Vasculitis associated with rheumatoid arthritis: a case-control study.
The aim of this study was to determine the clinical correlates and predictors of rheumatoid vasculitis (RV). A retrospective cohort of patients with RV evaluated at a tertiary referral centre between 1 January 2000 and 1 January 2010 was identified. RV cases were compared in a 1:2 ratio to controls (RA without vasculitis) to identify risk factors for developing RV. Eighty-six RV cases (58% women, 88% white) were identified. Histopathological confirmation was available for 58% of patients. Cutaneous vasculitis was the most common presentation, followed by vasculitic neuropathy. The median age at presentation was 63 years and the median duration of RA was 10.8 years. One third were current smokers. The majority were seropositive and had elevated inflammatory markers. Treatment was with a range of immunomodulating agents. At 6 months, 38% of patients achieved complete remission, 52% had partial improvement and 10% noted no clinical improvement. Thirty-six per cent relapsed by 5 years and 26% died. After adjusting for age and disease duration, current smoking at RA diagnosis [odds ratio (OR) 1.98], coexistent peripheral vascular disease (OR 3.98), cerebrovascular disease (OR 6.48), severe RA (OR 2.02) (characterized by radiographic erosions, nodulosis on clinical examination or requirement of joint surgery) and the use of biologics (OR 2.80) were found to increase the odds for developing RV; the use of HCQ (OR 0.54, CI 0.31, 0.94) and low-dose aspirin (OR 0.42, CI 0.21, 0.85) was associated with decreased odds for developing RV. This largest single-centre series of patients with RV suggests that even in recent years, RV remains a serious complication of RA and is associated with significant mortality.


Juvenile arteritis revisited. Buerger's disease-Takayasu's disease.
Thromboangiitis obliterans is defined as an inflammatory disease involving small and medium sized arteries and veins. As no clinical symptoms, signs, radiological or laboratory abnormalities nor pathological features are specific, the diagnosis is usually made according the criteria proposed by Adar in a young smoker, male or female, with distal arterial occlusions sometimes associated with thrombophlebitis and with negative aetiological investigations. Recently, rheumatic manifestations were identified in about 10% of patients. If new developments in vascular medicine, as ultrasound explorations or CT scan limit the indications for angiography, others, especially in the field of thrombophilia, make more difficult the differential diagnosis. If the strong link between the disease activity and smoking habits is confirmed, medical or surgical approach remain disappointing. Takayasu's disease or non specific aorto-arteritis is an inflammatory disease of young women that primarily affects the aorta its main branches and the pulmonary arteries. The disease often start in children. The prevalence of the disease as the arterial lesions show geographical variations. That and the different associations with infectious, rheumatic or systemic diseases could justify to consider Takayasu's disease as a syndrome. B-mode ultrasonography and electron beam computed tomography are usually sufficient to characterize the arterial involvement and are essential for the follow up of patients. In some rare cases arterial biopsy is necessary to confirm the diagnosis. The surgical treatment concerns specific lesions with ischemic symptoms and failure of the medical approach, however endovascular techniques are often discussed in first intention. During inflammatory phases with evolutive lesions corticosteroids are often used. In case of failure cyclophosphamide or methotrexate have been used.


How AI can learn from the law: putting humans in the loop only on appeal.
While the literature on putting a "human in the loop" in artificial intelligence (AI) and machine learning (ML) has grown significantly, limited attention has been paid to how human expertise ought to be combined with AI/ML judgments. This design question arises because of the ubiquity and quantity of algorithmic decisions being made today in the face of widespread public reluctance to forgo human expert judgment. To resolve this conflict, we propose that human expert judges be included via appeals processes for review of algorithmic decisions. Thus, the human intervenes only in a limited number of cases and only after an initial AI/ML judgment has been made. Based on an analogy with appellate processes in judiciary decision-making, we argue that this is, in many respects, a more efficient way to divide the labor between a human and a machine. Human reviewers can add more nuanced clinical, moral, or legal reasoning, and they can consider case-specific information that is not easily quantified and, as such, not available to the AI/ML at an initial stage. In doing so, the human can serve as a crucial error correction check on the AI/ML, while retaining much of the efficiency of AI/ML's use in the decision-making process. In this paper, we develop these widely applicable arguments while focusing primarily on examples from the use of AI/ML in medicine, including organ allocation, fertility care, and hospital readmission.


[Contributions of proteomics in the study of diabetes].
The incidence of type 2 diabetes mellitus (T2D) is growing rapidly due to aging, urbanization, changes in lifestyle, and increasing prevalence of obesity. In T2D, chronic hyperglycemia leads to macro and micro vascular complications, which currently are serious problem for health systems worldwide. The complexity of T2D and its complications requires study skills of high performance that provide important information in the understanding of the pathophysiology of the disease and biological pathways involved in development of T2D and its complications. In this work we describe the recent contributions of proteomics in the study of T2D and discuss its importance in the identification of therapeutic targets and biomarkers that help to improve the diagnosis of T2D, monitor the disease progression, and the development of new drugs to improve treatment and reduce its complications.


Outcome of recurrent uterine papillary serous carcinoma treated with platinum-based chemotherapy.
The aim of this study was to estimate the outcome and response to platinum-based chemotherapy (CT) in patients with recurrent uterine papillary serous carcinoma (UPSC). Patients with recurrent UPSC from 2000 to 2012 were included retrospectively. All patients received platinum-based CT for recurrent disease. Platinum-free interval was divided into less than 6 months (platinum resistant) and 6 months or longer (platinum sensitive). Twenty-two patients with recurrent UPSC were included. The median age was 66.5 years. The majority of the patients initially presented with advanced-stage disease (68%). A total of 84% (18/22) received adjuvant CT; all regimens were platinum based.The overall response rate (RR) and stable disease were 50% and 36.4%. The mean duration of response and stable disease were 9.4 and 5.6 months. Among the platinum-sensitive group, the overall RR was 64.7% compared with 0% in the platinum-resistant group. Among the patients who received prior adjuvant platinum-based CT, the RR was 38.8% compared with 100% among those who did not receive adjuvant CT. When stratified by platinum-based regimen, those who received the platinum-taxane regimen had a higher RR compared with those who received the platinum-gemcitabine regimen (62.5% vs 20%) among those who received prior adjuvant platinum therapy. The median progression-free survival and overall survival for the entire cohort were 8.4 and 24.9 months, respectively. The median progression-free survival was significantly longer for platinum-sensitive disease compared with platinum-resistant disease (10.2 vs 3.3 months, respectively; P = 0.002). Similarly, the median overall survival was longer for platinum-sensitive disease compared with platinum-resistant disease (27.1 vs 13.7 months, respectively). However, this difference was not statistically significant (P = 0.15). Platinum-based CT is an active regimen in recurrent UPSC even if patients received prior adjuvant platinum CT. Platinum-free interval predicts response and outcome of platinum-based CT in recurrent setting such as in ovarian cancer. Plantinum-taxane is more active than platinum-gemcitabine in recurrent UPSC.


Tracing life: the history, concept and goals of the new permanent exhibition in the Berlin Museum of Medical History at the Charité.
The Berlin Museum of Medical History at the Charité has been in existence since 1998. The institution aims to showcase medicine, yet it wants to show not only what medicine is but also and especially, how medicine came to be what it represents today. In its new permanent exhibition, opened on 25 October 2007, the museum takes a look at the development of medicine from a western, natural historical and scientific perspective over the last three centuries.


Comparison of efficacy of topical clindamycin and nicotinamide combination with plain clindamycin for the treatment of acne vulgaris and acne resistant to topical antibiotics.
A total of 75 patients with inflammatory acne vulgaris were divided into three groups. Group A was treated with combination of 4% nicotinamide and 1% clindamycin combination, Group B was treated with plain 1% clindamycin and Group C which was considered to have resistance to local antibiotics due to no response to treatment was treated with the combination. At the end of 8 weeks the results were compared. It was concluded that addition of nicotinamide was of not much value in treating inflammatory acne and results were some as for plain clindamycin and also the combination did not offer much relief in treatment of resistant acne.


Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated. We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing. Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different. In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).


[The use of piribedil for the prevention of falls in elderly patients with metabolic syndrome].
Effects of pirebedil used to prevent falls in elderly patients with metabolic syndrome are discussed. A prospective controlled study showed that therapy with pirebedil significantly decreases the frequency of falls, reduces severity of pro-inflammatory and pro-oxidative activities, improves cognitive abilities. Prevention of falls by virtue of improved cognitive abilities is a new clinical effect of pirebedil and gives reason to recommend it for the treatment of geriatric patients with metabolic syndrome.


