[CAN POST-TRAUMATIC STRESS DISORDER BE PREVENTED WITH GLUCOCORTICOIDS?]
Glucocorticoids (GCs) play a major role in orchestrating the complex physiological and behavioral reactions essential for the maintenance of homeostasis. These compounds enable the organism to prepare for, respond to and cope with the acute demands of physical and emotional stressors. The appropriate GC release, commensurate with stressor severity, enables the body to properly contain stress responses so as to promote recovery by rapidly restoring homeostasis. Indeed, inadequate GC release following stress not only delays recovery by disrupting biological homeostasis in the short run but can also interfere with the processing or interpretation of stressful information that results in long-term disruptions in memory integration. While conventional wisdom holds that people who develop post-traumatic stress disorder (PTSD) following exposure to extreme trauma might have sustained elevations in GCs, several studies have reported that lower cortisol levels in the acute aftermath of trauma are predictors for subsequent PTSD symptoms. Therefore, it is possible that the administration of exogenous cortisol immediately after exposure to a trauma might alter the trajectory of trauma exposure by promoting recovery. Our group has initiated a series of studies examining the role of GCs in susceptibility to "PTSD-like behaviors" in a well-validated animal model for PTSD. The results of these studies highlight the importance of an initial bolus of endogenous corticosteroids in the normative response to stress as a key to a return to homeostasis. Aberrations in the normative response play an equally pivotal role in determining long-term cyto-architecture, and also localized brain biomolecular and overall neuro-hormonal disruptions underlying the PTSD-like behavioral responses in animals, and may be related to the emotional and behavioral symptoms of PTSD in patients. The data provides initial evidence that a single dose of hydrocortisone administered in the acute aftermath of trauma promotes recovery while promoting enhanced synaptic plasticity and connectivity in the secondary prevention of PTSD. We suggested that exogenous hydrocortisone, if given during the 'window of opportunity' - right after the exposure and before consolidation of the traumatic memory - may promote the restoration of homeostasis by constraining central nervous system activity.


Immunosuppressive properties of monoclonal antibodies and human polyclonal alloantibodies to the R80K protein of trophoblast.
The R80K protein on human trophoblast is antigenically polymorphic, and in all placentae of successful pregnancies, the protein is covered by maternal alloantibody. Alloantibody eluted from human placenta has been shown to inhibit killing by human NK cells. Do those antibodies to R80K that inhibit NK killing also affect the murine abortion models? We made three murine monoclonal antibodies to conserved epitopes, on human R80K, all of which also reacted with the homologous murine molecule. One antibody only, BA11, suppressed NK cytotoxicity to K562 and of mouse spleen NK cells to murine trophoblast. All three were tested in mouse models of abortion: the CBA x DBA/2 model with a high resorption rate of F1 embryos compared with the parental strains, an endotoxin induced abortion/resorption model and a third model in which the pregnant mouse is subject to sonic stress. Those IgG antibodies eluted from microvesicles which bound to K562, and one of the three monoclonals, BA11, inhibited NK killing. The antibodies react with the murine molecule, and BA11 inhibited abortion in all three mouse abortion models. This reinforces the thesis that interference with NK killing can influence abortion/resorption in mice, and the BA11 antibody may effect similar results in analogous human situations.


Which is the better treatment for the removal of large biliary stones? Endoscopic papillary large balloon dilation versus endoscopic sphincterotomy.
We evaluated the efficacy and cost-effectiveness of endoscopic papillary large balloon dilation (EPLBD) for large common bile duct (CBD) stone removal compared with endoscopic sphincterotomy (EST). A total of 1,580 patients who underwent endoscopic CBD stone extraction between January 2001 and July 2010 were reviewed. The following inclusion criteria were applied: choledocholithiasis treated by EPLBD with minor EST or EST with mechanical lithotripsy; and follow-up >9 months after treatment. Forty-nine patients with EPLBD and 41 with EST were compared. There was no significant difference in the complication rates and stone recurrence rates between the two groups. However, significantly more endoscopic retrograde cholangiopancreatography (ERCP) sessions were required in the EST group to achieve the complete removal of stones (1.7 times vs 1.3 times; p=0.03). The mean cost required for complete stone removal per patient was significantly higher in the EST group compared to the EPLBD group (USD $1,644 vs $1,225, respectively; p=0.04). Dilated CBD was the only significant factor associated with recurrent biliary stones (relative risk, 1.09; 95% confidence interval, 1.02 to 1.17; p=0.02). EPLBD is the better treatment (compared to EST) for removing large CBD stones because EPLBD requires fewer ERCP sessions and is less expensive.


