Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion.
Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P4 ) promotes CCA in the uterine epithelium and previous studies indicated that P4 activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine-specific Rb1 knockout mice. We observe persistent cell proliferation of the Rb1-deficient uterine epithelium until embryo attachment, loss of epithelial necroptosis, and trophoblast phagocytosis, which correlates with subsequent embryo invasion failure, indicating that Rb1-induced CCA and necroptosis of uterine epithelium are involved in embryo invasion. Pre-implantation P4 supplementation is sufficient to restore these defects and embryo invasion. In Rb1-deficient uterine epithelial cells, TNFα-primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P4 through the upregulation of TNF receptor type 2. TNFα is expressed in the luminal epithelium and the embryo at the embryo attachment site. These results provide evidence that uterine Rb1-induced CCA is involved in TNFα-primed epithelial necroptosis at the implantation site for successful embryo invasion.


Molecular interactions of graphene oxide with human blood plasma proteins.
We investigate the molecular interactions between graphene oxide (GO) and human blood plasma proteins. To gain an insight into the bio-physico-chemical activity of GO in biological and biomedical applications, we performed a series of biophysical assays to quantify the molecular interactions between GO with different lateral size distributions and the three essential human blood plasma proteins. We elucidate the various aspects of the GO-protein interactions, particularly, the adsorption, binding kinetics and equilibrium, and conformational stability, through determination of quantitative parameters, such as GO-protein association constants, binding cooperativity, and the binding-driven protein structural changes. We demonstrate that the molecular interactions between GO and plasma proteins are significantly dependent on the lateral size distribution and mean lateral sizes of the GO nanosheets and their subtle variations may markedly influence the GO-protein interactions. Consequently, we propose the existence of size-dependent molecular interactions between GO nanosheets and plasma proteins, and importantly, the presence of specific critical mean lateral sizes of GO nanosheets in achieving very high association and fluorescence quenching efficiency of the plasma proteins. We anticipate that this work will provide a basis for the design of graphene-based and other related nanomaterials for a plethora of biological and biomedical applications.


Effect of an organic acids based feed additive and enrofloxacin on the prevalence of antibiotic-resistant E. coli in cecum of broilers.
Increasing antibiotic resistance is a major public health concern. Fluoroquinolones are used to treat and prevent poultry diseases worldwide. Fluoroquinolone resistance rates are high in their countries of use. The aim of this study was to evaluate the effect of an acids-based feed additive, as well as fluoroquinolone antibiotics, on the prevalence of antibiotic-resistant E. coli. A total of 480 broiler chickens (Ross 308) were randomly assigned to 3 treatments: a control group receiving a basal diet; a group receiving a feed additive (FA) based on formic acid, acetic acid and propionic acid; and an antibiotic enrofloxacin (AB) group given the same diet, but supplemented with enrofloxacin in water. A pooled fecal sample of one-day-old chicks was collected upon arrival at the experimental farm. On d 17 and d 38 of the trial, cecal samples from each of the 8 pens were taken, and the count of E. coli and antibiotic-resistant E. coli was determined.The results of the present study show a high prevalence of antibiotic-resistant E. coli in one-day-old chicks. Supplementation of the diet with FA and treatment of broilers with AB did not have a significant influence on the total number of E. coli in the cecal content on d 17 and d 38 of the trial. Supplementation with FA contributed to better growth performance and to a significant decrease (P ≤ 0.05) in E. coli resistant to ampicillin and tetracycline compared to the control and AB groups, as well as to a decrease (P ≤ 0.05) in sulfamethoxazole and ciprofloxacin-resistant E. coli compared to the AB group. Treatment with AB increased (P ≤ 0.05) the average daily weight compared to the control group and increased (P ≤ 0.05) the number of E. coli resistant to ciprofloxacin, streptomycin, sulfamethoxazole and tetracycline; it also decreased (P ≤ 0.05) the number of E. coli resistant to cefotaxime and extended spectrum beta-lactamase- (ESBL-) producing E. coli in the ceca of broilers.


Development of host-dependent high-grade tumor-specific immunity through a novel mechanism triggered by the Lyt-2+ tumor-specific T cell clone (K7L) that induces temporal growth of L1210 leukemia-K7L-variant.
When a murine leukemia L1210-specific Lyt-2+ T cell clone, K7L, was injected i.p. into CD2F1 mice together with L1210, the normal growth of L1210 in the peritoneal cavity of the mice at the early stage (days 0 to 5) was strongly inhibited, but L1210 grew progressively at the middle-stage (days 5 to 10), and then was rejected at the late stage (days 10 to 20). The mice thus survived for long times (more than 60 days), whereas the normal control injected with L1210 alone died within 14 days. The L1210 that grew at the middle stage in mice initially inoculated with L1210 together with K7L was a K7L-insensitive (K7L-) variant. All of eight tumor clones established from L1210-K7L- by limiting dilution was insensitive to the antitumor activity of K7L, and this property of tumor clones was stable after repeated in vitro passage. The initial depression of the L1210 growth by K7L followed by growth and rejection of the variant L1210-K7L- by the host T cell activity was then found to prepare a strong, long-lasting (more than 3 mo) immunity to protect mice against the high-dose (10(7) cells per mouse) challenge of original L1210. Corresponding to this result, definite tumor (L1210)-specific cytotoxic T lymphocyte (CTL) activity against both variant and original L1210 targets was developed by antigen (L1210) restimulation in the culture of spleen cells from these mice, but was not increased to a detectable level before L1210-K7L- variant started to grow. It was suggested that the 1210-K7L- variant and the original L1210 should have the common tumor-specific antigen that was independent of the K7L-reactive antigen, and that original L1210, whose growth was retarded by K7L, primed the host with the common antigen to be enormously boosted by the subsequently growing L1210-K7L- variant.


β-catenin aggregation in models of ALS motor neurons: GSK3β inhibition effect and neuronal differentiation.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. A 20% of familial ALS cases are associated with mutations in the gene coding for superoxide dismutase 1 (SOD1). The accumulation of abnormal aggregates of different proteins is a common feature in motor neurons of patients and transgenic ALS mice models, which are thought to contribute to disease pathogenesis. Developmental morphogens, such as the Wnt family, regulate numerous features of neuronal physiology in the adult brain and have been implicated in neurodegeneration. β-catenin is a central mediator of both, Wnt signaling activity and cell-cell interactions. We previously reported that the expression of mutant SOD1 in the NSC34 motor neuron cell line decreases basal Wnt pathway activity, which correlates with cytosolic β-catenin accumulation and impaired neuronal differentiation. In this work, we aimed a deeper characterization of β-catenin distribution in models of ALS motor neurons. We observed extensive accumulation of β-catenin supramolecular structures in motor neuron somas of pre-symptomatic mutant SOD1 mice. In cell-cell appositional zones of NSC34 cells expressing mutant SOD1, β-catenin displays a reduced co-distribution with E-cadherin accompanied by an increased association with the gap junction protein Connexin-43; these findings correlate with impaired intercellular adhesion and exacerbated cell coupling. Remarkably, pharmacological inhibition of the glycogen synthase kinase-3β (GSK3β) in both NSC34 cell lines reverted both, β-catenin aggregation and the adverse effects of mutant SOD1 expression on neuronal differentiation. Our findings suggest that early defects in β-catenin distribution could be an underlying factor affecting the onset of neurodegeneration in familial ALS.


A quantitative method for estimation of volume changes in arachnoid foveae with age.
Age-related changes of arachnoid foveae have been described, but objective, quantitative analyses are lacking. A new quantitative method is presented for estimation of change in total volume of arachnoid foveae with age. The pilot sample consisted of nine skulls from the Palmer Anatomy Laboratory. Arachnoid foveae were filled with sand, which was extracted using a vacuum pump. Mass was determined with an analytical balance and converted to volume. A reliability analysis was performed using intraclass correlation coefficients. The method was found to be highly reliable (intraobserver ICC = 0.9935, interobserver ICC = 0.9878). The relationship between total volume and age was then examined in a sample of 63 males of accurately known age from the Hamann-Todd collection. Linear regression analysis revealed no statistically significant relationship between total volume and age, or foveae frequency and age (alpha = 0.05). Development of arachnoid foveae may be influenced by health factors, which could limit its usefulness in aging.


Viral particles of endogenous betaretroviruses are released in the sheep uterus and infect the conceptus trophectoderm in a transspecies embryo transfer model.
The sheep genome contains multiple copies of endogenous betaretroviruses highly related to the exogenous and oncogenic jaagsiekte sheep retrovirus (JSRV). The endogenous JSRVs (enJSRVs) are abundantly expressed in the uterine luminal and glandular epithelia as well as in the conceptus trophectoderm and are essential for conceptus elongation and trophectoderm growth and development. Of note, enJSRVs are present in sheep and goats but not cattle. At least 5 of the 27 enJSRV loci cloned to date possess an intact genomic organization and are able to produce viral particles in vitro. In this study, we found that enJSRVs form viral particles that are released into the uterine lumen of sheep. In order to test the infectious potential of enJSRV particles in the uterus, we transferred bovine blastocysts into synchronized ovine recipients and allowed them to develop for 13 days. Analysis of microdissected trophectoderm of the bovine conceptuses revealed the presence of enJSRV RNA and, in some cases, DNA. Interestingly, we found that RNAs belonging to only the most recently integrated enJSRV loci were packaged into viral particles and transmitted to the trophectoderm. Collectively, these results support the hypothesis that intact enJSRV loci expressed in the uterine endometrial epithelia are shed into the uterine lumen and could potentially transduce the conceptus trophectoderm. The essential role played by enJSRVs in sheep reproductive biology could also be played by endometrium-derived viral particles that influence development and differentiation of the trophectoderm.


