long-term functional outcomes, following pharyngolaryngectomy and free jejunal reconstruction. A total of 19 patients, each undergoing a pharyngolaryngectomy with free jejunal graft was included. Each had a primary tracheoesophageal puncture for insertion of an indwelling voice prosthesis for speech. Functional outcomes of speech and swallow were assessed by a qualified speech pathologist. The impact on patients' quality of life was assessed under 4 domains: impairment, disability, handicap, and well being. The mean time period to follow-up was 4 years. Eighteen of the 19 patients were tolerating an oral diet, with one patient reliant on percutaneous endoscopic gastrostomy feeds. Seventeen patients (89%) were assessed as either having either no--or only a mild degree--of dysphagia, with no evidence of aspiration. Of the 19 patients, 15 were utilizing tracheosophageal speech for communication with 11 (73%) having no--or only a mild degree--of dsyphonia. Patients assessed as having no evidence of dysphagia or dysphonia also reported reduced levels of handicap and distress compared with patients experiencing any degree of dysphagia (P = 0.46) or dysphonia (P = 0.01). While rates of pharyngolaryngectomy increase, most patients have a poor long-term prognosis, heightening the significance of postoperative outcomes. The results of this study highlight the importance of speech and swallow outcomes, and demonstrate the direct correlation between these functions and resultant quality of life.


Modeling pediatric head trauma: mechanisms of degeneration and potential strategies for neuroprotection.
We have developed a model for head trauma in infant rats in an attempt to study mechanisms of neurodegeneration in the developing brain and were able to morphologically characterize two distinct types of brain damage. The first type or primary damage evolved within 4 hrs after trauma and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hrs and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus, hippocampal dentate gyrus and striatum. Histological evidence of delayed cell death was preceded by decrease of bcl-2- in conjunction with increase of c-jun-mRNA-levels, already evident at 1 hr after trauma. Increase of CPP32-like activity and elevated concentrations of oligonucleosomes in affected brain regions represented additional findings to indicate that this secondary disseminated degenerative reaction is apoptotic in nature. At the age of 7 days, secondary apoptotic damage was more severe than primary excitotoxic damage, but its severity declined with increasing age. In 7-days-old rats, NMDA antagonists protected against primary excitotoxic damage but increased severity of secondary apoptotic damage whereas the free radical scavenger SPBN, the tumor necrosis factor (TNF) inhibitor pentoxifylline and the antioxidant N-acetylcystein mitigated apoptotic damage. These findings demonstrate that in the developing rat brain apoptosis and not excitotoxicity determines neuropathologic outcome following head trauma. Whereas radical scavengers and TNF-inhibitors may prove useful in treatment of pediatric head trauma, great caution should be applied in regards to the use of NMDA antagonists because of the inherent risk of apoptosis promotion.


The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in the rat.
The effects of N-acylglucosamines on insulin release have been studied. N-Acylglucosamines stimulated insulin release from rat islets in vitro only if a sub-stimulatory concentration of glucose was also present, and this secretory response was abolished by mannoheptulose. In perifused islets the rapidity of the secreotry response to N-acetyl-D-glucosamine was similar to that observed with D-glucose. Increasing acyl-chain length from N-acetyl- to N-hexanoyl-D-glucosamine impaired the secretory response; however, N-dichloroacetyl-D-glucosamine was a more potent stimulator of release than was N-acetyl-D-glucosamine. Polymers of N-acetyl-D-glucosamine containing two to six monomers linked alpha1-4 did not stimulate insulin release; glucosamine linked to dextran via a propionyl or hexanoyl spacer group was also without insulin-releasing ability. N-Acylglucosamines were also effective in eliciting insulin release in vivo when injected into conscious rats. At the dose used (86 mumol), N-acetylgucosamine elicited a rapid rise in plasma-insulin concentration; N-butyrylglucosamine was less effective, and there was little or no response to N-hexanoylglucosamine. The response to N-dichloroacetyl-glucosamine was greater than that to N-acetylglucosamine; an increase in plasma insulin concentration could be elicited by N-dichloroacetylglucosamine at a dose (17 mumol) at which neither glucose nor N-acetylglucosamine was effective. The secretory response to acetylglucosamine is not mediated by conversion into glucose. Rates of (pro)-insulin biosynthesis by rat islets have been measured (Pro)-insulin biosynthesis was stimulated by glucose, and this response was abolished by mannoheptulose. N-Acetylglucosamine also stimulated (pro)-insulin biosynthesis; this effect of N-acetylglucosamine did not require the presence of glucose, and was not abolished by mannoheptulose. It is concluded that there are differences in signal reception and/or transduction for the processes of insulin biosynthesis and release.


Ultra-low-dose non-contrast CT and CT angiography can be used interchangeably for assessing maximal abdominal aortic diameter.
Routine CT scans may increasingly be used to document normal aortic size and to detect incidental abdominal aortic aneurysms. To determine whether ultra-low-dose non-contrast CT (ULDNC-CT) can be used instead of the gold standard CT angiography (CTA) for assessment of maximal abdominal aortic diameter. This retrospective study included 50 patients who underwent CTA and a normal-dose non-contrast CT for suspected renal artery stenosis. ULDNC-CT datasets were generated from the normal-dose non-contrast CT datasets using a simulation technique. Using the centerline technique, radiology consultants (n = 4) and residents (n = 3) determined maximal abdominal aortic diameter. The limits of agreement with the mean (LOAM) was used to access observer agreement. LOAM represents how much a measurement by a single observer may plausibly deviate from the mean of all observers on the specific subject. Observers completed 1400 measurements encompassing repeated CTA and ULDNC-CT measurements. The mean diameter was 24.0 and 25.0 mm for CTA and ULDNC-CT, respectively, yielding a significant but minor mean difference of 1.0 mm. The 95% LOAM reproducibility was similar for CTA and ULDNC-CT (2.3 vs 2.3 mm). In addition, the 95% LOAM and mean diameters were similar for CTA and ULDNC-CT when observers were grouped as consultants and residents. Ultra-low-dose non-contrast CT exhibited similar accuracy and reproducibility of measurements compared with CTA for assessing maximal abdominal aortic diameter supporting that ULDNC-CT can be used interchangeably with CTA in the lower range of aortic sizes.


Low-load high-repetition resistance training improves strength and gait speed in middle-aged and older adults.
To determine the effect of 26 weeks of low-load high-repetition resistance training (BodyPump™) on maximal strength, gait speed, balance and self-reported health status in healthy, active middle-aged and older adults. Two-group randomised control trial. Sixty-eight apparently healthy, active adults aged over 55 years completed either 26 weeks of BodyPump™ training (PUMP) or served as control participants (CON). The BodyPump™ group (n = 32, age = 66 ± 4 years) trained twice per week for 26 weeks while the control group (n = 36, age = 66 ± 5 years) continued with their normal activities. Leg-press and Smith-machine bench-press one repetition maximum (1RM), gait speed, balance, and self-reported health status were all assessed at baseline and follow-up. Significant group-by-time interactions in favour of the BodyPump™ group were found for leg-press 1RM (PUMP + 13%, CON + 3%, p = 0.007, partial eta(2) = 0.11), Smith-machine bench-press 1RM (PUMP + 14%, CON +5%, p = 0.001, partial eta(2) = 0.18), normal gait speed (PUMP + 23%, CON +9 %, p = 0.028, partial eta(2) = 0.08) and single leg balance right (PUMP + 24%, CON - 7%, p = 0.006, partial eta(2) = 0.12). There were no group-by-time interactions for health status measures. Three participants in the BodyPump™ group withdrew from training due to injury or fear of injury related to training. Low-load high-repetition resistance training in the form of BodyPump™ is effective at improving maximal strength, gait speed and some aspects of standing balance in adults over 55 years. The training was well tolerated by the majority of participants.


Comparative genomic analysis between Corynebacterium pseudotuberculosis strains isolated from buffalo.
Corynebacterium pseudotuberculosis is a Gram-positive, pleomorphic, facultative intracellular pathogen that causes Oedematous Skin Disease (OSD) in buffalo. To better understand the pathogenic mechanisms of OSD, we performed a comparative genomic analysis of 11 strains of C. pseudotuberculosis isolated from different buffalo found to be infected in Egypt during an outbreak that occurred in 2008. Sixteen previously described pathogenicity islands (PiCp) were present in all of the new buffalo strains, but one of them, PiCp12, had an insertion that contained both a corynephage and a diphtheria toxin gene, both of which may play a role in the adaptation of C. pseudotuberculosis to this new host. Synteny analysis showed variations in the site of insertion of the corynephage during the same outbreak. A gene functional comparison showed the presence of a nitrate reductase operon that included genes involved in molybdenum cofactor biosynthesis, which is necessary for a positive nitrate reductase phenotype and is a possible adaptation for intracellular survival. Genomes from the buffalo strains also had fusions in minor pilin genes in the spaA and spaD gene cluster (spaCX and spaYEF), which could suggest either an adaptation to this particular host, or mutation events in the immediate ancestor before this particular epidemic. A phylogenomic analysis confirmed a clear separation between the Ovis and Equi biovars, but also showed what appears to be a clustering by host species within the Equi strains.