Kaiser Permanente of Ohio's Encounter System.
In 1988, Kaiser Permanente of Ohio began planning for the development of a cost-effective electronic medical record system for ambulatory care. If created the "Encounter System," a multifunctional ambulatory clinical database to enhance physician practice, perform quality assurance evaluations, help with physician management, and improve the care of its patients. The author discusses the functions of this successful electronic database and how it evolved.


Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model.
The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.


Theoretical study of intracellular stress fiber orientation under cyclic deformation.
We studied stress fiber orientation under a wide range of uniaxial cyclic deformations. We devised and validated a hypothesis consisting of two parts, as follows: (1) a stress fiber aligns to avoid a mechanical stimulus in the fiber direction under cyclic deformation. This means that, among all allowable directions, a stress fiber aligns in the direction which minimizes the stimulus, i. e., the summation of the changes in length of the stress fiber over one stretch cycle; and (2) there is a limit in the sensitivity of the cellular response to the mechanical stimulus. Due to this sensing limit, the orientation angle in stress fibers is distributed around the angle corresponding to the minimum stimulus. To validate this hypothesis, we approximated an anisotropic deformation of the membrane on which cells were to be cultured. We then obtained the relationships between the stretch range and the fiber angle in the undeformed state which minimize the mechanical stimuli, assuming that the membrane on which stress fibers and cells adhered was homogeneous and incompressible. Numerical simulation results showed that the proposed hypothesis described our previous experimental results well and was consistent with the experimental results in the literature. The simulation results, taking account of the second part of the hypothesis with a small value for the limit in sensitivity to the mechanical stimulus, could explain why cell orientation is distributed so widely with cyclic stretch ranges of <10%. The proposed hypothesis can be applied to various types of deformation because the mechanical stimulus is always sensed and accumulates under cyclic deformation without the necessity of a reference state to measure the stimulus.


Turners's syndrome associated with lymphoedema, diagnosed in the newborns.
It is known from literature that about 30% of all female patients with Turner's sydrome have a lymphoedema at the feet and hands. The article discusses as possible reason a congenital defect of the lymphatic system: The vessels are thin-walled, extended and have few valves or none at all. In two phenotypically normal, mature newborn, an analysis of the chromosomes was performed because of marked lymphoedema of the lower extremities, confirming the suspected diagnosis of Turner's syndrome. Hence, it is concluded that Turner's syndrome must always be suspected if there is a congenital lymphoedema of the lower extremities and especially also of the region of the neck.


Cost-effectiveness of pneumococcal polysaccharide vaccination in adults: a systematic review of conclusions and assumptions.
Streptococcus pneumoniae infections in adults are associated with substantial morbidity, mortality, and costs. A literature review was conducted to identify strengths and limitations of the cost-effectiveness of pneumococcal polysaccharide vaccine studies. A comparative analysis of the impact of model parameters on cost-effectiveness ratios was complemented by systematic assessment of the studies. We identified 11 economic evaluations of pneumococcal polysaccharide vaccine (PPV-23) in adults. In general, all 11 studies found that vaccination with PPV-23 is a cost-effective, and in some cases a cost-saving strategy for the prevention of invasive pneumococcal disease (IPD). The systematic assessment indicated that the results of the cost-effectiveness studies of PPV-23 are influenced by the values applied to vaccine efficacy, IPD incidence and case-fatality.


Medium-Throughput Detection of Hsp90/Cdc37 Protein-Protein Interaction Inhibitors Using a Split Renilla Luciferase-Based Assay.
The protein-folding chaperone Hsp90 enables the maturation and stability of various oncogenic signaling proteins and is thus pursued as a cancer drug target. Folding in particular of protein kinases is assisted by the co-chaperone Cdc37. Several inhibitors against the Hsp90 ATP-binding site have been developed. However, they displayed significant toxicity in clinical trials. By contrast, the natural product conglobatin A has an exceptionally low toxicity in mice. It targets the protein-protein interface (PPI) of Hsp90 and Cdc37, suggesting that interface inhibitors have an interesting drug development potential. In order to identify inhibitors of the Hsp90/Cdc37 PPI, we have established a mammalian cell lysate-based, medium-throughput amenable split Renilla luciferase assay. This assay employs N-terminal and C-terminal fragments of Renilla luciferase fused to full-length human Hsp90 and Cdc37, respectively. We expect that our assay will allow for the identification of novel Hsp90/Cdc37 interaction inhibitors. Such tool compounds will help to evaluate whether the toxicity profile of Hsp90/Cdc37 PPI inhibitors is in general more favorable than that of ATP-competitive Hsp90 inhibitors. Further development of such tool compounds may lead to new classes of Hsp90 inhibitors with applications in cancer and other diseases.