Xylarianaphthol-1, a novel dinaphthofuran derivative, activates p21 promoter in a p53-independent manner.
Xylarianaphthol-1, a novel dinaphthofuran derivative, was isolated from a marine sponge-derived fungus of order Xylariales on the guidance of a bioassay using the transfected human osteosarcoma MG63 cells (MG63(luc+)). The chemical structure of xylarianaphthol-1 was determined from the (1)H and (13)C NMR analysis and was further confirmed by the total synthesis. Xylarianaphthol-1 activated p21 promoter stably transfected in MG63 cells dose-dependently. Expression of p21 protein in the wild-type MG63 cells was also increased by xylarianaphthol-1 treatment.


Exploitation of surrogate variables in random forests for unbiased analysis of mutual impact and importance of features.
Random forest is a popular machine learning approach for the analysis of high-dimensional data because it is flexible and provides variable importance measures for the selection of relevant features. However, the complex relationships between the features are usually not considered for the selection and thus also neglected for the characterization of the analysed samples. Here we propose two novel approaches that focus on the mutual impact of features in random forests. Mutual forest impact (MFI) is a relation parameter that evaluates the mutual association of the features to the outcome and, hence, goes beyond the analysis of correlation coefficients. Mutual impurity reduction (MIR) is an importance measure that combines this relation parameter with the importance of the individual features. MIR and MFI are implemented together with testing procedures that generate P-values for the selection of related and important features. Applications to one experimental and various simulated datasets and the comparison to other methods for feature selection and relation analysis show that MFI and MIR are very promising to shed light on the complex relationships between features and outcome. In addition, they are not affected by common biases, e.g. that features with many possible splits or high minor allele frequencies are preferred. The approaches are implemented in Version 0.3.3 of the R package RFSurrogates that is available at github.com/AGSeifert/RFSurrogates and the data are available at doi.org/10.25592/uhhfdm.12620.


[Effect of acetylcholine and histamine on electrolyte and catecholamine content of vessel walls exposed to x-rays and cystamine].
Experiments on adult rats have shown that a single rectal x-ray irradiation is accompanied by a decrease in the content of adrenaline, noradrenaline and potassium and by a increase in sodium and calcium concentration in vascular tissue. The degree of these shifts depends on the time elapsed after exposure to x-rays. X-Ray injury produces specific changes in the biochemical response of the vascular wall to different doses of acetylcholine and histamine during varying times of x-ray-induced pathology. Pretreatment (before irradiation) with radioprotectors (cistamine) lowers the damaging effect of radiation and promotes the normalization of the vascular tissue response to the administration of mediator agents.


Social listening - revealing Parkinson's disease over day and night.
Nocturnal symptoms in Parkinson's disease are often treated after management of daytime manifestations. In order to better understand the unmet needs of nocturnal symptoms management, we analyzed the characteristics and burden of nocturnal symptoms from patients' perspectives and explored their changes over time. Overall symptoms (occurring at day or night) were collected to compare whether the unmet needs related to nocturnal symptoms and to overall symptoms are different. We used a Social Listening big-data technique to analyze large amounts of Parkinson's disease symptoms in dialogues available from social media platforms in 2016 to 2018. These symptoms were classified as either overall symptoms or nocturnal symptoms. We used share of voice (SOV) of symptoms as a proportion of total dialogues per year to reflect the characteristics of symptoms. Negative sentiment score of symptoms was analyzed to find out their related burden. We found the SOV for overall motor symptoms was 79% and had not increased between 2016 and 2018 (79%, p = 0.5). The SOV for non-motor symptoms was 69% and had grown by 7% in 2018 (p < 0.01). The SOV for motor complications was 9% and had increased by 6% in 2018 (p < 0.01). The SOV of motor symptoms was larger than non-motor symptoms and motor complications (p < 0.01). The SOV of non-motor symptoms was larger than motor complications (p < 0.01). For nocturnal symptoms, 45% of the analyzed PD population reported nocturnal symptoms in 2018, growing by 6% (p < 0.01). The SOV for nocturnal-occurring motor symptoms was higher than most non-motor symptoms. However, non-motor symptoms had the higher increases and evoked higher negative sentiment regardless of whether they occurred during the day or night. For symptoms that can occur at either day or night, each nocturnal symptom was rated with a higher negative sentiment score than the same symptom during the day. The growing SOV and the greater negative sentiment of nocturnal symptoms suggest management of nocturnal symptoms is an unmet need of patients. A greater emphasis on detecting and treating nocturnal symptoms with 24-h care is encouraged.


Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7.
Recent studies have shown that stromal fibroblasts have a more profound influence on the initiation and progression of carcinoma than was previously appreciated. This study aimed at investigating the reciprocal relationship between cancer cells and their associated fibroblasts at both the molecular and cellular level in oral squamous cell carcinoma (OSCC). To identify key molecular regulators expressed by carcinoma-associated fibroblasts (CAF) that promote cancer cell invasion, microarrays were performed by comparing cocultured OSCC cells and CAF with monoculture controls. Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. Cytokine antibody array analysis of the supernatant from OSCC cell culture revealed that interleukin-1alpha was an inducer of CCL7 secretion by CAF. This study confirms the reciprocal relationship of the molecular crosstalk regulating the invasion of OSCC and describes new potential targets for future therapy.


Complementary and alternative medicine for the treatment of depressive disorders in women.
Complementary and alternative medicine (CAM) therapies are commonly practiced in the United States and are used more frequently among women than men. This article reviews several CAM treatments for depressive disorders in women, with a focus on major depressive disorder across the reproductive life cycle. The CAM therapies selected for this review (ie, S-adenosylmethionine, omega-3 fatty acids, St John's wort, bright light therapy, acupuncture, and exercise) were based on their prevalence of use and the availability of randomized, placebo-controlled data. Further study is necessary to delineate the role of specific CAM therapies in premenstrual syndrome, premenstrual dysphoric disorder, antepartum and postpartum depression, lactation, and the menopausal transition.


Feasibility and acceptability of HIV self-testing among pre-exposure prophylaxis users in Kenya.
HIV testing is key to the delivery of pre-exposure prophylaxis (PrEP): testing HIV-uninfected at-risk persons is the first step for PrEP initiation and ongoing HIV testing is an essential part of PrEP delivery. Thus, novel and cost-effective HIV-testing approaches to streamline delivery of PrEP are urgently needed. Within a demonstration project of PrEP for HIV prevention among high-risk HIV serodiscordant couples in Kenya (the Partners Demonstration Project), we conducted a pilot evaluation of HIV self-testing. Clinic visits were scheduled quarterly and included in-clinic HIV testing using fingerstick rapid HIV tests and refills of PrEP prescriptions. HIV oral fluid self-test kits were provided for participants to use in the two-month interval between scheduled quarterly clinic visits. Acceptability of HIV self-testing was assessed using both quantitative and qualitative methods. We found that 222 of 226 (98%) HIV-uninfected persons who were offered accepted self-testing. Nearly all (96.8%) reported that using the self-testing kit was easy. More than half (54.5%) reportedly did not share the HIV results from self-testing with anyone and almost all (98.7%) the participants did not share the HIV self-testing kits with anyone. Many participants reported that HIV self-testing was empowering and reduced anxiety associated with waiting between clinic HIV tests. HIV self-testing was highly acceptable and may therefore be a feasible strategy to efficiently permit routine HIV testing between PrEP refills.


Three dimensional digital holographic profiling of micro-fibers.
A method to measure the size, orientation, and location of opaque micro-fibers using digital holography is presented. The method involves the recording of a digital hologram followed by reconstruction at different depths. A novel combination of automated image analysis and statistical techniques, applied on the intensity of reconstructed digital holograms is used to accurately determine the characteristics of the micro-fibers. The performance of the proposed method is verified with a single fiber of known length and orientation. The potential of the method for measurement of fiber length is further demonstrated through its application to a suspension of fibers in a liquid medium.


A new method for the evaluation of vaccine safety based on comprehensive gene expression analysis.
For the past 50 years, quality control and safety tests have been used to evaluate vaccine safety. However, conventional animal safety tests need to be improved in several aspects. For example, the number of test animals used needs to be reduced and the test period shortened. It is, therefore, necessary to develop a new vaccine evaluation system. In this review, we show that gene expression patterns are well correlated to biological responses in vaccinated rats. Our findings and methods using experimental biology and genome science provide an important means of assessment for vaccine toxicity.


Comparison of the Therapeutic Effects of Adipose- and Bone Marrow-Derived Mesenchymal Stem Cells on Renal Fibrosis.
Mesenchymal stem cells (MSCs) have attracted a great deal of interest as a therapeutic tool for renal fibrosis. Although both adipose-derived and bone marrow-derived MSCs (ADSCs and BMSCs, respectively) suppress renal fibrosis, which of these two has a stronger therapeutic effect remains unclear. This study aimed to compare the antifibrotic effects of ADSCs and BMSCs extracted from adipose tissue and bone marrow derived from the same rats. When cultured in serum-containing medium, ADSCs had a more potent inhibitory effect than BMSCs on renal fibrosis induced by ischemia-reperfusion injury in rats. ADSCs and BMSCs cultured in serum-free medium were equally effective in suppressing renal fibrosis. Mice infused with ADSCs (serum-containing or serum-free cultivation) had a higher death rate from pulmonary embolism than those infused with BMSCs. In vitro, mRNA levels of tissue factor, tumor necrosis factor-α-induced protein 6 and prostaglandin E synthase were higher in ADSCs than in BMSCs, while that of vascular endothelial growth factor was higher in BMSCs than in ADSCs. Although ADSCs had a stronger antifibrotic effect, these findings support the consideration of thromboembolism risk in clinical applications. Our results emphasize the importance of deciding between ADSCs and BMSCs based upon the target disease and culture method.


