[Not Available].
Kant's discussion of the ethical implications of smallpox inoculation is presented here. In four fragments Kant analyzes the moral legitimacy of endangering other people in medical practice and especially endangering people who are incapable of giving consent. In addition, we re-evaluate the alleged "success story" of the development of smallpox prevention and review the technical and theoretical difficulties of smallpox inoculation at the time of Kant.


Areca nut chewing and systemic inflammation: evidence of a common pathway for systemic diseases.
Areca nut, the seed of fruit of an oriental palm, known as Areca catechu, is commonly chewed in many countries. Diabetes, hypertension, cardiovascular diseases, oropharyngeal and oesophageal cancers have been associated with areca nut chewing and the mechanism by which areca nut chewing increases the risk of systemic diseases remains elusive. We hypothesize that systemic inflammation may be elevated among areca nut users, which is linked with many systemic diseases. Therefore, this present study was conducted to examine the systemic inflammation among areca nut chewers and healthy controls. This was an observational cross sectional study carried out on areca nut chewers and healthy individuals in Karachi, Pakistan. Participants were selected from a region of the city by invitation request sent from door to door. Information was collected regarding the socio-demographic profile and the pattern of use, and a blood sample was obtained to measure the level of C-reactive protein (CRP). We carried out multiple logistic regressions to investigate the association between socio-demographic profile, areca nut chewing and CRP levels. We carried out final analysis on 1112 individuals of which 556 were areca nut chewers and 556 were the age, gender and area matched controls. Areca nut chewers had a significantly higher proportion of men (15.1%, n = 84) who had an elevated CRP (>10 mg/dl) as compared to controls (5.2%, n = 29). Multivariate analyses showed that areca nut chewers had significantly higher odds of an elevated CRP (OR = 3.23, 95% CI 2.08-5.02, p value <0.001) as compared to controls. Increase in amount of areca nut consumption had a significant dose-response relationship with systemic inflammation (p for trend <0.001). Further analysis revealed that areca nut chewers with tobacco additives were two times more likely to have an elevated CRP as compared to raw areca nut users. These associations remained unchanged after adjustments for age, BMI and years of full time education. Areca nut chewing has a significant association with systemic inflammation. Further work is required to confirm that systemic inflammation is the main pathway by which areca nut use increases the risk of systemic diseases.


An alternative surgical approach to a difficult case of Mirizzi syndrome: a case report and review of the literature.
Mirizzi syndrome (MS) is an uncommon complication of gallstone disease and occurs in approximately 1% of all patients suffering from cholelithiasis. The syndrome is characterized by extrinsic compression of the common hepatic duct frequently resulting in clinical presentation of intermittent or constant jaundice. Most cases are not identified preoperatively. Surgery is the indicated treatment for patients with MS. We report here a 71-year-old male patient referred to the surgical outpatient department for diffuse upper abdominal pain and mild jaundice (bilirubin rate: 4.2 mg/dL). Ultrasound examination revealed a stone in the cystic duct compressing the common hepatic duct. The patient had a history of gastrectomy for gastric ulcer 30 years ago. MRCP revealed a stone impacted in the cystic duct causing obstruction of the common hepatic duct by extrinsic compression. With these findings the preoperative diagnosis was indicative of MS. At laparotomy a moderately shrunken gallbladder was found embedded in adhesions containing a large stone which was palpable in the common bile duct. The anterior wall of the body of the gallbladder was opened by an incision which extended longitudinally along the gallbladder towards the common bile duct. The stone measuring 3.0 cm in diameter, was then removed setting astride a large communication with the common bile duct. A Roux-en-Y cholecysto-choledocho-jejunostomy was performed. The subhepatic region was drained. The patient had an uneventful recovery. He was discharged eleven days after operation and remained well after a 30-mo follow-up.


Glutathione homeostasis is disturbed in CD4-positive lymphocytes of HIV-seropositive individuals.
Numerous in vitro tests have suggested that a disturbed cellular glutathione homeostasis plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. Using validated high-performance liquid chromatography (HPLC) methods, glutathione concentrations were determined in plasma and in cytosol of CD4+ lymphocytes and CD14+ cells of HIV-seropositive individuals and healthy control subjects. We measured concentrations of total glutathione, which is the sum of reduced (GSH) and oxidised (GSSG) glutathione and mixed disulphides of which there are two fractions: soluble mixed disulphides (GSSR) and protein bound glutathione (ProSSG). Also, non-protein-bound glutathione was measured, which is the sum of GSH, GSSG and GSSR. Thirty-five healthy control subjects and 35 HIV-infected individuals participated in the study. We found that in CD4+ lymphocytes from HIV-seropositive individuals, total glutathione levels were significantly higher than in healthy control subjects, whereas the fraction of non-protein-bound glutathione was not different. This can only be explained by an increase in the protein-bound fraction of glutathione indicating the presence of oxidative stress in CD4+ lymphocytes of HIV-seropositive individuals. Glutathione measurements of cytosol of CD14+ cells and plasma were, however, not compatible with significant increased oxidation. Glutathione precursors (cysteine, cysteinylglycine, glutamylcysteine and homocysteine) and products of lipid peroxidation (thiobarbituric acid-reactive substances) were also measured in plasma and did not differ between healthy control subjects and HIV-seropositive individuals. We conclude that the glutathione homeostasis is disturbed in CD4+ lymphocytes of HIV-seropositive individuals. The glutathione redox dysbalance in CD4+ lymphocytes could be important in the pathogenesis of HIV infection and have implications for therapy.


REPRODUCTIVE BEHAVIOR IN THE SPIDER CRAB, LIBINIA EMARGINATA (L.).
1. Data concerning reproductive behavior and development in the spider crab, Libinia emarginata (L.) are recorded. Ovigerous females were collected from early June to early September. Females are apparently able to produce at least 3-4 consecutive broods of 25 days development each during a breeding season. 2. Two distinct reproductive behavior patterns are associated with the release of zoea on the 25th day of development, i.e., mating and obstetrical behavior. These male-female associations are stereotyped behaviors. The position of the bodies of the male and female differ in the two behavior patterns. 3. The predictability of onset of these behaviors and the specificity of the patterns suggest their possible initiation by pheromone(s).


Intravenous versus oral iron therapy for postpartum anaemia.
Postpartum iron deficiency anaemia (IDA) is common in women. Most women are treated with either oral iron supplementation or blood transfusion. Hence, the aim of our study was to compare the effect of treatment with either oral ferrous sulphate or intravenous ferrous sucrose on postpartum IDA. A single centre, prospective randomised controlled trial. Women's Centre, John Radcliffe Hospital, Oxford, UK. Forty-four women with haemoglobin (Hb) of <9 g/dl and ferritin of <15 microgram/l at 24-48 hours postdelivery. Women were randomised to receive either oral ferrous sulphate 200 mg twice daily for 6 weeks (group O) or intravenous ferrous sucrose 200 mg (Venofer; Vifor International Ltd, St Gallen, Switzerland), two doses given on days 2 and 4 following recruitment (group I). were analysed by the Students t-test, chi-square test and analysis of variance. Hb, haematocrit, red cell indices, ferritin and serum iron levels were measured on days 0, 5, 14 and 40. Results By day 5, the Hb level in women treated with intravenous iron had risen from 7.3 +/- 0.9 to 9.9 +/- 0.7 g/dl, while there was no change in those treated with oral iron. Women treated with intravenous iron had significantly higher Hb levels on days 5 and 14 (P < 0.01) than those treated with oral iron; although by day 40, there was no significant difference between the two groups. Throughout the study, ferritin levels rose rapidly in those treated with intravenous iron and remained significantly higher than in those treated with oral iron (P < 0.01). Intravenous iron sucrose increases the Hb level more rapidly than oral ferrous sulphate in women with postpartum IDA. It also appears to replenish iron stores more rapidly. However, this study was not large enough to address the safety of this strategy.


Immunotherapy of allergic diseases using probiotics or recombinant probiotics.
Allergic diseases affect up to 30% of the western population, and their prevalence is increasing. Probiotics are able to modulate the mucosal immune response, and clinical trials demonstrated that specific strains, especially lactic acid bacteria (LAB) ones, reduce allergic symptoms. Moreover, the use of recombinant probiotics has been evaluated as possible strategies for the immunotherapy of allergic diseases. The production and delivery of allergens by recombinant LAB in concert with their ability to induce a Th1-type immune response have been shown to be a promising mucosal vaccination strategy in mouse model. The aim of this article is to review the applications of probiotics in allergy immunotherapy with a special focus on recombinant LAB delivering proteins or DNA.


Effects of qualitative feed restriction during rearing on the performance of broiler breeders during rearing and lay.
To prevent health and fertility problems associated with excessive weight gain, broiler breeders are severely feed restricted during rearing, which may affect welfare. We compared the effects of an experimental ad libitum feeding regimen based on qualitative restriction of food intake with conventional quantitative food restriction on the performance of female broiler breeders during rearing and lay. During rearing up to 20 wk of age, control birds were fed restricted amounts of standard broiler breeder mash once daily. Experimental birds had ad libitum access to the same standard mash mixed with 400 g of oat hulls/kg of feed and increasing concentrations of Ca propionate, an appetite suppressant. Mean total mash intake during rearing was 8.12 kg and did not differ between treatments. Both control and experimental birds showed an almost linear growth curve, treatment mean body weights were always within 100 g of the target weight line, and treatments did not differ for body weight uniformity. Groups were subjected to the same quantitative feed restriction from during lay. Feeding regimen during rearing did not affect number of eggs produced, egg weight, or egg quality up to 46 wk of age. We concluded that it may not be necessary to subject chicks to severe quantitative feed restriction to achieve desirable growth curves and body weight uniformity during rearing. Qualitative restriction of feed intake can achieve desirable growth curves in ad libitum fed chicks during rearing, and such a feeding regimen does not have negative effects on hen performance during lay.