Anergy induction by dimeric TCR ligands.
T cells that recognize particular self Ags are thought to be important in the pathogenesis of autoimmune diseases. In multiple sclerosis, susceptibility is associated with HLA-DR2, which can present myelin-derived peptides to CD4(+) T cells. To generate molecules that target such T cells based on the specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion protein with a bound peptide from myelin basic protein (MBP). Soluble, dimeric DR2/MBP peptide complexes activated MBP-specific T cells in the absence of signals from costimulatory or adhesion molecules. This initial signaling through the TCR rendered the T cells unresponsive (anergic) to subsequent activation by peptide-pulsed APCs. Fluorescent labeling demonstrated that anergic T cells were initially viable, but became susceptible to late apoptosis due to insufficient production of cytokines. Dimerization of the TCR with bivalent MHC class II/peptide complexes therefore allows the induction of anergy in human CD4(+) T cells with a defined MHC/peptide specificity.


Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups.
The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.


Cellular Ser/Thr-kinase assays using generic peptide substrates.
High-throughput cellular profiling has successfully stimulated early drug discovery pipelines by facilitating targeted as well as opportunistic lead finding, hit annotation and SAR analysis. While automation-friendly universal assay formats exist to address most established drug target classes like GPCRs, NHRs, ion channels or Tyr-kinases, no such cellular assay technology is currently enabling an equally broad and rapid interrogation of the Ser/Thr-kinase space. Here we present the foundation of an emerging cellular Ser/Thr-kinase platform that involves a) coexpression of targeted kinases with promiscuous peptide substrates and b) quantification of intracellular substrate phosphorylation by homogeneous TR-FRET. Proof-of-concept data is provided for cellular AKT, B-RAF and CamK2delta assays. Importantly, comparable activity profiles were found for well characterized B-Raf inhibitors in TR-FRET assays relying on either promiscuous peptide substrates or a MEK1(WT) protein substrate respectively. Moreover, IC(50)-values correlated strongly between cellular TR-FRET assays and a gold standard Ba/F3 proliferation assay for B-Raf activity. Finally, we expanded our initial assay panel by screening a kinase-focused cDNA library and identified starting points for >20 cellular Ser/Thr-kinase assays.


Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women?
In the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little definitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The specific cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p-hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be confirmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of: data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the first evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantification and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health.


Minimalistic splint design: a rationale told in a personal style.
Theoretic clinical reasoning is becoming increasingly important in splint construction. The purpose of this paper is to present an algorithm of decision steps that will help therapists consider all aspects of splint making proactively, so that they can take the necessary steps to be successful. A decision flowchart is presented and discussed in detail. An extra dimension of splint design is emphasized-namely, frugality in structure, technique, and cost. The paper concludes that the use of a comprehensive decision algorithm provides the basis for successful working technique and that the ability to create minimal-design splints is more a state of mind than a technical skill.


In vitro differentiation of porcine blood CD163- and CD163+ monocytes into functional dendritic cells.
Swine monocytes constitute a heterogeneous cell population containing subsets with distinct functional capacities or representing different maturational stages. Based on the expression of CD163, we have recently identified two monocyte subpopulations. In this study, we investigate the ability of both CD163- and CD163+ monocytes to differentiate into dendritic cells (DCs) in the presence of GM-CSF and IL-4. Monocyte differentiation into DC is accompanied by an up-regulation of the expression of swine leukocyte antigen (SLA) I, SLA II and CD80/86 molecules, and a decrease in the expression of CD14, CD16 and CD163. These DC express the pan-myeloid marker SWC3 and display typical dendritic cytoplasmic projections. When monocytes are split into CD163+ and CD163- cells, both subsets give rise to DC. However, compared to CD163- monocyte-derived DC (MoDC), CD163+ MoDC appear to have reached a more advanced stage of maturation, expressing higher levels of SLA II and CD80/86 and inducing more efficiently proliferation of T cells to recall antigens and alloantigens.