Risk of cancer with metal-on-metal hip replacements: population based study.
To assess the risk of cancer associated with modern primary metal-on-metal hip replacements. Population based study. Nationwide retrospective comparative register. 10,728 patients who underwent metal-on-metal total hip arthroplasty and 18,235 patients who underwent conventional metal-on-polyethylene, ceramic-on-polyethylene, and ceramic-on-ceramic total hip arthroplasty (the non-metal-on-metal cohort) in the Finnish Arthroplasty Register 2001-10. Data on cancer cases up to 2010 for these cohorts were extracted from the Finnish Cancer Registry. The relative risk of cancer was expressed as the ratio of observed to expected number of cases from the Finnish population--that is, the standardised incidence ratio. The relative risk of cancer in the metal-on-metal cohort compared with the non-metal-on-metal cohort was estimated with analyses of these ratios and Poisson regression. The overall risk of cancer in patients with metal-on-metal hip implants was similar to that in the Finnish population (378 observed v 400 expected, standardised incidence ratio 0.95, 95% confidence interval 0.85 to 1.04). The overall risk of cancer in patients with metal-on-metal hip implants was also no higher than in patients who had received non-metal-on-metal hip implants (relative risk 0.92, 0.81 to 1.05). Metal-on-metal hip replacements are not associated with an increased overall risk of cancer during a mean follow-up of four years.


Pediatric tracheotomy. Controversies in management.
The technique which should be used for pediatric tracheotomy is controversial. The literature is reviewed regarding animal and human data, and our experience at Henry Ford Hospital with the flap technique is reported. Flap tracheotomy is believed to be a safe technique in children.


Acupuncture for Breathlessness in Advanced Diseases: A Systematic Review and Meta-analysis.
Nonpharmacological approaches are effective strategies for difficult to palliate breathlessness. Although acupuncture is effective for dyspnea in early-stage chronic obstructive pulmonary disease (COPD), little is known about its effects in patients with advanced (non)malignant diseases. The objective of this study was to identify and examine the evidence of acupuncture on breathlessness in advanced malignant and nonmalignant diseases. Systematic literature review of randomized controlled trials of acupuncture and acupressure searched in five databases. Included were adult participants with at least 25% having advanced diseases such as cancer or COPD with severe breathlessness. Primary outcome was severity of dyspnea on Visual Analogue Scale or Borg Scale. Secondary outcomes included quality of life, function, and acceptability. Data were pooled using a random effects model of standardized mean differences. Twelve studies with 597 patients (347 COPD, 190 advanced cancer) were included. For breathlessness severity, significant differences were obtained in a meta-analysis (10 studies with 480 patients; standardized mean difference (SMD) = -1.77 [95% CI -3.05, -0.49; P = 0.007; I2 = 90%]) and in a subgroup analysis of using sham acupuncture control groups and a treatment duration of at least three weeks (6 studies with 302 patients; SMD = -2.53 [95% CI -4.07, -0.99; P = 0.001; I2 = 91%]). Exercise tolerance (6-minute walk test) improved significantly in the acupuncture group (6 studies with 287 patients; SMD = 0.93 [95% CI 0.27, 1.59; P = 0.006; I2 = 85%]). In four of six studies, quality of life improved in the acupuncture group. Acupuncture improved breathlessness severity in patients with advanced diseases. The methodological heterogeneity, low power, and potential morphine-sparing effects of acupuncture as add-on should be further addressed in future trials.


Analysis of prognostic factors in therapeutic responses to interferon in patients with chronic hepatitis C.
The genotype of hepatitis C virus (HCV) and the amount of HCV RNA are often used to predict the efficacy of interferon (IFN) therapy on chronic hepatitis C. In addition to these factors, there may be several factors related to the host. Therefore, the authors undertook a retrospective study in which physical findings and laboratory data before therapy were evaluated by multiple logistic analysis. Two-hundred and five cases with chronic hepatitis C treated with interferon were analyzed in this study. Sustained virological response was observed with 68 cases. Multiple logistic analysis was performed with 29 explanatory variables including HCV genotype, HCV RNA, IFN types, and total dose, along with gender, age, alcohol consumption, body mass index (BMI), histological findings of liver biopsy, platelet counts, and laboratory data of serum enzymes. Analysis on the factors that correlated well with therapeutic efficacy revealed that genotype 2a, 2b showed higher therapeutic responses than genotype 1b with reference to HCV genotypes, and higher IFN dose or lower HCV RNA levels gave better results. With reference to host factors, higher total protein level, lower levels of BMI, total bilirubin, and aspartate aminotransferase were highly correlated with therapeutic efficacy. HCV genotypes and HCV RNA levels have been already identified as prognostic factors. However, the high correlation values of BMI and the total protein level are new findings. It is suggested that probability estimation of therapeutic effects using the logistic regression equation may be a good tool for predicting therapeutic efficacy of IFN therapy on individual cases.


Inflammatory bowel disease Part 1: ulcerative colitis--pathophysiology and conventional and alternative treatment options.
Ulcerative colitis (UC), a subcategory of inflammatory bowel disease, afflicts 1-2 million people in the United States, and many more worldwide. Although the exact cause of ulcerative colitis remains undetermined, the condition appears to be related to a combination of genetic and environmental factors. While conventional treatments can be effective in maintaining remission and decreasing the length of active disease periods, the treatments are not without side effects, and a significant number of people suffering from UC fail to respond to even the strongest drugs. This article reviews potential unconventional treatments - transdermal nicotine, heparin, melatonin, DHEA, probiotics, fiber, dietary changes, botanicals, essential fatty acids, and other nutrients - that may be considered in conjunction with conventional approaches or as part of a comprehensive alternative treatment protocol. In addition this review addresses risk factors, pathogenesis, nutrient deficiencies, conventional treatment approaches, and extra-intestinal manifestations of the disease.


Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating β7+ T Cells in Crohn's Disease: Report of the TOSCA Study.
Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4β7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut]. We hypothesised that this selective agent would not affect central nervous system immune surveillance. Cerebrospinal fluid from five healthy volunteers, and from 10 patients with Crohn's disease previously treated with immunosuppressants, was evaluated to assess the feasibility of the study. Subsequently, 39 patients with active Crohn's disease and previous immunosuppression were evaluated over 12 weeks of PF-00547659-induction therapy. We measured total lymphocytes, T cell subsets in cerebrospinal fluid, and circulating β7+ memory cells. Disease activity was assessed using the Harvey-Bradshaw Index. Patients treated with PF-00547659 had no reduction of cerebrospinal fluid lymphocytes, T-lymphocyte subsets, or CD4:CD8 ratio, whereas circulating β7+ memory cells increased significantly. A total of 28/35 [80%] patients had a clinical response and 27/34 [79%] had disease remission. Treatment-related adverse events, none serious, were reported in 23/49 [47%] patients. In patients with active Crohn's disease, natalizumab therapy increases the risk for PML, and the increased risk is thought to be associated with iatrogenic leukopenia within the CNS. PML under PF-00547659 may be a lesser concern, as this agent did not reduce lymphocytes or T cell subsets in the cerebrospinal fluid.


Large deletions and splicing-site mutations in the STK11 gene in Peutz-Jeghers Chilean families.
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous melanocytic macules, gastrointestinal hamartomatous polyposis and an increased risk of various neoplasms. Germline mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a cause for PJS. The aim of this study was to characterize the genotype of Chilean PJS patients. Mutation screening of 13 patients from eight PJS families was performed using a single strand conformation polymorphism analysis, DNA sequencing and multiplex ligation-dependent probe amplification assay. The breakpoints of the genomic rearrangements were assessed by a long-range polymerase chain reaction and sequencing. The results revealed the existence of seven different pathogenic mutations in STK11 gene in seven unrelated families, including three point mutations and four large genomic deletions. Three of these point mutations (43%, 3/7) may be considered as novel. Our results showed that a germline mutation is present in STK11 in 88% of probands fulfilling the diagnostic criteria of PJS. In this study, the combination of two different experimental approaches in the screening of the STK11 in PJS, led to a higher percentage of mutation detection.