Function and fate of myofibroblasts after myocardial infarction.
The importance of cardiac fibroblasts in the regulation of myocardial remodelling following myocardial infarction (MI) is becoming increasingly recognised. Studies over the last few decades have reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of extracellular matrix turnover, but are integrally involved in all aspects of the repair and remodelling of the heart that occurs following MI. The plasticity of fibroblasts is due in part to their ability to undergo differentiation into myofibroblasts. Myofibroblasts are specialised cells that possess a more contractile and synthetic phenotype than fibroblasts, enabling them to effectively repair and remodel the cardiac interstitium to manage the local devastation caused by MI. However, in addition to their key role in cardiac restoration and healing, persistence of myofibroblast activation can drive pathological fibrosis, resulting in arrhythmias, myocardial stiffness and progression to heart failure. The aim of this review is to give an appreciation of both the beneficial and detrimental roles of the myofibroblast in the remodelling heart, to describe some of the major regulatory mechanisms controlling myofibroblast differentiation including recent advances in the microRNA field, and to consider how this cell type could be exploited therapeutically.


Validation of the Chinese version of the Coma Recovery Scale-Revised (CRS-R).
This study aims to validate the Chinese version of the Coma Recovery Scale-Revised (CRS-R). One hundred sixty-nine patients were assessed with both the CRS-R and the Glasgow Coma Scale (GCS), diagnosed as being in unresponsive wakefulness syndrome (UWS, formerly known as vegetative state), minimally conscious state (MCS), or emergence from MCS (EMCS). A subgroup of 50 patients has been assessed twice by the same rater, within 24 h. Patient outcome was documented six months after assessment. The internal consistency for the CRS-R total score was excellent (Cronbach's α = 0.84). Good test-retest reliability was obtained for CRS-R total score and subscale scores (intra-class correlation coefficient [ICC] = 0.87 and ICC = 0.66-0.84, respectively). Inter-rater reliability was high (ICC = 0.719; p < 0.01). Concurrent validity was good between CRS-R total scale and GCS total scale. Diagnostic validity was excellent compared with GCS (emerged from UWS: 24%; emerged from MCS: 28%). When considering patient outcome, diagnostic validity was good. In addition, false-positive rates have been detected for both diagnoses. The Chinese version of the CRS-R is a reliable and sensitive tool and can discriminate patients in UWS, MCS, and EMCS successfully.


NPQ(T) : a chlorophyll fluorescence parameter for rapid estimation and imaging of non-photochemical quenching of excitons in photosystem-II-associated antenna complexes.
In photosynthesis, light energy is absorbed by light-harvesting complexes and used to drive photochemistry. However, a fraction of absorbed light is lost to non-photochemical quenching (NPQ) that reflects several important photosynthetic processes to dissipate excess energy. Currently, estimates of NPQ and its individual components (qE , qI , qZ and qT ) are measured from pulse-amplitude-modulation (PAM) measurements of chlorophyll fluorescence yield and require measurements of the maximal yield of fluorescence in fully dark-adapted material (Fm ), when NPQ is assumed to be negligible. Unfortunately, this approach requires extensive dark acclimation, often precluding widespread or high-throughput use, particularly under field conditions or in imaging applications, while introducing artefacts when Fm is measured in the presence of residual photodamaged centres. To address these limitations, we derived and characterized a new set of parameters, NPQ(T) , and its components that can be (1) measured in a few seconds, allowing for high-throughput and field applications; (2) does not require full relaxation of quenching processes and thus can be applied to photoinhibited materials; (3) can distinguish between NPQ and chloroplast movements; and (4) can be used to image NPQ in plants with large leaf movements. We discuss the applications benefits and caveats of both approaches.


Predicting Outcomes of Penetrating Cardiovascular Injuries at a Rural Center by Different Scoring Systems.
To compare the anatomical and physiological scoring systems and the outcomes of surgical management of penetrating cardiovascular trauma at a rural center. Seventy-seven patients underwent emergency surgery at our center between January/2012 and October/2018 due to penetrating cardiovascular trauma. Injury Severity Score (ISS), Revised Trauma Score (RTS), New Injury Severity Score (NISS), and Trauma and Injury Severity Score (TRISS) were calculated. The validation of these risk scores to predict mortality was assessed by the area under the receiver operating characteristic curve analysis. All trauma scores were correlated with mortality. As ISS, NISS, and TRISS values increased and RTS values decreased, the mortality rate increased. The area under the curve (AUC) in the receiver operating characteristic curve analysis was 0.943 for TRISS, 0.915 for RTS, 0.890 for ISS, and 0.896 for NISS (P<0.001 for each). Logistic regression analysis revealed that scores were correlated with mortality (P<0.001 for each). By investigating cardiac injuries alone, only TRISS and RTS results correlated with mortality for cardiac injuries (Mann-Whitney U test, P=0.003 and P=0.01, respectively). The AUC was only statistically significant for TRISS and RTS (AUC=0.929, P<0.05 for both). For vascular injuries, all the scores were significantly correlated with in-hospital mortality (Mann-Whitney U test, P<0.001 for each). TRISS had the highest AUC (AUC=0.946, P<0.001). TRISS has the highest predictivity for in-hospital mortality in patients with penetrating cardiovascular trauma.


The effect of Metformin on endometrial tumor-regulatory genes and systemic metabolic parameters in polycystic ovarian syndrome--a proof-of-concept study.
The aim of this proof-of-concept study was to determine the effects of three-month Metformin therapy on the expression of tumor-regulatory genes (p53, cyclin D2 and BCL-2) in the endometrium of women with polycystic ovary syndrome (PCOS). A total of 40 women, aged between 21 and 45 years with PCOS (Rotterdam criteria) were recruited. The participants were assessed at pre- and 3-month-post-Metformin therapy for the menstrual regularities, weight reduction, Ferriman Galway scores, fasting blood glucose (FBG), total cholesterol, LDL, HDL and p53, BCL-2 and cyclin D2 gene expression. Five participants conceived spontaneously after the initial recruitment. Majority (68%) resumed regular menstrual cycles after Metformin. There were significant reduction in BMI (p = 0.001), weight (p = 0.001) and Ferriman Galway scores (p = 0.001). A significant improvement was seen in mean FBG (p = 0.002), total cholesterol (p = 0.001), LDL (p = 0.003) and HDL cholesterol levels (p = 0.015). Tumor suppressor gene (p53) was significantly up-regulated after Metformin (10 out of 14 women), with p value 0.016. BCL-2 and cyclin D2 (oncogenes) were slightly up-regulated without significant difference (p = 0.119 and 0.155, respectively). In conclusion, Metformin therapy improved clinical and metabolic parameters in women with PCOS and up-regulated p53 tumor suppressor gene significantly. Further studies are however required to independently validate our findings.


Refinement of the Central Steps of Substrate Transport by the Aspartate Transporter GltPh: Elucidating the Role of the Na2 Sodium Binding Site.
Glutamate homeostasis in the brain is maintained by glutamate transporter mediated accumulation. Impaired transport is associated with several neurological disorders, including stroke and amyotrophic lateral sclerosis. Crystal structures of the homolog transporter GltPh from Pyrococcus horikoshii revealed large structural changes. Substrate uptake at the atomic level and the mechanism of ion gradient conversion into directional transport remained enigmatic. We observed in repeated simulations that two local structural changes regulated transport. The first change led to formation of the transient Na2 sodium binding site, triggered by side chain rotation of T308. The second change destabilized cytoplasmic ionic interactions. We found that sodium binding to the transiently formed Na2 site energized substrate uptake through reshaping of the energy hypersurface. Uptake experiments in reconstituted proteoliposomes confirmed the proposed mechanism. We reproduced the results in the human glutamate transporter EAAT3 indicating a conserved mechanics from archaea to humans.


Reestablishment of Notopygos megalops McIntosh, description of N. caribea sp. n. from the Greater Caribbean and barcoding of "amphiamerican" Notopygos species (Annelida, Amphinomidae).
The species of the genus Notopygos Grube, 1855 are characterized by an ovate body, a prominent caruncle with three lobes, dendritic branchiae, and double dorsal cirri. Twenty-two species belonging to Notopygos have been described, mostly from the Indo-Pacific region. In America, few species are frequently recorded: Notopygos crinita Grube, 1855 from St. Helena Island (Atlantic) and Notopygos ornata Grube and Ørsted in Grube 1857 from Costa Rica (Pacific). Notopygos crinita is a widely distributed species in the Western Atlantic with additional reports in the Mediterranean Sea (as a questionable alien species) and in the Pacific Ocean. However, only the genus features have been considered, consequently some records could be misidentifications. During a revision of materials from collections and the barcode project, 'Mexican Barcode of Life, MEXBOL', we found specimens of Notopygos megalops and an undescribed species from reef zones in the Caribbean; the former had been considered a junior synonym of Notopygos crinita. Herein, Notopygos megalops is reestablished and Notopygos caribeasp. n. is described. A morphological and DNA barcode approach was used to explain the records of Notopygos ornata in the Atlantic and to show the differences with the new species, since both species share features such as complex pigmentation patterns, and circular projections in the median lobe of the caruncle.


Designing m-learning for junior registrars--activation of a theoretical model of clinical knowledge.
The MINI-project aims at supporting junior registrars in the learning process of how to utilize their theoretical knowledge from Medical School in everyday clinical reasoning and practice. Due to the nature of the work--concurrent moving, learning and producing--we designed an m-learning application. This paper introduces the possibilities and challenges for design of the m-learning application based on a) analytical findings on learning and mobility as derived from the design case--an emergency medical ward b) theoretical perspectives on medical knowledge, and c) presentation of the design of an m-learning application. The design process was based on user-driven innovation and the paper discusses considerations on how to combine user-drive and generic models.


Social stressors as antecedents of change.
The potential importance of social stressors as shapers of long-term change in adult functioning has been recognized in recent theoretical work. This paper evaluated the impact of several types of stressors, including life events, transitions, hassles, and societal problems such as war or economic depression on happiness and symptoms. The role of selected social and psychological characteristics also was explored. Respondents included 62 men and 72 women who were interviewed four times over an 11-year period. Life stage, symptoms, and self-criticism at baseline were found to predict subsequent stress history, and the stress measures themselves were intercorrelated over time. In the prediction phase of the study, the stress measures made the greatest contribution to the prediction of happiness for both men and women, whereas both initial symptom level and social stressors contributed to the prediction of symptoms manifest at the 11-year follow up.