Lectins in human pathogenic fungi.
Lectins are carbohydrate-binding proteins widely distributed in nature. They constitute a highly diverse group of proteins consisting of many different protein families that are, in general, structurally unrelated. In the last few years, mushroom and other fungal lectins have attracted wide attention due to their antitumour, antiproliferative and immunomodulatory activities. The present mini-review provides concise information about recent developments in understanding lectins from human pathogenic fungi. A bibliographic search was performed in the Science Direct and PubMed databases, using the following keywords "lectin", "fungi", "human" and "pathogenic". Lectins present in fungi have been classified; however, the role played by lectins derived from human pathogenic fungi in infectious processes remains uncertain; thus, this is a scientific field requiring more research. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).


Equitable access to healthcare services and income replacement for cancer: is critical illness insurance a help or a hindrance?
Canada's publicly funded healthcare system ensures that medically necessary hospital and physician services are available without financial barriers, but not all community-based care is covered. Consequently, many patients experience financial shocks (FS) related to community-based healthcare services not funded by government, and perhaps also from lost income, a situation that may be difficult for patients to avoid. Critical illness insurance (CII) offers a patient-funded alternative to those who qualify and desire protection against FS, leaving those without CII exposed. The author discusses the benefits and limitations of CII to mitigate financially derived healthcare access inequities, using cancer as an example.


[Aromatherapy and nursing: historical and theoretical conception].
Aromatherapy is a Practical or Complementary Health Therapy that uses volatile concentrates extracted from plants called essential oils, in order to improve physical, mental and emotional well-being. Aromatherapy has been practiced historically and worldwide by nurses and, as in Brazil is supported by the Federal Nursing Council, it is relevant to discuss this practice in the context of Nursing through Theories of Nursing. This study of theoretical reflection, exploratory and descriptive, aims to discuss the pharmacognosy of essential oils, the historical trajectory of Aromatherapy in Nursing and the conceptions to support Aromatherapy in light of eight Nursing Theorists (Florence Nightingale, Myra Levine, Hildegard Peplau, Martha Rogers, Callista Roy, Wanda Horta, Jean Watson and Katharine Kolcaba), contributing to its inclusion as a nursing care practice.


US emergency department use by children, 2001-2010.
Children commonly use emergency departments (EDs) for a variety of health care needs. We describe recent trends in US ED use by children. This is a cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey, a nationally representative sample of ED visits, and US Census data between 2001 and 2010. We examined demographic trends, visit characteristics, insurance status, disposition, hospital variables, diagnoses, reason for visit, and resource use among patients younger than 19 years. Linear regression was used to evaluate significance of trends. Approximately one quarter of all ED visits was made by patients younger than 19 years. Emergency department visits by children increased 14.4% between 2001 and 2010 (P = 0.04); the rate of visits increased from 36.4 to 40.6 per 100 population. Trauma is the most common reason for pediatric ED visits. Black children had the highest rate of ED use (61.9 per 100 in 2010). Visit rates by Hispanic children were relatively low but increased by 82.7% since 2001 (P = 0.00). The proportion of ED visits by Medicaid beneficiaries rose from 32.0% to 51.9% (P = 0.00). The volume and frequency of diagnostic testing, administration of intravenous fluids, medication administration, and discharge prescriptions increased. Visits with computed tomography or magnetic resonance imaging almost doubled from 3.1% of the visits in 2001 to 6.6% of the visits in 2010 (P = 0.00). The use of ED by children is growing faster than population growth, and the intensity of ED care has risen sharply. Hispanic children and Medicaid beneficiaries represent the fastest growing populations of children using the ED.


Perioperative Management of Endocrine Active Adrenal Tumors.
Endocrine active adrenal tumors are associated with a relevant risk of complications during surgery, either due to direct hemodynamic effects of the hormone excess or due to hormone related comorbidities. Over the last decades, careful preoperative evaluation and improved peri-interventional medical management of affected patients has resulted in a significant reduction of perioperative complications. In addition, improvement in anesthesia and surgical techniques with the feasibility of laparoscopic adrenalectomy have contributed to reduce morbidity. Nevertheless, there are still several challenges to be considered in the perioperative care of these patients. Due to the rarity of functionally active adrenal tumors, there are no prospective data available to guide clinical management. Accordingly, most recommendations are based on retrospective data analysis, expert opinion or carry weak evidence based on small series or case reports. The aim of this review is to summarize the current knowledge and to suggest practical approaches to reduce perioperative complications in endocrine active adrenal tumors. This review exclusively deals with data from adult patients with functionally active adrenal tumors.


Pegylated Interferon-Induced Sarcoidosis Presenting With Anterior Uveitis in a Patient with Chronic Hepatitis C - Case Report.
Sarcoidosis is a chronic inflammatory systemic disorder of unknown etiology. It is known to be triggered by an autoimmune process, and is currently recognized as a rare adverse event to interferon therapy for Hepatitis C Virus Infection. Clinical presentation of interferon-triggered sarcoidosis is varied, but ocular manifestation as a first symptom was only once, previously reported. We report the case of a 32 year old woman, infected with hepatitis C, for whom antiviral therapy was initiated. Prior to treatment, the patient had outstanding medical history. Three months from the initiation, patient accused pain and redness of the left eye and mild visual loss. The diagnosis of Interferon induced sarcoidosis was established. We are presenting this case because it illustrates the possibility of sudden and severe complications and we want to emphasize the importance of performing ophthalmological examination in patients treated with pegylated interferon α.


Evaluation of Provider Assessment of Clinical History When Using the HEART Score.
The HEART Score is a clinically validated risk stratification tool for patients with chest pain. Using five parameters (History, Electrocardiogram, Age, Risk factors, and Troponin), this instrument categorizes patients as low, moderate, or high risk for major adverse cardiac events within six weeks after evaluation. Of these parameters, History is the most subjective, as providers independently assign their level of clinical suspicion. Overestimation of history, and ultimately the HEART Score, can result in increased resource utilization, expense, and patient risk. We sought to evaluate bias in provider assessment of history when determining the HEART Score. Emergency medicine (EM) and Cardiology providers received surveys with one of two versions of clinical vignettes randomized at the question level and were asked to estimate the history component of the HEART Score. Vignettes differed by age, risk factors, sex, and socioeconomic status (SES), but both versions should have received the same score for history. Statistical analysis was then used to assess differences in history assessment between vignettes. Of the 884 responses analyzed, most providers overestimated the historical portion of the HEART Score when assessing risk factors, patient distress, age, and lower SES. Many underestimated history with knowledge of a previous negative stress test. When controlling for specialty, the universal theme was overestimation by EM providers and underestimation by cardiologists. Despite the presence of hypertension, gender differences, and the appearance of mild distress, cardiologists were more likely to correctly estimate history compared to EM providers. SES consideration generally led to an underestimation of history by cardiologists. These findings were all statistically significant. Our study demonstrates that both EM and cardiology providers overestimate history when considering prognosticators that are frequently viewed as concerning. Further education on proper usage of the HEART Score is needed for more appropriate scoring of history and improved resource allocation for hospital systems.


Detection and Analysis of Corrosion and Contact Resistance Faults of TiN and CrN Coatings on 410 Stainless Steel as Bipolar Plates in PEM Fuel Cells.
Bipolar Plates (BPPs) are the most crucial component of the Polymer Electrolyte Membrane (PEM) fuel cell system. To improve fuel cell stack performance and lifetime, corrosion resistance and Interfacial Contact Resistance (ICR) enhancement are two essential factors for metallic BPPs. One of the most effective methods to achieve this purpose is adding a thin solid film of conductive coating on the surfaces of these plates. In the present study, 410 Stainless Steel (SS) was selected as a metallic bipolar plate. The coating process was performed using titanium nitride and chromium nitride by the Cathodic Arc Evaporation (CAE) method. The main focus of this study was to select the best coating among CrN and TiN on the proposed alloy as a substrate of PEM fuel cells through the comparison technique with simultaneous consideration of corrosion resistance and ICR value. After verifying the TiN and CrN coating compound, the electrochemical assessment was conducted by the potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) tests. The results of PDP show that all coated samples have an increase in the polarization resistance (Rp) values (ranging from 410.2 to 690.6 Ω·cm2) compared to substrate 410 SS (230.1 Ω·cm2). Corrosion rate values for bare 410 SS, CrN, and TiN coatings were measured as 0.096, 0.032, and 0.060 mpy, respectively. Facilities for X-ray Diffraction (XRD), Scanning Electron Microscope (FE-SEM, TeScan-Mira III model and made in the Czech Republic), and Energy Dispersive X-ray Spectroscopy (EDXS) were utilized to perform phase, corrosion behavior, and microstructure analysis. Furthermore, ICR tests were performed on both coated and uncoated specimens. However, the ICR of the coated samples increased slightly compared to uncoated samples. Finally, according to corrosion performance results and ICR values, it can be concluded that the CrN layer is a suitable choice for deposition on 410 SS with the aim of being used in a BPP fuel cell system.


