Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.
Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.


Current situation and issue of Industrial Accident Compensation insurance.
Industrial Accident Compensation Insurance (IACI) has a history of about 50 yr, and is the oldest social insurance system in Korea. After more than 20 times of revision improvements in benefits, its contents and claim systems have been upgraded. It became the protector of injured workers and their families, and at the same time became the system which could cope with both financial burden of employers and their responsibilities. However, there are some issues to be reformed to upgrade the IACI: 1) the problems in the approval system of occupational diseases, 2) quality improvement of workers' compensation medical care, 3) vocational rehabilitation and return to work, 4) workers' compensation premiums and out-of-pocket money of injured workers, 5) issues in application of IACI. Growth of IACI cannot be achieved by an effort of an individual. Efforts by workers, owners, and government, in addition to physicians and welfare professionals toward the same goal are required for the next level improvement of IACI.


Use of doxapram as an arousal agent in outpatient general anaesthesia.
In a double-blind study of 100 outpatients receiving an anaesthetic sequence of methohexitone, nitrous oxide and halothane, significant shortening of recovery time was produced by the i.v. administration of doxapram hydrochloride at the end of anaesthesia. Comparable recovery times were obtained following the administration of 80 mg to female patients and 95 mg to male patients. There was no evidence that the administration of doxapram caused cardiac arrhythmia.


Pseudobulbar Affect Presenting as Hypomania.
Pseudobulbar affect (PBA) is a behavioral syndrome associated with various neurological conditions that typically manifests as uncontrollable laughing or crying. PBA can significantly impact the quality of life of patients affected as these spells can be inappropriate to the social setting or incompatible with the patient's emotional state. The underlying mechanism of PBA appears to be associated with disinhibition in neuronal pathways involving dopamine, serotonin, and glutamate, but the exact mechanism remains unclear. One hypothesis for the pathology of PBA is that it is the result of disruption of the corticopontine-cerebellar circuits, impairing cerebellar modulation of affect, and leading to uncontrolled emotional lability. Stroke, and other neurological disorders, interrupt these neuronal circuits causing disinhibition of the voluntary control of emotional expression. It is extremely important to recognize and appropriately diagnose the condition. We present a case report of an 85-year-old female patient who presented with a thalamic stroke, and she subsequently developed hypomania with symptoms of decreased need for sleep, mood lability, pressured speech, and religious preoccupation. This case discusses a unique presentation of PBA with hypomania.


Getting in touch--3D printing in forensic imaging.
With the increasing use of medical imaging in forensics, as well as the technological advances in rapid prototyping, we suggest combining these techniques to generate displays of forensic findings. We used computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) and surface scanning with photogrammetry in conjunction with segmentation techniques to generate 3D polygon meshes. Based on these data sets, a 3D printer created colored models of the anatomical structures. Using this technique, we could create models of bone fractures, vessels, cardiac infarctions, ruptured organs as well as bitemark wounds. The final models are anatomically accurate, fully colored representations of bones, vessels and soft tissue, and they demonstrate radiologically visible pathologies. The models are more easily understood by laypersons than volume rendering or 2D reconstructions. Therefore, they are suitable for presentations in courtrooms and for educational purposes.


Antimicrobial prescribing in hospitalized adults stratified by age: data from the ESAC point-prevalence surveys.
Geriatric infectious diseases are a major health care issue. Infections in the elderly occur more frequently than in younger adults, are often associated with higher morbidity and mortality, and may present atypically. Elderly patients are also often taking multiple medications, which increases the likelihood of drug-drug interactions. Dosing decisions should take into consideration the reduced lean body mass and declining renal function in this age group. Antimicrobial prescribing in three age groups (65-74, 75-84 and ≥85 years) was compared with a reference age group (18-64 years), with the aim of identifying quality of care indicators specific to the elderly. The ESAC (European Surveillance of Antimicrobial Consumption) final phase performed two hospital point-prevalence surveys in 2008 and 2009, respectively, using the defined daily dose (DDD) and Anatomical Therapeutic Chemical (ATC) classification system. The prescribed daily dose (PDD) was compared with the DDD. Differences in prescribing were assessed using multivariate logistic regression analyses. The majority of patients (19,549 [64% of 30,836]) were from Northern Europe and 13,830 (48%) belonged to the reference group. The largest proportion of patients was admitted through the hospital's medical specialty (55% of patients) [range: 49% in the reference group to 72% in the ≥85 years age group]. Penicillins were the most frequently used antimicrobials in all age groups (range: 32% in the reference group to 41% in the ≥85 years age group). Multivariate analyses showed three significant variations between the 65-74 years age group and the reference group (quinolones: odds ratio [OR] 1.17 [95% CI 1.05, 1.29]; tetracyclines: OR 1.58 [95% CI 1.26, 1.98]; aminoglycosides: OR 0.81 [95% CI 0.70, 0.93]). The number of significant variations increased to seven and eight in the 75-84 and ≥85 years age groups, respectively. A lower likelihood for PDD > DDD was observed in the 65-74 years age group for three parenteral antimicrobials (amoxicillin/clavulanic acid, gentamicin and vancomycin). This was reiterated in the older age groups (75-84 and ≥85 years), where piperacillin/tazobactam, meropenem and oral ciprofloxacin also showed a lower likelihood for PDD > DDD. Despite the methodology not being dedicated to elderly patients, the study identified elevated use of antimicrobial agents that are associated with serious adverse effects or a narrow therapeutic index as a target for quality of care improvement in elderly patients.


The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.
The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding-induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor-kappaB activation in a TLR4-dependent MyD88-independent manner. While TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.


Rubus suavissimus S. Lee Extract Alleviates Oxidative Stress and Inflammation in H2O2-Treated Retinal Pigment Epithelial Cells and in High-Fat Diet-Fed Mouse Retinas.
Age-related macular degeneration (AMD) is the most common cause of visual disorders in the aged population and is characterized by the formation of retinal pigment epithelium (RPE) deposits and dysfunction/death of the RPE and photoreceptors. It is supposed that both oxidative stress and inflammation play a critical role in the pathogenesis of AMD. The development of therapeutic strategies against oxidative stress and inflammation in AMD is urgently needed. Rubus suavissimus S. Lee (RS), a medicinal plant growing in the southwest region of China, has been used as an herbal tea and medicine for various diseases. In this project, we evaluate the therapeutic potential of RS extract for AMD. We prepared RS extracts from dried leaves, which contained the main functional compounds. RS extract significantly increased cell viability, upregulated the expression of antioxidant genes, lowered the generation of malondialdehyde and reactive oxygen species, and suppressed inflammation in H2O2-treated human RPE cells. In the in vivo study, treatment with RS extract attenuated body weight gain, lowered cholesterol and triglyceride levels in the liver and serum, increased antioxidant capacity, and alleviated inflammation in the retina and RPE/choroid of mice fed a high-fat diet. Our findings suggest that RS extract offers therapeutic potential for treating AMD patients.


The Efficacy of Budesonide, Levocabastine, and Their Combination in Treatment of Vasomotor Rhinitis.
Relevant studies have demonstrated that glucocorticoids and antihistamines, such as budesonide and azelastine, are effective in the treatment of vasomotor rhinitis, with their combined use being more effective than that of a single drug. The aim of this study was to assess the improvement in the symptoms of patients following the combined administration of these drugs. We conducted a single-center randomized study on 42 patients. Participants were randomly treated with budesonide, levocabastine hydrochloride, or their combination for 2 weeks. The visual analog scale (VAS) score and levels of eosinophil cationic protein (ECP), histamine (HA), leukotriene B4 (LTB4), and vasoactive intestinal peptide (VIP) in nasal secretions were evaluated before and after treatment. The symptoms of patients were improved in all 3 treatment groups compared with those before treatment. Following combined treatment, the improvement in symptoms of nasal obstruction, runny nose, nasal itching, and sneezing was much greater than those in the groups treated with budesonide or levocabastine hydrochloride alone (p = 0.04, 0.004, 0.005, 0.004, respectively). The decreased levels of these inflammatory mediators were significantly different between the different treatment groups. Budesonide or levocabastine hydrochloride alone improved the nasal symptoms of patients with vasomotor rhinitis and reduced the levels of ECP, HA, LTB4, and VIP in nasal secretions. However, their combination improved the symptoms of patients more significantly than each drug alone.


Factors Associated with Marital Satisfaction and Quality of Life in Family Caregivers of Patients with Mental Disorders.
(1) Background: The aim of this research was to analyze factors associated with quality of life (QoL) and marital satisfaction in married family caregivers of patients with mental disorders. (2) Methods: A cross-sectional study was conducted in all community mental health services in Goiania municipality, Brazil, in 2016-2017. Married family caregivers of patients with severe and persistent mental disorders were recruited and their QoL and marital satisfaction was assessed by using the World Health Organization Quality of Life Instrument Abbreviated version (WHOQOL-BREF) and Marital Satisfaction Scale. Multiple linear regressions were performed to identify factors associated with QoL and marital satisfaction. (3) Results: For 163 family caregivers, the psychological and environmental QoL domains presented the best and the worst scores, respectively. Factors independently associated with better QoL for caregivers were male caregiver, the younger age of a caregiver, >8 years of schooling, ≥5 years as a caregiver who performed physical activities, caregiver without chronic disease, and no patient's crisis in the last 30 days. Factors independently associated with marital satisfaction of the caregiver were male caregiver, caregiver with >8 years of schooling, caregiver who received support by relatives to care for the patient, caregiver who performed physical activities, no patient's crisis in the last 30 days, and patient hospitalization in the last six months; (4) Conclusions: The main predictor for marital satisfaction was support by relatives, and for QoL it was no patient's crisis in the last 30 days.