Surgical Resection of Bertolotti Syndrome.
Background: Bertolotti syndrome is the association of lumbosacral transitional vertebrae and low back pain or sciatica. Lumbosacral transitional vertebrae are vertebrae with large transverse processes that (1) articulate or fuse with the sacrum or ilium and (2) have a caudal disc space. Bertolotti syndrome is relatively common, with an incidence of 4.6% to 7% in patients with low back pain. The exact etiology of Bertolotti syndrome remains uncertain, although several hypotheses have been proposed. Case Report: A 17-year-old male presented with a long history of low back pain refractory to conservative treatment including medications, activity modification, and physical therapy. Unilateral Bertolotti syndrome was suspected. The diagnosis was confirmed with bupivacaine injection at the transitional articulation. The patient was treated with surgical resection of his enlarged left-sided L5 transverse process, resulting in complete resolution of pain. Conclusion: Lumbosacral transitional vertebrae are relatively common, so Bertolotti syndrome should be on the list of differential diagnoses for low back pain.


Recurrent urinary tract infections in children.
Urinary tract infections are common in children and present in various ways. Diagnosis is based on findings of pyuria and bacteriuria. Management includes adequate and timely investigation, appropriate antibiotics, treatment of underlying contributing factors, and follow-up advice.


Integrin-linked kinase is required for TGF-β1 induction of dermal myofibroblast differentiation.
Cutaneous repair after injury requires activation of resident dermal fibroblasts and their transition to myofibroblasts. The key stimuli for myofibroblast formation are activation of transforming growth factor-β (TGF-β) receptors and mechanotransduction mediated by integrins and associated proteins. We investigated the role of integrin-linked kinase (ILK) in TGF-β1 induction of dermal fibroblast transition to myofibroblasts. ILK-deficient fibroblasts treated with TGF-β1 exhibited attenuation of Smad 2 and 3 phosphorylation, accompanied by impaired transcriptional activation of Smad targets, such as α-smooth muscle actin. These alterations were not limited to Smad-associated TGF-β1 responses, as stimulation of noncanonical mitogen-activated protein kinase pathways by this growth factor was also diminished in the absence of ILK. ILK-deficient fibroblasts exhibited abnormalities in the actin cytoskeleton, and did not form supermature focal adhesions or contractile F-actin stress fibers, indicating a severe impairment in their capacity to differentiate into myofibroblasts. These defects extended to the inability of cells to contract extracellular matrices when embedded in collagen lattices. We conclude that ILK is necessary to transduce signals implicated in the transition of dermal fibroblasts to myofibroblasts originating from matrix substrates and TGF-β1.


Deep learning-based end-to-end 3D depth recovery from a single-frame fringe pattern with the MSUNet++ network.
Deep learning (DL)-based single-frame fringe pattern to 3D depth reconstruction methods have aroused extensive research interest. The goal is to estimate high-precision 3D shape from a single frame of fringe pattern with limited information. Therefore, the purpose of this work attempts to propose an end-to-end DL-based 3D reconstruction method from the single fringe pattern with excellent capability of achieving high accuracy depth recovery and geometry details preservation of tested objects. We construct a multi-scale feature fusion convolutional neural network (CNN) called MSUNet++, which incorporates discrete wavelet transform (DWT) in data preprocessing for extracting high-frequency signals of fringe patterns as input of the network. Additionally, a loss function that combines structural similarity with edge perception is established. Through these measures, high-frequency geometry details of the reconstruction results can be obviously enhanced, while the geometric shape can be effectively maintained. Ablation experiments are involved in validating the effectiveness of our proposed solution. 3D reconstructed results and analysis of generalization experiments on different tested samples imply that the proposed method in this research enjoys capabilities of higher accuracy, better detail preservation, and robustness in comparison with the compared methods.


A Multi-Pronged Approach to Diversifying the Workforce.
The biomedical workforce continues to lack diversity, despite growing evidence demonstrating the advantages of diverse teams in workplaces for creativity and innovation. At the University of Pittsburgh Institute for Clinical Research Education, we have taken a multi-pronged, collaborative approach to enhance the diversity of our trainees and scholars. We started by implementing a program for postdoctoral fellows and junior faculty, the Career Education and Enhancement for Health Care Research Diversity (CEED) program. We then built on this program and created a sister program for medical students (CEED II). These two programs were intended to build a local community of diverse researchers. Following the success of these programs, we extended our efforts and pursued federal funding to establish other programs. Our first funded program was designed to teach leadership and career coaching skills to mentors who are committed to mentoring people from diverse backgrounds, the Professional Mentoring Skills Enhancing Diversity (PROMISED) program. We then partnered with minority serving institutions to create a fellowship in translational research skills training, Leading Emerging and Diverse Scientists to Success (LEADS), training in patient-centered outcomes research, Expanding National Capacity in PCOR through Training (ENACT), and a year-long fellowship to work with a specific mentor at Pitt, the Clinical and Translational Science (CTS) Fellowship (TL1). With recognition that much work remains to be done, we believe these programs represent a small but positive step toward diversifying the biomedical workforce.


Men's Decision-Making to Become Nurses: Gendered Influences and Fit With Gender Role Conflict Theory.
Patriarchy has been offered as the foundational paradigm for gendered issues in nursing; however, operationalization of this paradigm in order to improve nursing workforce gender diversity is challenging. The qualitative arm of the present study explored men's decision-making to become nurses within a larger gendered context. Findings were then assessed for fit with Gender Role Conflict Theory. Findings suggest that men undergo a process in which contrasting influences are considered. The findings' congruence with gender role conflict theoretical assumptions suggests suitable conceptual fit for male recruitment and retention actions and further research.


Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry.
Some Ki-1 lymphomas carry a specific chromosomal translocation, t(2;5)(p23;q35). We have recently found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in a human Ki-1 lymphoma with this translocation. Subsequent cDNA cloning showed that p80 is a fusion protein of two different genes on chromosome 2p23 and 5q35, the novel tyrosine kinase gene and nucleophosmin gene, respectively. In this study, we intended to detect p80 on lymphoma tissues with immunologic methods. Thus, we developed rabbit polyclonal antibody using a synthetic peptide corresponding to a part of its kinase domain. The antibody (anti-p80) immunoprecipitated and immunoblotted p80 specifically from AMS3. Then, to examine whether t(2;5)(p23;q35) was present on biopsied lymphomas, reverse transcriptase-polymerase chain reaction (RT-PCR) covering the fusion junction of p80 mRNA was performed. Among 10 Ki-1 lymphomas and 10 additional lymphomas other than the Ki-1 lymphomas, expression of p80 mRNA was detected in three cases exclusively. When these 20 cases and additional 30 lymphomas were immunostained with anti-p80, positive staining was noted exclusively in the three cases found by PCR to have harbored the p80 mRNA. Thus, the present immunostaining, as well as PCR, was shown to be efficient for detecting lymphomas producing this chimeric protein/mRNA.


Osteocartilaginous flap technique for acquired and congenital saddle nose deformities.
This paper illustrates the objective possible applications of the osteocartilaginous flap technique in solving the functional and aesthetic problems associated with saddle nose deformities, the pathogenesis of which essentially relates to: (1) congenital saddle noses; (2) post-traumatic saddle noses; and (3) saddle noses resulting from previous surgery on the septum. This technique is suggested as an alternative to a combination of other methods (such as septoplasty, bone, or cartilage grafts) to restore the inhalatory function of the internal nasal valve and the integrity of the nasal support structures using locally available tissues. The authors prefer to use this technique in the treatment of serious congenital or acquired saddle nose deformities and to assign composite grafts a supplementary function only. The different stages of this surgical procedure are analyzed and the results are assessed during short- and medium-term follow-up.


Individual and 'national' healthcare rights: Analysing the potential conflicts.
Individual rights to healthcare (RTHCs) are increasingly common in law. Yet even plausible theoretical defences thereof raise a classic problem in the philosophy of rights: How do individual rights relate to 'collective' rights within the same domain? Collective rights are common in international law and in the domestic laws of states that recognize RTHCs. These collective rights often include health-related components. There are at least prima facie plausible reasons to think that such collective 'health rights' should exist. A complete account of health rights should thus explain how individual and collective health rights claims relate to one another and what one should do in cases where the claims conflict. This work contributes to our understanding of health rights by analysing the relationship between individual RTHCs and a plausible candidate collective health right, namely a sub-state national right to control healthcare law and policy. It argues that concerns about rights conflicts in this context make sense, but genuine conflicts between individual health rights and national control over healthcare are rare. The strongest cases for sub-state national 'self-determination' rights do not implicate healthcare, or tend not to provide reasons to override any individual RTHCs. Conflicts are possible in rare cases and may even favour fulfilling the collective rights claims. Yet individual RTHCs remain important even in those cases. Individual rights remain useful measures for evaluating the exercise of collective rights: exercises that violate (or even fail to fulfil) individual health rights are worse for so doing.


The management of cervical intra-epithelial neoplasia.
The aim of this article is to discuss the management of a woman with cervical intra-epithelial neoplasia based on current scientific knowledge of disease progression from cervical pre-cancer to invasive squamous cancer. Interpretation of cytology (Papanicolou Smear) results and the currently advocated treatment modalities are also discussed.