Evaluation and management of lower gastrointestinal bleeding.
Lower gastrointestinal bleeding (LGIB) is a common cause of presentation to the emergency department and hospital admissions. The incidence of LGIB increases with age and the most common etiologies are diverticulosis, angiodysplasia, malignancy and anorectal diseases. Foremost modality for evaluation and treatment of LGIB is colonosopy. Other diagnostic tools such as nuclear scintigraphy, computed tomography, angiography and capsule endoscopy are also frequently used in the workup of LGIB. Choice of treatment modality depends on the hemodynamic status of the patient, rate of bleeding, expertise and available resources. We present a comprehensive review of the evaluation and management of LGIB.


Scientific opinion on an alternative method for the hygienic treatment of bovine colostrum through a series of filtration steps.
An alternative method to the HTST treatment (High Temperature Short Time pasteurisation at 72 °C for at least 15 seconds or equivalent pasteurisation effect achieving a negative reaction to a phosphatase test), approved for the treatment of bovine colostrum (Category 3 material), was assessed. The purpose of the alternative method, based on a series of filtration steps, is the production of Colostrinov, a product whose main ingredient is bovine colostrum, to be used for foal nutrition. Since the filtration techniques used are known to eliminate particles of the size of bacteria, fungi and protozoa from liquids, it is reasonable to assume that the microfiltration process reduces these contaminants to a level at least equivalent to the treatment required by the legislation. Owing to their small size, viruses are not retained by the mechanical effect of the filters but they may be retained by physico-chemical interactions with the surface of the filter, depending on the surface properties of the viruses and those of the filter, as well as on the properties of the surrounding liquid. From the information provided by the applicant, it cannot be concluded whether or not the microfiltration process reduces the relevant viral contaminants to a level at least equivalent to a single HTST treatment as required by the legislation.


Ethical issues in environmental health research.
Environmental health research encompasses a wide range of investigational topics, study designs, and empirical methodologies. As that arm of public health research concerned with understanding the health effects of the many environments in which humans live and work, the field is intimately connected with social concerns about environmental quality and disparities of power and privilege that place differential burdens upon members of underserved communities. Environmental health researchers thus engage many ethical and social issues in the work they do. These issues relate to the choice of research topics to study, the methods employed to examine these topics, the communication of research findings to the public, and the involvement of scientific experts in the shaping of environmental policy and governmental regulation. These and other topics are reviewed in this article. These ethical, legal, and social issues are becoming increasingly more complex as new genetic and molecular techniques are used to study environmental toxicants and their potential influence on human and ecologic health.


Towards symbiosis in knowledge representation and natural language processing for structuring clinical practice guidelines.
The successful adoption by clinicians of evidence-based clinical practice guidelines (CPGs) contained in clinical information systems requires efficient translation of free-text guidelines into computable formats. Natural language processing (NLP) has the potential to improve the efficiency of such translation. However, it is laborious to develop NLP to structure free-text CPGs using existing formal knowledge representations (KR). In response to this challenge, this vision paper discusses the value and feasibility of supporting symbiosis in text-based knowledge acquisition (KA) and KR. We compare two ontologies: (1) an ontology manually created by domain experts for CPG eligibility criteria and (2) an upper-level ontology derived from a semantic pattern-based approach for automatic KA from CPG eligibility criteria text. Then we discuss the strengths and limitations of interweaving KA and NLP for KR purposes and important considerations for achieving the symbiosis of KR and NLP for structuring CPGs to achieve evidence-based clinical practice.


Risk Factors for Cardiovascular Diseases among Diabetic Patients In Southwest Ethiopia.
Studies on cardiovascular risk factors among diabetic persons in Ethiopia are lacking. The objective of this study was to determine the prevalence of the cardiovascular risk factors (hypertension, obesity, physical inactivity, dyslipidemia and smoking) among diabetic patients at the diabetic clinic of Jimma University Specialized Hospital. A cross-sectional study was conducted from October to December 2007. Three hundred one individuals were randomly selected from 950 patients on follow-up. Data were collected using a structured format and appropriate equipments and reagents. Laboratory data were recorded in a separate checklist. The data were entered into SPSS for Windows version 12. Multivariate regression analysis was carried out to identify predictors of hypertension, obesity and dyslipidemia. Two hundred and fifty six (85.1%) of the sample participated in the study. The prevalence of hypertension, obesity, dyslipidemia, physical inactivity and current smoking was 46.5%, 23.4%, 63.5%, 55.1% and 5.5% respectively. Age ≥ 45 years, type 2 diabetes and obesity were predictors of hypertension. Females were less likely to be hypertensive (OR =2.26, 3.37, 3.79 and 0.48 respectively). Type 2 diabetics and females were more while rural diabetics were less likely to be obese. (OR =6.08, 4.17 and 0.37 respectively). Female gender, hypertension and fasting blood glucose ≥ 180mg/dl were predictors of dyslipidemia. Alcohol users were less likely to be dyslipidemic. (OR =4.25, 3.5, 3.56 and 0.39, respectively) Hypertension, obesity, dyslipidemia and physical inactivity were common while smoking was uncommon among diabetic patients in Jimma University Specialized Hospital. Type 2 DM was a predictor of hypertension and obesity. Diabetic women were more likely to be obese and dyslipidemic. We recommend screening and management of these risk factors.


Outcomes of delivering a fertility preservation service for women with cancer over a 12-year period at a UK assisted conception unit.
This service evaluation aimed to appraise the delivery of a fertility preservation service for women with cancer which was established in 2005 as part of an Assisted Conception Unit. First, the ACU-database was interrogated between 08/2005 and 01/2017; revealing 174 women received referrals over the 12-year period with a steady referral increase each year. Demographic analyses revealed factors, such as being partnered, to be strong indicators of whether women would seek FP or not. To improve service provision, women who had consented to be contacted for audit, administrative and research purposes, received questionnaires to ascertain their perspectives on the FP decision-making process, their outcomes and ACU after-care. The majority perceived their experience as excellent due to the care they received from ACU staff, speed and efficiency in service delivery. The increasing number of referrals since 2005 is reassuring. However, this audit also highlighted shortcomings of the service, such as limited awareness of the fertility counselling service and lack of after-care.IMPACT STATEMENTWhat is already known on this subject? There has been an increase in women diagnosed with cancer undergoing fertility preservation (FP) before starting potential gonadotoxic treatment. Offering FP to these women is essential as the ability to have future children is often perceived as equally as important as survivorship, and a source of hope for the future.What do the results of this study add? This study presents a service evaluation, across a 12-year period, of delivering FP services to women with cancer in one UK Assisted Conception Unit (ACU). Women's experiences of the service were evaluated to enhance service delivery and make recommendations for clinical practice.What are the implications of these findings for clinical practice and/or future research? The current service evaluation demonstrated increased rates of FP referral over a 12-year period for women with cancer. While this increasing number is reassuring and reflecting increased awareness among professionals and patients; shortcomings in the care pathway were also found: women reported limited opportunity to see fertility counsellors and desired better after care. This information may also be of benefit to other ACUs seeking to enhance and improve service provision in the care of women with cancer, contemplating fertility preservation.


The reliability of an Arabic version of the self-administered standardized chronic respiratory disease questionnaire (CRQ-SAS).
To produce a conceptually equivalent Arabic version to the original Self-Administered Chronic Respiratory Disease Questionnaire with standardized dyspnea domain (CRQ-SAS) and to assess its reliability. The study was carried out in two stages: stage I which was the translation of the CRQ-SAS questionnaire from the English to the Arabic language, and stage II which represented the test-retest reliability for patients receiving usual care for COPD who were not yet admitted to the pulmonary rehabilitation program. Forty five patients with stable COPD were enrolled in this study. Strong test-retest reliability was found for the four domains of the CRQ-SAS, with the intra-class correlation coefficient of 0.97 for each of the domains. The association between most parameters and the four domains of CRQ-SAS were not found to be statistically significant, as measured by Pearson correlation. The number of exacerbations was negatively correlated with the dyspnea domain (correlation = -0.36, p-value = 0.02). The disease duration was negatively correlated with the domain fatigue (correlation = -0.35, p-value = 0.02). The correlation between FEV1/FVC ratio and emotion domain was -0.30 (p-value = 0.05). The mastery domain was negatively correlated with FEV1/FVC ratio with a correlation of -0.27 with borderline statistical significance (p-value = 0.07). The Arabic translation of the CRQ-SAS was found to be reliable to assess the quality of life among patients with COPD.


Groundwater contamination in the Gulf Cooperation Council (GCC) countries: a review.
Groundwater quality levels are currently deteriorating in Gulf Cooperation Council (GCC) countries due to excessive surface and subsurface human activities. Agricultural and industrial activities, landfill seepage and seawater intrusion have been attributed to the deterioration of groundwater quality in GCC states. Such a deterioration of groundwater quality could affect water security in the region, including human health and the ecosystem. Therefore, this review aims to identify the key causes of groundwater contamination across the GCC countries from the published literature. In addition, the review summarizes the major components of the groundwater contaminants across the GCC countries. The results have shown that heavy metals, several cations and anions are the leading cause of groundwater pollution. In most cases, the level of metals and ion contaminants exceeds both the local and international water quality standards. The results have observed the presence of high levels of coliform and radioactive elements in groundwater, especially Uranium and Radium, thereby posing additional risk to human health through consumption. Considering the scarcity of freshwater resources in GCC, urgent actions are required from the decision-makers and relevant regulatory bodies to set up and implement long-term mitigation strategies and stringent policies that will protect the groundwater resources from the adverse effects of anthropogenic activities.