The COVID-19 Pandemic and Paradigm Change in Global Scientific Research.
The current pandemic has rocked the lives of human beings every-where in ways never imagined, forcing us to question where our civilization is headed. In this article, we explore and discuss scien-tifi c evidence that helps explain recent events in the context of the COVID-19 pandemic.COVID-19 is caused by infection with a zoonotic-origin novel virus, SARS-CoV-2, that is genetically close to two coronavirus types iso-lated in bats. The transmission dynamics to humans from the original and intermediary hosts remain poorly understood, but it is highly likely that the SARS-CoV-2 virus infected humans after undergoing an inter-species transfer from bats to an intermediate species, and from there to human beings. Crossing the species barrier is largely fostered by industrial-scale agricultural practices that simplify original ecosystem connections by reducing biodiversity, facilitating the emergence of new infectious diseases. The scientifi c community has played an exemplary role in responding to this global emergency, working to fi nd timely, relevant solutions for governments and society as a whole. We need to take this opportunity to promote a global and open science that delves into the interrelation-ships of the biological, environmental, social and economic dimen-sions of this and other diseases while questioning current modes of production and their impact on the environment, and thus on human health worldwide. Keywords: Coronavirus infections; communicable diseases; zoonoses; ecosystems; technology, industry, and agriculture; pandemics; global health; Mexico.


Ginsenoside Rb3 ameliorates myocardial ischemia-reperfusion injury in rats.
Panax ginseng C. A. Mey (Araliaceae) has been widely used in clinic for treatment of cardiovascular diseases in China. Ginsenoside Rb3 is the main chemical component of Panax ginseng. The aim of this study was to evaluate the effect of ginsenoside Rb3 on myocardial ischemia-reperfusion injury in rats. Sprague--Dawley rats were orally treated with Rb3 (5, 10 or 20 mg/kg) daily for 3 days followed by subjecting to left anterior descending coronary artery ligation for 30 min and reperfusion for 24 h. This study showed that ginsenoside Rb3 treatment resulted in a reduction in myocardial infarct size. Ginsenoside Rb3 significantly attenuated the changes of creatine kinase activity and lactate dehydrogenase activity. The cardioprotective effect of ginsenoside Rb3 was further confirmed by histopathological examination. Ginsenoside Rb3 alleviated the increase of malondialdehyde content and the decrease of superoxide dismutase activity in left ventricle. Treatment with ginsenoside Rb3 also decreased plasma endothelin and angiotensin II levels. These findings suggested that ginsenoside Rb3 possesses the effect against myocardial IR injury and the underlying mechanism is related to its antioxidant activity and microcirculatory improvement.


Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey.
Children living with HIV who are not diagnosed in infancy often remain undiagnosed until they present with advanced disease. Provider-initiated testing and counselling (PITC) in health facilities is recommended for high-HIV-prevalence settings, but it is unclear whether this approach is sufficient to achieve universal coverage of HIV testing. We aimed to investigate the change in community burden of undiagnosed HIV infection among older children and adolescents following implementation of PITC in Harare, Zimbabwe. Over the course of 2 years (January 2013-January 2015), 7 primary health clinics (PHCs) in southwestern Harare implemented optimised, opt-out PITC for all attendees aged 6-15 years. In February 2015-December 2015, we conducted a representative cross-sectional survey of 8-17-year-olds living in the 7 communities served by the study PHCs, who would have had 2 years of exposure to PITC. Knowledge of HIV status was ascertained through a caregiver questionnaire, and anonymised HIV testing was carried out using oral mucosal transudate (OMT) tests. After 1 participant taking antiretroviral therapy was observed to have a false negative OMT result, from July 2015 urine samples were obtained from all participants providing OMTs and tested for antiretroviral drugs to confirm HIV status. Children who tested positive through PITC were identified from among survey participants using gender, birthdate, and location. Of 7,146 children in 4,251 eligible households, 5,486 (76.8%) children in 3,397 households agreed to participate in the survey, and 141 were HIV positive. HIV prevalence was 2.6% (95% CI 2.2%-3.1%), and over a third of participants with HIV were undiagnosed (37.7%; 95% CI 29.8%-46.2%). Similarly, among the subsample of 2,643 (48.2%) participants with a urine test result, 34.7% of those living with HIV were undiagnosed (95% CI 23.5%-47.9%). Based on extrapolation from the survey sample to the community, we estimated that PITC over 2 years identified between 18% and 42% of previously undiagnosed children in the community. The main limitation is that prevalence of undiagnosed HIV was defined using a combination of 3 measures (OMT, self-report, and urine test), none of which were perfect. Facility-based approaches are inadequate in achieving universal coverage of HIV testing among older children and adolescents. Alternative, community-based approaches are required to meet the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of diagnosing 90% of those living with HIV by 2020 in this age group.


Recombinant fish neurotrophin-6 is a heparin-binding glycoprotein: implications for a role in axonal guidance.
Neurotrophin-6 (NT-6) was identified in the teleost fish Xiphophorus as a new member of the neurotrophin gene family. NT-6 binds specifically the glycosaminoglycan heparin. In this study NT-6 was expressed in a stably transfected mammalian cell line, and in insect cells via a recombinant baculovirus. It was purified to homogeneity and characterized by MS and N-terminal sequencing. NT-6 from both expression systems was proteolytically processed at one of two protease cleavage motifs and was found to be glycosylated. It supported the survival of embryonic chick sensory neurons; half-maximal survival was observed at 100 ng/ml. Furthermore, NT-6 elicited neurite outgrowth in explanted embryonic dorsal root ganglia. Addition of heparin into the medium did not potentiate the activity of NT-6 in survival assays. However, when a sensory ganglion explant was cultured in a collagen gel matrix assay adjacent to a heparin bead coated with NT-6, neurite outgrowth directed towards the bead was observed. This indicated that NT-6 was slowly released from the heparin bead generating a concentration gradient of NT-6 instrumental for axonal guidance in vitro. Thus the interaction of NT-6 with heparin might not be required for the activation of the cellular receptor for NT-6 on responsive cells but rather may serve to control, in vivo, the distribution of NT-6.


Sea Urchin Extracellular Proteins Design a Complex Protein Corona on Titanium Dioxide Nanoparticle Surface Influencing Immune Cell Behavior.
Extensive exploitation of titanium dioxide nanoparticles (TiO2NPs) augments rapid release into the marine environment. When in contact with the body fluids of marine invertebrates, TiO2NPs undergo a transformation and adhere various organic molecules that shape a complex protein corona prior to contacting cells and tissues. To elucidate the potential extracellular signals that may be involved in the particle recognition by immune cells of the sea urchin Paracentrotus lividus, we investigated the behavior of TiO2NPs in contact with extracellular proteins in vitro. Our findings indicate that TiO2NPs are able to interact with sea urchin proteins in both cell-free and cell-conditioned media. The two-dimensional proteome analysis of the protein corona bound to TiO2NP revealed that negatively charged proteins bound preferentially to the particles. The main constituents shaping the sea urchin cell-conditioned TiO2NP protein corona were proteins involved in cellular adhesion (Pl-toposome, Pl-galectin-8, Pl-nectin) and cytoskeletal organization (actin and tubulin). Immune cells (phagocytes) aggregated TiO2NPs on the outer cell surface and within well-organized vesicles without eliciting harmful effects on the biological activities of the cells. Cells showed an active metabolism, no oxidative stress or caspase activation. These results provide a new level of understanding of the extracellular proteins involved in the immune-TiO2NP recognition and interaction in vitro, confirming that primary immune cell cultures from P. lividus can be an optional model for swift and efficient immune-toxicological investigations.