[Situation and correlated behavior of HIV infection among currently married MSM in Gansu province].
To explore the situation of HIV infection among currently married MSM and the features of related sexual behavior on both males and females in Gansu province. By "Place the recruitment" methodology, 297 currently married MSM were recruited in Lanzhou and Tianshui cities of Gansu province. Participants filled in a questionnaire and underwent HIV antibody testing. SPSS 17.0 software was used to analyze the result and differences between positive HIV MSM and negative HIV MSM. Possible factors that influencing the HIV infection among currently married MSM were analyzed. Among those currently married MSM, the HIV positive rate was 4.7%. 94.6% participants admitted having had anal sex with male partners in the past 6 months while 30.9% participants had more than 2 male sex partners in the past week, with the rate of condoms use as 45.9%. 69.0% of the participants had sex with females in the past 6 months, with the rate of condoms use as 24.9%. 59.0% of the participants did not use condoms when having sexual relations with partners. Among HIV positive married MSM, the rate of AIDS awareness was 64.3% and 7.1% of them ever having had HIV testing last year and 92.9% of them had anal sex with males. In the recent 6 months, 14.3% had ever used condom each time when having anal sex with males. 35.7% of the cases ever having had sex with females, with the rate of condom use as 60.0%. HIV prevalence, low AIDS awareness, low HIV rate of testing and high rate of unprotected sex behavior with either sex partners were found among currently married MSM in Gansu province. of this study called for behavioral intervention and HIV testing measures should be taken immediately.


Helix stop and start signals in peptides and proteins. The capping box does not necessarily prevent helix elongation.
Recently, several papers have addressed the existence of helix stop signals at the beginning of alpha-helices. It has been indicated that the existence of a reciprocal backbone-side-chain hydrogen-bond interaction, designated the capping box, could be one of these signals. The fingerprint sequence of this capping box is Ser/Thr-X-X-Glu/Gln. In the fifth alpha-helix of the chemotactic alpha/beta parallel protein CheY there is such a sequence in the middle of the helix. In a peptide corresponding to this alpha-helix the capping box is bypassed, as deduced from NMR analysis. However, making the peptide shorter so that the capping box fingerprint is closer to the beginning of the peptide results in the formation of the capping box. These results indicate that, although the capping box could play a role in stabilizing and nucleating helical peptides in solution, it is not necessarily a stop signal and can be bypassed when favourable interactions exist between the surrounding residues.


Ultrashort echo time magnetic resonance imaging of the osteochondral junction.
Osteoarthritis is a common chronic degenerative disease that causes pain and disability with increasing incidence worldwide. The osteochondral junction is a dynamic region of the joint that is associated with the early development and progression of osteoarthritis. Despite the substantial advances achieved in the imaging of cartilage and application to osteoarthritis in recent years, the osteochondral junction has received limited attention. This is primarily related to technical limitations encountered with conventional MR sequences that are relatively insensitive to short T2 tissues and the rapid signal decay that characterizes these tissues. MR sequences with ultrashort echo time (UTE) are of great interest because they can provide images of high resolution and contrast in this region. Here, we briefly review the anatomy and function of cartilage, focusing on the osteochondral junction. We also review basic concepts and recent applications of UTE MR sequences focusing on the osteochondral junction.


The extraordinary antioxidant activity of vitamin E phosphate.
The antioxidant activities of RRR-vitamin E (VE), all-rac-vitamin E (all-rac-VE), trolox, RRR-vitamin E acetate (VEA), all-rac-vitamin E phosphate (VEP) and RRR-vitamin E succinate (VES) were compared. In this study, the rank order in the inhibition of lipid peroxidation (LPO) of VE and its derivatives was trolox>VE approximately all-rac-VE>VEA>VES. VE and trolox inhibited LPO in non-heated and heated rat liver microsomes. It has generally been accepted that this is due to scavenging of free radicals by these antioxidants, and during this protection the antioxidants are oxidized. VEA and VES have to be converted into VE by esterases to obtain antioxidant activity against LPO. VEP, however, had a potent antioxidant effect of its own without conversion to VE. In contrast to VE, VEP is not consumed during this protection. Of the compounds tested, VEP is the most potent in induction of hemolysis of erythrocytes. EPR experiments using the spin label 16-doxylstearic acid showed that VEP reduces membrane fluidity, in contrast to VE. This indicates that VEP acts as a detergent and forms a barrier that might inhibit the transfer of radicals from one polyunsaturated fatty acid to another. This new mechanism may form the basis for a new class of antioxidants.


Development of a transferable bimolecular fluorescence complementation system for the investigation of interactions between poly(3-hydroxybutyrate) granule-associated proteins in Gram-negative bacteria.
Poly(3-hydroxybutyrate) (PHB) granules are organelle-like multienzyme-polymer complexes (carbonosomes) and are widespread storage compounds in prokaryotes. The interaction of three PHB granule-bound proteins (PHB synthase PhaC1, phasin PhaP5, and PHB/DNA binding protein PhaM) was studied in vivo by bimolecular fluorescence complementation (BiFC) microscopy in Ralstonia eutropha. To this end, a mobilizable 2-plasmid system for arabinose-controlled expression of protein fusions with the N-terminal (YN) and C-terminal (YC) parts of the enhanced yellow fluorescent protein (eYfp) in Gram-negative bacteria was developed. Both plasmids were stably expressed in Escherichia coli and in transconjugants of R. eutropha. Homo-oligomerization of PhaC1, PhaP5, and PhaM and interactions between PhaC1 and PhaM and between PhaM and PhaP5 were detected in R. eutropha and colocalized with PHB granules under PHB-permissive conditions. PhaM-PhaC1 complexes were detected near the midcell/nucleoid region in the absence of PHB. Expression of BiFC complexes in R. eutropha with PhaM (PhaM homo-oligomers or PhaM-PhaC1 or PhaM-PhaP5 complexes) resulted in substantial cell elongation compared to wild-type cells and in BiFC signals that were generally located near the midcell/nucleoid region. Western blot analysis of wild-type cell extracts and proteome analysis of PHB granule-bound proteins revealed that PhaM and PhaP5 are expressed in R. eutropha and that PhaM is constitutively expressed independently of the presence or absence of PHB. Size exclusion chromatography analysis in combination with cross-linking experiments of purified PhaP5-His6 and PhaM-His6 showed that PhaP5 forms dimers and that PhaM is present in oligomeric (dodecamer) form. Implications of this finding for subcellular PHB localization and initiation of PHB granule formation in R. eutropha will be discussed.


Effects of lithium on age-related decline in mitochondrial turnover and function in Caenorhabditis elegans.
Aging has been associated with the accumulation of damages in molecules and organelles in cells, particularly mitochondria. The rate of damage accumulation is closely tied to the turnover of the affected cellular components. Perturbing mitochondrial turnover has been shown to significantly affect the rate of deterioration of mitochondrial function with age and to alter lifespan of model organisms. In this study, we investigated the effects of upregulating autophagy using lithium in Caenorhabditis elegans. We found that lithium treatment increased both the lifespan and healthspan of C. elegans without any significant change in the mortality rate and oxidative damages to proteins. The increase in healthspan was accompanied by improved mitochondrial energetic function. In contrast, mitochondrial DNA copy number decreased faster with age under lithium. To better understand the interactions among mitochondrial turnover, damage, and function, we created a mathematical model that described the dynamics of functional and dysfunctional mitochondria population. The combined analysis of model and experimental observations showed how preferential (selective) autophagy of dysfunctional mitochondria could lead to better mitochondrial functionality with age, despite a lower population size. However, the results of model analysis suggest that the benefit of increasing autophagy for mitochondrial function is expected to diminish at higher levels of upregulation due to a shrinking mitochondrial population.


Incidence and risk factors for H5 highly pathogenic avian influenza infection in flocks of apparently clinically healthy ducks.
A prospective longitudinal study was conducted on 96 smallholder duck farms in Indonesia over a period of 14 months in 2007 and 2008 to monitor bird- and flock-level incidence rates of H5 highly pathogenic avian influenza (HPAI) infection in duck flocks, and to identify risk factors associated with these flocks becoming H5 seropositive. Flocks that scavenged around neighbouring houses within the village were at increased risk of developing H5 antibodies, as were flocks from which carcases of birds that died during the 2 months between visits were consumed by the family. Duck flock confinement overnight on the farm and sudden deaths of birds between visits were associated with lower risk of the flock developing H5 antibodies. Scavenging around neighbouring houses and non-confinement overnight are likely to be causal risk factors for infection. With this study we have provided insights into farm-level risk factors of HPAI virus introduction into duck flocks. Preventive messages based on these risk factors should be included in HPAI awareness programmes.


Antioxidant and cytotoxic activities of three species of tropical seaweeds.
Three species of seaweeds (Padina tetrastromatica, Caulerpa racemosa and Turbinaria ornata) are widely consumed by Asians as nutraceutical food due to their antioxidant properties. Studies have shown that these seaweeds exhibit bioactivities which include antimicrobial, antiviral, anti-hypertensive and anticoagulant activities. However, investigations into the mechanisms of action pertaining to the cytotoxic activity of the seaweeds are limited. The aim of this study was to determine the antioxidant and cytotoxic activities of whole extracts of P. tetrastromatica, C. racemosa and T. ornata, including the cellular events leading to the apoptotic cell death of the extract treated-MCF-7 cells. Bioassay guided fractionation was carried out and the compounds identified. Powdered samples were sequentially extracted for 24 h. Their antioxidant activities were assessed by the DPPH radical, superoxide, nitric oxide and hydroxyl radical scavenging assays. The cytotoxic activity of the extract-treated MCF-7cells was assessed using the MTT assay. The most potent fraction was subjected to bioassay guided fractionation with column chromatography. All the fractions were tested for cytotoxic activity, caspase activity and effect on DNA fragmentation. All three seaweeds showed potent radical scavenging activities in the various assays. The activity of the cellular antioxidant enzymes, superoxide dismutase, catalase and glutathione reductase, in MCF-7 cells, decreased in a time-dependent manner. The partially purified fractions exhibited higher cytotoxic activity, as assessed by the MTT assay, than the whole extracts in the breast adenocarcinoma cell line, MCF-7. LC-MS analysis revealed the presence of bioactive alkaloids such as camptothecin, lycodine and pesudopelletierine. Based on the results obtained, all three seaweeds are rich sources of enzymatic and non-enzymatic antioxidants which could contribute to their reported medicinal benefits.