Use of ELISA for detection of immunoglobulins G and M that recognize Salmonella dublin lipopolysaccharide for prediction of carrier status in cattle.
Immunoglobulin reactions to Salmonella dublin in serum and milk from 4 groups of lactating cows were measured by an indirect ELISA. The groups consisted of (1) cows that were natural carriers of S dublin in the mammary gland, (2) experimentally infected cows that did not become carriers, (3) cows inoculated with a commercial S dublin bacterin, and (4) cows used as S dublin-negative controls. Milk and serum samples were obtained at monthly intervals. Models for predicting carrier status were developed by use of stepwise logistic regression. Independent variables consisted of serum and milk IgG and IgM titers to S dublin lipopolysaccharide and a ratio of IgG to IgM. The utility of a single sample vs multiple samples obtained at 1-month or 2-month intervals was tested by comparison of goodness-of-fit chi 2 P values for 8 models predicting carrier status. Immunoglobulin reactions specific to S dublin were a significant predictor of carrier status (P less than 0.001). Serum IgG titers specific for S dublin were the most important variable for predicting carrier status. Two serum IgG titers to S dublin obtained 2 months apart was a better predictor of carrier status than measurement of the IgG:IgM ratio from a single serum sample. Immunoglobulin recognizing S dublin epitopes also were detected in milk samples. In milk, performing 2 ELISA 60 days apart to determine IgG and IgM reactions to S dublin appeared to be useful for the prediction of carrier status, but was not as accurate as models for serum immunoglobulin reactions.


Rats self-administer nonrewarding brain stimulation to ameliorate aversion.
Hypothalamic stimulation in rats both reduces escape from noxious hindbrain stimulation and sustains self-administration only when hindbrain stimulation is inescapable. Self-administration reflects an aversion-ameliorative action of brain stimulation and not a positive reinforcement process. The psychophysical testing used is offered as a model for establishing the analgesic properties of brain stimulation.


[Diagnosis and treatment of non-Hodgkin lymphoma in Netherlands: variation in guidelines and in practice].
To investigate current guidelines for diagnosis and treatment of intermediate or high grade non-Hodgkin's lymphoma (NHL), stage I-IV (Burkitt's and lymphoblastic lymphoma excluded) and to compare this with current clinical practice. Descriptive. An inventory of guidelines for diagnosis and treatment of NHL of the Regional Cancer Centres (RCCs) was made in mid-1998, an enquiry containing questions about the practical situation concerning the diagnosis and treatment of NHL patients was sent to 59 internists-haematologists in non-university hospitals of the RCC regions Amsterdam, Rotterdam and South. Apart from the standard diagnostics, the RCCs recommended several examinations for staging. For the initial staging the haematologists not always requested the recommended CTs of chest and abdomen and most of them did no restaging after the last course of chemotherapy. Half of them left the assessment of lymph node biopsy samples to a lymphoma panel. The recommended primary treatment consisted mainly of chemotherapy with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP). In certain regions, the schedule was slightly changed, with additional tenoposide and bleomycin (CHVmP/BV). The treatment schedules were heterogeneous, especially for stage I NHL. In leukopenia and/or thrombocytopenia, postponement was recommended, but dosage reduction was carried out immediately, especially in older patients, sometimes with administration of a haemopoietic growth factor. Recurrence NHL was treated in accordance with the guidelines with second-line chemotherapy, if possible followed by peripheral stem cell transplantation in a haematooncological centre. Considering these results development of national guidelines for NHL would seem to be desirable.


Recovery from Cyclophosphamide Overdose in a Dog.
An adult female spayed dog was evaluated after inadvertently receiving a total dose of 1,750 mg oral cyclophosphamide, equivalent to 2,303 mg/m2, over 21 days (days -21 to 0). Nine days after the last dose of cyclophosphamide (day +9), the dog was evaluated at Perth Veterinary Specialists. Physical examination revealed mucosal pallor, a grade 2/6 systolic heart murmur, and severe hemorrhagic cystitis. Severe nonregenerative pancytopenia was detected on hematology. Broad spectrum antibiotics, two fresh whole blood transfusions, granulocyte colony stimulating factor, and tranexamic acid were administered. Five days after presentation (day +14), the peripheral neutrophil count had recovered, and by 12 days (day +21) the complete blood count was near normal. A second episode of thrombocytopenia (day +51) was managed with vincristine, prednisolone, and melatonin. The dog made a complete recovery with no long-term complications at the time of writing. To the author's knowledge, this is the highest inadvertently administered dose of cyclophosphamide to result in complete recovery.