[Heat and Fever in ancient Greek physiology].
This paper aims at clarifying the relationship of physiological heat and pathological heat(fever) using the theoretical scheme of Georges Canguilhem as is argued in his famous book The Normal and the Pathologic. Ancient authors had presented various views on the innate heat and pathological heat. Some argued that there is only pathological heat while others, like Galen, distinguished two different kinds of heat. Galen was the first medial author who had the clear notion of the relationship between the normal heat and the pathological heat. He conceptualized their difference as the heat conforming to nature (kata phusin) and the heat against nature (para phusin). However, the Peripatetic authors, such as ps-Alexander Aphrodisias, who laid more emphasis on physiology tended to regard pathology in continuation with physiology as Claude Bernard attempted to do it. Therefore, Canguilhem's theoretical scheme turns out to be very useful in analysing the relationship of normal heat and pathological heat as is manifested in ancient Greek physiology.


Coffee Intake and Neurocognitive Performance in HIV/HCV Coinfected Patients (ANRS CO13 HEPAVIH).
Coffee is one of the most consumed beverages worldwide. Previous research has demonstrated its neuroprotective effects in the elderly. People coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) experience an accelerated aging process and cognitive impairment, which significantly impair quality of life and may affect disease-related dimensions such as treatment adherence. This study aimed to analyse the relationship between regular coffee intake and neurocognitive performance (NCP) in HIV-HCV coinfected people. We used data from 139 coinfected patients who participated in both the ANRS CO13 HEPAVIH cohort and the HEPAVIH-Psy cross-sectional survey. Linear regression models adjusting for potential sociodemographic (age, gender, educational level), clinical (liver disease status, ongoing HCV treatment, HIV viral load, major depressive disorder) and socio-behavioural (cannabis use) correlates of NCP were used. Our results showed significant, positive associations between elevated coffee intake (ECI) (three or more cups of coffee per day) and NCP in verbal fluency, psychomotor speed (coding) and executive functioning. ECI might therefore preserve neurocognitive functioning in people living with HIV and HCV.


Functional Metagenomics of a Biostimulated Petroleum-Contaminated Soil Reveals an Extraordinary Diversity of Extradiol Dioxygenases.
A metagenomic library of a petroleum-contaminated soil was constructed in a fosmid vector that allowed heterologous expression of metagenomic DNA. The library, consisting of 6.5 Gb of metagenomic DNA, was screened for extradiol dioxygenase (Edo) activity using catechol and 2,3-dihydroxybiphenyl as the substrates. Fifty-eight independent clones encoding extradiol dioxygenase activity were identified. Forty-one different Edo-encoding genes were identified. The population of Edo genes was not dominated by a particular gene or by highly similar genes; rather, the genes had an even distribution and high diversity. Phylogenetic analyses revealed that most of the genes could not be ascribed to previously defined subfamilies of Edos. Rather, the Edo genes led to the definition of 10 new subfamilies of type I Edos. Phylogenetic analysis of type II enzymes defined 7 families, 2 of which harbored the type II Edos that were found in this work. Particularly striking was the diversity found in family I.3 Edos; 15 out of the 17 sequences assigned to this family belonged to 7 newly defined subfamilies. A strong bias was found that depended on the substrate used for the screening: catechol mainly led to the detection of Edos belonging to the I.2 family, while 2,3-dihydroxybiphenyl led to the detection of most other Edos. Members of the I.2 family showed a clear substrate preference for monocyclic substrates, while those from the I.3 family showed a broader substrate range and high activity toward 2,3-dihydroxybiphenyl. This metagenomic analysis has substantially increased our knowledge of the existing biodiversity of Edos.


[Diphtheria polyneuropathy in adults].
Neurological manifestations of diphtheria have been studied in 32 adults. The main syndromes of peripheral nervous system damage of diphtheria etiology are presented. The pathogenic mechanisms of the development of neurological complications and the efficacy of multiple-modality restorative therapy were considered.


Regulation of oral antigen delivery early in life: Implications for oral tolerance and food allergy.
The increasing incidence of food allergy remains a significant public health concern. Food allergy is partially due to a lack, or loss of tolerance to food allergens. Clinical outcomes surrounding early life practices, such as breastfeeding, antibiotic use and food allergen exposure, indicate the first year of life in children represents a unique time for shaping the immune system to reduce allergic outcomes. Animal models have identified distinctive aspects of when and where dietary antigens are delivered within the intestinal tract to promote oral tolerance prior to weaning. Additionally, animal models have identified contributions from maternal proteins from breast milk and bacterial products from the gut microbiota in regulating dietary antigen exposure and promoting oral tolerance, thus connecting decades of clinical observations on the benefits of breastfeeding, early food allergen introduction and antibiotic avoidance in the first year of life in reducing allergic outcomes. Here, we discuss how exposure to gut luminal antigens, including food allergens, is regulated in early life to generate protective tolerance and the implications of this process for preventing and treating food allergies.


Quantitative trait locus mapping for fire blight resistance in an F2 population of Malus fusca MAL0045 uncovers novel resistance loci.
Several fire blight resistance loci in Malus genotypes map on different linkage groups (LGs) representing chromosomes of the domesticated apple. Prior genetics studies primarily focus on F1 populations. A strong resistance QTL explained up to 66% of phenotypic variance in an F1 progeny derived from crossing the highly resistant wild apple genotype Malus fusca MAL0045 and the highly susceptible apple cultivar 'Idared', was previously mapped on LG10 (Mfu10) of MAL0045. Strains of the causative bacterial pathogen, Erwinia amylovora, notably those that show a single nucleotide polymorphism in the avrRpt2EA effector protein sequence at position 156, e.g. Ea3049, are more virulent and overcome some known fire blight resistance donors and their QTLs. However, MAL0045 is resistant to Ea3049 and Mfu10 is not overcome, but most of the F1 progeny were highly susceptible to this strain. This phenomenon led to the assumption that other putative resistance factors not segregating in the F1 progeny might be present in the genome of MAL0045. Here we crossed F1 progeny together to obtain 135 F2 individuals. Facilitated by genotyping-by-sequencing and phenotypic assessments, we identified and mapped two novel resistance QTLs in these F2 individuals on LGs 4 and 15, which were not identified in the F1. To our knowledge, these are the first resistance QTLs mapped in F2 progeny in Malus. In addition, we report that neither MAL0045 nor Mfu10 is broken-down by a highly aggressive US strain, LA635, after analyses in the original F1 individuals.


Identification of side population cells in mouse primordial germ cells and prenatal testis.
In mammals, the stem cells of spermatogenesis are derived from an embryonic cell population called primordial germ cells (PGCs). Spermatogonial stem cells displaying the "side population" (SP) phenotype have been identified in the immature and adult mouse testis, but noting is known about the expression of the SP phenotype during prenatal development of germ cells. The SP phenotype, defined as the ability of cells to efflux fluorescent dyes such as Hoechst, is common to several stem/progenitor cell types. In the present study, we analyzed and characterized the Hoechst SP via cytofluorimetric analysis of disaggregated gonads at different time points during embryonic development in mice. To directly test the hypothesis that the SP phenotype is a feature of germ cell lineage, experiments were performed on transgenic animals expressing enhanced green fluorescent protein (EGFP) under the control of the Oct4 promoter, to identify early germ cells up to PGCs. We found that prenatal gonads contain a fraction of SP cells at each stage analyzed, and the percentage of cells in the SP fraction decreases as development proceeds. Surprisingly, more than 50% of the PGCs displayed the SP phenotype at 11.5 dpc (days post coitum). The percentage of germ cells with the SP phenotype decreased steadily with development, to less than 1% at 18.5 dpc. Cytofluorimetric analysis along with immunocytochemistry performed on sorted cells indicated that the SP fraction of prenatal gonads, as in the adult testis, was heterogeneous, being composed of both somatic and germ cells. Both cell types expressed the ABC transporters Abcg2, Abcb1a, Abcb1b and Abcc1. These findings provide evidence that the SP phenotype is a common feature of PGCs and identifies a subpopulation of fetal testis cells including prospermatogonia whose differentiation fate remains to be investigated.