Evaluating a web-based clinical decision support system for language disorders screening in a nursery school.
Early and effective identification of developmental disorders during childhood remains a critical task for the international community. The second highest prevalence of common developmental disorders in children are language delays, which are frequently the first symptoms of a possible disorder. This paper evaluates a Web-based Clinical Decision Support System (CDSS) whose aim is to enhance the screening of language disorders at a nursery school. The common lack of early diagnosis of language disorders led us to deploy an easy-to-use CDSS in order to evaluate its accuracy in early detection of language pathologies. This CDSS can be used by pediatricians to support the screening of language disorders in primary care. This paper details the evaluation results of the "Gades" CDSS at a nursery school with 146 children, 12 educators, and 1 language therapist. The methodology embraces two consecutive phases. The first stage involves the observation of each child's language abilities, carried out by the educators, to facilitate the evaluation of language acquisition level performed by a language therapist. Next, the same language therapist evaluates the reliability of the observed results. The Gades CDSS was integrated to provide the language therapist with the required clinical information. The validation process showed a global 83.6% (122/146) success rate in language evaluation and a 7% (7/94) rate of non-accepted system decisions within the range of children from 0 to 3 years old. The system helped language therapists to identify new children with potential disorders who required further evaluation. This process will revalidate the CDSS output and allow the enhancement of early detection of language disorders in children. The system does need minor refinement, since the therapists disagreed with some questions from the CDSS knowledge base (KB) and suggested adding a few questions about speech production and pragmatic abilities. The refinement of the KB will address these issues and include the requested improvements, with the support of the experts who took part in the original KB development. This research demonstrated the benefit of a Web-based CDSS to monitor children's neurodevelopment via the early detection of language delays at a nursery school. Current next steps focus on the design of a model that includes pseudo auto-learning capacity, supervised by experts.


Mutation in the Endo-β-1,4-glucanase (KORRIGAN) Is Responsible for Thick Leaf Phenotype in Sorghum.
Sorghum [Sorghum bicolor (L.) Moench] is an important crop for food, feed, and fuel production. Particularly, sorghum is targeted for cellulosic ethanol production. Extraction of cellulose from cell walls is a key process in cellulosic ethanol production, and understanding the components involved in cellulose synthesis is important for both fundamental and applied research. Despite the significance in the biofuel industry, the genes involved in sorghum cell wall biosynthesis, modification, and degradation have not been characterized. In this study, we have identified and characterized three allelic thick leaf mutants (thl1, thl2, and thl3). Bulked Segregant Analysis sequencing (BSAseq) showed that the causal mutation for the thl phenotype is in endo-1,4-β-glucanase gene (SbKOR1). Consistent with the causal gene function, the thl mutants showed decreased crystalline cellulose content in the stem tissues. The SbKOR1 function was characterized using Arabidopsis endo-1,4-β-glucanase gene mutant (rsw2-1). Complementation of Arabidopsis with SbKOR1 (native Arabidopsis promoter and overexpression by 35S promoter) restored the radial swelling phenotype of rsw2-1 mutant, proving that SbKOR1 functions as endo-1,4-β-glucanase. Overall, the present study has identified and characterized sorghum endo-1,4-β-glucanase gene function, laying the foundation for future research on cell wall biosynthesis and engineering of sorghum for biofuel production.


REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.
The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.


Idiopathic granulomatous mastitis: rare but important.
A 61-year-old woman attended the breast clinic with unresolving mastitis and an associated mass, following failed treatment with antibiotics. Triple assessment confirmed idiopathic granulomatous mastitis. Unresponsive to further conservative management and steroid therapy, she underwent surgical excision and made uneventful recovery. No evidence of recurrence was detected at 18 months follow-up.


Properties of Metal Hydrides of the Iron Triad.
Metal hydride complexes are essential intermediates in hydrogenation reactions. The hydride-donor ability determines the scope of use of these complexes. We present a new, simple mass-spectrometry method to study the hydride-donor ability of metal hydrides using a series of 18 iron, cobalt, and nickel complexes with N- and P-based ligands (L). The mixing of [(L)MII(OTf)2] with NaBH4 forms [(L)MII(BH4)]+ (M = Fe, Co, Ni) that can be detected by electrospray ionization mass spectrometry. Energy-resolved collision-induced dissociations of [(L)MII(BH4)]+ provide threshold energies (ΔECID) for the formations of [(L)MII(H)]+ that correlate well with the hydride donor ability of the metal hydride complexes. We studied the vibrational and electronic spectra of the generated metal hydrides, assigned their structure and spin state, and demonstrated a good correlation between ΔECID and the M-H stretching vibration frequencies. The ΔECID also correlates with reaction rates for hydride transfer reactivity in the gas phase and known reactivity trends in the solution phase.


The clinical characteristics, biochemical parameters and insulin response to oral glucose tolerance test (OGTT) in 25 transfusion dependent β-thalassemia (TDT) patients recently diagnosed with diabetes mellitus (DM).
Patients with transfusion dependent β-thalassemia (TDT) are at high risk for developing, over the time, a form of diabetes distinct from type 1 and type 2 diabetes, but with similarities to both. The aim of this study is to describe the clinical and laboratory data, and the insulin secretion and sensitivity, in TDT patients , recently diagnosed with diabetes mellitus (DM). The medical records of 25 TDT patients with DM, diagnosed by standardized oral glucose tolerance test (OGTT) and insulin secretion, were analysed; data were compared to TDT patients without diabetes and to a group of healthy subjects. Natural history of glucometabolic status before the diagnosis of DM was also reviewed. On average, the TDT patients with DM were younger compared to TDT patients without diabetes. The mean age at diagnosis of DM in female and male TDT patients was 24.0 ± 7.1 years and 31.9 ± 5.6 years, respectively (P: 0.007). Serum alanine aminotransferase values, basal insulin levels and prevalence of hypogonadism were consistently higher in TDT patients with DM compared to those without diabetes. Decreased insulin secretion and increased insulin resistance was observed in patients with DM. The natural history of glucometabolic status in TDT patients is characterized by a deterioration of glucose tolerance over time. Iron overload and liver dysfuction are the main factors responsible for glucose disturbances (GD) in TDT patients. The therapeutic approach must be individualized and followed by a multidisciplinary team.


Rad53 regulates the lifetime of Rdh54 at homologous recombination intermediates.
Rdh54 is a conserved DNA translocase that participates in homologous recombination (HR), DNA checkpoint adaptation, and chromosome segregation. Saccharomyces cerevisiae Rdh54 is a known target of the Mec1/Rad53 signaling axis, which globally protects genome integrity during DNA metabolism. While phosphorylation of DNA repair proteins by Mec1/Rad53 is critical for HR progression little is known about how specific post translational modifications alter HR reactions. Phosphorylation of Rdh54 is linked to protection of genomic integrity but the consequences of modification remain poorly understood. Here, we demonstrate that phosphorylation of the Rdh54 C-terminus by the effector kinase Rad53 regulates Rdh54 clustering activity as revealed by single molecule imaging. This stems from phosphorylation dependent and independent interactions between Rdh54 and Rad53. Genetic assays reveal that loss of phosphorylation leads to phenotypic changes resulting in loss-of-heterozygosity (LOH) outcomes. Our data highlight Rad53 as a key regulator of HR intermediates through activation and attenuation of Rdh54 motor function.


Fucosyltransferase genes are dispersed in the genome: FUT7 is located on 9q34.3 distal to D9S1830.
Synthesis of A, B, H, Lewis and related histo-blood group antigens is catalyzed by different fucosyltransferases. Enzymatic acceptor specificity and tissue expression permit the definition of 2 types of alpha-2-fucosyltransferases and 5 types of alpha-3-fucosyltransferases encoded by specific genes registered as FUT1 to FUT7. We have previously assigned FUT4 to 11q21, the cluster FUT1-FUT2 to 19q13.3 and the cluster FUT6-FUT3-FUT5 to 19p13.3. The last gene cloned (FUT7) encodes an alpha-3-fucosyltransferase expressed in leukocytes which synthesizes the sialyl Lĕ antigen, a selectin ligand. We have localized this gene by PCR assay using somatic cell hybrids, which retain rearrangements of chromosome 9 characterized in respect with the genetic microsatellite map, and then by screening a cosmid library. We assign FUT7 to chromosome band 9q34.3 telomeric to D9S1830 and close to the genes ABC2 and C8G.


Circadian rhythms in rats: effects of random lighting.
Increase in body weight, spontaneous running activity, and adrenal cortical function have been studied in rats exposed to a random lighting schedule. In two separate experiments, grouped control animals were given 12 or 14 hours of light alternating with 12 or 10 hours of darkness, respectively, while coresponding grouped experimental animals were given the same total amounts of light and darkness per 24 hour period in a randomized pattern. Random light for periods of 17 to 40 days exerted no influence on growth rate, on weights of endocrine organs, or on adrenal response to adrenocorticotrophic hormone. However, the physiological fluctuation of group running activity and adrenal steroid secretion was abolished. Group desynchronization and the development of circadian rhythms having periods both shorter and longer than 24 hours appear to have replaced the synchronized group rhythmicity.