Dynamics of the mitotic spindle--potential therapeutic targets.
Inhibition of mitosis is a useful strategy for treating diseases involving excessive cell proliferation. Antimitotic drugs currently in clinical use perturb microtubule dynamics and thereby disrupt the function of the mitotic spindle. Protein regulators of microtubule dynamics and microtubule motors are also essential for mitotic spindle function. In this chapter, we evaluate the potential of these proteins as candidate targets for antimitotic drugs. We review in depth a number of proteins of particular interest, highlighting their known functions in mitosis and the effects of their inhibition on cell cycle progression.


Increased cerebrospinal fluid levels of S100B protein in rat model of mania induced by ouabain.
Bipolar disorder is a chronic and severe mental disorder. Recently, new animal models have emerged to further investigate underlying mechanisms of bipolar disorder such as ouabain-induced hyperactivity in rats. In this study, we investigated the cerebrospinal fluid levels of S100B protein as a putative marker of astrocytic activity in bipolar mania induced by intracerebroventricular administration of ouabain in rats. Ouabain induced a two-fold increase in crossing responses in the open field test and increased 30% the cerebrospinal fluid concentration of S100B, as compared to vehicle group. Our findings reinforce the role of astroglial cells in the pathogenesis of bipolar disorder and S100B protein as a marker of bipolar mania.


Features of replicative senescence induced by direct addition of antennapedia-p16INK4A fusion protein to human diploid fibroblasts.
The p16INK4A cyclin-dependent kinase (Cdk) inhibitor is now recognized as a major tumor suppressor that is inactivated by a variety of mechanisms in a wide range of human cancers. It is also implicated in the mechanisms underlying replicative senescence since p16INK4A RNA and protein accumulate as cells approach their proscribed limit of population doublings in tissue culture. To obtain further evidence of its role in senescence, we have sought ways of overexpressing p16INK4A in primary human diploid fibroblasts (HDF). To circumvent the low transfection efficiency of primary cells we have exploited a recombinant form of the full-length p16INK4A protein fused to a 16 amino acid peptide from the Drosophila antennapedia protein. This peptide has the capacity to cross both cytoplasmic and nuclear membranes allowing the direct introduction of the active protein to primary cells. Here, we show that antennapedia-tagged wild-type p16INK4A protein, but not a functionally compromised tumor-specific variant, causes G1 arrest in early passage HDFs by inhibiting the phosphorylation of the retinoblastoma protein. Significantly, the arrested cells display several phenotypic features that are considered characteristic of senescent cells. These data support a role for p16INK4A in replicative senescence and raise the possibility of using the antennapedia-tagged protein therapeutically.


First World Conference on Nanomedicine and Drug Delivery.
The Institute of Holistic Medical Sciences (IHMS), Kottayam, Kerala, India, the Institute of Macromolecular Science and Engineering (IMSE), Kottayam, Kerala, India and Mathew Ayurveda und Venen Klinik (MUVK), Klagenfurt, Austria, have jointly conducted a 3-day world conference on nanomedicine and drug delivery (WCN 2010) in Kottayam, Kerala, India from 16-18 April 2010. Nanomedicine is defined as the application of nanotechnology to achieve breakthroughs in healthcare. It exploits the improved and often novel physical, chemical and biological properties of materials at the nanometer scale. It has the potential to enable early detection and prevention and to improve diagnosis, treatment and follow-up of diseases. Nanomedicine is a very special area of nanotechnology because it is an extremely large field ranging from in vivo and in vitro diagnostics to therapy including targeted delivery and regenerative medicine; it interfaces nanomaterials (e.g., surfaces and particles) or analytical instruments with 'living' human material (cells, tissue and body fluids) and it creates new tools and methods that impact significantly on existing practices.


Quantitative analysis of pursuit ocular movements in Parkinson's disease by using a video-based eye tracking system.
The purpose of this study is to assess the efficacy and the tolerability of a new vision-based non-intrusive eye tracker in a population composed of normal controls and in patients affected by nonadvanced Parkinson's disease (PD). PD patients characteristically have difficulty in sustaining repetitive motor actions. Previous studies showed a progressive bradykinesia and hypokinesia of pursuit ocular movements (POM) in advanced PD. We found that the values of POM were lower in PD patients than in normal controls (p < 0.001). In PD patients, the values correlated closely with Hoehn and Yahr stage and Unified Parkinson Disease Rating Scale motor subscore (p < 0.001, for both). Our data suggest that deficit in POM occurs also in nonadvanced PD patients and it is closely correlated with clinical scores. Thus, this vision-based system can be considered a new method to provide, noninvasively, measures of POM dysfunctions and can be used as reliable indices of disease severity in PD patients.