Trends in outcomes with adoption of indocyanine green angiography in postmastectomy reconstruction.
Indocyanine green angiography (ICGA) aims to reduce ischaemic complications by supplementing intraoperative perfusion assessment of mastectomy flaps. Learning curves for this technology have not been analysed. We evaluated changes in patient outcomes with increasing case volume after ICGA adoption in postmastectomy reconstruction. Single-institution retrospective analysis of 320 implant-based reconstructions following mastectomy using ICGA from 2015, when it was introduced, to 2021. Cases chronologically divided into tertiles and complications amongst groups evaluated. Trends in ischaemic complications plotted using weighted moving average. CUSUM analysis determined after how many cases plateau was reached. Number of ischaemic complications prior to plateau calculated with AUC analysis. Ischaemic complications decreased over time (Group 1, 15.1%; Group 2, 11.2%; Group 3, 4.7%, P = 0.034). Cases of delayed reconstruction increased over time (Group 1, 6.6%; Group 2, 28%; Group 3, 22.4%; P < 0.001). Our institution reached plateau of 10% ischaemic complications after 160 cases. Mean incidence of ischaemic complications decreased from 16.9% during the first 160 cases to 3.8% after plateau was reached (P < 0.001). Eleven extra breasts (6.9%) experienced ischaemic complications, that may have been avoided if operated by surgeons after the first 160 cases. There was increased tendency towards a conservative approach of delaying reconstruction and decreased rates of ischaemic complications with increasing case volume after ICGA implementation. A significant number of cases were needed to reach plateau of minimal ischaemic complications. This data could encourage development of standardized protocols for this technology to shorten learning curves for improved patient outcomes.


[A new benzoquinone-containing antimetastatic product].
An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) was invented by Hungarian chemists under the trade--name of AVEMAR. The following biological effects of this product were observed. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes of mice. The same treatment shortens the survival time of skin grafts in co-isogenic mouse skin transplantation model, which points to immune-reconstructive effect of MSC. Highly significant anti-metastatic effect of MSC was observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic activity of MSC--besides the immune reconstitution--may also due to the cell-adhesion inhibitory, cell proliferation inhibitory, apoptosis-enhancing and antioxidant effects, which were also observed in our in vitro experiments. Based on the biological effects of MSC--which is non-toxic, according to subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immunedeprivation.


Prolactin in hypertensive men with androgen deficiency: an éminence grise?
Introduction: Considering significant gap of convincing knowledge in the field of cardiovascular effects of prolactin and its role as a stress hormone in men precise investigations of these peculiarities has become necessary. The aim of this study was to find out the relationship of prolactin concentration with parameters of arterial stiffness in hypertensive men with low testosterone. Materials and methods: In total 83 men were examined including 27 apparently healthy individuals as the control group. Physical examination, ABPM, non-invasive evaluation of arterial stiffness and central hemodynamics parameters, answering AMS questionnaire, evaluation of total testosterone and prolactin levels using ELISA were performed. Results: Initially 56 hypertensive patients were divided into 2 groups with regard to their total testosterone level: group 1 included 31 hypogonadal men, group 2 - 25 male patients who had their testosterone concentrations within the normal range. Prolactin levels appeared to be significantly higher in hypertensive men with lower testosterone, they had more unfavorable parameters of arterial stiffness and the difference between 1 and 2 group in terms of central aoSBP and aoPWV became statistically significant. Prolactin concentration was not related with RWTT and index Aix% 75, a significant correlation was observed between prolactin and aoPWV. A strong correlation was found between prolactin concentration and psychological symptoms in AMS. Conclusion: Our study suggests the positive association of prolactin concentration with psychological domain of andropause symptoms and worse parameters of arterial stiffness among hypertensive men with androgen deficiency.


Spatial sparsity based indoor localization in wireless sensor network for assistive healthcare.
Indoor localization is one of the key topics in the area of wireless networks with increasing applications in assistive healthcare, where tracking the position and actions of the patient or elderly are required for medical observation or accident prevention. Most of the common indoor localization methods are based on estimating one or more location-dependent signal parameters like TOA, AOA or RSS. However, some difficulties and challenges caused by the complex scenarios within a closed space significantly limit the applicability of those existing approaches in an indoor assistive environment, such as the well-known multipath effect. In this paper, we develop a new one-stage localization method based on spatial sparsity of the x-y plane. In this method, we directly estimate the location of the emitter without going through the intermediate stage of TOA or signal strength estimation. We evaluate the performance of the proposed method using Monte Carlo simulation. The results show that the proposed method is (i) very accurate even with a small number of sensors and (ii) very effective in addressing the multi-path issues.


Collaboration for rare disease drug discovery research.
Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives.


Combined liver transplantation and off-pump coronary artery bypass grafting: a report of two cases.
Liver transplantation (LT) is the most effective treatment modality in patients with end-stage liver disease (ESLD). With the increased prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD), coupled with a steady increase in the age of transplant population, liver transplant candidates are at increased risk for coronary artery disease (CAD). Improvements in anesthesia, surgical experiences, and increased effectiveness of drugs have facilitated concurrent surgical interventions in transplantation, allowing for orthotopic LT to be performed in elderly patients with a high incidence of coexisting diseases, especially those of the cardiovascular system. In this study, we present two cases of combined off-pump coronary artery bypass surgery and living donor liver transplantation. A 68-year-old male patient with ESLD due to chronic hepatitis C infection and multi-vessel CAD, and a 65-year-old female patient with NAFLD cirrhosis and multi-vessel CAD were referred to our institution for an LT evaluation. We performed combined living donor LT and off-pump coronary artery bypass surgery in both patients. Both the first and second patients were alive with good liver and cardiac function at the 25 and 15 months after surgery, respectively. Combined off-pump coronary artery bypass surgery and living donor LT are an alternative treatment for patients with severe CAD and ESLD. We consider that combined coronary artery bypass graft surgery and LT can be safely performed by experienced anesthesia and surgical teams in selected patients.


[Clinical studies of faropenem in the field of obstetrics and gynecology].
The clinical effect of faropenem was evaluated in 165 ambulatory patients with various infections in the field of obstetrics and gynecology at 10 institutions in Yamagata Prefecture. The results obtained are summarized below. 1. The rate of efficacy, as determined from the clinical effect following 3- to 7-day repeated administration at a dose of 600 mg/day, was 97.9% (46/47) for intrauterine infections, 92.0% (23/25) for adnexitis, 93.8% (15/16) for external genital infections, 88.9% (8/9) for mastitis, 94.0% (63/67) for cystitis, and 100% (1/1) for cervicitis. The overall efficacy rate was estimated to be 94.5% (156/165). 2. The rate of clinical efficacy, as classified by isolate, was high, 95.1% for Gram-positive bacteria, 100% for Gram-negative bacteria, and 100% for anaerobes. As for bacteriological response classified by isolate, the eradication rate was high, 91.4% (74/81) for Gram-positive bacteria, 98.4% (62/63) for Gram-negative bacteria, 89.5% (17/19) for anaerobes, and 93.9% (153/163) in all. 3. No adverse reactions or laboratory abnormalities were observed in any patient. The results presented suggest that faropenem is a highly safe and effective antibiotic for the treatment of obstetric or gynecological infections of various kinds in an ambulatory setting.


Diverse origins of multiple ovarian teratomas in a single individual.
Centromere heteromorphisms and enzyme markers were examined in cells cultured from seven benign ovarian teratomas arising in a single patient. Three of the teratomas were homozygous for all eight enzyme and centromere markers found to be heterozygous in the host. The other four tumors were heterozygous at the centromeres of chromosomes 1, 16, 17, and 18, as in the patient, but were homozygous for at least one of the enzyme markers. The linkage phases of the heterozygous enzyme markers phosphogluconate dehydrogenase and phosphoglucomutase 1 and the chromosome 1 centromere heteromorphism were established for the patient and for three of the heterozygous teratomas by analysis of Chinese hamster-human somatic cell hybrids. The linkage phase of these markers in homozygous and heterozygous tumors was in every case different from that in the host. The finding of heterozygous centromeres in ovarian teratomas excludes suppression of meiosis II as a mechanism for their origin, and we suggest rather that they arise by failure of meiosis I. The linkage phases in the fully homozygous tumors are most readily derived from that in the patient, we suggest, by endoreduplication of a haploid gamete. The varied origin of ovarian teratomas has important implications for the suitability of such material for centromere-based gene mapping.


High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration.
Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.


Cervical Excision Procedure: A Trend of Decreasing Length of Excision Observed in a Multicenter Survey.
The aim of the present study was to observe the trend of length of cone excisions in women treated with cervical excision procedure in five institutions of Central and Northern Italy. A multicenter retrospective cohort study was conducted on women who underwent a cervical excision procedure between January 2006 and December 2014. The pertinent clinical, histopathological, and sociodemographic characteristics of each woman were collected. In particular, the length of the cone specimen was evaluated and all of the factors that potentially influenced the length of excision were considered. A total of 1482 women who underwent a cervical excision procedure from January 2006 to December 2014 were included. A mean (SD) cone length of 12.9 (5.0) mm was reported, and mostly, a significant decrease during the whole study period emerged. Age (r = 0.1, p = .007) and preoperative diagnosis of glandular lesions (r = 0.1, p < .001) were significantly related to the length of cone excision on multivariate analysis. Compared with the carbon dioxide laser excisional procedure, loop electrosurgical excision procedure showed a negative correlation with the length of excision (r = -0.2, p < .001). During the study period, a significant decrease in the length of cone excision was observed, probably reflecting the gynecologists' acquired awareness of the increased risk of adverse obstetric outcomes for future pregnancies in the case of wide cone excisions.