[Stress and allostatic load: perspectives in psycho-oncology].
Since its origins as a scientific field back in the late seventies, psycho-oncology has remained notably descriptive. Few conceptual advances have been achieved in the study of psychodynamics and biological underpinnings of psychological adjustment to the experience of cancer. Moreover, the specific aspects of psychopathological responses to cancer, as well as their optimal pharmacological management remain poorly understood. On the other hand, recent years have been characterized by significant progress in the delineation of biological mechanisms of stress and its consequences for the brain, body, and general health. In this paper, we examine the applicability of the concept of allostatic load to the study of stress and psychopathology related to the cancer experience. While homeostasis refers to maintaining specific biological parameters constant, allostasis can be defined as the process of maintaining stability through change. In this context, excessive or dysregulated activity of allostatic (adaptive) systems leads to deleterious effects for the brain (reduced neurogenesis, altered cell death processes, and dendritic branching) and body (increased cardiovascular risk). These damaging effects of cumulated stress have been refered to as the allostatic load, or the cost inflicted to the organism in order to maintain stability. We hypothesize that the concept of allostatic load is particularly relevant to the multiple, repeated and chronic stressors associated with the experience of cancer. In the light of this model, we propose a new classification of psychopathological conditions in psycho-oncology: the cancer-specific stress syndrome, with its three clinical subtypes (depressive, post-traumatic, and dysallostatic). Suggestions are formulated for some biological correlates of psychodynamic processes and for the study of innovative pharmacological approaches in the treatment of stress-related disorders in oncology (anticonvulsants, CRH antagonists, 5HT-1A receptor agonists...).


[Characterization of mechanical in vitro hemolysis and sub-hemolysis. 2: Variables of state and dimensionless characteristic values of hemolysis].
Blood damaging effects of artificial perfusion devices such as assist devices, heart valve prostheses, for example, must be evaluated in vitro before being used in the clinical setting. For this purpose, mainly animal blood has been used, and a number of associated problems are currently being discussed. Differences in the use of the term hemolysis--meaning breakdown of erythrocytes or increased plasma hemoglobin, result in incompatibility among different authors. In addition, subhemolytic damage and its quantification has not been investigated to any extent. Another problem are the differences in the mechanical fragility of erythrocytes from different animal species, and the question of transferability to the in vivo situation. Furthermore, the variability of mechanical stability within a given species is often greater than the differences between one species and another. International efforts are now being made to standardize haemolytic test conditions and the present study is meant as a contribution to this. In the first part we describe an extension of our LYSE number model. Characteristically, the model uses dimensionless similarity numbers, LY and MY, thus making the results obtained under different test conditions comparable with one another. The LY number reflects the breakdown of cells (decreasing hematocrit), the MY number an increase in plasma hemoglobin. Differences between LY and MY are an indication of subhemolytic events.


Long-range ion-water and ion-ion interactions in aqueous solutions.
Using small-angle X-ray scattering (SAXS), we obtained direct experimental evidence on the structure of hydrated polyatomic anions, with hydration effects starkly different from those of cations (J. Chem. Phys., 2011, 134, 064513). We propose that the size and charge density of the naked ions do not sufficiently account for the differences in the SAXS curves. For cations, the ion-ion contribution gives a prominent first-order diffraction peak, whereas for anions, the low-Q enhancement in the SAXS curves indicates density inhomogeneities as a result of ion-water interactions.


Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.
Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into "primary" and "secondary" psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional "fearlessness," while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths.


Salivary interleukin-17A and interferon-γ levels are elevated in children with food allergies in China.
Food allergies have a substantial impact on patient health, but their mechanisms are poorly understood, and strategies for diagnosing, preventing, and treating food allergies are not optimal. This study explored the levels of and relationship between IL-17A and IFN-γ in the saliva of children with food allergies, which will form the basis for further mechanistic discoveries as well as prevention and treatment measures for food allergies. A case-control study with 1:1 matching was designed. Based on the inclusion criteria, 20 case-control pairs were selected from patients at the Skin and Allergy Clinic and children of employees. IL-17A and IFN-γ levels in saliva were measured with a Luminex 200 instrument. A general linear model was used to analyze whether the salivary IL-17A and IFN-γ levels in the food allergy group differed from those in the control group. The general linear model showed a significant main effect of group (allergy vs. healthy) on the levels of IL-17A and IFN-γ. The mean IL-17A level (0.97 ± 0.09 pg/ml) in the food allergy group was higher than that in the healthy group (0.69 ± 0.09 pg/ml). The mean IFN-γ level (3.0 ± 0.43 pg/ml) in the food allergy group was significantly higher than that in the healthy group (1.38 ± 0.43 pg/ml). IL-17A levels were significantly positively related to IFN-γ levels in children with food allergies (r=0.79) and in healthy children (r=0.98). The salivary IL-17A and IFN-γ levels in children with food allergies were higher than those in healthy children. This finding provides a basis for research on new methods of diagnosing food allergies and measuring the effectiveness of treatment.


Coexistence of spondyloarthritis and joint hypermobility syndrome: rare or unknown association?
We report two cases of siblings presenting coexisting non-radiographic axial spondyloartrhritis and joint hypermobility syndrome, complaining of back pain with morning stiffness, enthesitis, peripheral arthralgia, high erythrocyte sedimentation rate and C-reactive protein level and positive HLA-B27. The association of these two conditions is rare, but especially interesting in view of their contrasting features, one causing axial skeleton stiffness, the other a wider range of peripheral joint movements. Coexistence of these two opposite disorders causes confusion in diagnosis and management, resulting in lower quality of life for patients, as they are in pain from the early stages. Therefore, this association is suspected in young individuals with back pain and physical exam findings of peripheral joint hypermobility and axial skeleton loss of mobility.


The p53 Isoform Deltap53 lacks intrinsic transcriptional activity and reveals the critical role of nuclear import in dominant-negative activity.
The transcription factor p53 is one of the most frequently mutated tumor suppressors. Recent progress has unraveled several novel isoforms of p53. Intriguingly, one of the p53 isoform, Deltap53, which lacks part of the DNA binding domain, was reported to be transcriptionally active toward some p53 target genes and is critical for the intra-S phase checkpoint. Here, we show that, in contrast to full-length p53, ectopically expressed Deltap53 neither transactivated the promoters of p21(CIP1/WAF1) or murine double minute-2 (MDM2) nor repressed the cyclin B1 promoter in unstressed H1299 cells. Due to the deletion of a nuclear localization signal, Deltap53 was not imported into the nucleus. Engineering of nuclear localization signals to Deltap53 restored nuclear accumulation. However, the nuclear-targeting Deltap53 remained inactive, indicating that the lack of intrinsic activity of Deltap53 was not simply due to subcellular localization but to its incomplete DNA binding domain. Similar to p53, Deltap53 was subjected to MDM2-mediated ubiquitination/proteolysis. The cytoplasmic localization of Deltap53 correlated with the instability of the protein because forcing Deltap53 into the nucleus increased its stability. Although Deltap53 could form a complex with p53 and stimulated the cytoplasmic retention of p53, it was not a robust inhibitor of p53. Targeting Deltap53 into the nucleus enhanced the dominant-negative activity of Deltap53. These observations underscore the critical role of subcellular localization in the dominant-negative action of p53.


Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides.
On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J ), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (23-33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (Ki = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.


Sirtuin 6 Attenuates Kaposi's Sarcoma-Associated Herpesvirus Reactivation by Suppressing Ori-Lyt Activity and Expression of RTA.
Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8 [HHV-8]), upon being reactivated, causes serious diseases in immunocompromised individuals. Its reactivation, especially how the cellular regulating mechanisms play roles in KSHV gene expression and viral DNA replication, is not fully understood. In searching for the cellular factors that regulate KSHV gene expression, we found that several histone deacetylases (HDACs) and sirtuins (SIRTs), including HDACs 2, 7, 8, and 11 and SIRTs 4 and 6, repress KSHV ori-Lyt promoter activity. Interestingly, the nuclear protein SIRT6 presents the greatest inhibitory effect on ori-Lyt promoter activity. A more detailed investigation revealed that SIRT6 exerts repressive effects on multiple promoters of KSHV. As a consequence of inhibiting the KSHV promoters, SIRT6 not only represses viral protein production but also inhibits viral DNA replication, as investigated in a KSHV-containing cell line, SLK-iBAC-gfpK52. Depletion of the SIRT6 protein using small interfering RNA could not directly reactivate KSHV from SLK-iBAC-gfpK52 cells but made the reactivation of KSHV by use of a small amount of the reactivator (doxycycline) more effective and enhanced viral DNA replication in the KSHV infection system. We performed DNA chromatin immunoprecipitation (ChIP) assays for SIRT6 in the SLK-iBAC-gfpK52 cell line to determine whether SIRT6 interacts with the KSHV genome in order to exhibit regulatory effects. Our results suggest that SIRT6 interacts with KSHV ori-Lyt and ORF50 promoters. Furthermore, the SIRT6-KSHV DNA interaction is significantly negated by reactivation. Therefore, we identified a cellular regulator, SIRT6, that represses KSHV replication by interacting with KSHV DNA and inhibiting viral gene expression.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is a pathogen causing cancer in the immune-deficient population. The reactivation of KSHV from latency is important for it to be carcinogenic. Our finding that SIRT6 has inhibitory effects on KSHV reactivation by interacting with the viral genome and suppressing viral gene expression is important because it might lead to a strategy of interfering with KSHV reactivation. Overexpression of SIRT6 repressed the activities of several KSHV promoters, leading to reduced gene expression and DNA replication by KSHV in a KSHV bacterial artificial chromosome-containing cell line. Depletion of SIRT6 favored reactivation of KSHV from SLK-iBACV-gfpK52 cells. More importantly, we reveal that SIRT6 interacts with KSHV DNA. Whether the interaction of SIRT6 with KSHV DNA occurs at a global level will be further studied in the future.


Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor.
Human DNA topoisomerase I, known for its DNA-relaxing activity, is possibly one of the kinases phosphorylating members of the SR protein family of splicing factors, in vivo. Little is known about the mechanism of action of this novel kinase. Using the prototypical SR protein SF2/ASF (SRp30a) as model substrate, we demonstrate that serine residues phosphorylated by topo I/kinase exclusively located within the most extended arginine-serine repeats of the SF2/ASF RS domain. Unlike other kinases such as cdc2 and SRPK1, which also phosphorylated serines at the RS domain, topo I/kinase required several SR dipeptide repeats. These repeats possibly contribute to a versatile structure in the RS domain thereby facilitating phosphorylation. Furthermore, far-western, fluorescence spectroscopy and kinase assays using the SF2/ASF mutants, demonstrated that kinase activity and binding were tightly coupled. Since the deletion of N-terminal 174 amino acids of Topo I destroys SF2/ASF binding and kinase activity but not ATP binding, we conclude that at least two distinct domains of Topo I are necessary for kinase activity: one in the C-terminal region contributing to the ATP binding site and the other one in the N-terminal region that allows binding of SF2/ASF.


[Peripheral proliferative vitreoretinopathy in intermediary uveitis].
Certain types of intermediary uveitis are accompanied by proliferative vitreoretinopathy and retinal detachment. As a rule both complications are confined to the fundus periphery; they often occur simultaneously but they are not always related to one another. Exudate plaques and/or neovascularizations at the base of the vitreous are the precursors of peripheral proliferative vitreoretinopathy. Clinical findings and their therapeutic consequences are discussed.


Longitudinal associations between personality profile stability and adjustment in college students: distinguishing among overall stability, distinctive stability, and within-time normativeness.
In the present study, longitudinal associations of 3 aspects of personality profile stability (i.e., overall stability, distinctive stability, and within-time normativeness) with 3 adjustment measures (i.e., depressive symptoms, self-esteem, and delinquency) were examined, using 4 waves of longitudinal data on a Belgian college sample (N=565). Longitudinal path models revealed strong longitudinal associations between adjustment and overall stability. Subsequent analyses showed that it is not the degree to which one's personality profile consistently diverges from the average personality profile within a population (i.e., distinctive stability) that is related to adjustment but the degree to which a personality profile of an individual matches the average personality profile within the sample at a certain point in time (i.e., within-time normativeness). The current study thereby underscores the importance of distinguishing normativeness and distinctiveness when examining personality profile stability.


Film retakes in digital and conventional radiography.
To determine the film-retake rates and causes in digital radiography comparison to conventional X-rays method. Comparative study. Radiology Department, Aga Khan University Hospital, Karachi, from January 2004 to December 2006. X-rays of different body parts, conducted during the year 2004, with conventional radiography (n=170300), and in 2006 with digital radiography (n=174550), were included in this study. Measurements were done for number of X-rays re-take due to different quality control reasons for both the conventional and digital radiography. Quality control reasons included underexposure, overexposure, positioning errors, patient movements, portable X-rays, grid cutoff, and others (i.e. equipment related) due to which X-ray quality was questionable. Results were expressed in percentages. A total of 9423 X-rays (5.5%) were repeated in conventional radiography (n=170300) due to underexposure (38%), overexposure (28.5%), positioning errors (25%), portable procedures (4%), patient movement (2%), grid cut-off (0.5%), and others (2%). Underexposure was the most frequently responsible factor for the X-ray repetition as compared to other factors (p<0.001). In digital radiography (n=174550), 1464 X-rays (1%) needed to be repeated, which was significantly less in comparison to X-ray repetition in conventional method of radiography (5.5%) [p<0.001]. In digital radiography, the most frequent factor for X-ray re-take was positioning error (435, 30%). Digital radiography is associated with significantly lesser number of re-take X-rays as compared to conventional radiography, hence minimizes the exposure of the patients to unnecessary radiations due to re-take X-rays. Positioning error remains a problem even in digital radiography, emphasizing training need for technologists.


Recent advances in the mechanism of hydrogen sulfide in wound healing in diabetes.
Wound healing difficulties in diabetes continue to be a clinical challenge, posing a considerable burden to patients and society. Recently, exploration of the mechanism of wound healing and associated treatment options in diabetes has become topical. Of note, the positive role of hydrogen sulfide in promoting wound healing has been demonstrated in recent studies. Hydrogen sulfide is a confirmed gas transmitter in mammals, playing an essential role in pathology and physiology. This review describes the mechanism underlying the role of hydrogen sulfide in the promotion of diabetic wound healing and the potential for hydrogen sulfide supplementation as a therapeutic application.


Efficacy and Safety of Cariprazine in Acute Management of Psychiatric Disorders: a Meta-Analysis of Randomized Controlled Trials.
Cariprazine is a new atypical antipsychotic drug approved for the treatment of schizophrenia and bipolar disorders. we searched the published randomized controlled-trials (RCT) to review cariprazine efficacy and tolerability using the databases (PubMed, EUDRACT, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials) for cariprazine role in managing the following psychiatric conditions (schizophrenia, bipolar mania, bipolar depression and major depressive disorder). A meta-analysis was conducted using the identified 13 clinical trials to assess efficacy using with the outcomes: positive and negative syndrome scale (PANSS), clinical global impressions - severity of Illness (CGI-S), young mania rating scales (YMRS), Montgomery Asberg depression rating scale (MADRS) and Hamilton rating scale for depression (HAM-D). The risk of discontinuation due to adverse effects and common side effects were examined. The mean difference in change from baseline for PANSS was -6.23 (95% Confidence Interval (CI) -7.18, -5.28) favoring cariprazine treatment (p<0.00001). Similarly, mean difference for CGI-S was -0.36 (95% CI -0.41, -0.30), YMRS -5.64 (95% CI -6.86, -4.43), MADRS -1.43 (95% CI -1.88, -0.99) and HAM-D -1.52 (95% CI -2.28, -0.76). The risk ratio (RR) of discontinuing due to adverse events was 1.18 (95% CI 1.01, 1.38) meaning risk increased by 18% in cariprazine group with RR for EPS related side effects 2.82 (95% CI 2.47, 3.22) reflecting an increased risk of experiencing EPS related side effects by 182%. Cariprazine was also associated with an increased incidence of side effects such as akathisia, nausea and insomnia. Cariprazine demonstrates significant improvements in symptom intensity control in patients suffering from psychiatric conditions including schizophrenia, bipolar disorders and depression and is considered well-tolerated with similar rates of trials discontinuation; however, cariprazine was associated with a higher risk of EPS side effects. These findings will guide psychiatrists and pharmacists in their clinical role for supporting psychiatric patients care.


Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker.
Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489.


Deploying Big Data to Crack the Genotype to Phenotype Code.
Mechanistically connecting genotypes to phenotypes is a longstanding and central mission of biology. Deciphering these connections will unite questions and datasets across all scales from molecules to ecosystems. Although high-throughput sequencing has provided a rich platform on which to launch this effort, tools for deciphering mechanisms further along the genome to phenome pipeline remain limited. Machine learning approaches and other emerging computational tools hold the promise of augmenting human efforts to overcome these obstacles. This vision paper is the result of a Reintegrating Biology Workshop, bringing together the perspectives of integrative and comparative biologists to survey challenges and opportunities in cracking the genotype to phenotype code and thereby generating predictive frameworks across biological scales. Key recommendations include promoting the development of minimum "best practices" for the experimental design and collection of data; fostering sustained and long-term data repositories; promoting programs that recruit, train, and retain a diversity of talent; and providing funding to effectively support these highly cross-disciplinary efforts. We follow this discussion by highlighting a few specific transformative research opportunities that will be advanced by these efforts.