Global analysis of seed transcriptomes reveals a novel PLATZ regulator for seed size and weight control in soybean.
Seed size and weight are important factors that influence soybean yield. Combining the weighted gene co-expression network analysis (WGCNA) of 45 soybean accessions and gene dynamic changes in seeds at seven developmental stages, we identified candidate genes that may control the seed size/weight. Among these, a PLATZ-type regulator overlapping with 10 seed weight QTLs was further investigated. This zinc-finger transcriptional regulator, named as GmPLATZ, is required for the promotion of seed size and weight in soybean. The GmPLATZ may exert its functions through direct binding to the promoters and activation of the expression of cyclin genes and GmGA20OX for cell proliferation. Overexpression of the GmGA20OX enhanced seed size/weight in soybean. We further found that the GmPLATZ binds to a 32-bp sequence containing a core palindromic element AATGCGCATT. Spacing of the flanking sequences beyond the core element facilitated GmPLATZ binding. An elite haplotype Hap3 was also identified to have higher promoter activity and correlated with higher gene expression and higher seed weight. Orthologues of the GmPLATZ from rice and Arabidopsis play similar roles in seeds. Our study reveals a novel module of GmPLATZ-GmGA20OX/cyclins in regulating seed size and weight and provides valuable targets for breeding of crops with desirable agronomic traits.


Comparative pharmacokinetics of paclitaxel after oral administration of Taxus yunnanensis extract and pure paclitaxel to rats.
Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and C(max) of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel.


An antibody reactivity-based assay for diagnosis of invasive candidiasis using protein array.
The increased incidence of invasive candidiasis and of patients at risk requires early diagnosis and treatment to improve prognosis and survival. The aim of this study was to set up a ten-protein array-based immunoassay to assess the IgG antibody responses against ten well-known immunogenic C. albicans proteins (Bgl2, Eno1, Pgk1, Pdc11, Fba1, Adh1, Als3, Hwp1, Hsp90 and Grp2) in 51 patients with invasive candidiasis (IC) and in 38 culture-negative controls (non-IC). Antibody levels were higher against Bgl2, Eno1, Pgk1, Als3, Hwp1 and Grp2, than against Adh1, Pdc11, Fba1 and Hsp90, irrespectively of the patient group considered. Moreover, the IgG levels against Bgl2, Eno1, Pgk1 and Grp2 were significantly higher in IC than in non-IC patients. Furthermore, the ROC curves generated by the analysis of the antibody responses against Bgl2, Grp2 and Pgk1 displayed AUC values above 0.7, thus discriminating IC and non-IC patients. According to these results, the employment of the microarray immunoassay (a rapid, sensitive and multiparametric system), in parallel with conventional diagnostics, can help to spot IC patients. This ultimately will allow to initiate an early, focused and optimized antifungal therapy.


Key Challenges for In Vitro Testing of Tobacco Products for Regulatory Applications: Recommendations for the In Vitro Mouse Lymphoma Assay.
The Institute for In Vitro Sciences (IIVS) is sponsoring a series of workshops to develop recommendations for optimal scientific and technical approaches for conducting in vitro assays to assess potential toxicity within and across traditional tobacco and various tobacco and nicotine next-generation products (NGPs), including Heated Tobacco Products (HTPs) and Electronic Nicotine Delivery Systems (ENDS). This report was developed by a working group composed of attendees of the seventh IIVS workshop, 'Approaches and recommendations for conducting the mouse lymphoma gene mutation assay (MLA) and introduction to in vitro disease models', which was held virtually on 21-23 June 2022. This publication provides a background overview of the MLA, and includes the description of assay conduct and data interpretation, key challenges and recommended best practices for evaluating tobacco and nicotine products, with a focus on the evaluation of NGPs, and a summary of how the assay has been used to evaluate and compare tobacco and nicotine products.


A 2-Hydroxyisoquinoline-1,3-Dione Active-Site RNase H Inhibitor Binds in Multiple Modes to HIV-1 Reverse Transcriptase.
The RNase H (RNH) function of HIV-1 reverse transcriptase (RT) plays an essential part in the viral life cycle. We report the characterization of YLC2-155, a 2-hydroxyisoquinoline-1,3-dione (HID)-based active-site RNH inhibitor. YLC2-155 inhibits both polymerase (50% inhibitory concentration [IC50] = 2.6 μM) and RNH functions (IC50 = 0.65 μM) of RT but is more effective against RNH. X-ray crystallography, nuclear magnetic resonance (NMR) analysis, and molecular modeling were used to show that YLC2-155 binds at the RNH-active site in multiple conformations.


Statins and the primary prevention of cardiovascular events.
Cardiovascular disease remains the leading cause of death in both men and women in the United States. Treating elevated low-density lipoprotein (LDL) cholesterol has been shown to be very effective in reducing the rate of coronary heart disease (CHD) in primary prevention trials; however, the data are not as robust for treating individuals categorized at either lower risk for CHD or with below-average LDL cholesterol levels. The next frontier for investigation will include strategies to determine who in these lower risk categories should be treated with statins. The growing epidemics of obesity, diabetes, and metabolic syndrome also loom as major problems that need to be incorporated into any strategy that focuses on the prevention of cardiovascular disease. In individuals with multiple cardiovascular risk factors, combination therapies tailored to address each individual's risk profile need to be considered to best decrease the likelihood of their first coronary event.


Current practice in managing patients on anticoagulants and/or antiplatelet agents around the time of gastrointestinal endoscopy -- a nation-wide survey in Germany.
Anticoagulants and antiplatelet agents are widely used in the prophylaxis and management of thromboembolic and cardiovascular diseases. Gastrointestinal bleeding is a well-known complication of these agents. Modification of anticoagulant and antiplatelet therapy is often required in patients undergoing surgical procedures and specific recommendations for the perioperative period have been issued. Fewer data exist with regard to the use of these agents around the time of endoscopic procedures. A survey of the American Society for Gastrointestinal Endoscopy (ASGE), performed several years ago, showed a wide variation between endoscopists in the management of anticoagulants and antiplatelet agents in the periendoscopic period. Subsequently, guidelines have been proposed by the ASGE as well as the German Society for Gastroenterology (DGVS). The aim of this study was to investigate the current practices among German endoscopists regarding the use of these medications in patients undergoing endoscopic procedures and to assess their adherence to published guidelines. Our data demonstrate that, in spite of the dissemination of guidelines, there is still a wide variation in the periendoscopic management of patients who are at increased risk for bleeding due to anticoagulants, especially in patients taking antiplatelet agents.


Low plasma basic fibroblast growth factor is associated with laser photocoagulation treatment in adult type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial.
Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen that does not normally circulate. Yet plasma bFGF-like bioactivity was increased in association with persistent microalbuminuria and retinopathy in adult type 2 diabetes mellitus. In the present study, we tested whether plasma bFGF immunoreactivity (IR) could predict the need for laser treatment of diabetic retinopathy in a baseline subset of advanced type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial (mean: age, 59 years; diabetes duration, 11 years; baseline glycosylated hemoglobin, 9.5%). Plasma bFGF-IR was determined with a sensitive and specific 2-site enzyme-linked immunoassay in 172 patients at the baseline visit. Results were dichotomized at 4.5 pg/mL, the upper limit in healthy men. There was an unexpected significant association between low baseline plasma bFGF-IR level and the interim (4 years) need for laser treatment. First laser treatment was significantly more likely to be required in patients with low compared with high baseline bFGF (19% vs 6%, P = .03 for the difference). After adjusting for clinical risk factors, low vs high bFGF (hazard ratio [HR], 5.01; P = .012), duration of diabetes (HR, 1.05; P = .050), and low-density lipoprotein cholesterol concentration (HR, 0.98; P = .027) were all significantly associated with time to first laser occurrence. These and our prior results suggest that low plasma bFGF-IR may be a marker for the presence of anti-endothelial cell autoantibodies that may contribute to the need for laser photocoagulation treatment in adult men with advanced type 2 diabetes mellitus.


Antiviral drug discovery against SARS-CoV.
Severe Acute Respiratory Syndrome (SARS) is a life-threatening infectious disease caused by SARS-CoV. In the 2003 outbreak, it infected more than 8,000 people worldwide and claimed the lives of more than 900 victims. The high mortality rate resulted, at least in part, from the absence of definitive treatment protocols or therapeutic agents. Although the virus spreading has been contained, due preparedness and planning, including the successful development of antiviral drugs against SARS-CoV, is necessary for possible reappearance of SARS. In this review, we have discussed currently available strategies for antiviral drug discovery and how these technologies have been utilized to identify potential antiviral agents for the inhibition of SARS-CoV replication. Moreover, progress in the drug development based on different molecular targets is also summarized, including 1) Compounds that block the S protein-ACE2-mediated viral entry; 2) Compounds targeting SARS-CoV M(pro); 3) Compounds targeting papain-like protease 2 (PLP2); 4) Compounds targeting SARS-CoV RdRp; 5) Compounds targeting SARS-CoV helicase; 6) Active compounds with unspecified targets; and 7) Research on siRNA. This review aims to provide a comprehensive account of drug discovery on SARS. The experiences with the SARS outbreak and drug discovery would certainly be an important lesson for the drug development for any new viral outbreaks that may emerge in the future.