Accelerated telomere shortening and telomerase activation in Fanconi's anaemia.
Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia. FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P<0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P<0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls. A model for the FA disease process is proposed.


Mutations in C2ORF71 cause autosomal-recessive retinitis pigmentosa.
With a worldwide prevalence of 1 in 4,000, retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. More than 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in one Dutch and one Israeli family affected by arRP. The families were found to share a 5.9 Mb homozygous region on chromosome 2p23.1-p23.3. A missense variant in one of the genes residing in this interval, C2ORF71, has recently been reported to be associated with RP. C2ORF71, encoding a putative protein of 1,288 amino acids, was found to be specifically expressed in human retina. Furthermore, RT-PCR analysis revealed that in the mouse eye, C2orf71 is expressed as early as embryonic day 14. Mutation analysis detected a 1 bp deletion (c.946 del; p.Asn237MetfsX5) segregating with RP in the Dutch family, whereas a nonsense mutation (c.556C > T; p.Gln186X) was identified in the Israeli family. Microsatellite-marker analysis in additional Israeli families revealed cosegregation of a C2ORF71-linked haplotype in one other family, in which a 13 bp deletion (c.2756_2768 del; p.Lys919ThrfsX) was identified. Clinically, patients with mutations in C2ORF71 show signs of typical RP; these signs include poor night vision and peripheral field loss, typical retinal bone-spicule-type pigment deposits, pale appearance of the optic disk, and markedly reduced or completely extinguished electroretinograms. In conclusion, truncating mutations in C2ORF71 were identified in three unrelated families, thereby confirming the involvement of this gene in the etiology of arRP.


[Effect of a specific benzodiazepine antagonist RO 15-1788 on phenazepam-induced inhibition of the evoked potentials in hippocampal neurons].
It is suggested that the inhibitory action of phenazepam on the evoked potential (EP) in the CA1 area of the hippocamp in response to the stimulation of Schaffer's collaterals is mediated by phenazepam interaction with a specific benzodiazepine receptor (BR). Experiments were made to study the action of a specific benzodiazepine antagonist RO15-1788 on the phenazepam-induced inhibition in the hippocamp. After RO15-1788 administration (4 microM) the phenazepam-induced (2 microM) inhibition of evoked activity of hippocampal neurons was attenuated. The inhibition provoked by hexenal (2 microM) was not affected by antagonist administration. It is concluded that phenazepam effect on the EP is related to the interaction with BR. In most cases, RO15-1788 (4 microM) had an insignificant inhibitory effect on the EP. However, in individual experiments, it produced an opposite action, i. e. raised the evoked activity of neurons.


Involvement of sigma 1 receptors in methamphetamine-induced behavioral sensitization in rats.
MS-377 is a novel selective sigma(1) ligand, currently being developed for the treatment of schizophrenia. In the present study, we examined the effects of MS-377 on behavioral sensitization induced by subchronic treatment with methamphetamine. MS-377 was administered at doses of 1.875-15 mg/kg (p.o.), to rats, and methamphetamine was administered at doses of 2 mg/kg (i.p.), 60 min later once daily for 10 days. Repeated administration of methamphetamine caused enhanced stereotypy, and behavioral sensitization was developed. MS-377 did not affect the acute effects of methamphetamine. However, co-administration of MS-377 attenuated the development of methamphetamine-induced behavioral sensitization in a dose-dependent manner. These results suggested that sigma(1) receptors play an important role in the developmental period of behavioral sensitization induced by methamphetamine in rats.


Relationship between falls, knee osteoarthritis, and health-related quality of life: data from the Osteoarthritis Initiative study.
The purpose of this study was to examine the relationship between self-reported falls, doctor-diagnosed knee osteoarthritis (OA), and health-related quality of life (HRQoL). We hypothesized that falls and knee OA would be associated with poor HRQoL on both disease-specific and generic measures. This cross-sectional study used data from the publicly available Osteoarthritis Initiative data sets. A total of 4,484 subjects aged 45-79 years at baseline were divided into three subpopulations: those who had neither a history of falling nor doctor-diagnosed knee OA; those who had either a self-reported history of falling or doctor-diagnosed knee OA; and those who had both a self-reported history of falling and doctor-diagnosed knee OA. HRQoL was assessed using both disease-specific and generic measures. Multiple regression analyses were used to examine the relationship between self-reported falls, doctor-diagnosed knee OA, and HRQoL assessed using the Knee Injury and Osteoarthritis Outcome Score-Quality of Life (KOOS-QoL) subscale and two Short Form-12 (SF-12) summary scales. The models were adjusted for participant sociodemographic, lifestyle, and clinical characteristics. Falls and knee OA were significantly associated with lower scores on the KOOS-QoL (β= -34.4, standard error 2.27, P≤0.0001) and on the physical component scale of the SF-12 (β= -9.44, standard error 0.90, P<0.0001). No significant relationship was found with the mental component scale score when adjusted for sociodemographic, lifestyle, and clinical characteristics. When compared with those having neither a self-reported history of falling nor doctor-diagnosed knee OA and those with a self-reported history of falling or doctor-diagnosed knee OA, persons with both conditions (falls and knee OA) had significantly lower KOOS-QoL and physical component scale scores after adjusting for sociodemographic, lifestyle, and clinical characteristics. Future research should assess potential mediating factors in an effort to improve HRQoL in persons with knee OA who are at high risk of falling.


[Esthetic aspects of crowns and bridges].
By means of discussing several guiding principles a protocol is suggested and treatment procedures are outlined which will result in optimum esthetics in the fabrication of crowns and bridges. Some important considerations in restoring an occlusion with porcelain are discussed.


The power of negative mood in predicting posttraumatic stress disorder and alcohol abuse comorbidity.
Individuals with posttraumatic stress disorder (PTSD) show a high risk of developing substance use disorders (SUD). Many studies have shown that PTSD often precedes SUD, and some studies have been able to identify factors that might predict which individuals might develop subsequent SUD. Attempts to treat PTSD and SUD comorbidity have proven difficult, but new methods for simultaneous treatment have shown promise for treating PTSD. The ability to identify factors that predict PTSD/SUD comorbidity and the advent of new combined treatment methods warrant investigation of how differences in specific types of PTSD symptoms individuals experience might predict who will go on to develop SUD symptoms and thus benefit from new combined treatments. In this study, we analyzed which clusters of PTSD symptoms predicted whether individuals with PTSD met criteria for alcohol use disorder. Analyses revealed that frequency and intensity of negative alterations in cognition and mood predicted SUD, but re-experiencing symptoms, hyperarousal, and avoidance did not. Our results indicate that those who experience negative alterations in cognition and mood may be at increased risk of developing SUD, and that we may be able to predict which individuals in clinical settings will be strong candidates for new combined PTSD/SUD treatments. Further considerations for our results and for future directions are also discussed. (PsycINFO Database Record


Open lung biopsy in the diagnosis of Pneumocystis carinii pneumonia.
Lung biopsy remains the essential cornerstone in the diagnosis of pneumocystis pneumonia. Whatever technique can establish this diagnosis safely and early in order to get treatment started quickly should be used. Open lung biopsy remains a candidate for the diagnostic method of choice because if offers some advantages over percutaneous needle biopsy. There is a greater supply of competent thoracic surgeons in most hospitals than of physicians who are proficient with needle biopsy. The direct vision afforded by thoracotomy enables selective biopsy of grossly involved lung that can be appreciated by direct vision and palpation; needle biopsy is random and blind in its sampling. A more generous tissue specimen can be obtained for pathologic examination; the pathologic diagnosis of an "unsatisfactory specimen" is unlikely to result from open biopsy. Open lung biopsy achieves a higher diagnostic yield earlier in the pneumonitis when pneumocystis pneumonia is confined to the perihilar regions inaccessible to percutaneous needle biopsy. Better control of hemostasis is achieved by direct vision and ligature in a group of patients characteristically at high risk for bleeding tendencies, and pneumothorax is controlled in open biopsy; thoracostomy prevents the later, uncontroled collapse of the lung when the patient returns to the ward where there may be some diagnostic and therapeutic delay in the treatment of pneumothorax in a patient who can tolerate little further respiratory compromise.


Where's the impairment: an examination of factors that impact sustained attention following a stressor.
The impact of stress on cognitive functioning has been examined across multiple domains. However, few studies investigate both physical and psychological factors that impact cognitive performance. The current study examined the impact of a physical and psychosocial stressor on sustained attention and identified factors related to sustained attention, including cortisol, salivary alpha amylase (sAA) and mind wandering. A total of 53 participants completed either the socially evaluated cold pressor task or a control task followed by the sustained attention to response task with mind wandering measures. Participants also provided saliva samples following the attention task. Results indicate the stressor task did not impact mind wandering or sustained attention but increased cortisol and sAA. Mind wandering was negatively related to sustained attention and mediated the relationship between cortisol and sustained attention. The findings highlight the importance of examining multiple sources of stress-related cognitive impairments.