Discrimination in the metabolism of orally dosed ergocalciferol and cholecalciferol by the pig, rat and chick.
Vitamin D-deficient pigs, rats and chicks were repleted with four daily oral doses of crystalline ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) containing equal concentrations of each. At 24 h after the last dose, the plasma of each species was analysed for vitamin D and 25-hydroxyvitamin D by standard methods. The mean (+/- S.D.) ratios of plasma cholecalciferol to ergocalciferol concentration were 1.5 +/- 0.1 (pig). 1.7 +/- 0.1 (rat) and 6.3 +/- 1.2 (chick). The mean ratios of plasma 25-hydroxycholecalciferol to 25-hydroxyergocalciferol concentration were 4.0 +/- 0.1 (pig), 0.4 +/- 0.02 (rat) and 10.7 +/- 3.4 (chick). The mean plasma cholecalciferol/ergocalciferol ratios for the 24,25-dihydroxy-, 25,26-dihydroxy- and 1,25-dihydroxy-derivatives in the pig were 2.6 +/- 0.6, 5.8 +/- 1.3 and 5.8 +/- 0.8 respectively. This is the first evidence that mammals other than the New World monkey, like birds, discriminate between ergocalciferol and cholecalciferol. These data, therefore, suggest that species discrimination between the different forms of vitamin D is probably a general phenomenon in mammals. Moreover, this is the first indication of a species (rat) that discriminates against a cholecalciferol metabolite in favour of an ergocalciferol metabolite. Species discrimination against particular forms of vitamin D may be important to the choice of experimental animal models for studying the regulation of vitamin D metabolism and may also be an important consideration in dietary vitamin supplementation.


A proteomics perspective on viral DNA sensors in host defense and viral immune evasion mechanisms.
The sensing of viral DNA is an essential step of cellular immune response to infections with DNA viruses. These human pathogens are spread worldwide, triggering a wide range of virus-induced diseases, and are associated with high levels of morbidity and mortality. Despite similarities between DNA molecules, mammalian cells have the remarkable ability to distinguish viral DNA from their own DNA. This detection is carried out by specialized antiviral proteins, called DNA sensors. These sensors bind to foreign DNA to activate downstream immune signaling pathways and alert neighboring cells by eliciting the expression of antiviral cytokines. The sensing of viral DNA was shown to occur both in the cytoplasm and in the nucleus of infected cells, disproving the notion that sensing occurred by simple spatial separation of viral and host DNA. A number of omic approaches, in particular, mass-spectrometry-based proteomic methods, have significantly contributed to the constantly evolving field of viral DNA sensing. Here, we review the impact of omic methods on the identification of viral DNA sensors, as well as on the characterization of mechanisms involved in host defense or viral immune evasion.


The basic reproduction number R0 and effectiveness of reactive interventions during dengue epidemics: the 2002 dengue outbreak in Easter Island, Chile.
We use a stochastic simulation model to explore the effect of reactive intervention strategies during the 2002 dengue outbreak in the small population of Easter Island, Chile. We quantified the effect of interventions on the transmission dynamics and epidemic size as a function of the simulated control intensity levels and the timing of initiation of control interventions. Because no dengue outbreaks had been reported prior to 2002 in Easter Island, the 2002 epidemic provided a unique opportunity to estimate the basic reproduction number R0 during the initial epidemic phase, prior to the start of control interventions. We estimated R0 at 27.2 (95%CI: 14.8, 49.3). We found that the final epidemic size is highly sensitive to the timing of start of interventions. However, even when the control interventions start several weeks after the epidemic onset, reactive intervention efforts can have a significant impact on the final epidemic size. Our results indicate that the rapid implementation of control interventions can have a significant effect in reducing the epidemic size of dengue epidemics.