Vaccine Design Informed by Virus-Induced Immunity.
When an individual is exposed to a viral pathogen for the first time, the adaptive immune system is naive and cannot prevent virus replication. The consequence may be severe disease. At the same time, the host may rapidly generate a pathogen-specific immune response that will prevent disease if the virus is encountered again. Parvovirus B19 provides one such example. Children with sickle cell disease can experience life-threatening transient aplastic crisis when first exposed to parvovirus B19, but an effective immune response confers lifelong protection. We briefly examine the induction and benefits of virus-induced immunity. We focus on three human viruses for which there are no licensed vaccines (respiratory syncytial virus, human immunodeficiency virus type 1, and parvovirus B19) and consider how virus-induced immunity may inform successful vaccine design.


Calcium dynamics in microbialite-forming exopolymer-rich mats on the atoll of Kiritimati, Republic of Kiribati, Central Pacific.
Microbialite-forming microbial mats in a hypersaline lake on the atoll of Kiritimati were investigated with respect to microgradients, bulk water chemistry, and microbial community composition. O2, H2S, and pH microgradients show patterns as commonly observed for phototrophic mats with cyanobacteria-dominated primary production in upper layers, an intermediate purple layer with sulfide oxidation, and anaerobic bottom layers with sulfate reduction. Ca(2+) profiles, however, measured in daylight showed an increase of Ca(2+) with depth in the oxic zone, followed by a sharp decline and low concentrations in anaerobic mat layers. In contrast, dark measurements show a constant Ca(2+) concentration throughout the entire measured depth. This is explained by an oxygen-dependent heterotrophic decomposition of Ca(2+)-binding exopolymers. Strikingly, the daylight maximum in Ca(2+) and subsequent drop coincides with a major zone of aragonite and gypsum precipitation at the transition from the cyanobacterial layer to the purple sulfur bacterial layer. Therefore, we suggest that Ca(2+) binding exopolymers function as Ca(2+) shuttle by their passive downward transport through compression, triggering aragonite precipitation in the mats upon their aerobic microbial decomposition and secondary Ca(2+) release. This precipitation is mediated by phototrophic sulfide oxidizers whose action additionally leads to the precipitation of part of the available Ca(2+) as gypsum.


The effect of dydrogesterone on premenstrual symptoms. A double-blind, randomized, placebo-controlled study in general practice.
The effect of dydrogesterone on premenstrual symptoms was investigated in a double-blind, randomized, placebo-controlled study comprising 161 patients from unselected practice material. Dydrogesterone 10 mg twice daily from the 12th day until onset of the following menstrual period was compared with placebo throughout 3 cycles. No clinically relevant effect of dydrogesterone was found. There was an overall therapeutic effect in 52% of the patients on dydrogesterone, and in 44% of the placebo-treated patients. Therapeutic gain ranged between -7 and +23% (95% confidence limits). Type II error risk of failure to detect a therapeutic gain of 20% was 6%. A significant effect of dydrogesterone was found on decreased libido, and statistical significance was nearly achieved for the symptoms irritability and headache. The significant effect on libido can be attributed to mass significance.


Automatic Prioritization of Self-Referential Stimuli in Working Memory.
People preferentially attend to external stimuli that are related to themselves compared with others. Whether a similar self-reference bias applies to internal representations, such as those maintained in working memory (WM), is presently unknown. We tested this possibility in four experiments, in which participants were first trained to associate social labels (self, friend, stranger) with arbitrary colors and then performed a delayed match-to-sample spatial WM task on color locations. Participants consistently responded fastest to WM probes at locations of self-associated colors (Experiments 1-4). This self-bias was driven not by differential exogenous attention during encoding or retrieval (Experiments 1 and 2) but by internal attentional prioritization of self-related representations during WM maintenance (Experiment 3). Moreover, self-prioritization in WM was nonstrategic, as this bias persisted even under conditions in which it hurt WM performance. These findings document an automatic prioritization of self-referential items in WM, which may form the basis of some egocentric biases in decision making.


Understanding and improving patient compliance.
The problem of patient compliance, as well as the ability of the physician to understand, detect, and improve compliance are described in relation to a new model of health decisions and patient behavior. The health decision model combines decision analysis, behavioral decision theory, and health beliefs. This model provides a framework for modifying general health beliefs; treatment recommendations; experience with therapeutic regimens and health care providers; patient knowledge and social interaction patterns. Physicians, guided by certain ethical restraints, are in a unique position of responsibility and opportunity to actively encourage patient compliance with treatment.


Valence-difference contrast measurements utilizing X-ray anomalous scattering.
Anomalous scattering experiments with X-ray wavelengths close to an absorption edge have made it possible to determine independently the behaviour of ions in different valence states. The anomalous scattering factors of Fe(2+) and Fe(3+) obtained from both absorption and diffraction data have a large difference in f' between the two kinds of ions. Using a valence-difference contrast method, Bragg and diffuse scattering measurements were carried out for single crystals of Fe(3)O(4) at low temperatures. The results demonstrate the ability of the contrast method to resolve charge ordering and valence fluctuation details.


The detection of early femoro-distal vein graft stenosis by treadmill exercise testing.
A prospective study of 125 femoro-distal vein bypass grafts (103 patients) was undertaken to assess the role of treadmill exercise testing in the detection and correction of early vein graft stenosis. Patients were followed at 1,3,6,12 months and then annually with routine clinical assessment, palpation of pulses and resting Doppler ankle/brachial index. In addition, the Doppler index was repeated after 5 minutes exercise on a treadmill set at 5 degrees and 3 km/hr. Follow-up has been carried out for a mean of 24 months (range 3-48 months) and during that time 30 vein grafts (28 patients) were submitted to angiography. This revealed vein graft stenosis in 15, native vessel disease in 11 and no morphologic abnormality in 4. One additional graft was suspected to have a stenosis but occluded before angiography could be carried out. At the time of detection by the treadmill test, 8 of the 15 (53%) confirmed vein graft stenoses, and 4 of 11 (36%) native vessel stenoses would not have been detected by clinical assessment or resting Doppler pressure measurements. The 15 vein graft stenoses which were corrected all remain patent, suggesting that treadmill testing is of value in the detection and prevention of early femoro-distal vein graft occlusion.


MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition.
The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TSKI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TSKI4 cells restores epithelial features, including cell-cell adhesion and barrier formation. These data define a role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes.


A Modified Technique for Percutaneous Dilatational Tracheostomy.
Purpose: Percutaneous dilatational tracheostomy (PDT) is widely used in mechanical ventilation patients to facilitate weaning. This modified technique aims to reduce accidental intraprocedural airway loss and desaturation associated with current PDT techniques. Materials and Methods: This is a single-center, prospective cohort study of 100 patients who underwent a modified technique between September 8, 2022, and January 18, 2023. The procedure was performed at Shiraz University of medical science at the tertiary center, Namazi teaching hospital. In this method instead of withdrawing the endotracheal tube (ETT) up close to the vocal cord and subglottic area at the beginning of the procedure, which is a common theme in PDT techniques with accidental extubation risk, we kept the ETT and gradually withdraw it. Results: Of the 100 patients, the average age was 53.5 years, and 66% were males. On average, the procedure lasted 255 (67) seconds. All patients successfully underwent PDT with no life-threatening complications, accidental intraprocedural airway loss, or desaturation. Conclusions: As a result of this modified technique, PDT for airway management can be a safe and low-complication procedure without the risk of accidental intraprocedural airway loss. Moreover, omitting bronchoscopy and sonography during these procedures is cost-effective and secure.


[Vaccination of ferrets (Putorius furo) against rabies using a tissue vaccine].
The use of live tissue rabies vaccine from Vnukovo-32 strain produced by the Bioveta National Corporation at Ivanovice na Hané was tested on 15 ferrets (Putorius furo L. 1758). The 21st day after subcutaneous application of 3 ml of vaccine, the average titre of virus-neutralizing antibodies was 1 : 71.4, and after subcutaneous and intramuscular application of 1 ml of vaccine the average titre was 1:20.6 and 1 : 15.6, respectively. The challenge test was performed 52 weeks after vaccination: a dose of 10(5) MICLD50 of the street rabies virus was applied i. m. to the neck muscle. All the vaccinated animals survived. As indicated by the results of the trials, a good tolerance and full immunity of vaccinates to the infection with the street rabies virus was maintained for one year. 1 ml of vaccine diluted according to instructions and applied s. c. or i. m. was found to be sufficient.


Quantitative and morphological changes of Langerhans cells in Bowen's disease from patients with chronic arsenicism.
Langerhans cells (LCs) are considered to be responsible for the immunologic presentation of tumor-associated antigens and play a role in the elimination of neoplastic clones. Ultraviolet light B can cause dysfunction and loss of LCs. Both the number and dendritic morphology of LCs are known to be diminished in squamous cell carcinomas from sun-exposed skin. The effects of arsenics on LCs are unknown. Using an OKT-6 monoclonal antibody to stain intraepithelial LCs, we compared their number and morphology in Bowen's lesions and in the perilesional skin from sun-protected sites in ten patients with chronic arsenicism. There was a significant reduction in the numbers of LCs in the Bowen's lesions as compared to the perilesional skin specimens. Loss of dendrites was observed in all Bowen's lesions and in seven of the perilesional skin specimens. Ultrastructurally, the LCs showed an absence of dendrites, but the Birbeck granules were preserved. Since the specimens were not from sun-exposed skin in our study, the findings may be related to chronic arsenic intoxication. The morphologic alteration of LCs observed in the perilesional skin further suggests an arsenic-related systemic dysfunction of the LCs, which in turn may contribute to the development of skin cancers in these patients.


[Aging-associated changes in cardiac function and their prevention].
Aging associated changes in cardiac contraction, Ca(2+) homeostasis and their neurohumoral regulations have been studied using rodents. The changes can be understood not only to reduce energy consumption but also to be susceptible to Ca(2+) overload, possibly leading arrhythmia and cell death. N-3 polyunsaturated fatty acid is reported to prevent cardiac Ca(2+) overload. Its content in the cellular membrane is reduced in aged cardiomyocytes, suggesting that the aging-associated change in n-3 fatty acid content is related to the changes in cardiac function. Ingestion balance between n-3 and n-6 fatty acids may affect on the risk of cardiovascular diseases associated with aging.


Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant.
Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.


Structural and Raman spectroscopic characterization of pyroxene-type compounds in the CaCu1-xZnxGe2O6 solid-solution series.
Pyroxene-type germanate compounds with the composition CaCuGe2O6-CaZnGe2O6 have been synthesized via a solid-state ceramic sintering route. Phase-pure polycrystalline and small single-crystal material was obtained all over the series, representing a complete solid-solution series. Differential thermal analysis, single-crystal X-ray diffraction and Raman spectroscopy were used to characterize phase stability, phase changes and structural alterations induced by the substitution of Cu2+ with Zn2+. Whereas pure CaCuGe2O6 exhibits P21/c symmetry with a strong distortion of the M1 octahedra and two different Ge sites, one of them with an unusual fivefold coordination, the replacement of Cu2+ by Zn2+ induces a chemically driven phase change to the C2/c symmetry. The phase change takes place around Zn2+ contents of 0.12 formula units and is associated with large changes in the unit-cell parameters. Here, the increase of c by as much as 3.2% is remarkable and it is mainly controlled by an expansion of the tetrahedral chains. Further differences between the P21/c and C2/c structures are a more regular chain of edge-sharing M1 octahedra as a consequence of more and more reduced Jahn-Teller distortion and a less kinked, symmetry-equivalent tetrahedral chain. The coordination of the Ca site increases from sevenfold to eightfold with large changes in the Ca-O bond lengths during the phase change. Raman spectroscopy was mainly used to monitor the P21/c to C2/c phase change as a function of composition, but also as a function of temperature and to follow changes in specific Raman modes throughout the solid-solution series.


Induced expression of class II transplantation antigens in the cartilage-pannus junction in RA: chronic synovitis as a model system for aberrant T-lymphocyte activation.
An induced expression of class II transplantation antigens is seen on synovial cells in human arthritides such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS) as well as in some experimental animal models for arthritis, i.e. in collagen arthritis in mice and rats and in adjuvant arthritis in rats. In this paper, additional original data are presented concerning the expression of HLA-DR, DP, and DQ antigens on macrophage-like and fibroblast-like cells within the cartilage-pannus junction in RA. The functional implications of this induced synovial class II antigen expression is discussed against the background of both in vitro experiments on human synovial cells and in vivo experiments in the animal arthritis models.


Equilibrium of adsorption of mixed milk protein/surfactant solutions at the water/air interface.
Ellipsometry and surface profile analysis tensiometry were used to study and compare the adsorption behavior of beta-lactoglobulin (BLG)/C10DMPO, beta-casein (BCS)/C10DMPO and BCS/C12DMPO mixtures at the air/solution interface. The adsorption from protein/surfactant mixed solutions is of competitive nature. The obtained adsorption isotherms suggest a gradual replacement of the protein molecules at the interface with increasing surfactant concentration for all studied mixed systems. The thickness, refractive index, and the adsorbed amount of the respective adsorption layers, determined by ellipsometry, decrease monotonically and reach values close to those for a surface covered only by surfactant molecules, indicating the absence of proteins from a certain surfactant concentration on. These results correlate with the surface tension data. A continuous increase of adsorption layer thickness was observed up to this concentration, caused by the desorption of segments of the protein and transforming the thin surface layer into a rather diffuse and thick one. Replacement and structural changes of the protein molecules are discussed in terms of protein structure and surface activity of surfactant molecules. Theoretical models derived recently were used for the quantitative description of the equilibrium state of the mixed surface layers.


Stepping-stones and dispersal flow: establishment of a meta-population of Milu (Elaphurus davidianus) through natural re-wilding.
The Milu (Père David's deer, Elaphurus davidianus) became extinct in China in the early 20(th) century but was reintroduced to the country. The reintroduced Milu escaped from a nature reserve and dispersed to the south of the Yangtze River. We monitored these accidentally escaped Milu from 1995 to 2012. The escaped Milu searched for vacant habitat patches as "stepping stones" and established refuge populations. We recorded 122 dispersal events of the escaped Milu. Most dispersal events occurred in 1998, 2003, 2006 and 2010. Milu normally disperse in March, July and November. Average dispersal distance was 14.08 ± 9.03 km, with 91.41% shorter than 25 km. After 5 generations, by the end of 2012, 300 wild Milu were scattered in refuge populations in the eastern and southern edges of the Dongting Lake. We suggest that population density is the ultimate cause for Milu dispersal, whereas floods and human disturbance are proximate causes. The case of the Milu shows that accidentally escaped animals can establish viable populations; however, the dispersed animals were subject to chance in finding "stepping stones". The re-wilded Milu persist as a meta-population with sub-populations linked by dispersals through marginal habitats in an anthropogenic landscape.


Assessment of Inflammasome Formation by Flow Cytometry.
Inflammasomes are large protein complexes formed in response to cellular stresses that are platforms for recruitment and activation of caspase 1. Central to most inflammasome functions is the adapter molecule ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain) that links the inflammasome initiator protein to the recruited caspases. ASC is normally diffuse within the cell but within minutes of inflammasome activation relocates to a dense speck in the cytosol. The dramatic redistribution of ASC can be monitored by flow cytometry using parameters of fluorescence peak height and width when immunostained or tagged with a fluorescent protein. This can be used to define cells with active inflammasomes within populations of primary macrophages and monocytes, allowing quantification of responses and flow-sorting of responding cells. Protein structural requirements for ASC speck formation and recruitment of caspases to ASC specks can be assessed by expressing components in HEK293 cells. This provides rapid quantification of responding cell number and correlation with the expression level of inflammasome components within single cells. © 2016 by John Wiley & Sons, Inc.


Management of the condyle following the resection of tumours of the mandible.
The aim of this study was to assess the management of the condyle during the restoration of mandibular defects following tumour resection. A total of 41 patients who underwent simultaneous tumour resection and reconstruction with vascularized iliac myocutaneous flaps for mandibular defects, from September 2010 to October 2014, were included. These patients were divided into three groups: group 1, condyle preserved; group 2, condyle sacrificed; group 3, condyle frozen. Patients were followed up at 1, 3, 6, and 12 months for the evaluation of appearance, occlusion, and speech. The TMJ disability index (DI) and craniomandibular index (CMI) differed significantly according to the method of management, as well as the position and morphology of the reconstructed condyle (P<0.01); however, no statistically significant difference in mandible movement was observed between the groups. The DI and CMI values were significantly lower in group 1 patients compared to group 2 and group 3 patients. The results showed that TMJ function in group 1 patients was superior to that in group 2 and group 3 patients, and that function in group 3 patients was better than that in group 2 patients. In conclusion, the condyle should be preserved when benign mandibular lesions are situated near the condyle, as preservation has a positive effect on TMJ function and mandible movement.


Bioactive Compounds and Their Neuroprotective Effects in Diabetic Complications.
Hyperglycemia, hyperlipidemia and impaired insulin signaling during the development of diabetes can cause diabetic complications, such as diabetic neuropathy, resulting in significant morbidity and mortality. Although various therapeutics are available for the treatment of diabetic neuropathy, no absolute cure exists, and additional research is necessary to comprehensively understand the underlying pathophysiological pathways. A number of studies have demonstrated the potential health benefits of bioactive compounds, i.e., flavonoids and vitamins, which may be effective as supplementary treatments for diabetes and its complications. In this review, we highlight the most recent reports about the mechanisms of action of bioactive compounds (flavonoids and vitamins) possessing potential neuroprotective properties in diabetic conditions. Additional clinical studies are required to determine the appropriate dose and duration of bioactive compound supplementation for neuroprotection in diabetic patients.


Investigating the possible pain attenuating mechanisms of pregabalin in chronic constriction injury-induced neuropathic pain in rats.
Aim of the study: The current study was aimed to investigate the neuropathic pain attenuating mechanism of pregabalin using chronic constriction injury (CCI) model in rats. Material and Methods: The sciatic nerve was ligated by placing four loose ligatures around it to induce neuropathic pain. The pain development in terms of cold allodynia, mechanical hyperalgesia, and heat hyperalgesia was assessed on the 7th and 14th day after surgery, using acetone drop, pinprick, and hot plate tests. On the 14th day after the injury, pain parameters were assessed 30 minutes after administration of pregabalin (30 mg/kg) and sodium nitroprusside (5 mg/kg) in CCI-subjected rats. Results: CCI led to induction of neuropathic pain, which was more prominent on 14th day in comparison to 7th day. A single administration of pregabalin and sodium nitroprusside on 14th day, markedly reduced pain parameters and increased serum nitrite levels. Pretreatment with L-NAME abolished neuropathic pain attenuating effects of pregabalin suggesting that pregabalin may increase the levels of nitric oxide to mitigate neuropathic pain. Pretreatment with naloxone significantly abrogated pain attenuating effects of pregabalin and sodium nitroprusside in CCI-subjected rats suggesting that pregabalin and nitric oxide-mediated analgesic action are mediated through release of endogenous opioids. Moreover, naloxone failed to modulate pregabalin-induced increase in nitric oxide levels suggesting that the opioid system does not control the nitric oxide levels, and opioids may be downstream modulators of nitric oxide. Conclusion: Pregabalin may increase the release of nitric oxide, which may increase the release of endogenous opioids to attenuate neuropathic pain in CCI subjected rats.