Agile Robotic Fliers: A Morphing-Based Approach.
The aerial robot presented here for the first time was based on a quadrotor structure, which is capable of unique morphing performances based on an actuated elastic mechanism. Like birds, which are able to negotiate narrow apertures despite their relatively large wingspan, our Quad-Morphing robot was able to pass through a narrow gap at a high forward speed of 2.5 m.s- 1 by swiftly folding up the structure supporting its propellers. A control strategy was developed to deal with the loss of controllability on the roll axis resulting from the folding process, while keeping the robot stable until it has crossed the gap. In addition, a complete recovery procedure was also implemented to stabilize the robot after the unfolding process. A new metric was also used to quantify the gain in terms of the gap-crossing ability in comparison with that observed with classical quadrotors with rigid bodies. The performances of these morphing robots are presented, and experiments performed with a real flying robot passing through a small aperture by reducing its wingspan by 48% are described and discussed.


Liquid chromatographic determination of inhibition of monoamine oxidase activity in platelet rich plasma of depressed patients treated with phenelzine.
Monitoring platelet monoamine oxidase activity in plasma of depressed patients receiving monoamine oxidase inhibitors is used as an indicator of therapeutic dosage and efficacy. In this study enzyme activity in platelets vs platelet rich plasma was compared. An aliquot of platelet rich plasma (PRP) was incubated with 4-hydroxy-3-methoxy-benzylamine as substrate. After stopping the enzymatic reaction, m-hydroxybenzaldehyde was added to the mixture as internal standard. The reaction mixture was extracted with toluene to isolate vanillin, the deamination product of the substrate, and the internal standard. The toluene layer was collected and back extracted into dilute tetramethylammonium hydroxide. An aliquot of the aqueous layer was chromatographed on a non-silica resin base reversed phase column with an alkaline phase. The peaks were detected by an absorbance detector at 350 nm. There was no significant difference in the decrease of monoamine oxidase activity when determined using platelet rich plasma versus washed platelets.


"Scholasticism Is a Daughter of Judaism": The Discovery of Jewish Influence on Medieval Christian Thought.
This article retells the surprising discovery of a considerable Jewish influence on Christian scholasticism in the Middle Ages. While most students of Albert the Great and Thomas Aquinas knew that both had read Jewish philosophy, only the rediscovery of especially Maimonides's Guide of the Perplexed by Jewish philosophers in the nineteenth century showed the whole extent of the scholastics' dependence on Jewish predecessors - especially where they do not refer to them specifically. This Jewish discovery naturally faced Catholic resistance, if not denial, and turns thus into an interesting chapter in the history of theological ideas.


Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging.
While bone marrow edema (BME) detected by magnetic resonance imaging (MRI) is a biomarker of arthritis, its nature remains poorly understood due to the limitations of clinical studies. In this study, MRI of murine arthritis was used to elucidate its cellular composition and vascular involvement. BME was quantified using normalized bone marrow intensity (NBMI) from precontrast MRI and normalized marrow contrast enhancement (NMCE) following intravenous administration of gadopentate dimeglumine. Wild-type (WT) and tumor necrosis factor (TNF)-transgenic mice were scanned from 2 to 5 months of age, followed by histologic or fluorescence-activated cell sorting (FACS) analysis of marrow. In efficacy studies, TNF-transgenic mice were treated with anti-TNF or placebo for 8 weeks, and then were studied using bimonthly MRI and histologic analysis. NBMI values were similar in WT and TNF-transgenic mice at 2 months. The values in WT mice steadily decreased thereafter, with mean values becoming significantly different from those of TNF-transgenic mice at 3.5 months (mean +/- SD 0.29 +/- 0.08 versus 0.46 +/- 0.13; P < 0.05). Red to yellow marrow transformation occurred in WT but not TNF-transgenic mice, as observed histologically at 5 months. The marrow of TNF-transgenic mice that received anti-TNF therapy converted to yellow marrow, with lower NBMI values versus placebo at 6 weeks (mean +/- SD 0.26 +/- 0.07 versus 0.61 +/- 0.22; P < 0.05). FACS analysis of bone marrow revealed a significant correlation between NBMI values and CD11b+ monocytes (R2 = 0.91, P = 0.0028). Thresholds for "normal" red marrow versus pathologic BME were established, and it was also found that inflammatory marrow is highly permeable to contrast agent. BME signals in TNF-transgenic mice are caused by yellow to red marrow conversion, with increased myelopoiesis and increased marrow permeability. The factors that mediate these changes warrant further investigation.


Interference by anti-cancer chemotherapeutic agents in the MTT-tumor chemosensitivity assay.
One of the major goals of oncology is to predict the response of patients with cancer to chemotherapeutic agents by employing laboratory methods variously called 'tumor chemosensitivity assays', 'drug response assays', or 'drug sensitivity assays', in vitro. The MTT assay is one of the methods used to predict the drug response in malignancies. However, it may suffer from interference by the anticancer drugs with the MTT assay. The MTT assay, a colorimetric viability assay, was checked in a cell-free system in terms of its possible chemical interactions with 22 different anticancer drugs. It was found that epirubicine, paclitaxel, doxetaxel, and cisplatin caused a relatively significant increase in absorbance values, resulting in the MTT assay giving rise to false results (untrue increase in viability) although most of the drugs tested did not seem to cause any significant change. It was concluded that before employing the MTT assay, drugs (or any kind of substances) to be included in the assay should be checked first in terms of possible chemical interactions with MTT, otherwise it may be impossible to evaluate the MTT viability assay results correctly.


A model-based consecutive scanline tracking method for extracting vascular networks from 2-D digital subtraction angiograms.
We propose a new model-based algorithm for the automated tracking of vascular networks in 2-D digital subtraction angiograms. Consecutive scanline profiles are fitted by a parametric imaging model to estimate local vessel center point, radius, edge locations and direction. An adaptive tracking strategy is applied with appropriate termination criteria to track each vessel segment. When tracking stops, to prevent premature termination and to detect bifurcations, a look ahead detection scheme is used to search for possible continuation points of the same vessel segment or those of its bifurcated segments. The proposed algorithm can automatically extract the majority of the vascular network without human interaction other than initializing the start point and direction. Compared to other tracking methods, the proposed method highlights accurate estimation of local vessel geometry. Accurate geometric information and a hierarchical vessel network are obtained which can be used for further quantitative analysis of arterial networks to obtain flow conductance estimates.


Prognostic value of p53 and bcl-2 expression in patients treated with breast conservative therapy.
Prognostic value of p53 and bcl-2 expression on treatment outcome in breast cancer patients has been extensively evaluated, but the results were inconclusive. We evaluated the prognostic significance of these molecular markers in patients treated with breast conserving surgery and radiotherapy. One hundred patients whose immunostaining of p53 and bcl-2 expression was available among 125 patients who underwent radiotherapy after breast conserving surgery and axillary lymph node dissection were enrolled into this study. Eighty-seven patients also received adjuvant chemotherapy and/or hormonal therapy. Conventional clinicopathologic variables and treatment-related factors were also considered. The 5-yr loco-regional relapse-free and distant metastasis-free survival rates were 91.7% and 90.9%, respectively. On univariate analysis, age, T stage and the absence of bcl-2 & estrogen receptor (ER) expression were associated with loco-regional relapse-free survival. When incorporating these variables into Cox proportional hazard model, only bcl-2(-)/ER(-) phenotype was an adverse prognostic factor (P=0.018). As for the distant metastasis-free survival, age, T stage, and p53 expression were significant on univariate analysis. However, p53 expression was the only prognosticator on multivariate analysis (P=0.009). A bcl-2(-)/ER(-) phenotype and p53 expression are useful molecular markers predicting loco-regional relapse-free and distant metastasis-free survival, respectively, in patients treated with breast conserving surgery and radiotherapy.


Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial using bupropion.
We report a reanalysis of data from a prior study describing the event history of quitting smoking aided by bupropion, using recurrent-event models to determine the effect of the drug on occurrence of lapses and recoveries from lapse (resumption of abstinence). Data were collected on 1,070 subjects across two similar double-blind randomized clinical trials of bupropion versus placebo and fitted with separate Cox regression models for lapse and recovery. Analyses were split using discrete time-varying covariates between the treatment (weeks 1-10) and follow-up phases (end of treatment to 12 months). Bupropion was associated with slower lapse during treatment for both sexes, and being female was associated with faster lapse across both phases. Drug did not affect time to recovery for males but was associated with faster recovery among females, allowing women to recover as quickly as men. High levels of nicotine dependence did not affect time to lapse but were associated with slower recovery from lapse across treatment and follow-up phases. During the treatment phase, higher levels of baseline depression symptoms had no effect on time to lapse but were associated with slower recovery from lapse. Results highlight the asymmetry in factors preventing lapse versus promoting recovery. Specifically, dependence, depression symptoms, and a sex x drug interaction were found to affect recovery but not lapse. Further research disentangling lapse and recovery events from summary abstinence measures is needed to help us develop interventions that take advantage of bupropion at its best and that compensate where it is weak.