Factor analysis of proton MR spectroscopic imaging data in HIV infection: metabolite-derived factors help identify infection and dementia.
To develop a relevant pathophysiologic model of human immunodeficiency virus (HIV)-associated dementia by studying regional variations in metabolite levels measured with magnetic resonance (MR) spectroscopic imaging and their relationship to immunologic measures and cognitive dysfunction. This was a HIPAA-compliant, institutional review board-approved study involving written informed consent. Distributions of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) concentrations in 94 subjects (20 seronegative controls and 74 HIV-positive subjects; 34 of the HIV-positive subjects having HIV-associated dementia; 63 men, 31 women; mean age, 40 years) were determined with proton (hydrogen 1 [(1)H]) MR spectroscopic imaging. HIV-positive subjects underwent neuropsychological testing and blood and cerebrospinal fluid (CSF) analysis. Factor analysis was utilized to determine associations between metabolites across regions. Analysis of variance and t tests were used to isolate differences between cohorts. A "Cho factor" differentiated seronegative controls from HIV-infected cohorts, indicating elevated Cho levels across deep gray and white matter regions of HIV-positive individuals. An "NAA factor" differentiated those with dementia from those without and correlated best with psychomotor and executive function tests. A "Cr factor" indicated Cr elevations correlated with CSF monocyte chemoattractant protein-1 levels. NAA and Cr factor scores were strongly weighted to metabolite changes in white matter regions. These results highlight the importance of white matter involvement in HIV-associated dementia and support the current pathogenesis model of glial cell proliferation in HIV infection, denoted by regional Cho elevations, and neuronal dysfunction and/or death, denoted by NAA decreases, associated with dementia. Factor analysis of MR spectroscopic imaging data is a useful method for determining regional metabolic variations in HIV infection and its neuropsychological correlates.


Functional interaction and partial homology between human immunodeficiency virus and neuroleukin.
Dementia is common in patients with AIDS, but the mechanism by which the human immunodeficiency virus type 1 (HIV-1) causes the neurological impairment is unknown. In this study the possibility that an antigen of HIV-1 suppresses neuronal responses to neurotrophic factors was examined. Both HIV-1 and a related retrovirus, simian immunodeficiency virus (SIV), inhibited the growth of sensory neurons from chick dorsal root ganglia in medium containing neuroleukin (NLK) but not in medium containing nerve growth factor. An unrelated type D retrovirus, simian acquired immunodeficiency syndrome virus, did not affect the growth of neurons in the presence of either neurotrophic factor. The inhibition by HIV-1 of neuron growth in the presence of NLK was found to be due to the gp120 envelope glycoprotein. Regions of sequence homology between gp120 and NLK may account for this inhibitory property of gp120 and functional interactions between gp120 and NLK may be important in the pathogenesis of the AIDS dementia complex.


Lymphocytes, lymphokines, and hematopoiesis.
It may be conclusively said that lymphocytes (T cells) produce an array of very powerful hematopoietic peptides, at least one of which (IL-3) appears to be exclusive. All are able to induce proliferation of stem cells of varying commitment, and in combination can reproduce virtually the entire sequence of hematopoietic cell production from the earliest stem cell, for example the HPP stem cells, which responds to T lymphokines in vitro or IL-3 in vivo, to a fully differentiated myeloid cell. Many T lymphokines can be demonstrated to exert highly significant changes in both hematopoiesis and lymphopoiesis in vivo. Thus, IL-3 suppresses NK development, thought to be partly responsible for hybrid resistance, as well as augmenting Ig responses [perhaps through an action on pre-B cells] and stimulating hematopoiesis. The effect on hematopoiesis is probably direct, because infused IL-3 is readily detectable when bound to the surfaces of cells both in the marrow and spleen. It is therefore somewhat surprising that the regulatory role of T cells themselves is less well defined. This arises variously from the availability of purified or recombinant products that replace crude T cell supernates, the complexity of analyzing a multicell system in which very many growth factors cannot be controlled for experimentally, and a certain lag in understanding the basic biology of T cells. This last is perhaps due to the historical recognition of the T cell as an immunocyte, which had led it to be principally investigated in an immunological context. The advent of molecular genetics has resulted in a reappraisal of the interrelationships between many cells, and growth-factor technology has been led to the realization that immune reactivity is perhaps only one function of the T-cell system, and that the classic concept of "immune surveillance" is only a part of a perhaps much wider "surveillance" system in which peptide growth factors and T cells play an exceedingly important role. A pertinent observation concerns abrogation of renal allograft rejection in rats by preoperation injection of donor blood. Although the allografts survive well, the graft is infiltrated by allospecific and nonspecific cytotoxic T cells and expresses donor class I and II antigens in a manner equal to that of a rejecting graft. What, therefore, is the role of lymphokines in this situation--Which of them are expressed, do they activate target cells, and what is the network that controls the macrophages and dendritic cells involved in allograft rejection?(ABSTRACT TRUNCATED AT 400 WORDS)


Melding Vapor-Phase Organic Chemistry and Textile Manufacturing To Produce Wearable Electronics.
Body-mountable electronics and electronically active garments are the future of portable, interactive devices. However, wearable devices and electronic garments are demanding technology platforms because of the large, varied mechanical stresses to which they are routinely subjected, which can easily abrade or damage microelectronic components and electronic interconnects. Furthermore, aesthetics and tactile perception (or feel) can make or break a nascent wearable technology, irrespective of device metrics. The breathability and comfort of commercial fabrics is unmatched. There is strong motivation to use something that is already familiar, such as cotton/silk thread, fabrics, and clothes, and imperceptibly adapt it to a new technological application. (24) Especially for smart garments, the intrinsic breathability, comfort, and feel of familiar fabrics cannot be replicated by devices built on metalized synthetic fabrics or cladded, often-heavy designer fibers. We propose that the strongest strategy to create long-lasting and impactful electronic garments is to start with a mass-produced article of clothing, fabric, or thread/yarn and coat it with conjugated polymers to yield various textile circuit components. Commonly available, mass-produced fabrics, yarns/threads, and premade garments can in theory be transformed into a plethora of comfortably wearable electronic devices upon being coated with films of electronically active conjugated polymers. The definitive hurdle is that premade garments, threads, and fabrics have densely textured, three-dimensional surfaces that display roughness over a large range of length scales, from microns to millimeters. Tremendous variation in the surface morphology of conjugated-polymer-coated fibers and fabrics can be observed with different coating or processing conditions. In turn, the morphology of the conjugated polymer active layer determines the electrical performance and, most importantly, the device ruggedness and lifetime. Reactive vapor coating methods allow a conjugated polymer film to be directly formed on the surface of any premade garment, prewoven fabric, or fiber/yarn substrate without the need for specialized processing conditions, surface pretreatments, detergents, or fixing agents. This feature allows electronic coatings to be applied at the end of existing, high-throughput textile and garment manufacturing routines, irrespective of dye content or surface finish of the final textile. Furthermore, reactive vapor coating produces conductive materials without any insulating moieties and yields uniform and conformal films on fiber/fabric surfaces that are notably wash- and wear-stable and can withstand mechanically demanding textile manufacturing routines. These unique features mean that rugged and practical textile electronic devices can be created using sewing, weaving, or knitting procedures without compromising or otherwise affecting the surface electronic coating. In this Account, we highlight selected electronic fabrics and garments created by melding reactive vapor deposition with traditional textile manipulation processes, including electrically heated gloves that are lightweight, breathable, and sweat-resistant; surface-coated cotton, silk, and bast fiber threads capable of carrying large current densities and acting as sewable circuit interconnects; and surface-coated nylon threads woven together to form triboelectric textiles that can convert surface charge created during small body movements into usable and storable power.


Gait characteristics of persons with bilateral transtibial amputations.
The gait characteristics of persons with unilateral transtibial amputations are fairly well documented in the literature. However, much less is known about the gait of persons with bilateral transtibial amputations. This study used quantitative gait analysis to investigate the gait characteristics of 19 persons with bilateral transtibial amputations. To reduce variability between subjects, we fitted all subjects with Seattle Lightfoot II feet 2 weeks before their gait analyses. The data indicated that subjects walked with symmetrical temporospatial, kinematic, and kinetic parameters. Compared with nondisabled controls, the subjects with amputations walked with slower speeds and lower cadences, had shorter step lengths and wider step widths, and displayed hip hiking during swing phase. Additionally, compared with the nondisabled controls walking at comparable speeds, the subjects with amputations demonstrated reduced ankle dorsiflexion and knee flexion in stance phase, reduced peak ankle plantar flexor moment, reduced positive ankle power (i.e., energy return) in late stance, and increased positive and negative hip power. These results demonstrate the deficiencies in current prosthetic componentry and suggest that further research is needed to enhance prosthesis function and improve gait in persons with amputations.


Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva.
Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1R206H (referred to as Acvr1cR206H/+ ) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1cR206H/+ lesions and in Acvr1cR206H/+ mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1cR206H/+ mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1R206H in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.


Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2- Early Breast Cancer.
To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental (v control) arm; secondary end points included distant DFS, overall survival, and translational research. Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority (P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% (P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.


Hexavalent chromium removal from aqueous solution by algal bloom residue derived activated carbon: equilibrium and kinetic studies.
A novel approach to prepare activated carbon from blue-green algal bloom residue has been tried for first time and its adsorption capability to remove hexavalent chromium Cr(VI) from aqueous solution has been examined. For this algal bloom residue derived activated carbon, the physical characters regarding adsorption capability were analyzed by scanning electron microscope (SEM), energy dispersive X-ray spectroscope (EDS) and Fourier transform infrared (FTIR) spectroscopy. Batch studies showed that initial pH, absorbent dosage, and initial concentration of Cr(VI) were important parameters for Cr(VI) absorption. It was found that initial pH of 1.0 was most favorable for Cr(VI) removal. The adsorption process followed the pseudo-second-order equation and Freundlich isotherm. The maximum adsorption capacity for Cr(VI) was 155.52 mg g(-1) in an acidic medium, which is comparable to best result from activated carbons derived from biomass. Therefore, this work put forward a nearly perfect solution which on one hand gets rid of environment-unfriendly algae residue while on the other hand produces high-quality activated carbon that is in return advantageous to environment protection.


Hyperkalemia in patients with heart failure: incidence, prevalence, and management.
Multilevel inhibition of neurohormonal activation using angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin receptor blockers, and aldosterone antagonists is the cornerstone of modern heart failure treatment. Use of these agents in optimal doses is associated with significant improvements in heart failure-associated morbidity and mortality but also may increase serum potassium. Because potassium excretion already is impaired in many heart failure patients because of advanced age, diabetes, or chronic kidney disease, the risk of life-threatening hyperkalemia during treatment is significant. This review discusses the mechanisms, incidence, predictors, and management of hyperkalemia in heart failure, emphasizing the importance of careful patient selection for medical treatment and regular surveillance of potassium and creatinine.


MRI-visible perivascular spaces: relationship to cognition and small vessel disease MRI markers in ischaemic stroke and TIA.
MRI-visible perivascular spaces (PVS) are potential neuroimaging markers of cerebral small vessel disease, but their functional significance and mechanisms remain uncertain. We investigated the association between PVS and cognitive impairment, and other MRI markers of small vessel disease, in a patient cohort of ischaemic stroke/transient ischaemic attack (TIA) referrals. Data were collected from a prospective observational database. Standardised detailed neuropsychological testing was performed. A validated visual rating scale on T2-weighted MRI was used to categorise PVS severity; validated scales were used to assess white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes. We included 246 patients (45.1% female, mean age 62 years). No significant association between PVS severity grade in any brain region and impairment in any cognitive domain was identified. In multivariable analysis, WMH and hypertension (but not age) were independently associated with basal ganglia PVS severity (OR: 1.27; p<0.0001 and OR: 4.89; p=0.013, respectively). Increasing PVS severity in the basal ganglia was associated with lacunar stroke subtype (p<0.0001). Age and hypertension (but not WMH or lacunar stroke subtype) were independently associated with centrum semiovale PVS severity (OR: 1.19; p=0.013 and OR: 3.71; p=0.007, respectively). PVS do not have an independent association with cognitive impairment in patients with ischaemic stroke or TIA. The associations with clinical-radiological factors are consistent with the hypothesis that PVS reflect cerebral small vessel disease; the different associations for basal ganglia and centrum semiovale PVS might indicate different underlying small vessel arteriopathies according to PVS anatomical distribution, but this requires further study.


Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte.
Minimal change nephropathy (MCN) is the third most common cause of primary nephrotic syndrome in adults. Most patients with MCN respond to corticosteroid therapy, but relapse is common. In children, steroid-dependent patients are often given alternative agents to spare the use of steroids and to avoid the cumulative steroid toxicity. In this respect, levamisole has shown promise due to its ability to effectively maintain remission in children with steroid-sensitive or steroid-dependent nephrotic syndrome. Despite clinical effectiveness, there is a complete lack of molecular evidence to explain its mode of action and there are no published reports on the use of this compound in adult patients. We studied the effectiveness of levamisole in a small cohort of adult patients and also tested the hypothesis that levamisole's mode of action is attributable to its direct effects on podocytes. In the clinic, we demonstrate that in our adult patients, cohort levamisole is generally well tolerated and clinically useful. Using conditionally immortalized human podocytes, we show that levamisole is able to induce expression of glucocorticoid receptor (GR) and to activate GR signalling. Furthermore, levamisole is able to protect against podocyte injury in a puromycin aminonucleoside (PAN)-treated cell model. In this model the effects of levamisole are blocked by the GR antagonist mifepristone (RU486), suggesting that GR signalling is a critical target of levamisole's action. These results indicate that levamisole is effective in nephrotic syndrome in adults, as well as in children, and point to molecular mechanisms for this drug's actions in podocyte diseases.


Near Infrared Spectroscopy Enables Differentiation of Mechanically and Enzymatically Induced Cartilage Injuries.
This study evaluates the feasibility of near infrared (NIR) spectroscopy to distinguish between different cartilage injury types associated with post-traumatic osteoarthritis and idiopathic osteoarthritis (OA) induced by mechanical and enzymatic damages. Bovine osteochondral samples (n = 72) were subjected to mechanical (n = 24) and enzymatic (n = 36) damage; NIR spectral measurements were acquired from each sample before and after damage, and from a separate control group (n = 12). Biomechanical measurements were then conducted to determine the functional integrity of the samples. NIR spectral variations resulting from different damage types were investigated and the samples classified using partial least squares discriminant analysis (PLS-DA). Partial least squares regression (PLSR) was then employed to investigate the relationship between the NIR spectra and biomechanical properties of the samples. Results of the study demonstrate that substantial spectral changes occur in the region of 1700-2200 nm due to tissue damages, while differences between enzymatically and mechanically induced damages can be observed mainly in the region of 1780-1810 nm. We conclude that NIR spectroscopy, combined with multivariate analysis, is capable of discriminating between cartilage injuries that mimic idiopathic OA and traumatic injuries based on specific spectral features. This information could be useful in determining the optimal treatment strategy during cartilage repair in arthroscopy.


Active site-targeted carbon dots for the inhibition of human insulin fibrillation.
Carbon nano-dots (C-Dots) possess great benign properties, making them ideal for use in biomedical fields, especially due to their high aqueous solubility, outstanding photoluminescence (PL), favorable biocompatibility, low toxicity, chemical inertness, and easy functionalization properties. Herein, the C-Dots with sizes of about 2.4 ± 0.9 nm and containing the groups -OH, C[double bond, length as m-dash]C and C[double bond, length as m-dash]O, were shown to prolong the lag phase of human insulin (HI) fibrillation following a dose-dependent manner in an in vitro study. The spontaneous growth of fibrils after a lag phase was accompanied by exothermic heat, determined by isothermal titration calorimetry (ITC), demonstrating the inhibitory effect of C-Dots. Moreover, as the dose of C-Dots was increased to 4 mg mL-1, the fibrillation process could be totally deterred for more than half a month. However, the deterrent effect of the C-Dots on HI fibrillation disappeared when just a few fibril seeds were added. This is because the association constant of HI monomers interacting with fibril seeds (K2: 1.56 × 105 M-1) is much larger than that with C-Dots (K2: 8.28 × 103 M-1), as determined by analyzing the ITC results. An ''active-site targeted'' inhibitory mechanism has also been proposed. The "active site" is mainly on the B-chain of HI, and the ITC results show that the binding between the C-Dots and HI monomers is mainly driven by the electrostatic force. This is the first time that the anti-fibrillation mechanism in the presence of C-Dots has been analyzed by ITC. These results indicate that ITC is a promising approach for comprehensively clarifying the mechanisms of protein fibrillation inhibition.


Verbal intelligence and sleep disorders in children with ADHD.
In the present study, WISC-III Verbal IQ and sleep disorders in children with Attention Deficit Hyperactivity Disorder (ADHD) and controls who were matched for age and sex were assessed. 18 children with ADHD, 14 boys and 4 girls, and 18 controls, 14 boys and 4 girls, participated. Polysomnographs were performed for all ADHD children during their night sleep. The Greek version of WISC-III was used to evaluate Verbal IQ. Analysis of the polysomnographs showed that the quality of night sleep of the children with ADHD was very poor, including apneas, low desaturation rates, and awakenings in combination with limb activity and snoring. This agreed with their low Verbal IQ, which was up to 20 points lower than the controls' Verbal IQ. Sleep disorders in ADHD children could contribute to lower Verbal IQ.