Grading contact lens-related microbial keratitis: relevance to disease burden.
To describe a clinical grading system for epidemiological investigation of presumed contact lens related microbial keratitis (MK) and investigate the relationship to associated costs and disease duration. Eligible cases identified via surveillance required positive culture or presence of at least one clinical criterion: part of the lesion within the central 4 mm of the cornea, any anterior chamber reaction, or significant pain. Two reviewers graded cases as severe MK with vision loss (two lines), severe MK without vision loss (positive culture or central location, peripheral but >2 mm or with a hypopyon) or mild MK (remainder). The medical care, pathology, and medications comprised direct costs and loss of income, assistance of carers, and purchase of spectacles comprised indirect costs; these were calculated in Australian dollars (AU$). Duration of disease was estimated from duration of symptoms (days). Outcome measures were compared between categories using a one way analysis of variance (ANOVA). There were 47 of 278 (16.3%) severe with vision loss, 137 of 278 (49.3%) severe without vision loss, and 94 of 278 (33.8%) mild MK. The disease duration was 18 (6 to 95) [median (inter-quartile range)] for severe cases with vision loss, 7 (4 to 14) for severe cases without vision loss, and 4 (3 to 7) days for mild MK (ANOVA, p < 0.001). Associated costs were AU$5515 (2784 to 9437) for severe cases with vision loss, AU$1596 (774 to 4888) for severe cases without vision loss, and AU$795 (527 to 1234) for the mild MK (ANOVA, p < 0.001). Costs and symptom duration were greatest for severe disease with vision loss, less for the severe disease without vision loss, and lowest for the mild disease (p < 0.003). The comparison of disease burden lends support to this clinical grading system and the concept that the severity of MK can be stratified to identify those that might be of non-infectious etiology or have a microbial cause of low virulence with minimal morbidity.


Visual presentation modality's superiority in the detection of concealed information: A comparison of the efficiencies of the P300-based Complex Trial Protocol in visual versus auditory modalities.
Some studies have shown a superiority of visual vs. auditory item presentation in the Complex Trial Protocol (CTP), which is a countermeasure-resistant version of the P300-based Concealed Information Test (CIT). But those studies used elaborately- rehearsed autobiographical information as stimuli, instead of incidentally-acquired crime-related information. Thus, the relative superiority of the visual as opposed to the auditory modality in detecting episodic crime-related information is still unknown. The present study also improved on the usual mock crime scenario by adding a mock disposal task between a mock theft and administration of a CTP test to increase stimulus saliency. In this CTP, the probe and the irrelevant items were presented visually or acoustically on alternating trials, while target and non-target stimuli were simultaneously presented in visual and auditory modalities. The results showed that the P300 amplitude differences of probe minus irrelevant items presented in the visual modality were significantly larger compared to the auditory modality, and the detection rate of the guilty participants was also significantly higher for the visual (14/16) versus auditory modality (5/16). These results suggest a superiority of visual vs. auditory presentation when a CTP is used to detect crime-related information in a mock crime scenario.


Use of CA-125 response to predict survival parameters of patients with advanced ovarian carcinoma.
The prognostic value of serum CA-125 levels both before chemotherapy and after each cycle of one or two courses was assessed in 48 patients with advanced ovarian adenocarcinoma. All patients received a minimum of six courses of either cyclophosphamide and cisplatinum (CP) or cyclophosphamide, doxorubicin and cisplatinum (CAP). Patients with serum CA-125 values below the normal value of 35 U/ml after two courses had a significantly longer median survival (p < 0.0001) and longer disease-free survival (p = 0.007) than did those patients whose CA-125 levels dropped to normal after the third or a later course of chemotherapy. A response in CA-125 levels after the first two courses of chemotherapy may indicate which patients should continue with the current chemotherapy regimen and which patients should be offered salvage therapy.


[Malignant meningeal "histiocytosis"].
Two cases of patients with unusual pleomorphic tumors in the meninges are reported. Histologically and immunohistologically, the tumor cells may be histiocytic in appearance. Computed tomography and magnetic resonance imaging scans, however, revealed no lesions in the parenchyma or in the meninges. The cytological examination of the cerebrospinal fluid revealed only a light lymphocytic reaction without tumor cells in both cases and thus led to misinterpretations as meningoencephalitis. One patient presented psychiatric symptoms. Related clinical problems and the possible histogenesis of the tumors are discussed.


The Basal Forebrain Modulates Neuronal Response in an Active Olfactory Discrimination Task.
Successful completion of sensory decision-making requires focusing on relevant stimuli, adequate signal/noise ratio for stimulus discrimination, and stimulus valence evaluation. Different brain regions are postulated to play a role in these computations; however, evidence suggests that sensory and decision-making circuits are required to interact through a common neuronal pathway to elicit a context-adequate behavioral response. Recently, the basal forebrain (BF) region has emerged as a good candidate, since its heterogeneous projecting neurons innervate most of the cortical mantle and sensory processing circuits modulating different aspects of the sensory decision-making process. Moreover, evidence indicates that the BF plays an important role in attention and in fast modulation of neuronal activity that enhance visual and olfactory sensory perception. Here, we study in awake mice the involvement of BF in initiation and completion of trials in a reward-driven olfactory detection task. Using tetrode recordings, we find that BF neurons (including cholinergics) are recruited during sensory discrimination, reward, and interestingly slightly before trial initiation in successful discrimination trials. The precue neuronal activity was correlated with animal performance, indicating that this circuit could play an important role in adaptive context-dependent behavioral responses.


Screening for in vitro cytotoxic activity of seaweed, Sargassum sp. against Hep-2 and MCF-7 cancer cell lines.
Discovery of anticancer drugs that kill or disable tumor cells in the presence of normal cells without undue toxicity is a potential challenge for therapeutic care. Several papers in the literature have emphasized the potential implications of marine products such as seaweeds which exhibit antitumor activity. Study attempts to screen the antitumor effect of Sargassum sp, against chosen cell lines such as MCF-7 (Breast cancer) and Hep-2 (Liver Cancer). Ethanol extract of Sargassum sp. was concentrated using a Soxhlet apparatus and dissolved in DMSO. In vitro cytotoxic activity of Sargassum sp at various concentrations (100 μg/ml-300 μg/ml) screened for antitumor effect against the chosen cell lines using MTT assay (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, a yellow tetrazole). The study documented that the percentage of cell viability has been reduced with increased concentration, as evidenced by cell death. Sargassum sp extract shows potential cytotoxic activity (P≤0.05) with IC50 of 200 μ g/ml and 250 μg/ml against Hep-2 and MCF-7 cell lines respectively. The ethanol fraction of Sargassum sp induced cell shrinkage, cell membrane blebbing and formation of apoptotic bodies with evidence of bioactive components as profound influencing factors for anti-tumor effects. Further research need to be explored for the successful application of Sargassum sp as a potent therapeutic tool against cancer.


Crystal structure, Raman spectroscopy, and ab initio calculations of a new bialkali alanate K2LiAlH6.
A new bialkali alanate K2LiAlH6 was synthesized at 320-330 degrees C and 100-700 bar. It was structurally characterized by powder X-ray diffraction. It crystallizes in space group R3m (No. 166) with unit cell parameters a = 5.62068(8) and c = 27.3986(6) A. The Li and K cation sites are mutually exclusive, and Rietveld refinement finds no cation mixing. First-principles total energy calculations were performed for nine competing database structures of the stoichiometry A2BCX6, taken from fluoride and oxide compounds in the Inorganic Crystal Structure Database (ICSD). The relaxed structures were compared via their total energies and their agreement with experimental diffraction spectra. Two database structures K2LiAlF6 (R3m) and Cs2NaAlF6 (C2/m) were found to have the lowest total energies, but with the Rietveld method the K2LiAlF6 structure type was shown to be the most favorable. Ab initio total energy calculations support the validity of the structure determination. First-principles calculations also indicate that cation mixing is energetically unfavorable. Hydride properties such as plateau pressure are therefore more difficult to manipulate through alloying in this class of compounds.


Cellular responses to electrospun membranes made from blends of PLLGA with PEG and PLLGA-b-PEG.
Control of cellular responses is crucial for the use of electrospun membranes in biomedical applications, including tissue engineering or biomedical devices. However, it is still unclear whether adhesion and proliferation of fibroblasts is stimulated or inhibited on polyethylene glycol (PEG)-modified electrospun membranes. In this study, poly(L-lactide-co-glycolide) (PLLGA)-PEG copolymer and pure PEG were blended with PLLGA, and then electrospun onto nonwoven membranes. The effects of blending of PLLGA-PEG or pure PEG on the adsorption of proteins, and further on the adhesion and proliferation of L929 fibroblasts on the electrospun membranes were investigated. Addition of PLLGA-PEG or PEG significantly improved the hydrophilicity of the electrospun membranes. Pure PEG had no obvious effects on the growth of L929 fibroblasts; in contrast, PLLGA-PEG significantly inhibited the adsorption of proteins and the proliferations of the cells on the electrospun membranes. In response to diminished protein adsorption, mRNA expression of genes related to cell adhesion and migration was up-regulated. The limited effects of pure PEG were probably caused by its preferential dissolution, whereas membrane-confined PLLGA-PEG displayed excellent performance on the inhibition of protein adsorption and cell proliferation.


Effect of In Vitro Gastrointestinal Digestion on Phytochemicals and Antioxidant Activities in Cherry Tomatoes (Solanum lycopersicum var. cerasiforme).
We investigated the impact of simulated in vitro gastrointestinal digestion on the levels of total polyphenols, total flavonoids, carotenoids, and antioxidant capacity in cherry tomatoes. The initial total polyphenol content of fresh tomatoes was 220.51 μg GAE/g, which decreased to 203.24 μg GAE/g after 120 min of stomach treatment and further decreased to 138.23 μg GAE/g after 120 min of small intestine treatment. Similarly, the initial total flavonoid content in fresh tomatoes was 43.28 μg QE/g, but after 120 min of small intestine digestion, it decreased by approximately 50.72% to 21.33 μg QE/g. Lycopene, lutein, and β-carotene also experienced a decrease of 69.71∼78.38% during the digestion process compared to fresh tomatoes. The antioxidant activity exhibited a reduction of 34.95∼37.67% compared to fresh tomatoes after digestion in the stomach and intestines. The bioactive compounds present in tomatoes undergo decomposition and conversion into other substances during digestion, and these degradation products are believed to inhibit the growth of SK-Hep1 human hepatoma cells while enhancing antioxidant activity within the intracellular environment.