Categorizing and individuating others: the neural substrates of person perception.
People are remarkably adroit at understanding other social agents. Quite how these information-processing abilities are realized, however, remains open to debate and empirical scrutiny. In particular, little is known about basic aspects of person perception, such as the operations that support people's ability to categorize (i. e., assign persons to groups) and individuate (i. e., discriminate among group members) others. In an attempt to rectify this situation, the current research focused on the initial perceptual stages of person construal and considered: (i) hemispheric differences in the efficiency of categorization and individuation; and (ii) the neural activity that supports these social-cognitive operations. Noting the greater role played by configural processing in individuation than categorization, it was expected that performance on the former task would be enhanced when stimuli (i. e., faces) were presented to the right rather than to the left cerebral hemisphere. The results of two experiments (Experiment 1--healthy individuals; Experiment 2--split-brain patient) confirmed this prediction. Extending these findings, a final neuroimaging investigation revealed that individuation is accompanied by neural activity in regions of the temporal and prefrontal cortices, especially in the right hemisphere. We consider the implications of these findings for contemporary treatments of person perception.


[The role of interleukin-6 in rheumatoid arthritis].
Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infections and malignancy remain a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. Tocilizumab has been assessed in a number of studies in recent years, mainly in patients with rheumatoid arthritis. Data from randomized controlled clinical trials demonstrate the effectiveness of tocilizumab in improving the signs and symptoms of RA. In addition, it appears that such inhibition of IL-6 can have positive effects on functional status, an important outcome for RA patients. Finally, data suggest that treatment with this agent may also inhibit the progression of disease as assessed radiographically. Data from recent studies will help to refine the ultimate use of this novel approach to treatment, and help clinicians to optimize therapy using this approach.


The stringent response of Mycobacterium tuberculosis is required for long-term survival.
The stringent response utilizes hyperphosphorylated guanine [(p)ppGpp] as a signaling molecule to control bacterial gene expression involved in long-term survival under starvation conditions. In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium tuberculosis contains a single homolog of these proteins (Rel(Mtb)) and responds to nutrient starvation by producing (p)ppGpp. A rel(Mtb) knockout strain was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The rel(Mtb) mutant displayed a significantly slower aerobic growth rate than the wild type in synthetic liquid media, whether rich or minimal. The growth rate of the wild type was equivalent to that of the mutant when citrate or phospholipid was employed as the sole carbon source. These two organisms also showed identical growth rates within a human macrophage-like cell line. These results suggest that the in vivo carbon source does not represent a stressful condition for the bacilli, since it appears to be utilized in a similar Rel(Mtb)-independent manner. In vitro growth in liquid media represents a condition that benefits from Rel(Mtb)-mediated adaptation. Long-term survival of the rel(Mtb) mutant during in vitro starvation or nutrient run out in normal media was significantly impaired compared to that in the wild type. In addition, the mutant was significantly less able to survive extended anaerobic incubation than the wild-type virulent organism. Thus, the Rel(Mtb) protein is required for long-term survival of pathogenic mycobacteria under starvation conditions.


Alternative femoral endarterectomies: technical aspects and short-term results.
Femoral endarterectomies are often performed by means of longitudinal arteriotomies with patching. Autologous and synthetic patches can be used. Synthetic patches in the groin may expose patients to infection. We present two alternative techniques for the treatment of femoral atherosclerotic lesions. The alternative endarterectomies (AE) included eversion (EE) and semi-closed endarterectomies (SCE). An EE with an oblique transection of a femoral bifurcation (FB) was used for lesions extending to the FB. The artery was reconstructed in an end-to-end manner. An SCE with a bovine pericardium patch (BPP) was used for lesions extending further. An arteriotomy was made from the superficial femoral artery just past the level of the profunda femoris opening (PFO). The plaque was cut proximally to the PFO, dissected circularly with a Swedish-type dissector, and then removed with Crile forceps. The distally remaining plaque was endarterectomized in a conventional manner. The arteriotomy was closed with a BPP. A total of 21 AEs were performed, 8 of which were accomplished in a hybrid setting. There were no periprocedural complications. One distal embolization after a balloon dilatation was registered during the early postoperative period. The median follow-up was 3 months. There were no deep wound infections, pseudoaneurysms, amputations, or deaths. A total of 20/21 patients reported complete symptom relief, with one requiring an additional femoro-popliteal bypass grafting owing to poor outflow. The primary patency rate of the endarterectomized segments was 100%. Alternative methods of local endarterectomy can extend the available range of procedures for patients suffering from chronic lower-limb ischemia. According to our results, these endarterectomy techniques are safe and could be taken into consideration, as they provide some advantages over conventional methods.


Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.
Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.


Janus kinase 2 inhibition by Licochalcone B suppresses esophageal squamous cell carcinoma growth.
Esophageal cancer (EC) is one of the leading causes to cancer death in the worldwide and major population of EC is esophageal squamous cell carcinoma (ESCC). Still, ESCC-targeted therapy has not been covered yet. In the present study we have identified that Licochalcone B (Lico B) inhibited the ESCC growth by directly blocking the Janus kinase (JAK) 2 activity and its downstream signaling pathway. Lico B suppressed KYSE450 and KYSE510 ESCC cell growth, arrested cell cycle at G2/M phase and induced apoptosis. Direct target of Lico B was identified by kinase assay and verified with in vitro and ex vivo binding. Computational docking model predicted for Lico B interaction to ATP-binding pocket of JAK2. Furthermore, treatment of JAK2 clinical medicine AZD1480 to ESCC cells showed similar tendency with Lico B. Thus, JAK2 downstream signaling proteins phosphorylation of STAT3 at Y705 and S727 as well as STAT3 target protein Mcl-1 expression was decreased with treatment of Lico B. Our results suggest that Lico B inhibits ESCC cell growth, arrests cell cycle and induces apoptosis, revealing the underlying mechanism involved in JAK2/STAT3 signaling pathways after Lico B treatment. It might provide potential role of Lico B in the treatment of ESCC.


Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway.
Here we identify a new gene, dark, which encodes a Drosophila homologue of mammalian Apaf-1 and Caenorhabditis elegans CED-4, cell-death proteins. Like Apaf-1, but in contrast to CED-4, Dark contains a carboxy-terminal WD-repeat domain necessary for interactions with the mitochondrial protein cytochrome c. Dark selectively associates with another protein involved in apoptosis, the fly apical caspase, Dredd. Dark-induced cell killing is suppressed by caspase-inhibitory peptides and by a dominant-negative mutant Dredd protein, and enhanced by removal of the WD domain. Loss-of-function mutations in dark attenuate programmed cell deaths during development, causing hyperplasia of the central nervous system, and other abnormalities including ectopic melanotic tumours and defective wings. Moreover, ectopic cell killing by the Drosophila cell-death activators, Reaper, Grim and Hid, is substantially suppressed in dark mutants. These findings establish dark as an important apoptosis effector in Drosophila and raise profound evolutionary considerations concerning the relationship between mitochondrial components and the apoptosis-promoting machinery.


The New Clinicopathologic and Molecular Findings in Myeloid Neoplasms With inv(3)(q21q26)/t(3;3)(q21;q26.2).
- Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast crisis of myeloproliferative neoplasms. Recent advances on myeloid neoplasms with inv(3)/t(3;3) with regard to clinicopathologic features and novel molecular or genomic findings warrant a comprehensive review on this topic. - To review the clinicopathologic features and molecular as well as genomic alterations in myeloid neoplasms with inv(3)/t(3;3). - The data came from published articles in English-language literature. - At the clinicopathologic front, recent studies on MDS with inv(3)/t(3;3) have highlighted their overlapping clinicopathologic features with and similar overall survival to that of inv(3)/t(3;3)-harboring AML regardless of the percentage of myeloid blasts. On the molecular front, AML and MDS with inv(3)/t(3;3) exhibit gene mutations, which affect the RAS/receptor tyrosine kinase pathway. Furthermore, functional genomic studies using genomic editing and genome engineering have shown that the reallocation of the GATA2 distal hematopoietic enhancer to the proximity of the promoter of ectopic virus integration site 1 (EVI1) without the formation of a new oncogenic fusion transcript is the molecular mechanism underlying these inv(3)/t(3;3) myeloid neoplasms. Although the AML and MDS with inv(3)/t(3;3) are listed as a separate category of myeloid malignancies in the 2008 World Health Organization classification, the overlapping clinicopathologic features, similar overall survival, and identical patterns at the molecular and genomic levels between AML and MDS patients with inv(3)/t(3;3) may collectively favor a unification of AML and MDS with inv(3)/t(3;3) as AML or myeloid neoplasms with inv(3)/t(3;3) regardless of the blast count.