An efficient multi-scale learning method for image super-resolution networks.
The image super-resolution (SR) operation holds multiple solutions with the one-to-many mapping from low-resolution (LR) to high-resolution (HR) space. However, the SR of different scales for the same image is usually regarded as independent tasks in the existing SR networks. Therefore, these networks are inflexible to effectively utilize feature learning experience and require much more computing time to recover HR images in higher resolutions. Recent arbitrary scale SR methods still cannot solve these problems. To efficiently and effectively recover HR images, this paper presents an efficient multi-scale learning method for image SR networks based on a novel self-generating (SG) mechanism. This method (briefly named SG-SR) utilizes the feature learning results of SR networks to generate upscale filters by using the novel SG upscale module, which is proposed to replace the traditional upscale module. For each scale factor, the SG upscale module provides the corresponding amount of the spatial weights to filter the LR tensor and then converts filtered tensors with the original tensor to corresponding HR images. The proposed method is evaluated through extensive experiments and compared with state-of-the-art (SOTA) methods on widely used benchmark datasets. The experimental results show that our method has superior performance compared with SOTA methods, and the SG upscale module can improve the performance of existing SR networks effectively. What is more, our module has a much less calculation cost than the other upscale modules.


Prolonged metronidazole administration with protracted radiotherapy: a pilot study on response of advanced tumours.
In a pilot study, 2.5 g of metronidazole was administered in 3 divided daily doses for prolonged periods with protracted fractionated conventional radiotherapy. Total cumulative metronidazole dose was 94 g in 31 patients with head and neck carcinoma. In some others, lower dosage was used. Radiotherapy dose varied form 3000 rad in 5 patients to 7600 rad in 31 patients. Preliminary results with a minimum follow-up period of 6 months suggest enhanced tumour response without evident toxicity. The improved results, if sustained, may be speculatively explained by the combined or individual enhancement of effect due to the hypoxic radiosensitizer or by the high dose precision radiotherapy or by the specific elimination of the hypoxic tumour cells by cytotoxic effect of prolonged metronidazole administration. Controlled trials are now needed.


Effects of senescence-induced alteration in cytokinin metabolism on source-sink relationships and ontogenic and stress-induced transitions in tobacco.
Senescence and reserve mobilization are integral components of plant development, are basic strategies in stress mitigation, and regulated at least in part by cytokinin. In the present study the effect of altered cytokinin metabolism caused by senescence-specific autoregulated expression of the Agrobacterium tumefaciens IPT gene under control of the P(SAG12) promoter (P(SAG12)-IPT) on seed germination and the response to a water-deficit stress was studied in tobacco (Nicotiana tabacum L.). Cytokinin levels, sugar content and composition of the leaf strata within the canopy of wild-type and P(SAG12)-IPT plants confirmed the reported altered source-sink relations. No measurable difference in sugar and pigment content of discs harvested from apical and basal leaves was evident 72 h after incubation with (+)-ABA or in darkness, indicating that expression of the transgene was not restricted to senescing leaves. No difference in quantum efficiency, photosynthetic activity, accumulation of ABA, and stomatal conductance was apparent in apical, middle and basal leaves of either wild-type or P(SAG12)-IPT plants after imposition of a mild water stress. However, compared to wild-type plants, P(SAG12)-IPT plants were slower to adjust biomass allocation. A stress-induced increase in root:shoot ratio and specific leaf area (SLA) occurred more rapidly in wild-type than in P(SAG12)-IPT plants reflecting delayed remobilization of leaf reserves to sink organs in the transformant. P(SAG12)-IPT seeds germinated more slowly even though abscisic acid (ABA) content was 50% that of the wild-type seeds confirming cytokinin-induced alterations in reserve remobilization. Thus, senescence is integral to plant growth and development and an increased endogenous cytokinin content impacts source-sink relations to delay ontogenic transitions wherein senescence in a necessary process.


A process evaluation of a required primary care clerkship.
A process evaluation was implemented to guide faculty in developing a new required primary care clerkship. During the first eight months of the clerkship, 23 medical students were observed in a time and motion analysis and a study of the verbal content of the precepting interactions as students presented their patients to a preceptor. Students spent an average of 44% of their clinic time in examination rooms with patients, 21% interacting with preceptors and 13% waiting without interaction. The verbal behaviors accounting for 80% of the student-preceptor interaction time were case presentations (50%), direct or indirect questioning (16%), and making recommendations for management (13%).


Carers' quality of life and experiences of adult social care support in England.
Informal carers make a vital contribution to the well-being of the people they care for or look after. Against the policy background in England, the purpose of this study was to explore the views of carers who are in contact with adult social care support services. A qualitative study with 31 carers, who were recruited via local authorities and carers' organisations, was conducted between April and July 2012 to collect data on carers' experiences and perceptions of their quality of life (QoL) with and without adult social care and support for themselves or the person they look after. Through framework analysis, three key themes were identified: (i) definitions of social care services 'for' the carer or 'for' care recipient and social care outcomes; (ii) carers' access to social care services; and (iii) the meaning and value of informal care. We find that carers' QoL is affected by social care support directed at carers and support directed at those they care for, as well as access to services, the experience of stigma in communities, and in how individual needs and preferences are considered when making decisions about care. While there is much to welcome in the direction of policy in England, this study has shown that there are some gaps in thinking around these areas that will need to be addressed if the lives of carers are to be improved.


Glass transition temperature prediction of polymers through the mass-per-flexible-bond principle.
A semi-empirical method based on the mass-per-flexible-bond (M/f) principle was used to quantitatively explain the large range of glass transition temperatures (T(g)) observed in a library of 132 L-tyrosine derived homo, co- and terpolymers containing different functional groups. Polymer class specific behavior was observed in T(g) vs. M/f plots, and explained in terms of different densities, steric hindrances and intermolecular interactions of chemically distinct polymers. The method was found to be useful in the prediction of polymer T(g). The predictive accuracy was found to range from 6.4 to 3.7 K, depending on polymer class. This level of accuracy compares favorably with (more complicated) methods used in the literature. The proposed method can also be used for structure prediction of polymers to match a target T(g) value, by keeping the thermal behavior of a terpolymer constant while independently choosing its chemistry. Both applications of the method are likely to have broad applications in polymer and (bio)material science.


The thanatophoric dwarf. A report on two cases.
Two cases of thanatophoric dwarfism are presented. At external physical examination this anomaly is not readily distinguishable from achondroplasia and other forms of congenital disproportionate dwarfism. Radiologically, however, characteristic skeletal changes are demonstrable. The diagnosis can be made in utero. The clinical course is invariably fatal. The hereditary aspects, of importance for genetic counseling of parents, are still unexplained. The patients discussed show the typical thanatophoric skeletal changes in combination with a form of synostosis, i.e. bilateral radioulnar synostosis in one case, and synostosis of the coronal sutures and the lambdoid suture in the other. Emphasis is placed on the importance of radiological examination in cases of unexplained hydramnion and perinatal death.


Hematopoietic capacity of adult human skeletal muscle is negligible.
Using experimental mouse models, hematopoietic potential has been shown to exist within skeletal muscle. In humans, the clinical utility of using muscle-derived hematopoietic progenitors remains uncertain. Here, we evaluate the hematopoietic potential of human skeletal muscle. De novo adult muscle contained markedly reduced levels of hematopoietic colony-forming units (hCFU) and negligible responsiveness to hematopoietic ex vivo culture conditions that augment hematopoietic activity of fetal muscle. Neither fetal nor adult muscle yielded significant engraftment in transplanted immune-deficient mice. Although adult muscle possessed 1.5+/-0.9 hCFU/g, similar hematopoietic activity (2.3+/-0.17 hCFU) could also be demonstrated from as little as 3-10 microl of contaminating peripheral blood. We suggest that the clinical utility of adult skeletal muscle as an alternative source of hematopoietic cells in humans appears limited due to the low yield of blood-forming precursors and their lack of responsiveness to ex vivo expansion.


Developmental Effects on Auditory Neural Oscillatory Synchronization Abnormalities in Autism Spectrum Disorder.
Previous studies have found alterations in 40 Hz oscillatory activity in response to auditory stimuli in adults with Autism Spectrum Disorder (ASD). The current study sought to examine the specificity and developmental trajectory of these findings by driving the cortex to oscillate at a range of frequencies in both children and adults with and without ASD. Fifteen participants with ASD (3 female, aged 6-23 years) and 15 age-matched controls (4 female, aged 6-25 years) underwent dense-array EEG as they listened to a carrier tone amplitude-modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. EEG data were analyzed for inter-trial phase coherence (ITPC) and single-trial power (STP). Older participants with ASD displayed significantly decreased ability to phase-lock to the stimulus in the low gamma frequency range relative to their typically developing (TD) counterparts, while younger ASD and TD did not significantly differ from each other. An interaction between age and diagnosis suggested that TD and ASD also show different developmental trajectories for low gamma power; TD showed a significant decrease in low gamma power with age, while ASD did not. Regardless of age, increased low gamma STP was significantly correlated with increased clinical scores for repetitive behaviors in the ASD group, particularly insistence on sameness. This study contributes to a growing body of evidence supporting alterations in auditory processing in ASD. Older ASD participants showed more pronounced low gamma deficits than younger participants, suggesting an altered developmental trajectory for neural activity contributing to auditory processing deficits that may also be more broadly clinically relevant. Future studies are needed employing a longitudinal approach to confirm findings of this cross-sectional study.