Do African American adolescents internalize direct online discrimination? Moderating effects of vicarious online discrimination, parental technological attitudes, and racial identity centrality.
African American adolescents have become more active users of digital media, which may increasingly expose them to direct online discrimination based on their racial and gender identities. Despite well-documented impacts of offline discrimination, our understanding of if and how direct online discrimination affects African American adolescents similarly remains limited. Guided by intersectional and ecological frameworks, we examined the association between direct online discrimination and internalized computing stereotypes in African American adolescents. Further, we explored the moderating effects of systemic and individual factors - vicarious online discrimination, parental technological attitudes, and racial identity centrality - on this association by adolescent gender. Utilizing data from 1041 African American parent-adolescent dyads, we found a positive association between adolescents' direct online discrimination and internalized computing stereotypes. Surprisingly, greater vicarious online discrimination mitigated this association for both male and female adolescents. Further, parental technological attitudes and racial identity centrality mitigated this association only for female but not male adolescents. Our findings highlight the importance of understanding the impact of media on adolescents' online experiences from intersectional and systemic perspectives. We discuss the implications for prospective research and educational programs focused on African American adolescents' digital media use and online experiences.


Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.
Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells. While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products inhibit target proteins conserved from microorganisms to humans. These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells. In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.


Molecular and evolutionary basis of the cellular stress response.
The cellular stress response is a universal mechanism of extraordinary physiological/pathophysiological significance. It represents a defense reaction of cells to damage that environmental forces inflict on macromolecules. Many aspects of the cellular stress response are not stressor specific because cells monitor stress based on macromolecular damage without regard to the type of stress that causes such damage. Cellular mechanisms activated by DNA damage and protein damage are interconnected and share common elements. Other cellular responses directed at re-establishing homeostasis are stressor specific and often activated in parallel to the cellular stress response. All organisms have stress proteins, and universally conserved stress proteins can be regarded as the minimal stress proteome. Functional analysis of the minimal stress proteome yields information about key aspects of the cellular stress response, including physiological mechanisms of sensing membrane lipid, protein, and DNA damage; redox sensing and regulation; cell cycle control; macromolecular stabilization/repair; and control of energy metabolism. In addition, cells can quantify stress and activate a death program (apoptosis) when tolerance limits are exceeded.


Rapid and temporary improvement of depression and anxiety observed following niraparib administration: a case report.
Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.


A comparative analysis of converters of tabular data into image for the classification of Arboviruses using Convolutional Neural Networks.
Tabular data is commonly used in business and literature and can be analyzed using tree-based Machine Learning (ML) algorithms to extract meaningful information. Deep Learning (DL) excels in data such as image, sound, and text, but it is less frequently utilized with tabular data. However, it is possible to use tools to convert tabular data into images for use with Convolutional Neural Networks (CNNs) which are powerful DL models for image classification. The goal of this work is to compare the performance of converters for tabular data into images, select the best one, optimize a CNN using random search, and compare it with an optimized ML algorithm, the XGBoost. Results show that even a basic CNN, with only 1 convolutional layer, can reach comparable metrics to the XGBoost, which was trained on the original tabular data and optimized with grid search and feature selection. However, further optimization of the CNN with random search did not significantly improve its performance.


Ischemia modified albumin in the differential diagnosis of pleural effusions.
The differential diagnosis of pleural effusion often requires invasive procedures. Up to 25 percent of pleural effusions can remain undiagnosed with an unclear pathogenesis. Therefore new biological markers may increase diagnostic yield and provide better understanding of pathogenesis of pleural effusion. We hypothesized that new ischemia biomarker, "ischemia modified albumin (IMA)" would help in both the differentiation of the underlying etiologies and provide a better understanding of pathogenesis of pleural effusions. This study was done between December 2009 and September 2010 in the Department of Pulmonary Diseases of Gaziantep University Hospital. One hundred and sixteen subjects with pleural effusion were included. Pleural and blood IMA levels were measured by ELISA. The underlying etiologies of pleural effusions were as follows: transudates (n = 50), malignancy (n = 32), tuberculosis (n = 12), pulmonary thromboembolism (n = 6), pneumonia (n = 16). The median pleural IMA levels were significantly different between the groups (p < 0.000). There were no such differences in the blood levels of IMA. The most striking difference in the median pleural IMA levels was between transudates and exudates (7986 (25-75%, 5145-56.505) ng/mL; 3376 (25-75%, 1935-4660) ng/mL; respectively, p = 0.000). The area under the ROC curve was 0.837 ± 0.038 for the cut-off level higher than 4711 ng l/mL for the differentiation of transudates from exudates (sensitivity, 82%; specificity, 78%; 95% CI, 0.76 to 0.91; p = 0.0000). In conclusion, the pleural IMA levels are higher in transudates compared to exudates. No such differences were observed in blood levels of IMA suggesting that there are reasons other than ischemia that cause an increase in pleural fluid IMA levels.


[Primary carcinoma of the trachea. Report of 2 cases].
Tumours of the trachea remain relatively rare, the incidence of tracheal carcinomata is less than 0.1 per cent. Tumours of the larynx and lungs are, respectively, 75 and 180 times more frequent than malignant lesions of windpipe. Two patients with primary tracheal tumours were evaluated. The present study was undertaken in order to describe and analyse the most pertinent clinical and pathologic features of tracheal carcinomas as they relate to treatment and prognosis.


The NAD(P)H-utilizing glutamate dehydrogenase of Bacteroides thetaiotaomicron belongs to enzyme family I, and its activity is affected by trans-acting gene(s) positioned downstream of gdhA.
Previous studies have suggested that regulation of the enzymes of ammonia assimilation in human colonic Bacteroides species is coordinated differently than in other eubacteria. The gene encoding an NAD(P)H-dependent glutamate dehydrogenase (gdhA) in Bacteroides thetaiotaomicron was cloned and expressed in Escherichia coli by mutant complementation from the recombinant plasmid pANS100. Examination of the predicted GdhA amino acid sequence revealed that this enzyme possesses motifs typical of the family I-type hexameric GDH proteins. Northern blot analysis with a gdhA-specific probe indicated that a single transcript with an electrophoretic mobility of approximately 1.6 kb was produced in both B. thetaiotaomicron and E. coli gdhA+ transformants. Although gdhA transcription was unaffected, no GdhA enzyme activity could be detected in E. coli transformants when smaller DNA fragments from pANS100, which contained the entire gdhA gene, were analyzed. Enzyme activity was restored if these E. coli strains were cotransformed with a second plasmid, which contained a 3-kb segment of DNA located downstream of the gdhA coding region. Frameshift mutagenesis within the DNA downstream of gdhA in pANS100 also resulted in the loss of GdhA enzyme activity. Collectively, these results are interpreted as evidence for the role of an additional gene product(s) in modulating the activity of GDH enzyme activity. Insertional mutagenesis experiments which led to disruption of the gdhA gene on the B. thetaiotaomicron chromosome indicated that gdhA mutants were not glutamate auxotrophs, but attempts to isolate similar mutants with insertion mutations in the region downstream of the gdhA gene were unsuccessful.


Physical changes in human meibum with age as measured by infrared spectroscopy.
Both lipids and mucins contribute to the stability of the tear film and lipids may inhibit tears from evaporating. Younger people have lower lipid viscosity, higher lipid volume, and a lower rate of tear evaporation. Since age-related changes in human meibum composition and conformation have never been investigated, as a basis for the study of lipid-associated changes with meibomian gland dysfunction, we used the power of infrared spectroscopy to characterize hydrocarbon chain conformation and packing in meibum from humans without dry eye symptoms in relation to age and sex. Meibum from normal human donors ranging in age from 3 to 88 years was studied. Meibum phase transitions were quantified by fitting them to a 4-parameter 2-state sigmoidal equation. Human meibum order and phase transition temperatures decrease with age and this trend may be attributed to lipid compositional changes. If meibum has the same thermodynamic properties on the surface of the tears as it does on the lid margin, a decrease in lipid-lipid interaction strength with increasing age could decrease the stability of tears since lipid-lipid interactions on the tear surface must be broken for the tear film to break up. This study also serves as a foundation to examine meibum conformational differences in meibum from people with meibomian gland dysfunction.


Crystallization and preliminary X-ray analysis of the Escherichia coli adaptor protein ClpS, free and in complex with the N-terminal domain of ClpA.
Protein degradation in Escherichia coli is accomplished by a handful of large oligomeric complexes. In most cases, these proteolytic machines are comprised of a chaperone (e.g. ClpA) that is required to prepare the substrate for degradation by the peptidase (e.g. ClpP). Recently, it was shown that the substrate recognition of the chaperone ClpA could be modified by the adaptor protein ClpS. To investigate the structural implications of this change in substrate specificity, ClpS was crystallized alone and in complex with the N-terminal domain of ClpA (ClpA(N)). Crystals of ClpS diffract to 2.9 A resolution and belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 82.63, b = 145.67, c = 152.31 A. Two different crystal forms of the ClpA(N)-ClpS complex were characterized. Crystal form I (CFI) belongs to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 91.63, b = 112.47, c = 38.47 A; data to 1.92 A resolution were collected. Crystals of form II (CFII) belong to space group P4(1/3)2(1)2, with unit-cell parameters a = b = 93.57, c = 78.77 A, and diffract to 1.85 A resolution. Data sets collected from heavy-atom derivatives of CFI indicated the incorporation of Pt and Hg atoms. Structure solution using MIR and MAD methods is currently under way.


Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100.
Nuclear domains 10 (ND10s) are discrete subnuclear structures that contain the three major protein components promyelocytic leukaemia protein (PML), hDaxx and Sp100. Previous studies identified the ND10-components PML and hDaxx as cellular restriction factors that independently counteract human cytomegalovirus (HCMV) infection via the repression of viral immediate-early (IE) gene expression. Consequently, we asked whether Sp100 is likewise involved in this repressive activity. Infection of Sp100 knockdown (kd) cells with HCMV resulted in a significantly increased plaque-forming ability. In addition, ablation of Sp100 led to a considerable increase in the number of IE1-expressing cells, indicating that Sp100 suppresses the initiation of viral gene expression. Next, double-kd cells, lacking either Sp100/hDaxx or Sp100/PML, were generated. Here, infection resulted in an additional enhancement in HCMV replication efficacy compared with the single-kd cells. Thus, our results further strengthen the concept that the three major ND10-components independently contribute to the cellular restriction of HCMV replication.


ARL15, a GTPase implicated in rheumatoid arthritis, potentially repositions its truncated N-terminus as a function of guanine nucleotide binding.
The ADP ribosylation factor like protein 15 (ARL15) gene encodes for an uncharacterized GTPase associated with rheumatoid arthritis (RA) and other metabolic disorders. Investigation of the structural and functional attributes of ARL15 is important to position the protein as a potential drug target. Using spectroscopy, we demonstrated that ARL15 exhibits properties inherent of GTPases. The Km and Vmax of the enzyme were calculated to be 100 μM and 1.47 μmole/min/μL, respectively. The equilibrium dissociation constant (Kd) of GTP binding with ARL15 was estimated to be about eight-fold higher than that of GDP. Small Angle X-ray Scattering (SAXS) data indicated that in solution, the apo state of monomeric ARL15 adopts a shape characterized by a globe of maximum linear dimension (Dmax) of 6.1 nm, and upon binding to GTP or GDP, the vector distribution profile changes to peak-n-tail shoulder with Dmax extended to 7.6 and 7.7 nm, respectively. Structure restoration using a sequence-based template and experimental SAXS data provided the first visual insight revealing that the folded N-terminal in the unbound state of the protein may toggle open upon binding to guanine nucleotides. The conformational dynamics observed in the N-terminal region offer a scope to develop drugs that target this unique GTPase, potentially providing treatments for a range of metabolic disorders.


[The physician-patient relationship in post-modernism].
The doctor-patient relationship represents a particular link that goes beyond formality and it is projected in time, space and emotionalism. It takes place in the midst of a cultural, social, physiological, scientific and technical context which at the same time is conditioned by local, regional, national and foreign influences as a consequence of globalization. Different ethnical groups, social stratification, economic structures, philosophical concepts, religious beliefs and moral values play a pivotal role. The technological advances have shown an exponential increase during the last forty years. This phenomenon was accompanied by deep changes that varied from philosophical to strictly technical aspects which were significatively intensified during the post Second World War period. The consequences have been unfortunate for physicians and particularly for patients. Those consequences came out by philosophical reviews, the economical liberalism and neoliberalism development, a new concept for science, the priorization of technique development together with changes in both ethical value scales and economic & politic power hegemonies. The great reports of philosophy have tried to justify these social changes. The end of modern meta discourses such as Iluminism, Idealism, and Marxism, incited the liberal and neoliberal discourse. Knowledge has been affected not only in the research field but in the teaching field as well. Today, the discourse in vogue is the performance. The "organic conjugation" of technique and profit precedes its union with science. The State disengagement in managing the great social problems in many countries, the globalization and the concentration of the capital has redefined the power. Neither the patient nor the medicine escapes from this reality. The final results are generations of physicians quite right informed but unable to solve or even face the minimum problems of a patient, and what is worst, they run the risk of feeling frustrated and resentful. Everything is thought and done through technique, and there is a fact that appears to justify this action "The malpractice judgement industry". The economical monopoly of private or sindical Healthcare Providers and self-managed Hospitals projects are rapidly and notoriously modifying the medical labour market. There seems to exist only one element that the doctor and the patient have in common in this new culture: loneliness. There is also a human communication failure that separates them: the patient is in more need of human comprehension than ever before and the doctor has a cultural inability to offer it. To sum up, the relationship between the doctor and the patient is still a theme of deep preoccupation, even more nowadays when everything seems to indicate that this relationship has suffered a significant impairment.


Parenteral Antioxidant Supplementation at Birth Improves the Response to Intranasal Vaccination in Newborn Dairy Calves.
Newborn calves experience oxidative stress throughout the first month of their life, which is known to decrease lymphocyte functions relevant to vaccine responsiveness. Thus, this study aimed to determine the extent to which parenteral antioxidant supplementation given at birth improves the response to an intranasal viral vaccine in the first month of life of newborn dairy calves. For this, 21 calves were randomly assigned at birth to one of two commercially available antioxidant micronutrient supplements or a placebo group receiving 0.9% sterile saline (n = 7/group). Serum and nasal secretion samples were collected before administration of treatments and an intranasal vaccine against respiratory viruses (bovine herpesvirus type 1, bovine syncytial respiratory virus, and parainfluenza 3), and once weekly for the first four weeks of age. Systemic redox balance was determined in serum. Immunoglobulin A specific for bovine herpesvirus 1 and bovine syncytial respiratory virus was quantified in nasal secretions as a proxy to intranasal vaccine responsiveness. Our results showed that parenteral administration of antioxidants at birth improved calves' redox balance. Additionally, calves receiving antioxidant supplementation had higher concentrations of immunoglobulin A in their nasal secretions than calves in the control group. Thus, we conclude that supplementation of calves with antioxidants at birth could be a practical strategy to improve intranasal vaccine response. Future larger studies should evaluate the extent to which this increased mucosal response to intranasal vaccination could result in decreased calf morbidity and mortality.


Comparative characterization of bone marrow-derived mesenchymal stromal cells from four different rat strains.
Bone marrow (BM) multipotent mesenchymal stromal cells (MSC) hold great potential for cell-based regenerative medicine. Because of the growing use of autologous rat MSC transplantation in various rat models, there is a need to establish minimal criteria for rat MSC characterization independent of the specific strain employed in each study. We aimed to compare the phenotypic and functional traits of BM MSC from the four strains of rats commonly used in research: Fisher, Lewis, Sprague-Dawley and Wistar. Rat MSC were isolated from the BM of the four different rat strains in an identical fashion. Cells were characterized for their cell-surface phenotype in early and late passage. Functional mesenchymal differentiation capacities were examined following adipogenic and osteogenic inductions. Population doubling times were determined across the four strains throughout 10 passages. In vitro proliferation assays of immune cells were conducted following co-culture of spleen cells and MSC of the four different strains. We found that rat MSC from different strains exhibited similar cell-surface phenotype. Expansion rates and differentiation capacities of the MSC were also similar across the different strains. Co-culture of rat MSC with spleen cells obtained from rats of a different strain did not induce proliferation of immune cells. Our findings suggest that BM-derived MSC from different strains share similar characteristics, in contrast to the variations previously described in the characterization of mice MSC from different strains.


Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice.
L-histidine is one of the essential amino acids for humans, and it plays a critical role as a component of proteins. L-histidine is also important as a precursor of histamine. Brain histamine is synthesized from L-histidine in the presence of histidine decarboxylase, which is expressed in histamine neurons. In the present study, we aimed to elucidate the importance of dietary L-histidine as a precursor of brain histamine and the histaminergic nervous system. C57BL/6J male mice at 8 wk of age were assigned to 2 different diets for at least 2 wk: the control (Con) diet (5.08 g L-histidine/kg diet) or the low L-histidine diet (LHD) (1.28 g L-histidine/kg diet). We measured the histamine concentration in the brain areas of Con diet-fed mice (Con group) and LHD-fed mice (LHD group). The histamine concentration was significantly lower in the LHD group [Con group vs. LHD group: histamine in cortex (means ± SEs): 13.9 ± 1.25 vs. 9.36 ± 0.549 ng/g tissue; P = 0.002]. Our in vivo microdialysis assays revealed that histamine release stimulated by high K(+) from the hypothalamus in the LHD group was 60% of that in the Con group (P = 0.012). However, the concentrations of other monoamines and their metabolites were not changed by the LHD. The open-field tests showed that the LHD group spent a shorter amount of time in the central zone (87.6 ± 14.1 vs. 50.0 ± 6.03 s/10 min; P = 0.019), and the light/dark box tests demonstrated that the LHD group spent a shorter amount of time in the light box (198 ± 8.19 vs. 162 ± 14.1 s/10 min; P = 0.048), suggesting that the LHD induced anxiety-like behaviors. However, locomotor activity, memory functions, and social interaction did not differ between the 2 groups. The results of the present study demonstrated that insufficient intake of histidine reduced the brain histamine content, leading to anxiety-like behaviors in the mice.