Radiographic evaluation of spinal trauma.
This article reviews the general principles that apply to the radiographic evaluation of acute injury of the cervical and thoracolumbar spine and discusses the possible use of various imaging techniques.


Risk factors for self-reported carpal tunnel syndrome among hairstylists in Gaborone, Botswana.
Hairstylists form an occupational group whose tasks involve repetitive and forced movements of hands and wrists, thus posing a risk of developing carpal tunnel syndrome (CTS). This study assessed the prevalence of and factors associated with CTS symptoms among hairstylists in Gaborone, Botswana. A cross-sectional study was conducted using a self-administered questionnaire distributed among randomly selected hairstylists. The questionnaire gathered information on demographic characteristics, lifestyle, work-related characteristics and psychosocial factors. The Boston Carpal Tunnel Syndrome Questionnaire was used to determine the severity of CTS symptoms and its functional effects. Data were then analyzed using χ2 and logistic regression models. The level of significance was determined at p < 0.05. A total of 165 hairstylists took part in the study, with 92 (56%) of the respondents being females. The mean age (M±SD) of the respondents was 35.05±7.54 years with an age range of 22-63 years. Seventy-three (42.2%) hairstylists reported CTS symptoms, with the majority (73%) being females. Out of all the CTS cases, 53 (72.6%) and 16 (21.9%) had mild and moderate symptoms, respectively. Over 80% of the hairstylists did not know about CTS. Among individual factors, CTS symptoms were associated with being female (the odds ratio [OR] of 9.99, and the 95% confidence interval [CI]: 3.64-27.44), increasing age (OR 9.84, 95% CI: 2.74-35.36), the length of employment (OR 3.73, 95% CI: 1.39-9.95), hair washing (OR 2.88, 95% CI: 1.41-5.85), an awkward posture (OR 2.52, 95% CI: 1.03-6.19), and the use of a great muscular effort when performing a task (OR 2.39, 95% CI: 1.01-5.72). Perceived heavy workload and stressful work were also risk factors. The results suggest a high prevalence of CTS among female hairstylists in Gaborone, and also point out that individual, work-related and psychosocial factors are associated with this syndrome. Future large-scale research is needed to establish the extent of CTS countrywide to influence policy-making. Currently, CTS is not listed amongst occupational health diseases in Botswana. Int J Occup Med Environ Health. 2021;34(3):437-50.


Synthesis of gallic acid-grafted epoxidized natural rubber and its role in self-healable flexible temperature sensors.
Developing a flexible temperature sensor with appreciable sensitivity is critical for advancing research related to flexible electronics. Although various flexible sensors are available commercially, most such temperature sensors are made from polymeric materials obtained from petrochemical resources. Such sensors will contribute to electronic waste and increase the carbon footprint after usage. While there are reports on various sensors made from sustainable polymers, research related to developing self-healable flexible temperature sensors made from sustainable polymers is significantly less. Herein, we report on developing a flexible temperature sensor made of gallic acid-grafted epoxidized natural rubber and multi-walled carbon nanotubes. Various spectroscopic and thermal techniques vetted the modification of the epoxidized natural rubber. The highest grafting of 20.9% was achieved in the selected window of stoichiometry. A self-healing behavior was achieved by leveraging the FeCl3 based metal-ligand crosslinking of the composite. The healing efficiency was noted to be 31.2% for the composite material. The fabricated sensor demonstrated an electrical resistance of 4.46 × 103 Ω, thereby warranting the composite to demonstrate an Ohmic behavior in the I-V plot. Appropriate data fitting suggested a variable range hopping mechanism as causation towards excellent electrical conduction. The temperature sensitivity and the thermal index of the developed sensor were noted to be -0.17% °C-1 and 781.2 K, respectively, in the temperature range of 30 °C to 50 °C. The proposed method of fabricating sustainable, high-strength, self-healable, and robust temperature sensors and conductors is a unique and value-added approach for next-generation flexible electronics.


Judging roughness by sight--a 7-Tesla fMRI study on responsivity of the primary somatosensory cortex during observed touch of self and others.
Observing another person being touched activates our own somatosensory system. Whether the primary somatosensory cortex (S1) is also activated during the observation of passive touch, and which subregions of S1 are responsible for self- and other-related observed touch is currently unclear. In our study, we first aimed to clarify whether observing passive touch without any action component can robustly increase activity in S1. Secondly, we investigated whether S1 activity only increases when touch of others is observed, or also when touch of one's own body is observed. We were particularly interested in which subregions of S1 are responsible for either process. We used functional magnetic resonance imaging at 7 Tesla to measure S1 activity changes when participants observed videos of their own or another's hand in either egocentric or allocentric perspective being touched by different pieces of sandpaper. Participants were required to judge the roughness of the different sandpaper surfaces. Our results clearly show that S1 activity does increase in response to observing passive touch, and that activity changes are localized in posterior but not in anterior parts of S1. Importantly, activity increases in S1 were particularly related to observing another person being touched. Self-related observed touch, in contrast, caused no significant activity changes within S1. We therefore assume that posterior but not anterior S1 is part of a system for sharing tactile experiences with others.


Cardiovascular and musculoskeletal response to supervised exercise in patients with intermittent claudication.
Intermittent claudication occurs in 20% of the population older than 70 years, and treatment includes a supervised exercise program (SEP). Whereas there is evidence demonstrating walking improvements after an SEP, there are conflicting data on the physiologic changes behind this. This study aimed to explore and to identify the potential cardiovascular and musculoskeletal changes with exercise. This was a single-center study at a vascular unit in England. Following written informed consent, 109 patients were recruited for an SEP, three times per week for 12 weeks. Outcome measures included walking distances, quality of life, cardiorespiratory fitness, flow-mediated dilation, and muscle strength and endurance. For normal data, paired sample t-tests were performed to compare baseline data to all time points for significance. For nonparametric data, Wilcoxon signed rank tests were performed. Significance was set at P < .05. The association between functional improvement (ie, walking distance at 3 months after the SEP) and metabolic response and patients' characteristics was determined by multivariable regressions. Maximum walking distance significantly improved from baseline by 117% at 1 week, 143% at 4 weeks, and 143% at 12 weeks after exercise. Claudication distance also significantly improved from baseline by 222% at week 1, 393% at week 4, and 452% at week 12. Quality of life significantly improved at all time points in seven of nine domains of the 36-Item Short Form Health Survey and two of five domains of the Vascular Quality of Life questionnaire. Markers of cardiorespiratory fitness significantly improved at all time points. Flow-mediated dilation demonstrated a 50% improvement, but this was not statistically significant. Muscle strength and muscle endurance significantly improved at all time points. Multivariate regression demonstrated that the ventilatory anaerobic threshold and the physical component summary score for quality of life predicted improvements in 12-week walking distance. This study identified that the ventilatory anaerobic threshold and physical component summary scores from quality of life were the best predictors of improvement in an SEP. Future studies should prioritize these outcomes and assess whether different SEPs have similar effects. Cardiorespiratory fitness was also a predictor of outcome and should be prioritized in future studies alongside traditional measures.


Towards JPEG-Resistant Image Forgery Detection and Localization Via Self-Supervised Domain Adaptation.
With wide applications of image editing tools, forged images (splicing, copy-move, removal and etc.) have been becoming great public concerns. Although existing image forgery localization methods could achieve fairly good results on several public datasets, most of them perform poorly when the forged images are JPEG compressed as they are usually done in social networks. To tackle this issue, in this paper, a self-supervised domain adaptation network, which is composed of a backbone network with Siamese architecture and a compression approximation network (ComNet), is proposed for JPEG-resistant image forgery detection and localization. To improve the performance against JPEG compression, ComNet is customized to approximate the JPEG compression operation through self-supervised learning, generating JPEG-agent images with general JPEG compression characteristics. The backbone network is then trained with domain adaptation strategy to localize the tampering boundary and region, and alleviate the domain shift between uncompressed and JPEG-agent images. Extensive experimental results on several public datasets show that the proposed method outperforms or rivals to other state-of-the-art methods in image forgery detection and localization, especially for JPEG compression with unknown QFs.


Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study.
This study aims to investigate whether altered baseline brain activity exists in type 2 diabetes mellitus (T2DM) patients using resting-state functional magnetic resonance imaging (rs-fMRI) and whether abnormal neural activity in the middle temporal gyrus (MTG) is correlated with cognitive function. T2DM patients (n=28) were compared with nondiabetic age-, sex-, and education-matched control subjects (n=29) using rs-fMRI. We computed the amplitude of low-frequency fluctuations (ALFF) of fMRI signals to measure spontaneous neuronal activity and detect the relationship between rs-fMRI information and clinical data. Compared with healthy controls, T2DM patients had significantly decreased ALFF values in the bilateral middle temporal gyrus, left fusiform gyrus, left middle occipital gyrus, right inferior occipital gyrus; and increased ALFF values in both the bilateral cerebellum posterior lobe and right cerebellum culmen. Moreover, we found an inverse correlation between the ALFF values in the MTG and both the HbA1c (r=-0.451, p=0.016) and the score of Trail Making Test-B (r=-0.420, p=0.026) in the patient group. On the other hand, C-peptide level and pancreatic β-cell function had a positive correlation (r=0.429, p=0.023; r=0.453, p=0.016, respectively) with the ALFF value in the middle temporal gyrus. The present study confirms that T2DM patients have altered ALFF in many brain regions, which is associated with poor neurocognitive performances, severity of consistent hyperglycemic state and impaired β-cell function. ALFF disturbance in MTG may play a central role in cognitive decline associated with T2DM and serve as reference for future clinical diagnosis.


[Cohort study of seroepidemiology on hemorrhagic fever with renal syndrome].
A cohort study of seroepidemiology on hemorrhagic fever with renal syndrome (HFRS) was carried out in two villages, Jiande County, Zhejiang Province. 1325 persons who had not had antibodies to HFRS in 1987 were interviewed and re-examined in 1988. Seroconversion to HFRS antibodies was found in 30 persons (2.26%). Among them, were two clinical cases with an incidence rate of 0.151% and the rate of inapparent infection was 2.12%. Ratio of apparent to inapparent infection was 1:14. No infection was observed in children aged 2-4 years and subjects aged 60 years and over. The rate was lower in 5-14 years age group (1.42%) than in those of 15-59 age groups (1.47-4.26%). The infection rate in males (2.57%) was slightly higher than in females (1.96%). Results of stratified analysis and logistic regression analysis showed that living in houses located at the village periphery, having straw stack out of the house and rearing cat were risk factors of HFRS infection and their ORs were 3.0932, 3.3629, and 4.9970 respectively. Antibodies and antigens of HFRS were detected in A. agrarius and R. norvegicus captured in the villages.


An amygdala-cingulate network underpins changes in effort-based decision making after a fitness program.
When humans make decisions, objective rewards are mainly discounted by delay, risk and effort. Whereas recent research has demonstrated that several brain areas process costs and code subjective value in effort-based decision making, it remains obscure how neural activity patterns change when effort costs are reduced due to the acquisition of healthy habits, such as moving from sedentary to active lifestyles. Here, a sample of sedentary volunteers was behaviorally assessed and fMRI-scanned before and after completing a 3-month fitness plan. The impact of effort cost on decisions, measured as the constant defining a hyperbolic decaying function, was reduced after the plan. A logistic mixed model demonstrated that the explanatory power of effort decreased with time. At a neural level, there was a marginally significant disruption of effort-cost related functional activity in the anterior cingulate after the plan. Functional connectivity between the amygdala and anterior cingulate cortex was strengthened after habit acquisition. In turn, this interaction was stronger in those participants with lower effort discounting. Thus, we show for the first time changes in value-based decision making after moving from a sedentary to an active lifestyle, which points to the relevance of the amygdala-cingulate interplay when the impact of effort on decisions fades away.


Maturing out of alcohol dependence: the impact of transitional life events.
The purpose of this study was to investigate the effects of transitional life events related to education, employment, and family formation on the likelihood of recovery from alcohol dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), distinguishing the short- and long-term effects of these events and potential effect modification by treatment history, gender, and severity of dependence. This analysis is based on data from the Wave 1 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a cross-sectional, retrospective survey of a nationally representative sample of U.S. adults 18 years of age and older. The analytic sample consisted of 4,422 individuals with prior-to-past-year (PPY) onset of DSM-IV alcohol dependence. Time-dependent proportional hazards models were used to estimate the effects of completing school, starting full-time work, getting married, becoming separated/divorced/widowed, and becoming a parent on the outcomes of nonabstinent recovery (NR; e.g., low-risk asymptomatic drinking) and abstinent recovery (AR). Entry into and exit from a first marriage each increased the likelihood of NR during the first 3 years after those events occurred (hazard rate ratio [HRR] = 1.37 and 1.76, respectively). However, individuals who were still dependent 3 or more years after those events occurred had a decreased likelihood of subsequent NR (HRR = 0.70 for both events), as did those who were still dependent 3 or more years after completing schooling (HRR = 0.54). The likelihood of AR was more than doubled in the 3 years after first becoming a parent (HRR = 2.22) but was decreased among individuals still dependent 3 or more years after starting full-time work. For the outcome of NR, all of the negative effects associated with still being dependent 3 or more years after the occurrence of key life events were more strongly negative among individuals with less severe cases of dependence. Transitional life events demonstrate many effects on recovery, including both direct effects consistent with role socialization and associations more reflective of selectivity than causation. Taken as a whole, these events appear to contribute to (but by no means fully explain) the high rates of recovery from alcohol dependence that have been observed even in the absence of treatment.


Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo.
Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.


When the patient dies: helping the family and staff to cope.
1. Death of a family member or significant other is a traumatic experience for the survivors. Their psychological needs may be overlooked due to the discomfort of staff in dealing with matters related to death. 2. The nurse who has unresolved feelings concerning loss may lose control as well as lose professional effectiveness. 3. Failure by the nurse to recognize the dynamics of grief and attempts to prematurely end grieving can lead to serious consequences for survivors. Nurses who are aware of the needs of grieving persons can help to facilitate the process, cushion the trauma of loss, and set the basis for a healthy grieving process.


Community-based screening to detect school readiness problems in very preterm children.
Very preterm (VPT) children (≤32 weeks) have school readiness difficulties across multiple domains, but routine follow-up is often limited. We assessed the performance of VPT children on the Before School Check (B4SC), a community-based screening programme of school readiness at 4 years of age. VPT children discharged from Wellington and Auckland Neonatal Intensive Care Units (2005-2009) were compared to a national control cohort born during the same period. Outcome measures included Parental Evaluation of Developmental Status (PEDS), parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ-P and SDQ-T) and vision and hearing screening, and were related to perinatal and demographic characteristics obtained from the Australia and New Zealand Neonatal Network database. Of 1105 VPT children, 920 were matched to the B4SC database, of whom 814 (88%) had one or more B4SC screening outcomes recorded. Compared with controls, VPT children were more likely to have abnormal PEDS (odds ratio (OR) = 1.79, 1.53-2.10), SDQ-P (OR = 1.82, 1.49-2.23), SDQ-T (OR = 1.51, 1.10-2.06), vision (OR = 2.00, 1.54-2.60) and hearing (OR = 1.95, 1.65-2.31) screen outcomes. While VPT children with an abnormal screen were more likely to be referred for further assessment, only 34%, 22%, 94% and 51% with abnormal PEDS, SDQ or vision and hearing screen, respectively, had evidence of appropriate referral. School readiness difficulties were significantly associated with birthweight z-score ≤ -1, vaginal delivery, significant cranial ultrasound abnormalities, younger maternal age, higher deprivation neighbourhood and ventilation ≥72 h. Community-based screening may be useful for identifying VPT children with school readiness difficulties, but low referral rates may limit the effectiveness of such programmes.


[Education and research on mental health in Latin America: priorities and implementation].
This paper is based on a presentation delivered at a PAHO Regional Meeting on Mental Health. It focuses mainly on research issues and is to be considered as a preliminary prospective exercise. From a biomedical perspective, research in Latin America appears to be limited, but it is not clear to what extent. Costly technology, and scarce funding, together with the assumption that this type of research is a privilege of rich countries, are serious disadvantages, and yet, it need to be further promoted. Methodology of clinical and social research has grown in complexity. That is likely to be one of the reasons why local efforts are rarely internationally competitive. But there are groups in the Region that have shown that this can be achieved. Training of competent investigators and innovative means to shorten the scientific and technologic gap that separate us from developed countries are urgent, as Latin America has the potential to do better in research.