A spatio-temporally compensated acousto-optic scanner for two-photon microscopy providing large field of view.
Acousto-optic deflectors (AOD) are promising ultrafast scanners for non-linear microscopy. Their use has been limited until now by their small scanning range and by the spatial and temporal dispersions of the laser beam going through the deflectors. We show that the use of AOD of large aperture (13mm) compared to standard deflectors allows accessing much larger field of view while minimizing spatio-temporal distortions. An acousto-optic modulator (AOM) placed at distance of the AOD is used to compensate spatial and temporal dispersions. Fine tuning of the AOM-AOD setup using a frequency-resolved optical gating (GRENOUILLE) allows elimination of pulse front tilt whereas spatial chirp is minimized thanks to the large aperture AOD.


The effect of breastfeeding on postpartum fructosamine and HbA1c values after normal pregnancy.
Breastfeeding can lower postpartum oral glucose tolerance test results by 5%. Similar data do not exist regarding fructosamine and HbA1c. The primary outcome was to determine if breastfeeding would lower fructosamine values by 5%. At the 4-8 week postpartum visit, women with uncomplicated pregnancies were given a questionnaire and had blood drawn for fructosamine and HbA1c. Breastfeeding (n = 22) and non-breastfeeding women (n = 28) were demographically similar, including postpartum weight loss. The respective values among breastfeeding and non-breastfeeding women were: fructosamine 2.20 versus 2.21 mmol/L; HbA1c 5.2% versus 5.2%. Only two of the seven women with an HbA1c of 5.7% or more had an abnormal fructosamine. After uncomplicated pregnancies, breastfeeding was not associated with lower levels of postpartum fructosamine or HbA1c. Future research to improve screening for persistent postpartum dysglycemia in high-risk populations can utilize these tests without concern that results will be confounded by breastfeeding.


Common errors in disease mapping.
Many morbid-mortality atlases and small-area studies have been carried out over the last decade. However, the methods used to draw up such research, the interpretation of results and the conclusions published are often inaccurate. Often, the proliferation of this practice has led to inefficient decision-making, implementation of inappropriate health policies and negative impact on the advancement of scientific knowledge. This paper reviews the most frequent errors in the design, analysis and interpretation of small-area epidemiological studies and proposes a diagnostic evaluation test that should enable the scientific quality of published papers to be ascertained. Nine common mistakes in disease mapping methods are discussed. From this framework, and following the theory of diagnostic evaluation, a standardised test to evaluate the scientific quality of a small-area epidemiology study has been developed. Optimal quality is achieved with the maximum score (16 points), average with a score between 8 and 15 points, and low with a score of 7 or below. A systematic evaluation of scientific papers, together with an enhanced quality in future research, will contribute towards increased efficacy in epidemiological surveillance and in health planning based on the spatio-temporal analysis of ecological information.


Collecting Sexual Orientation and Gender Identity Information at Death.
Currently, no US jurisdiction or agency routinely or systematically collects information about individuals' sexual orientation and gender identity (SOGI) at the time of death. As a result, little is known about causes of death in people having a minority sexual orientation or gender identity. These knowledge gaps have long impeded identification of mortality disparities in sexual and gender minority populations and hampered the development of targeted public health interventions and prevention strategies. We offer observations about the possibilities and challenges of collecting and reporting accurate postmortem SOGI information on the basis of our past four years of working with death investigators, coroners, and medical examiners. This work was located primarily in New York, New York, and has extended from January 2015 to the present. Drawing on our experiences, we make recommendations for future efforts to include SOGI among the standard demographic variables used to characterize individuals at death.


[Which is the preferred perioperative beta-blocker?].
Guidelines on perioperative cardiovascular evaluation and management of patients undergoing non-cardiac surgery recommend initiation of beta-blocker therapy in at-risk patients who are undergoing intermediate- to high-risk surgery. Continuation of therapy in patients already receiving beta-blockers is also recommended. Recent literature, however, reported an increased risk of perioperative cardiovascular mortality among patients who continued with existing beta-blockade; most patients in this study were using metoprolol. There are important pharmacodynamic and pharmacokinetic differences between various beta-blockers, and these differences may explain the differences in clinical effects. Metoprolol has less beta1 receptor affinity compared with atenolol and bisoprolol, and beta1 receptor polymorphisms affect the clinical effects of metoprolol. Furthermore, metoprolol is dependent on activity of the CYP2D6 liver enzyme, which results in clinically important differences in plasma concentration. It is, therefore, wise to follow the European guidelines and to initiate beta-blocker therapy in the perioperative period with either atenolol or bisoprolol.


[The interaction between nucleus accumbens and amygdala in accelerating the release of enkephalins and beta-endorphin].
The functional relations between nucleus accumbens and amygdala were investigated with intracranial microinjection, push-pull perfusion and radioimmunoassay in the rabbit. Microinjection of morphine 20 micrograms into nucleus accumbens increased the immunoreactive (ir) enkephalin content in amygdala perfusate from a control level of 0.43 +/- 0.43 fmol/0.5 ml (normal saline group) to 61.6 +/- 16.3 fmol/0.5 ml (P less than 0.01); and ir-beta-endorphin content from 1.88 +/- 0.98 fmol/0.5 ml to 4.80 +/- 1.12 fmol/0.5 ml (P less than 0.05). On the other hand, microinjection of morphine into amygdala increased the release of ir-enkephalins (2.41 +/- 1.41 vs 34.6 +/- 8.4, P less than 0.01) and ir-beta-endorphin (1.79 +/- 0.64 vs 5.58 +/- 1.39 P less than 0.05) in the perfusates of N. accumbens. The results indicate the existence of reciprocal reinforcement of opioid release between the two nuclei, which may take part in a putative positive feedback mechanism in the cerebral analgesic system.


The temporal sequence of synaptic initiation, crossing over and synaptic completion.
Questions are raised as to the validity of arguments that crossover positions have been demonstrated to be normally established only during pachytene (after synapsis is maximal). An alternative and testable hypothesis is that crossover commitment can occur at events of synaptic initiation.-Measurements are presented of extents of pachytene synapsis and failure in and around a region of maize chromosome heterozygous for a short paracentric inversion, and these are compared to conjectured expectations from observations of crossover frequencies within the inversion. Various hypotheses consistent with the results are considered. It is pointed out that the hypothesis that increases in crossover frequency in the synapsed region of the inversion are compensatory to crossover inhibitions elsewhere requires complex assumptions: that the adjustment must take place among, not within cells and that the enhancement is preferentially expressed within the inversion instead of elsewhere in the genome. The hypothesis that the fixing and squashing procedure forces apart non-crossover regions previously synapsed but lacking a crossover also requires complex assumptions. The simplest hypothesis proposes that crossover commitment may determine synaptic expression. A role of the synaptonemal complex in the establishment of crossover sites is questioned or minimized.-Evidence is also presented with respect to conceivable function of the telomere in synaptic initiation. Restrictions on such a function, if it exists, seem to be required to account for the observations.


Kidney outer medulla mitochondria are more efficient compared with cortex mitochondria as a strategy to sustain ATP production in a suboptimal environment.
The kidneys receive ~25% of cardiac output, which is a prerequisite to maintain sufficient glomerular filtration rate. However, both intrarenal regional renal blood flow and tissue oxygen levels are heterogeneous with decreasing levels in the inner part of the medulla. These differences, in combination with the heterogeneous metabolic activity of the different nephron segment located in the different parts of the kidney, may constitute a functional problem when challenged. The proximal tubule and the medullary thick ascending limb of Henle are considered to have the highest metabolic rate, which is related to the high mitochondria content needed to sustain sufficient ATP production from oxidative phosphorylation to support high electrolyte transport activity in these nephron segments. Interestingly, the cells located in kidney medulla function at the verge of hypoxia, and the mitochondria may have adapted to the surrounding environment. However, little is known about intrarenal differences in mitochondria function. We therefore investigated functional differences between mitochondria isolated from kidney cortex and medulla of healthy normoglycemic rats by using high-resolution respirometry. The results demonstrate that medullary mitochondria had a higher degree of coupling, are more efficient, and have higher oxygen affinity, which would make them more suitable to function in an environment with limited oxygen supply. Furthermore, these results support the hypothesis that mitochondria of medullary cells have adapted to the normal hypoxic in vivo situation as a strategy of sustaining ATP production in a suboptimal environment.


Management of the anticoagulated trauma patient in the emergency department: a survey of current practice in England and Wales.
The aim of this study was to investigate current management of the anticoagulated trauma patient in the emergency departments (EDs) in England and Wales. A survey exploring management strategies for anticoagulated trauma patients presenting to the ED was developed with two patient scenarios concerning assessment of coagulation status, reversal of international normalised ratio (INR), management of hypotension and management strategies for each patient. Numerical data are presented as percentages of total respondents to that particular question. 106 respondents from 166 hospitals replied to the survey, with 24% of respondents working in a major trauma unit with a specialist neurosurgical unit. Variation was reported in the assessment and management strategies of the elderly anticoagulated poly-trauma patient described in scenario one. Variation was also evident in the responses between the neurosurgical and non-neurosurgical units for the head-injured, anticoagulated trauma patient in scenario two. The results of this study highlight the similarities and variation in the management strategies used in the EDs in England and Wales for the elderly, anticoagulated trauma patient. The variations in practice reported may be due to the differences evident in the available guidelines for these patients.