On the relative relevance of subject-specific geometries and degeneration-specific mechanical properties for the study of cell death in human intervertebral disk models.
Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro-mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration-dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration.


Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs.
We compared the effects of sustained isocapnic hypoxia (SIH; 20 min) and repetitive isocapnic hypoxia (RIH; 10 2-min episodes) on ventilation (VI), genioglossal (EMGgg) and diaphragmatic electromyographic (EMGdi) activities, and supraglottic airway resistance in 11 normal supine male subjects (36.6 +/- 2.2 yr) during wakefulness. Seven of the subjects had control measurements on a separate day. Desaturation was similar (arterial O2 saturation 80-84%) in the SIH and RIH protocols. SIH and RIH caused a biphasic ventilatory response: early augmentation of VI (169.5 +/- 6.9 and 168.9 +/- 4.3% of baseline, respectively; not significant) followed by a significant roll-off (VI after 20 min of cumulative hypoxia 153 +/- 4.0 and 150.8 +/- 10.2% respectively; not significant). Moving-time-average EMGdi signals (peak inspiratory and phasic) demonstrated a similar biphasic response in the two protocols. Mean EMGgg responses, however, differed. During SIH, peak inspiratory EMGgg increased early and remained elevated. Phasic and tonic EMGgg signals showed a similar trend. During RIH, early augmentation of peak inspiratory and phasic EMGgg signals was followed by a marked roll-off in activity such that by the 10th hypoxic episode neither value increased above baseline. In the 2-min periods between hypoxic episodes, there was a progressive suppression of peak inspiratory and phasic EMGgg values below baseline. Supraglottic airway resistance did not change significantly during either SIH or RIH. VI and phasic EMGs did not change during control experiments. We conclude that in awake normal male subjects SIH and RIH cause similar biphasic responses in VI and EMGdi activity. Phasic EMGgg activity responses differ between SIH and RIH: EMGgg remains augmented during SIH, whereas during RIH early augmentation is followed by marked suppression.


[Organization of work with nursing staff in Central City Hospital of Verkhnyaya Pyshma town during mass hospitalization of patients with pneumonia caused by Legionella].
Data on organization and carrying out of preventive and antiepidemic measures in hospital during hospitalization of more than 197 patients with Pontiac fever and pneumonia caused by Legionella were presented. Directions and formats of work with medical personnel, including those invited from other medical institutions, as well as their information support were determined. Optimal choice of organizational, and educational technologies, as well as ways to control of compliance with implemented measures by the staff allowed to prevent cases of nosocomial infections in patients and medical personnel.


Health-adjusted life expectancy at the local level in ontario.
Health expectancy measures are becoming a common method of combining information on mortality and health-related quality of life into one summary population health measure. However, health expectancy measures are infrequently measured at the local level, despite a shift toward health service planning to that level. Using a modified Sullivan method, we calculated health-adjusted life expectancy (HALE) for the 42 public health units in Ontario using life tables that were derived from mortality and population data for 1988-1992 and the Health Utilities Index from the 1990 Ontario Health Survey. There were large variations among health units in HALE at age 15 for both men (range: 51.3-58.2 years) and women (range: 56.6-62.9 years). Generally, rural and northern areas had the lowest HALE. Local differences in male HALE were greater than for life expectancy (7.1 versus 6.0 years). Despite a relatively large health survey (45,583 respondents, range: 729-1,746 per health unit), few HALE differences deviated significantly from the Ontario mean, raising concerns about the feasibility of estimating local health expectancy measures with adequate precision. Nevertheless, the wider local differences and different geographic distribution of local HALE compared with mortality measures, along with the additional benefit of being able to model the complex interaction of mortality and morbidity, suggest that HALE may be a useful population health measure.


Planomicrobium soli sp. nov., isolated from soil.
A Gram-staining-positive bacterium, designated strain XN13(T), was isolated from a soil sample collected from ALaShan National Geological Park in Inner Mongolia Autonomous Region, China and subjected to a taxonomic study using a polyphasic approach. Strain XN13(T) was found to have a range of chemical and morphological properties consistent with its classification in the genus Planomicrobium. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain XN13(T) was related to members of the genus Planomicrobium. The closest phylogenetic relatives were Planomicrobium okeanokoites NBRC 12536(T), Planomicrobium koreense JG07(T), Planomicrobium mcmeekinii S23F2(T) and Planomicrobium flavidum ISL-41(T) with 98.2%, 97.8%, 97.8% and 97.7% 16S rRNA gene sequence similarity, respectively. The major cellular fatty acids were anteiso-C(15 : 0), C(16 : 1)ω7c alcohol, iso-C(14 : 0) and C(16 : 1)ω11c. The predominant menaquinones were MK-8 and MK-7. The DNA G+C content was 40.3 mol%. The DNA-DNA relatedness values between strain XN13(T) and Planomicrobium okeanokoites KCTC 3672(T), Planomicrobium koreense KCTC 3684(T), P. mcmeekinii CGMCC 1.2724(T), Planomicrobium flavidum KCTC 13261(T), Planomicrobium chinense CGMCC 1.3454(T) and Planomicrobium glaciei CGMCC 1.6846(T) were 36%, 30%, 34%, 29%, 30% and 31%, respectively. The organism is different from recognized species of the genus Planomicrobium in several phenotypic characteristics. On the basis of phenotypic and genotypic properties, strain XN13(T) represents a novel species of the genus Planomicrobium, for which the name Planomicrobium soli sp. nov. is proposed. The type strain is XN13(T) ( = CGMCC 1.12259(T) = KCTC 33047(T)).


De novo assembly of transcriptome sequencing in Caragana korshinskii Kom. and characterization of EST-SSR markers.
Caragana korshinskii Kom. is widely distributed in various habitats, including gravel desert, clay desert, fixed and semi-fixed sand, and saline land in the Asian and African deserts. To date, no previous genomic information or EST-SSR marker has been reported in Caragana Fabr. genus. In this study, more than two billion bases of high-quality sequence of C. korshinskii were generated by using illumina sequencing technology and demonstrated the de novo assembly and annotation of genes without prior genome information. These reads were assembled into 86,265 unigenes (mean length = 709 bp). The similarity search indicated that 33,955 and 21,978 unigenes showed significant similarities to known proteins from NCBI non-redundant and Swissprot protein databases, respectively. Among these annotated unigenes, 26,232 a unigenes were separately assigned to Gene Ontology (GO) database. When 22,756 unigenes searched against the Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) database, 5,598 unigenes were assigned to 5 main categories including 32 KEGG pathways. Among the main KEGG categories, metabolism was the biggest category (2,862, 43.7%), suggesting the active metabolic processes in the desert tree. In addition, a total of 19,150 EST-SSRs were identified from 15,484 unigenes, and the characterizations of EST-SSRs were further compared with other four species in Fabraceae. 126 potential marker sites were randomly selected to validate the assembly quality and develop EST-SSR markers. Among the 9 germplasms in Caranaga Fabr. genus, PCR success rate were 93.7% and the phylogenic tree was constructed based on the genotypic data. This research generated a substantial fraction of transcriptome sequences, which were very useful resources for gene annotation and discovery, molecular markers development, genome assembly and annotation. The EST-SSR markers identified and developed in this study will facilitate marker-assisted selection breeding.


Prevalence of health-risk behavior among seventh grade students in North Carolina.
Data from 386 seventh grade students, 48% male and 65% white, were collected at two sites in North Carolina. The purpose of the study was to estimate the prevalence of alcohol and drug use among adolescents as part of a continuing study of preventive health behaviors. The data were collected anonymously from self-completed questionnaires and were analyzed by race and sex to determine knowledge of and attitudes toward alcohol and smoking, self-concept, and locus of control. Black boys had the highest prevalence of alcohol (16%) and tobacco (20%) use and at the same time had the lowest amount of knowledge about the dangers of the substances. White boys, while knowing more about the potential dangers, reported similar patterns of use. In general, girls used much less alcohol and tobacco and had higher levels of knowledge and more prudent attitudes. Boys, particularly blacks, were found to be at greater risk than girls of developing patterns of behavior that are associated with abuse of alcohol and heavy smoking. The findings suggest that health education to inform adolescents of the dangers of alcohol and smoking needs to be specific to cultural and sex groups.