Shot-noise-limited control-loop noise in an interferometer with multiple degrees of freedom.
Precise measurements, such as those made with interferometric gravitational-wave detectors, require the measurement device to be properly controlled so that the sensitivity can be as high as possible. Mirrors in the interferometer are to be located at specific operation points to isolate laser noise and to accumulate the signal in resonant cavities. On the other hand, rigid control of an auxiliary degree of freedom may result in imposing sensing noise of the control on the target object as excess force noise. Evaluation of this so-called loop noise is important in order to design a decent control scheme of the measurement device. In this paper, we show the method to calculate the level of loop noise, which has been recently implemented in simulation tools that are broadly used for designing gravitational-wave detectors.


Gastroduodenal outlet obstruction and palliative self-expandable metal stenting: a dual-centre experience.
Background. Self-expandable metal stents (SEMs) are increasingly being utilised instead of invasive surgery for the palliation of patients with malignant gastroduodenal outlet obstruction. Aim. To review two tertiary centres' experience with placement of SEMs and clinical outcomes. Methods. Retrospective analysis of prospectively collected data over 12 years. Results. Ninety-four patients (mean age, 68; range 28-93 years) underwent enteral stenting during this period. The primary tumour was gastric adenocarcinoma in 27 (29%) patients, pancreatic adenocarcinoma in 45 (48%), primary duodenal adenocarcinoma in 8 (9%), and cholangiocarcinoma and other metastatic cancers in 14 (16%). A stent was successfully deployed in 95% of cases. There was an improvement in gastric outlet obstruction score (GOOS) in 84 (90%) of patients with the ability to tolerate an enteral diet. Median survival was 4.25 months (range 0-49) without any significant differences between types of primary malignancy. Mean hospital stay was 3 days (range 1-20). Reintervention rate for stent related complications was 5%. Conclusion. The successful deployment of enteral stents achieves excellent palliation often resulting in the prompt reintroduction of enteral diet and early hospital discharge with minimal complications and reintervention.


Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage.
Vasoactive drugs are recommended to be started as soon as possible in suspected variceal bleeding, even before diagnostic endoscopy. However, it is still unclear whether the therapeutic efficacies of the various vasoactive drugs used are comparable. The aim of this prospective, multicenter, randomized, noninferiority trial was to characterize the effects of terlipressin, somatostatin, and octreotide when they are initiated before endoscopic treatment in patients with acute variceal bleeding. Patients with liver cirrhosis and significant upper gastrointestinal bleeding were randomly assigned to receive early administration of terlipressin, somatostatin, or octreotide, followed by endoscopic treatment. Patients with nonvariceal bleeding were excluded after endoscopy. The primary endpoint was 5-day treatment success, defined as control of bleeding without rescue treatment, rebleeding, or mortality, with a noninferiority margin of 0.1. In total, 780 patients with variceal bleeding were enrolled: 261 in the terlipressin group; 259 in the somatostatin group; and 260 in the octreotide group. At the time of initial endoscopy, active bleeding was noted in 43.7%, 44.4%, and 43.5% of these patients, respectively (P=0.748), and treatment success was achieved by day 5 in 86.2%, 83.4%, and 83.8% (P=0.636), with similar rates of control of bleeding without rescue treatment (89.7%, 87.6%, and 88.1%; P=0.752), rebleeding (3.4%, 4.8%, and 4.4%; P=0.739), or mortality (8.0%, 8.9%, and 8.8%; P=0.929). The absolute values of the lower bound of confidence intervals for terlipressin versus somatostatin, terlilpressin versus octreotide, and octreotide versus somatostatin were 0.095, 0.090, and 0.065, respectively. Hemostatic effects and safety did not differ significantly between terlipressin, somatostatin, and octreotide as adjuvants to endoscopic treatment in patients with acute gastroesophageal variceal bleeding.


[Immunohistochemical comparison between GCDFP-15 and estrogen and progesterone receptors in the diagnosis of metastatic carcinoma of the breast].
In the workup of tumors of unknown primary origin in women, a frequent consideration is breast carcinoma, because it is common and may initially present as metastasis. Describe and compare the immunohistochemical profile of hormonal receptors (estrogen receptor and progesterone receptor) and GCDFP-15 in lymph node metastatic breast carcinoma according the histological grade. Retrospective study analyzing 30 patients with identified primary breast cancer and lymph node metastasis. The cases were divided in three groups: grade I (well differentiated), grade II (moderately differentiated) and grade III (poorly differentiated). We used three antibodies (estrogen receptor, progesterone receptor and GCDFP-15) in the lymph node and compare the expression according the histological grade. In metastatic lymph node from grade I breast carcinomas the hormone receptors were 100% positive and GCDFP-15 was 80% positive. In grade II, estrogen receptor and progesterone receptor were positive in 90 and 40% respectively, and GCDFP-15 was positive in 80%. In grade III, estrogen receptor and progesterone receptor were positive in 30 and 50% respectively, and GCDFP-15 in 60%. The immunohistochemical expression of hormonal receptors and GCDFP-15 in metastatic breast carcinoma is related to histological grade in the breast.


Do clinical outcomes correlate with bone density after open reduction and internal fixation of tibial plateau fractures.
The operative management of tibial plateau fractures in elderly patients has historically led to inconsistent results, and these clinical outcomes were thought to be associated with poor bone quality often in elderly patients. The goal of this study was to investigate the relationship between bone density and subjective clinical outcome scores after open reduction and internal fixation of tibial plateau fractures. This is a retrospective cohort study from a single-surgeon conducted at an Academic, Level 1 Trauma Center. A preoperative computed tomography (CT) scan was obtained for all patients. Bone density of the distal femur was quantified with Hounsfield units (HU) as measured on axial CT scans. Inter-rater reliability of HU measurements was assessed using interclass correlation coefficients. Regression models controlling for age were used to identify relationships between bone density (HU) and the following variables: articular subsidence and 1-year subjective clinical outcomes scores [Knee Outcome Survey Activities of Daily Living Scale (KOS-ADLS), and Short-Form-36 (SF-36) physical and mental component scores (PCS, MCS)]. Sixty-one patients with a mean age of 59.3 years (range 27-85 years) and a minimum of 12 months of clinical follow-up were included in the study. The majority of the fractures (32 of 61) were classified as Schatzker II tibial plateau fractures, and there were 13 Schatzker V fractures, 11 Schatzker VI fractures, 2 Schatzker IV fractures and 1 Schatzker 1 fracture. HU measurements demonstrated an almost perfect inter-observer reliability (ICC = 0.97). Age was negatively correlated with HU measurements (r = -0.51, p < 0.001), and using a geriatric cut-off of 65 years of age, the geriatric group had a lower mean HU compared to the non-geriatric group (78.2 versus 114.8, p = 0.018). There was no significant relationship between bone quality, as assessed by distal femoral HU, and any subjective clinical outcome score. Inferior bone mineral density alone does not appear to affect clinical outcomes 1 year postoperatively when bone grafting is used to restore osseous voids. Poor bone quality should not be used as an indication for non-operative management of tibial plateau fractures.


Molecular epidemiology of tuberculosis in Cambodian children.
SUMMARY We analysed Mycobacterium tuberculosis strains from children, hospitalized from January 2004 to July 2008 in the largest paediatric hospital complex in Cambodia. Specimens were tested for drug susceptibility and genotypes. From the 260 children, 161 strains were available. The East African-Indian genotype family was the most common (59.0%), increasing in frequency with distance from the Phnom Penh area, while the frequency of the Beijing genotype family strains decreased. The drug resistance pattern showed a similar geographical gradient: lowest in the northwest (4.6%), intermediate in the central (17.1%), and highest in the southeastern (30.8%) parts of the country. Three children (1.9%) had multidrug-resistant tuberculosis. The Beijing genotype and streptomycin resistance were significantly associated (P < 0.001). As tuberculosis in children reflects recent transmission patterns in the community, multidrug resistance levels inform about the current quality of the tuberculosis programme.


[Functional state of the left ventricle of the heart in cardiocytotoxic shock].
Changes in the cardiodynamics and the contractile myocardium function under experimental shock caused by intracoronary injection of the anticardial cytotoxic serum were studied on 20 anesthetized dogs. Along with the symptoms of disturbance of the left ventricle function (a decrease of the systolic index, stroke work index of the left ventricle, rate of the intraventricular pressure rise, indices of myocardial contractility, ejection fraction) a decrease of the end-diastolic volume and pressure in the left ventricle was observed. These data show that disturbances in the cardiodynamics were cause not only by the cytotoxic heart damage, but also by derangement of the blood flow to the left heart.


Dual-Acting Small-Molecule Inhibitors Targeting Mycobacterial DNA Replication.
Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium and a causative agent of tuberculosis (TB), a disease that kills more than 1.5 million people worldwide annually. One of the main reasons for this high mortality rate is the evolution of new Mtb strains that are resistant to available antibiotics. Therefore, new therapeutics for TB are in constant demand. Here, we report the development of small-molecule inhibitors that target two DNA replication enzymes of Mtb, namely DnaG primase and DNA gyrase (Gyr), which share a conserved TOPRIM fold near the inhibitors' binding site. The molecules were developed on the basis of previously reported inhibitors for T7 DNA primase that bind near the TOPRIM fold. To improve the physicochemical properties of the molecules as well as their inhibitory effect on primase and gyrase, 49 novel compounds have been synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for both Mtb DnaG and Gyr that also showed inhibitory activity toward the fast-growing non-pathogenic model Mycobacterium smegmatis (Msmg).