Suppression of apoptosis by gonadotropin, 17beta-estradiol, and epidermal growth factor in rainbow trout preovulatory ovarian follicles.
In this study we present the first evidence for the occurrence of apoptotic cell death in ovarian follicles from teleost fish. Preovulatory ovarian follicles from mature hatchery-raised rainbow trout (Oncorhynchus mykiss) were collected and either immediately frozen in liquid nitrogen or incubated in serum-free medium at 18 degrees for 24 hr. The extent of ovarian apoptotic DNA fragmentation was determined using 3'-end labeling of DNA with [32P]dideoxy-ATP, size fractionation by agarose gel electrophoresis, and quantification of low-molecular-weight (<15 kb) DNA using autoradiography and liquid scintillation counting. The extent of apoptotic DNA fragmentation was eightfold greater in immediately frozen preovulatory follicles than in previtellogenic ovarian follicles collected from immature rainbow trout (P < 0.05), suggesting differences in the degree of apoptosis at different stages of follicular development. In preovulatory trout follicles, the extent of apoptotic DNA fragmentation was fivefold greater in follicles incubated for 24 hr. Treatment of incubated preovulatory follicles with either partially purified salmon gonadotropin SG-G100 (1 microg/ml) or epidermal growth factor (EGF; 100 ng/ml) suppressed apoptotic DNA fragmentation by 31 and 41%, respectively, in comparison to untreated incubated follicles (P < 0.01). Treatment of incubated follicles with 17beta-estradiol (1-100 ng/ml) caused a concentration-dependent suppression of apoptotic DNA fragmentation (P < 0.05). These results suggest that apoptosis is involved in teleost ovarian development and that several of the hormonal factors acting as follicle survival factors in mammalian and avian ovaries may play a similar role in teleost ovarian follicles.


Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation.
Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFA(SEP(N20)) and HFA(SEP(N80))) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFA(CCEP(N1)) and HFA(CCEP(N2))). HFA(SEP(N20)) showed the power peak in the frequency above 200 Hz, while HFA(CCEP(N1)) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFA(CCEP(N1)) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.


μEMA: Microinteraction-based Ecological Momentary Assessment (EMA) Using a Smartwatch.
Ecological Momentary Assessment (EMA) is a method of in situ data collection for assessment of behaviors, states, and contexts. Questions are prompted during everyday life using an individual's mobile device, thereby reducing recall bias and increasing validity over other self-report methods such as retrospective recall. We describe a microinteraction-based EMA method ("micro" EMA, or μEMA) using smartwatches, where all EMA questions can be answered with a quick glance and a tap - nearly as quickly as checking the time on a watch. A between-subjects, 4-week pilot study was conducted where μEMA on a smartwatch (n=19) was compared with EMA on a phone (n=14). Despite an ≈8 times increase in the number of interruptions, μEMA had a significantly higher compliance rate, completion rate, and first prompt response rate, and μEMA was perceived as less distracting. The temporal density of data collection possible with μEMA could prove useful in ubiquitous computing studies.


CD38/ADP-ribosyl cyclase: A new role in the regulation of osteoclastic bone resorption.
The multifunctional ADP-ribosyl cyclase, CD38, catalyzes the cyclization of NAD(+) to cyclic ADP-ribose (cADPr). The latter gates Ca(2+) release through microsomal membrane-resident ryanodine receptors (RyRs). We first cloned and sequenced full-length CD38 cDNA from a rabbit osteoclast cDNA library. The predicted amino acid sequence displayed 59, 59, and 50% similarity, respectively, to the mouse, rat, and human CD38. In situ RT-PCR revealed intense cytoplasmic staining of osteoclasts, confirming CD38 mRNA expression. Both confocal microscopy and Western blotting confirmed the plasma membrane localization of the CD38 protein. The ADP-ribosyl cyclase activity of osteoclastic CD38 was next demonstrated by its ability to cyclize the NAD(+) surrogate, NGD(+), to its fluorescent derivative cGDP-ribose. We then examined the effects of CD38 on osteoclast function. CD38 activation by an agonist antibody (A10) in the presence of substrate (NAD(+)) triggered a cytosolic Ca(2+) signal. Both ryanodine receptor modulators, ryanodine, and caffeine, markedly attenuated this cytosolic Ca(2+) change. Furthermore, the anti-CD38 agonist antibody expectedly inhibited bone resorption in the pit assay and elevated interleukin-6 (IL-6) secretion. IL-6, in turn, enhanced CD38 mRNA expression. Taken together, the results provide compelling evidence for a new role for CD38/ADP-ribosyl cyclase in the control of bone resorption, most likely exerted via cADPr.


Selection, follow-up, and analysis in the Birmingham Study.
The Birmingham, England, Cancer Registry is so organized that every case of cancer in its territory of 5,200,000 persons is included. This coverage allows the staff to detail every epidemiologic aspect of the cancer experience of a whole population. For example, this registry system made it possible for us not only to demonstrate that the Birmingham region had four times the incidence of scrotal cancer as another region had but to identify the locations and the specific practices in the workplace responsible for the excess. The result was the successful adoption of protective measures. Other instances are presented of the inestimable value of a population-based registry to cancer epidemiology.


Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography.
Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer's disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer's disease neuropathology) in patients presenting with CBS. In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal). A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen's kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD). Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.


Relationship of life expectancy with quality of life and health-related hope among Japanese patients receiving home medical care: The Zaitaku Evaluative Initiatives and Outcome Study.
Spiritual care for patients' quality of life (QOL) and hope should be included in home medical care for patients with limited life expectancy. This study aimed to analyze the associations between estimated life expectancy, QOL, and hope among patients receiving home medical care in Japan. This multicenter cross-sectional study involved 29 home medical care facilities in Japan. Patients were categorized by estimated life expectancy, as assessed by home medical care physicians. The outcomes were QOL measured via the Quality-of-Life Scale for Elderly Patients Receiving Professional Home Care (QOL-HC: higher score indicates better QOL), the domain scores of health-related hope ("health," "role and connectedness," and "something to live for"; higher scores indicate higher levels of hope), and life functioning measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0; higher score indicates worse functioning and disability). QOL-HC scores were significantly higher in patients with shorter life expectancy (< 6 m vs. ≥ 1 y, adjusted mean differences: 0.7 points [95%CI 0.1 to 1.3]). Regarding health-related hope, "something to live for" scores were associated with shorter life expectancy (< 6 m vs. ≥ 1 y, -17.7 points [-34.2 to -1.2]), whereas "role and connectedness" scores did not change remarkably with shorter life expectancy (< 6 m vs. ≥ 1 y, -3.3 points [-16.4 to 9.8]). Furthermore, shorter life expectancy was associated with higher WHODAS 2.0 scores (< 6 m vs. ≥ 1 y, 19.6 points [4.3 to 34.8]). Home medical care physicians who engage in spiritual care should facilitate thoughtful dialogue with their patients by recognizing declines in life functions and hope for fulfilment, which are associated with short life expectancy.


A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis.
Fructose-1,6-bisphosphatase deficiency is a rare inborn error of metabolism affecting gluconeogenesis with only sporadic reports on its molecular genetic basis. We report our experience with mutation analysis in 14 patients (13 families) with fructose-1,6-bisphosphatase deficiency using conventional Sanger sequencing and multiplex ligation-dependent probe amplification analysis, and we provide a mutation update for the fructose bisphosphatase-1 gene (FBP1). Mutations were found on both chromosomes in all of our 14 patients including 5 novel mutations. Among the novel mutations is a 5412-bp deletion (c.-24-26_170 + 5192del) including the entire coding sequence of exon 2 of FBP1 that was repeatedly found in patients from Turkey and Armenia which may explain earlier poorly defined findings in patients from this area. This deletion can be detected with specific primers by generation of a junction fragment and by MLPA and SNP array assays. MLPA analysis was able to detect copy number variations in two further patients, one heterozygous for a deletion within exon 8, another heterozygous for a novel deletion of the entire FBP1 gene. Based on our update for the FBP1 gene, currently listing 35 mutations worldwide, and knowledge of PCR conditions that allow simple detection of a common FBP1 deletion in the Armenian and Turkish population, molecular genetic diagnosis has become easier in FBP1 deficiency. Furthermore, MLPA analysis may plays a useful role in patients with this disorder.


Protecting embryos from stress: corticosterone effects and the corticosterone response to capture and confinement during pregnancy in a live-bearing lizard (Hoplodactylus maculatus).
Hormones in the embryonic environment, including those of the hypothalamo-pituitary-adrenal (HPA) axis, have profound effects on development in eutherian mammals. However, little is known about their effects in reptiles that have independently evolved viviparity. We investigated whether exogenous corticosterone affected embryonic development in the viviparous gecko Hoplodactylus maculatus, and whether pregnant geckos have a corticosterone response to capture and confinement that is suppressed relative to that in non-pregnant (vitellogenic) females and males. Corticosterone implants (5 mg, slow-release) administered to females in mid-pregnancy caused a large elevation of corticosterone in maternal plasma (P<0.001), probable reductions in embryonic growth and development (P=0.069-0.073), developmental abnormalities and eventual abortions. Cool temperature produced similar reductions in embryonic growth and development (P< or =0.036 cf. warm controls), but pregnancies were eventually successful. Despite the potentially harmful effects of elevated plasma corticosterone, pregnant females did not suppress their corticosterone response to capture and confinement relative to vitellogenic females, and both groups of females had higher responses than males. Future research should address whether lower maternal doses of corticosterone produce non-lethal effects on development that could contribute to phenotypic plasticity. Corticosterone implants also led to increased basking in pregnant females (P<0.001), and basal corticosterone in wild geckos (independent of reproductive condition) was positively correlated with body temperature (P<0.001). Interactions between temperature and corticosterone may have broad significance to other terrestrial ectotherms, and body temperature should be considered as a variable influencing plasma corticosterone concentrations in all future studies on reptiles.


Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity.
DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.