Development of full-thickness human skin equivalents with blood and lymph-like capillary networks by cell coating technology.
We developed a human skin equivalent (HSE) containing blood and lymph-like capillary networks using a cell coating technique, which is a rapid fabrication technology of three-dimensional cellular constructs by cell surface coating using layer-by-layer assembled nanofilms of extracellular matrices. The thickness of dermis consisting of normal human dermal fibroblasts was easily controlled from approximately 5 to 100 µm by altering the seeded cell number. Keratinocytes as a major cell population showed homogeneous differentiation on the surface of the dermis by lifting to air-liquid interface. Histological analysis revealed four distinct layers such as basal layer, spinous layer, granular layer, and cornified cell layer in the epidermis. Interestingly, the measurement of transepithelial electrical resistance (TEER) indicated prolongation of the attainment time for maximum value by increasing the number of the dermal fibroblasts, and the HSEs with six layers of dermis revealed the longest period maintaining over 500 Ω cm(2) of TEER. The co-sandwich culture of human umbilical vein endothelial cells and normal human dermal lymphatic microvascular endothelial cells within eight-layered dermis showed in vitro co-network formation of individual blood and lymph-like capillaries inside the dermis. This is the report for homogeneous full-thickness HSEs with blood and lymph capillary networks, which will be useful for biomedical and pharmaceutical applications.


Extreme weather-Wildfires & pregnancy.
As described in the previous chapter, Chapter 4: Air pollution and pregnancy, there is robust literature on the adverse health impacts of ambient air pollution on perinatal outcomes. With climate change contributing to more extreme weather patterns, wildfire events are becoming more intense and frequent. Wildfire smoke is a major contributor to poor air quality and data are beginning to emerge with respect to the negative impact on perinatal outcomes. The aim of this chapter is to provide an overview of the current literature on wildfire smoke exposure in pregnancy and associated adverse outcomes.


Pseudohypertension: a diagnostic dilemma.
Pseudohypertension is a condition in which the indirect measurement of intra-arterial pressure using a sphygmomanometer (cuff pressure) is artifactually high in comparison with directly measured intra-arterial pressure. If unrecognized, pseudohypertension may result in unwarranted and sometimes dangerous treatment. Pseudohypertension results from medial sclerosis and/or calcification of arteries, which markedly decrease their collapsibility. Both the systolic and diastolic pressures are affected. The literature concerning pseudohypertension is quite limited; indeed, the very frequency of the condition is unknown. Very high blood pressure in the absence of significant target organ impairment is an important clue to this subtype of hypertension and should lead to simple diagnostic techniques, such as Osler's maneuver (an attempt to palpate a pulseless radial artery) and radiographs of the soft tissues of the arms. The definitive diagnosis is made by comparing the intra-arterial pressure with the indirectly determined blood pressure.


RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks.
Hematological malignancies are characterised by a block in differentiation, which in many cases is caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein formed by the t(3;21) translocation linking two transcription factors required for normal hematopoiesis. RUNX1-EVI1 expression is found in myelodysplastic syndrome, secondary acute myeloid leukemia, and blast crisis of chronic myeloid leukemia; with clinical outcomes being worse than in patients with RUNX1-ETO, RUNX1 or EVI1 mutations alone. RUNX1-EVI1 is usually found as a secondary mutation, therefore the molecular mechanisms underlying how RUNX1-EVI1 alone contributes to poor prognosis are unknown. To address this question, we induced expression of RUNX1-EVI1 in hematopoietic cells derived from an embryonic stem cell differentiation model. Induction resulted in disruption of the RUNX1-dependent endothelial-hematopoietic transition, blocked the cell cycle and undermined cell fate decisions in multipotent hematopoietic progenitor cells. Integrative analyses of gene expression with chromatin and transcription factor binding data demonstrated that RUNX1-EVI1 binding caused the re-distribution of endogenous RUNX1 within the genome and interfered with both RUNX1 and EVI1 regulated gene expression programs. In summary, RUNX1-EVI1 expression alone leads to extensive epigenetic reprogramming which is incompatible with healthy blood production.


The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.
Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.


Failure of decellularized porcine small intestinal submucosa as a heart valved conduit.
Decellularized extracellular matrix made from porcine small intestinal submucosa, commercially available as CorMatrix (CorMatrix Cardiovascular, Inc, Roswell, Ga) is used off-label to reconstruct heart valves. Recently, surgeons experienced failures and words of caution were raised. The aim of this study was to evaluate decellularized porcine small intestinal submucosa as right-sided heart valved conduit in a xenogeneic animal model. A pulmonary valve replacement was performed with custom-made valved conduits in 10 lambs and 10 sheep (1 month [3 lambs and 3 sheep], 3 months [3 lambs and 3 sheep], 6 months [4 lambs and 4 sheep]). Valve function was assessed after implantation and before the animal was put to death. Explanted conduits were inspected macroscopically and analyzed using immunohistochemistry and scanning electron microscopy. They also underwent mechanical testing and testing for biochemical composition. All valved conduits were successfully implanted. Five sheep and 2 lambs died due to congestive heart failure within 2 months after surgery. In the animals that died, the valve leaflets were thickened with signs of inflammation (endocarditis in 4). Five sheep and 8 lambs (1 month: 6 out of 6 animals, 3 months: 4 out of 6 animals, 6 months: 3 out of 8 animals) survived planned follow-up. At the time they were put to death, 5 lambs had significant pulmonary stenosis and 1 sheep showed severe regurgitation. A well-functioning valve was seen in 4 sheep and 3 lambs for up to 3 months. These leaflets showed limited signs of remodeling. Fifty percent of sheep and 20% of lambs died due to valve failure before the planned follow-up period was complete. A well-functioning valve was seen in 35% of animals, albeit with limited signs of tissue remodeling at ≤3 months after implantation. Further analysis is needed to understand the disturbing dichotomous outcome before clinical application can be advised.


Members of the bHLH-PAS family regulate Shh transcription in forebrain regions of the mouse CNS.
The secreted protein sonic hedgehog (Shh) is required to establish patterns of cellular growth and differentiation within ventral regions of the developing CNS. The expression of Shh in the two tissue sources responsible for this activity, the axial mesoderm and the ventral midline of the neural tube, is regulated along the anteroposterior neuraxis. Separate cis-acting regulatory sequences have been identified which direct Shh expression to distinct regions of the neural tube, supporting the view that multiple genes are involved in activating Shh transcription along the length of the CNS. We show here that the activity of one Shh enhancer, which directs reporter expression to portions of the ventral midbrain and diencephalon, overlaps both temporally and spatially with the expression of Sim2. Sim2 encodes a basic helix-loop-helix (bHLH-PAS) PAS domain containing transcriptional regulator whose Drosophila homolog, single-minded, is a master regulator of ventral midline development. Both vertebrate and invertebrate Sim family members were found sufficient for the activation of the Shh reporter as well as endogenous Shh mRNA. Although Shh expression is maintained in Sim2(-)(/)(-) embryos, it was determined to be absent from the rostral midbrain and caudal diencephalon of embryos carrying a dominant-negative transgene that disrupts the function of bHLH-PAS proteins. Together, these results suggest that bHLH-PAS family members are required for the regulation of Shh transcription within aspects of the ventral midbrain and diencephalon.


Unusually high Deca-BDE concentrations and new flame retardants in a Canadian Arctic top predator, the glaucous gull.
Despite a sustained effort in surveying flame retardants (FRs) in wildlife from industrialized regions, their occurrence in birds or any other wildlife species spanning the Arctic regions, particularly in North America, has received limited attention. This study investigated in the top predator glaucous gull (Larus hyperboreus) breeding in the Eastern Canadian Arctic (Cape Dorset, Nunavut) a comprehensive suite of FRs including unstudied halogenated and non-halogenated FRs of potential health concern, along with legacy organochlorines and mercury. The influence of diet acquired locally and in wintering areas on the tissue contaminant profiles was also investigated using δ15N and δ13C signatures in liver and feathers. The principal constituent in the Deca-brominated diphenyl ether (BDE) mixture, BDE-209, was remarkably the most concentrated PBDE congener determined in liver samples of Eastern Canadian Arctic glaucous gulls. This suggests dietary exposure from the local marine food web and perhaps also from nearby community landfills. Moreover, this study revealed for the first time the presence of 16 emerging halogenated and non-halogenated FRs in glaucous gulls from this Arctic region including HBB, DDC-CO (anti and syn isomers), PBEB, EHTBB, BEHTBP as well as a series of organophosphate esters (OPEs) (TCEP, TCIPP, TPP, TDCIPP, TDBPP, TBNP, TBOEP, TBEP, TCrP, EHDPP, and TEHP). With the exception of BDE-209, concentrations of other halogenated FRs and organochlorines were found to be in the lower range in liver of Eastern Canadian Arctic glaucous gulls compared to individuals from other circumpolar populations (Svalbard and Greenland). Mercury and methylmercury concentrations, however, were greater than reported elsewhere for glaucous gull populations.