Review of prospects and challenges of eye tracking in volumetric imaging.
While eye tracking research in conventional radiography has flourished over the past decades, the number of eye tracking studies that looked at multislice images lags behind. A possible reason for the lack of studies in this area might be that the eye tracking methodology used in the context of conventional radiography cannot be applied one-on-one to volumetric imaging material. Challenges associated with eye tracking in volumetric imaging are particularly associated with the selection of stimulus material, the detection of events in the eye tracking data, the calculation of meaningful eye tracking parameters, and the reporting of abnormalities. However, all of these challenges can be addressed in the design of the experiment. If this is done, eye tracking studies using volumetric imaging material offer almost unlimited opportunity for perception research and are highly relevant as the number of volumetric images that are acquired and interpreted is rising.


DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France.
To investigate the association of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), 55 patients with PMR without giant cell arteritis, 203 patients with RA and 230 controls, all from the European population of Marseille, were HLA-DRB1 genotyped by PCR-SSO. HLA-DRB1*01 was significantly increased in both the PMR and RA groups compared to controls (35% versus 17%, P(c) < 0.05, and 41% versus 17%, P(c) < 0.001, respectively). HLA-DRB1*04 was significantly increased in the RA group compared to controls (48% versus 23%, P(c) < 0.001) but not in the PMR group. HLA-DRB1*04 subtype frequencies were significantly different between PMR patients and RA patients. Shared epitope-positive HLA-DRB1*04 alleles (DRB1*0401, 0404, 0405, 0408) were significantly overrepresented in RA patients compared to PMR patients and shared epitope-negative HLA-DRB1*04 alleles were overrepresented in PMR patients compared to RA patients. In conclusion, in the Mediterranean population studied, HLA-DRB1*01 is associated with RA and PMR whereas HLA-DRB1*04 is associated with RA only.


Developing hypnotic analogues of clinical delusions: mirrored-self misidentification.
Despite current research interest in delusional beliefs, there are no viable models for studying delusions in the laboratory. However, hypnosis offers a technique for creating transient delusions that are resistant to challenge. The aim of this study was to develop an hypnotic analogue of one important delusion, mirrored-self misidentification. Twelve high hypnotisable participants received an hypnotic suggestion to see either a stranger in the mirror, a mirror as a window, or a mirror as a window with a view to a stranger. Participants' deluded beliefs were challenged, and following hypnosis, Sheehan and McConkey's (1982) Experiential Analysis Technique was used to explore participants' phenomenological experience of the delusion. The majority of participants did not recognise their reflection in the mirror, described the person in the mirror as having different physical characteristics to themselves, and maintained their delusion when challenged. The hypnotic suggestion created a credible, compelling delusion with features strikingly similar to clinical cases of mirrored-self misidentification. Our findings suggest that Factor 2 within Langdon and Coltheart's (2000) two-factor framework may involve a lowering of the criteria used to accept or reject delusional hypotheses.


The Neural Correlates of Narcissism: Is There a Connection with Desire for Fame and Celebrity Worship?
(1) Objective: Narcissism is characterized by emotional regulation deficits, a lack of empathy for others, and extreme self-focus. Narcissism has also been linked to an increased desire for fame and celebrity worship. Here, the neuroscience underlying narcissism is examined in order to determine what regions and networks of the brain are altered when non-narcissistic individuals are compared to participants with both grandiose and vulnerable narcissism. (2) Methods: The behavioral relationships between grandiose narcissism and desire for fame and vulnerable narcissism and celebrity worship are explored, along with a possible relationship at the neural level between these constructs. In this paper, we review research demonstrating that increased levels of grandiose narcissism are associated with an increase in obsession with fame, while vulnerable narcissism is associated with celebrity worship. (3) Results: Based on current data, the frontal regions underlie narcissism and also likely underlie celebrity worship and desire for fame. This tenuous conclusion is based on a limited number of studies. (4) Conclusions: The brain areas associated with grandiose narcissism may be associated with an intense desire for fame as well, while brain regions associated with vulnerable narcissism may be similar in celebrity worshipers. Future research studies on the brain that are specifically designed to test these relationships at a neurological level are needed.


Effects of furazlocillin, a beta-lactam antibiotic which binds selectively to penicillin-binding protein 3, on Escherichia coli mutants deficient in other penicillin-binding proteins.
Furazlocillin binds selectively to penicillin-binding protein 3 (PBP-3), prevents septation of Escherichia coli, and allows the cells to form long filaments without lysis. The effect of furazlocillin on the morphology, autolysis, and murein synthesis of E. coli mutants deficient in either PBP-1A, PBP-1Bs, or PBP-2 was studied. The results reveal that PBP-1A and PBP-1Bs functions are not equivalent since furazlocillin affects the morphology, autolysis, and murein synthesis of PBP1A- mutants quite differently from that of PBP-1Bs mutants. Different "PBP-2-" mutants were found to respond to furazlocillin in dramatically different ways: strain LS-1 cells formed elongated rods with a central bulge which eventually lysed, whereas SP6 cells formed stable "barbells" in which the two daughter cells were well separated but remained connected by a thick central region.


Comparison of in vivo and in situ detection of hippocampal metabolites in mouse brain using 1 H-MRS.
The study of cerebral metabolites relies heavily on detection methods and sample preparation. Animal experiments in vivo require anesthetic agents that can alter brain metabolism, whereas ex vivo experiments demand appropriate fixation methods to preserve the tissue from rapid postmortem degradation. In this study, the metabolic profiles of mouse hippocampi using proton magnetic resonance spectroscopy (1 H-MRS) were compared in vivo and in situ with or without focused beam microwave irradiation (FBMI) fixation. Ten major brain metabolites, including lactate (Lac), N-acetylaspartate (NAA), total choline (tCho), myo-inositol (mIns), glutamine (Gln), glutamate (Glu), aminobutyric acid (GABA), glutathione (GSH), total creatine (tCr) and taurine (Tau), were analyzed using LCModel. After FBMI fixation, the concentrations of Lac, tCho and mIns were comparable with those obtained in vivo under isoflurane, whereas other metabolites were significantly lower. Except for a decrease in NAA and an increase in Tau, all the other metabolites remained stable over 41 hours in FBMI-fixed brains. Without FBMI, the concentrations of mIns (before 2 hours), tCho and GABA were close to those measured in vivo. However, higher Lac (P < .01) and lower NAA, Gln, Glu, GSH, tCr and Tau were observed (P < .01). NAA, Gln, Glu, GSH, tCr and Tau exhibited good temporal stability for at least 20 hours in the unfixed brain, whereas a linear increase of tCho, mIns and GABA was observed. Possible mechanisms of postmortem degradation are discussed. Our results indicate that a proper fixation method is required for in situ detection depending on the targeted metabolites of specific interests in the brain.


The predictive accuracy of the postvagotomy insulin test: A new interpretation.
Insulin-stimulated gastric secretion alone, without reference to basal secretion, has been examined in 45 male patients with duodenal ulcer in whom no gastric operation had been performed and in 124 patients following vagotomy for duodenal ulcer. Gastric juice was examined in terms not only of conventional indices, observed volume, titratable acidity and acid output, but also Vg, the volume corrected for pyloric loss and duodenal reflux. The range of secretion of the unoperated subjects was established in terms of peak and half-totwo-hour values for all indices. By reference to these ranges, secretion of postvagotomy subjects could be divided into two groups: (a) those with secretion within the preperative range, and (b) those with secretion less than the lower limit of the preoperative range. The best discrimination was given by Vg; those within the preoperative range (peak Vg in excess of 140 ml/hour and Vg half to two hours in excess of 105 ml/hour) had a 50% liability to recurrent ulcer, while those below the preoperative range had a zero liability to recurrent ulcer. Of the conventional indices acid output gave the best discrimination, which was almost as good as Vg. Peak acid output of 8 mmol/hour or acid output one half to two hours of 525 mmol/hour discriminated into two groups, with a 50% or zero liability to recurrent ulcer. Titratable acidity (Hollander's index of secretion), being highly susceptible to reflux, was not an adequate discriminant.


Influence of oral application of mycophenolic acid on the clinical health status of sheep.
Mycophenolic acid (MPA) is an immunosuppressive metabolite of various fungi, especially of Penicillium roqueforti, and can be found in considerable amounts in mouldy silage. The aim of this study was to investigate the effect of MPA on sheep. Thirty-six castrated male sheep aged 7 +/- 1 months were randomly divided into four groups of nine sheep. Different dosages of MPA were administered orally to all groups (group 1/2/3/4: 0/10/70/300 mg MPA/animal daily) for a period of 44 days. Throughout the trial, the sheep were examined daily. Jugular vein blood was taken twice weekly to analyse haematological and biochemical parameters. No significant influence was observed on the number of erythrocytes, thrombocytes, leucocytes (including differentiation), packed cell volume, haemoglobin-, glucose- and bilirubin-concentration, activity of alanine amino transferase, aspartate amino transferase and glutamate dehydrogenase. Even an oral application of up to 300 mg MPA/animal daily, which is equivalent to 5.4 mg/kg body weight, did not affect the sheep's general state of health and weight gain significantly. Mycophenolic acid and its glucuronide were analysed in plasma samples of groups treatments from day 1 on with mean concentrations up to 0.29 +/- 0.13 microg/ml (MPA) and 11.0 +/- 2.9 microg/ml (MPA glucuronide) respectively (group 4). There were no indications for a ruminal reduction of MPA. The postmortem dissection revealed minor alterations in lung, spleen, liver and kidneys, unrelated to the MPA dosage. The results of the study indicate that MPA concentrations occurring naturally in silage have no obvious impact on sheep health.