Targeting adenosinergic pathway and adenosine A2A receptor signaling for the treatment of COVID-19: A hypothesis.
The most serious health issue today is the rapid outbreak of Coronavirus Disease 2019 (COVID-19). More than 6,973,427 confirmed cases were diagnosed in nearly 213 countries and territories around the world and two international conveyances, causing globally over 400,000 deaths. Epidemiology, risk factors, and clinical characteristics of COVID-19 patients have been identified, but the factors influencing the immune system against COVID-19 have not been well established. Upon infection or cell damage, high amounts of adenosine triphosphate (ATP) are released from damaged cells, which serve as mediators of inflammation through purinergic cell surface receptor signaling. As a protective mechanism to prevent excessive damage to host tissue, adenosine counteracts ATP's effects by adenosine receptor stimulation to suppress the pro-inflammatory response. Adenosine is seen as a major obstacle to the efficacy of immune therapies, and the adenosinergic axis components are critical therapeutic targets for cancer and microbial infections. Pharmacologic inhibitors or antibodies specific to adenosinergic pathway components or adenosine receptors in microbial and tumor therapy have shown efficacy in pre-clinical studies and are entering the clinical arena. In this review, we provide a novel hypothesis explaining the potential for improving the efficiency of innate and adaptive immune systems by targeting adenosinergic pathway components and adenosine A2A receptor signaling for the treatment of COVID-19.


Influence of 12-Week Concurrent Training on Exosome Cargo and Its Relationship with Cardiometabolic Health Parameters in Men with Obesity.
Exosome release varies depending on the physiological state of the cell, so they could play a fundamental role in obesity, the biggest pandemic in today's societies. The beneficial effects that physical activity has both on weight and cardiovascular parameters may be mediated by exosomes released in response to exercise. Thus, we aimed (I) to study the influence of a 12-week CT intervention on exosome cargo modifications in men with obesity and (II) to determine whether changes in exosomes after the intervention were related to changes in cardiometabolic health parameters in our cohorts. An experimental, controlled design was performed in twelve (nine with valid data) adult male obese patients (mean values: 41.6 years old, 97.6 kg and 32.4 kg/m2) who were randomly divided into a control group (n = 4) and a training group (n = 5), which completed 36 sessions of CT (concurrent training) for 12 weeks. Before and after the training period, cardiometabolic health parameters were evaluated and blood samples to measure exosomes and proteins were drawn. No changes were observed in the levels of any exosomal markers and proteins; however, associations of changes between CD81 and both fat mass and weight, Flot-1 and VO2max, HSP70 and both CRP and left ventricle diastolic diameter or CD14 and leptin were found (all p ≤ 0.05). Although the current CT was not able to clearly modify the exosome cargo, a certain medium to large clinical effect was manifested considering the nature of this study. Moreover, the associations found between the promoted changes in cardiometabolic parameters and exosome-carried proteins could indicate a relationship to be considered for future treatments in patients with obesity.


Electrically-stimulated muscle hypertrophy in paraplegia: assessment by quantitative CT.
To identify the magnitude of muscle hypertrophy following electrically stimulated exercise in paraplegic subjects, we used quantitative CT (QCT) of the midthigh prior to and following 6 weeks of bicycle ergometry. Three patients who had suffered acute spinal cord injury were examined in this pilot investigation. Average absolute changes in muscle cross-sectional area by QCT were determined to be 10.6 cm2 (p = 0.042) at a distal site located 100 mm above the tibial plateau and 18.8 cm2 (p = 0.019) at a more proximal site (175 mm). Expressed as a percentage increase, these changes were likewise found to be significant. When the total thigh musculature was segmented into anterior and posterior regions, significant increases were observed only among the anterior muscle groups at both the distal and the proximal sites. Muscle hypertrophy as determined by standard anthropometric techniques at 200 mm above the patella was not found to be significant. We conclude that QCT is a valuable technique for discerning changes in muscle size during fitness training and that, in our population, it was capable of differentiating specific muscle compartment hypertrophy secondary to electrical stimulation.


The integration of 3D carbon-electrode dielectrophoresis on a CD-like centrifugal microfluidic platform.
We introduce the integration of a novel dielectrophoresis (DEP)-assisted filter with a compact disk (CD)-based centrifugal platform. Carbon-electrode dielectrophoresis (carbon-DEP) refers to the use of carbon electrodes to induce DEP. In this work, 3D carbon electrodes are fabricated using the C-MEMS technique and are used to implement a DEP-enabled active filter to trap particles of interest. Compared to traditional planar metal electrodes, 3D carbon electrodes allow for superior filtering efficiency. The system includes mounting modular 3D carbon-DEP chips on an electrically interfaced rotating disk. This allows simple centrifugal pumping to replace the large footprint syringe pump approaches commonly used in DEP systems. The advantages of the CD setup include not only a reduced footprint, but also complexity and cost reduction by eliminating expensive precision pumps and fluidic interconnects. To demonstrate the viability of this system we quantified the filter efficiency in the DEP trapping of yeast cells from a mix of latex and yeast cells. Results demonstrate selective filtering at flow rates up to 35 microl min(-1). The impact of electrode height, DEP chip misalignment and particle sedimentation on filter efficiency and the advantages this system represents are analyzed. The ultimate goal is to obtain an automated platform for bioparticle sorting with application in different fields such as point-of-care diagnostics and cell-based therapies.


Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study.
To assess the safety and efficacy of interleukin (IL)-6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation. We conducted an open-label study of sarilumab in severe COVID-19 pneumonia (PaO2/FiO2 <300 mm Hg) with hyperinflammation (elevated inflammatory markers and serum IL-6 levels). Sarilumab 400 mg was administered intravenously in addition to standard of care and results were compared with contemporary matched patients treated with standard of care alone. Clinical improvement, mortality, safety and predictors of response were assessed at 28 days. Twenty-eight patients were treated with sarilumab and 28 contemporary patients receiving standard of care alone were used as controls. At day 28 of follow-up, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group (clinical improvement 64%, mortality 18%; p=NS). Baseline PaO2/FiO2 ratio >100 mm Hg and lung consolidation <17% at CT scan predicted clinical improvement in patients treated with sarilumab. Median time to clinical improvement in patients with lung consolidation <17% was shorter after sarilumab (10 days) than after standard treatment (24 days; p=0.01). The rate of infection and pulmonary thrombosis was similar between the two groups. At day 28, overall clinical improvement and mortality in patients with severe COVID-19 were not significantly different between sarilumab and standard of care. Sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline.


Role of Biologic Therapies in the Rheumatic Manifestations of Inflammatory Bowel Disease: A Systematic Analysis.
In the recent years, there has been a growing recognition of the intricate relationship between inflammatory bowel disease (IBD) and extraintestinal manifestations (EIMs). EIMs of IBD include rheumatological, mucocutaneous, ocular, neurologic, pulmonary, cardiac, renal, hepatobiliary, and hematologic manifestations. Rheumatic manifestations are identified as the most common EIM, including axial and peripheral spondyloarthritis, arthralgia, sacroiliitis, enthesitis, and dactylitis. The convergence of the two distinct yet interconnected medical domains has spurred extensive research into the potential benefits of biological therapies as a treatment approach compared to the traditional method of treatment. This systematic review aims to assess the efficacy and overall impact of biological therapies in managing the rheumatic manifestations associated with IBD. Seventy-five articles from reputed journals published between January 1, 2013 and August 19, 2023 were reviewed. A set of eight papers were chosen for the focused study. The evaluation considered variables, such as rheumatic symptoms, in established IBD patients and compared the available biologic treatment and its benefits in alleviating rheumatic manifestations of IBD. By delving into the available literature and critically evaluating the relevant studies, this review shows insights into the role of biological therapies in the management of rheumatic symptoms in IBD. However, we must also address the limitations in implementing these since newer therapies are on the horizon. Hence, in-depth exploration and refinement of therapeutic strategies are needed to ultimately enhance patient care and quality of life for those affected by IBD. Infact, emerging artificial intelligence (AI) technologies are being used to improve the precision of diagnosis and enhance patient management.


Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain.
Human chromosomal band 11p15.5 has been shown to contain genes involved in the development of several pediatric and adult tumors and in Beckwith-Wiedemann syndrome (BWS). Overlapping P1 artificial chromosome clones from this region have been used as templates for genomic sequencing in an effort to identify candidate genes for these disorders. PowerBLAST identified several matches with expressed sequence tags (ESTs) from fetal brain and liver cDNA libraries. Northern blot analysis indicated that two of the genes identified by these ESTs encode transcripts of 1-1.5 kb with predominant expression in fetal and adult liver and kidney. With RT-PCR and RACE, full-length transcripts were isolated for these two genes, with the largest open reading frames encoding putative proteins of 253 and 424 amino acids. Database comparison of the predicted amino acid sequence of the larger transcript indicated homology to integral membrane organic cation transporters; hence, we designate this gene ORCTL2 (organic cation transporter-like 2). An expressed sequence polymorphism provided evidence that the ORCTL2 gene exhibits "leaky" imprinting in both human fetal kidney and human fetal liver. The mouse orthologue (Orctl2) was identified, and a similar polymorphism was used to demonstrate maternal-specific expression of this gene in fetal liver from interspecific F1 mice. The predicted protein of the smaller gene showed no significant similarity in the database. Northern and RACE analyses suggest that this gene may have multiple transcription start sites. Determination of the genomic structure in humans indicated that the 5'-end of this transcript overlaps in divergent orientation with the first two exons of ORCTL2, suggesting a possible role for antisense regulation of one gene by the other. We, therefore, provisionally name this second transcript ORCTL2S (ORCTL2-antisense). The expression patterns of these genes and the imprinted expression of ORCTL2 are suggestive of a possible role in the development of Wilms tumor (WT) and hepatoblastoma. Although SSCP analysis of 62 WT samples and 10 BWS patients did not result in the identification of any mutations in ORCTL2 or ORCTL2S, it will be important to examine their expression pattern in tumors and BWS patients, since epigenetic alteration at these loci may play a role in the etiology of these diseases.