Origins of the sarsen megaliths at Stonehenge.
The sources of the stone used to construct Stonehenge around 2500 BCE have been debated for over four centuries. The smaller "bluestones" near the center of the monument have been traced to Wales, but the origins of the sarsen (silcrete) megaliths that form the primary architecture of Stonehenge remain unknown. Here, we use geochemical data to show that 50 of the 52 sarsens at the monument share a consistent chemistry and, by inference, originated from a common source area. We then compare the geochemical signature of a core extracted from Stone 58 at Stonehenge with equivalent data for sarsens from across southern Britain. From this, we identify West Woods, Wiltshire, 25 km north of Stonehenge, as the most probable source area for the majority of sarsens at the monument.


Serum Uric Acid and Progression of Autosomal Dominant Polycystic Kidney Disease: Results from the HALT PKD Trials.
Epidemiological studies have suggested that elevated serum uric acid may contribute to the progression of chronic kidney disease. However, no large prospective study has examined whether hyperuricemia is an independent risk factor for the progression of autosomal dominant polycystic kidney disease (ADPKD). We measured uric acid in stored serum samples from the 2-year study visit of 671 participants from the HALT PKD multicenter trials. Participants were categorized according to uric acid tertiles. For Study A (participants aged 15-49 years with preserved kidney function, n=350), we used linear mixed effects models to examine the association between uric acid and repeated measures of height-adjusted total kidney volume (htTKV), the primary outcome for Study A. For Study B (participants aged 18-64 with decreased kidney function, n=321), we used Cox proportional hazards models to assess the hazard for the combined endpoint of 50% loss in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death, the primary outcome for Study B. To assess the association of uric acid with the slope of eGFR decline (secondary outcome of HALT A and B), we used linear mixed effects models for the combined population of Study A and B. In the unadjusted model, the annual change in htTKV was 2.7% higher in the highest uric acid tertile compared to the lowest (p<0.001), but this difference became insignificant after adjustment for gender. Men had faster TKV growth than women (p<0.001). There was no difference in eGFR decline between the 3 uric acid tertiles. Hazard ratios for the clinical endpoint were 2.9 (95% confidence interval, 1.9-4.4) and 1.8 (1.1-2.8) respectively in the high and medium uric acid groups in unadjusted and partially adjusted models (p<0.001), but the significance was lost after adjustment for baseline eGFR. Results were similar when uric acid was examined as a continuous variable. Elevated serum uric acid is not an independent risk factor for disease progression in ADPKD.


Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department.
Asthma is a chronic respiratory condition characterised by airways inflammation, constriction of airway smooth muscle and structural alteration of the airways that is at least partially reversible. Exacerbations of asthma can be life threatening and place a significant burden on healthcare services. Various guidelines have been published to inform management personnel in the acute setting; several include the use of a single bolus of intravenous magnesium sulfate (IV MgSO4) in cases that do not respond to first-line treatment. However, the effectiveness of this approach remains unclear, particularly in less severe cases. To assess the safety and efficacy of IV MgSO4 in adults treated for acute asthma in the emergency department. We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to 2 May 2014. We also searched www.ClinicalTrials.gov and reference lists of other reviews, and we contacted trial authors to ask for additional information. We included randomised controlled trials (RCTs) of adults treated in the emergency department (ED) for exacerbations of asthma if they compared any dose of IV MgSO4 with placebo. All review authors screened titles and abstracts for inclusion, and at least two review authors independently extracted study characteristics, risk of bias and numerical data. Disagreements were resolved by consensus, and we contacted trial investigators to obtain missing information.We analysed dichotomous data as odds ratios using study participants as the unit of analysis, and we analysed continuous data as mean differences or standardised mean differences using fixed-effect models. We rated all outcomes using GRADE and presented results in Summary of findings table 1.We carried out subgroup analyses on the primary outcome for baseline severity of exacerbations and whether or not ipratropium bromide was given as a co-medication. Unpublished data and studies at high risk of bias for blinding were removed from the main analysis in sensitivity analyses. Fourteen studies met the inclusion criteria, randomly assigning 2313 people with acute asthma to the comparisons of interest in this review.Most studies were double-blinded trials comparing a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes versus a matching placebo. Eleven were conducted at a single centre, and three were multi-centre trials. Participants in almost all of the studies had already been given at least oxygen, nebulised short-acting beta2-agonists and IV corticosteroids in the ED; in some studies, investigators also administered ipratropium bromide. Ten studies included only adults, and four included both adults and children; these were included because the mean age of participants was over 18 years.Intravenous MgSO4 reduced hospital admissions compared with placebo (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.60 to 0.92; I(2) = 28%, P value 0.18; n = 972; high-quality evidence). In absolute terms, this odds ratio translates into a reduction of seven hospital admissions for every 100 adults treated with IV MgSO4 (95% CI two to 13 fewer). The test for subgroup differences revealed no statistical heterogeneity between the three severity subgroups (I(2) = 0%, P value 0.73) or between the four studies that administered nebulised ipratropium bromide as a co-medication and those that did not (I(2) = 0%, P value 0.82). Sensitivity analyses in which unpublished data and studies at high risk for blinding were removed from the primary analysis did not change conclusions.Within the secondary outcomes, high- and moderate-quality evidence across three spirometric indices suggests some improvement in lung function with IV MgSO4. No difference was found between IV MgSO4and placebo for most of the non-spirometric secondary outcomes, all of which were rated as low or moderate quality (intensive care admissions, ED treatment duration, length of hospital stay, readmission, respiration rate, systolic blood pressure).Adverse events were inconsistently reported and were not meta-analysed. The most commonly cited adverse events in the IV MgSO4 groups were flushing, fatigue, nausea and headache and hypotension (low blood pressure). This review provides evidence that a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes reduces hospital admissions and improves lung function in adults with acute asthma who have not responded sufficiently to oxygen, nebulised short-acting beta2-agonists and IV corticosteroids. Differences in the ways the trials were conducted made it difficult for the review authors to assess whether severity of the exacerbation or additional co-medications altered the treatment effect of IV MgSO4. Limited evidence was found for other measures of benefit and safety.Studies conducted in these populations should clearly define baseline severity parameters and systematically record adverse events. Studies recruiting participants with exacerbations of varying severity should consider subgrouping results on the basis of accepted severity classifications.


Accessibility investigation of semi-volatile organic compounds in indoor dust estimated by multi-ratio equilibrium passive sampling.
Many semi-volatile organic compounds (SVOCs) accumulate in indoor dust, which serves as a repository for those compounds. The presence of SVOCs in indoor environments is of concern because many of them are suspected to have toxic effects. Total SVOC concentrations in the dust are generally used for exposure assessment to indoor contaminants, assuming that 100% of the SVOCs is accessible for human uptake. However, such an assumption may potentially lead to an overestimated risk related to dust exposure. We applied a multi-ratio equilibrium passive sampling (MR-EPS) for estimation of SVOC accessibility in indoor settled dust using silicone passive samplers and three particle size dust fractions, <0.25 mm, 0.25-0.5 mm, and 1-2 mm in dry and wet conditions. Equilibrations were performed at various sampler-dust mass ratios to achieve different degrees of SVOC depletion, allowing the construction of a desorption isotherm. The desorption isotherms provided accessible fractions (FAS), equivalent air concentrations (CAIR), dust-air partition coefficients (KDUST-AIR) and organic carbon-air partition coefficients (KOC-AIR). The highest FAS were observed in the <0.25 mm dust fraction in wet conditions which is relevant for exposure assessment via oral ingestion. The highest CAIR were estimated for several organophosphorus flame retardants (OPFRs), polycyclic aromatic hydrocarbons (PAHs) and synthetic musks. The logKOC-AIR did not differ between dust particle sizes in dry and wet conditions but within compound groups, different relationships with hydrophobicity were observed. Equivalent lipid-based concentrations (CL⇌DUST) calculated using available lipid-silicone partition coefficients (KLIP-SIL) were compared with lipid-based concentrations (CL) measured in human-related samples collected from Europeans. For hexachlorobenzene (HCB), CL⇌DUST, and CL were similar, indicating equilibrium attainment between environment and human samples. Lipid-based concentrations for persistent legacy contaminants were also similar but lower for PBDEs in human samples. Overall, accessibility estimation using MR-EPS in dust further contributes to human risk assessment.