Recovery of acetic acid from waste streams by extractive distillation.
Wastes have been considered to be a serious worldwide environmental problem in recent years. Because of increasing pollution, these wastes should be treated. However, industrial wastes can contain a number of valuable organic components. Recovery of these components is important economically. Using conventional distillation techniques, the separation of acetic acid and water is both impractical and uneconomical, because it often requires large number of trays and a high reflux ratio. In practice special techniques are used depending on the concentration of acetic acid. Between 30 and 70% (w/w) acetic acid contents, extractive distillation was suggested. Extractive distillation is a multicomponent-rectification method similar in purpose to azeotropic distillation. In extractive distillation, to a binary mixture which is difficult or impossible to separate by ordinary means, a third component termed an entrainer is added which alters the relative volatility of the original constituents, thus permitting the separation. In our department acetic acid is used as a solvent during the obtaining of cobalt(III) acetate from cobalt(II) acetate by an electrochemical method. After the operation, the remaining waste contains acetic acid. In thiswork, acetic acid which has been found in this waste was recovered by extractive distillation. Adiponitrile and sulfolane were used as high boiling solvents and the effects of solvent feed rate/solution feed rate ratio and type were investigated. According to the experimental results, it was seem that the recovery of acetic acid from waste streams is possible by extractive distillation.


Adaptive fuzzy sliding mode controller for linear systems with mismatched time-varying uncertainties.
A new design approach for an adaptive fuzzy sliding mode controller (AFSMC) for linear systems with mismatched time-varying uncertainties is presented. The coefficient matrix of the sliding function can be designed to satisfy a sliding coefficient matching condition provided time-varying uncertainties are bounded. With the sliding coefficient matching condition satisfied, an AFSMC is proposed to stabilize the uncertain system. The parameters of output fuzzy sets in the fuzzy mechanism are on-line adapted to improve the performance of the fuzzy sliding mode control system. The bounds of uncertainties are not required to be known in advance for the AFSMC. Stability of the fuzzy control system is guaranteed and the system is shown to be invariant on the sliding surface. Moreover, chattering around the sliding surface in sliding mode control can be reduced by the proposed design approach. Simulation results are included to illustrate the effectiveness of the proposed AFSMC.


Comparison of monovalent and divalent ion distributions around a DNA duplex with molecular dynamics simulation and a Poisson-Boltzmann approach.
The ion atmosphere created by monovalent (Na(+) ) or divalent (Mg(2+) ) cations surrounding a B-form DNA duplex were examined using atomistic molecular dynamics (MD) simulations and the nonlinear Poisson-Boltzmann (PB) equation. The ion distributions predicted by the two methods were compared using plots of radial and two-dimensional cation concentrations and by calculating the total number of cations and net solution charge surrounding the DNA. Na(+) ion distributions near the DNA were more diffuse in PB calculations than in corresponding MD simulations, with PB calculations predicting lower concentrations near DNA groove sites and phosphate groups and a higher concentration in the region between these locations. Other than this difference, the Na(+) distributions generated by the two methods largely agreed, as both predicted similar locations of high Na(+) concentration and nearly identical values of the number of cations and the net solution charge at all distances from the DNA. In contrast, there was greater disagreement between the two methods for Mg(2+) cation concentration profiles, as both the locations and magnitudes of peaks in Mg(2+) concentration were different. Despite experimental and simulation observations that Mg(2+) typically maintains its first solvation shell when interacting with nucleic acids, modeling Mg(2+) as an unsolvated ion during PB calculations improved the agreement of the Mg(2+) ion atmosphere predicted by the two methods and allowed for values of the number of bound ions and net solution charge surrounding the DNA from PB calculations that approached the values observed in MD simulations.


Biotransformation of tryptophan by Phaseolus vulgaris suspension culture.
The carboline alkaloids, harman and norharman, detected in the culture filtrate of Phaseolus vulgaris suspension culture are the two major products of the biotransformation of tryptophan by this culture. The peak concentration of harman and norharman in the medium was reached between the second and fourth day of fermentation, depending on the size of the inoculum. A supplement of 0.1 mg of tryptophan per ml of 67V medium (with a low basal concentration of 15 to 20 mug of tryptophan per ml medium) increased the peak concentration of harman by an average of 2.1 times and of norharman by an average of 4.7 times in medium.


Environmental control of dust mite allergens.
House dust mites are a major cause of allergic airway disease. Ninety percent of patients with asthma show dermal reactivity to house dust mite allergens. Control of these arachnids in the home environment can reduce the morbidity from atopic diseases and may moderate or even prevent the development of clinical disease in atopic individuals.


A series of naphthalimide derivatives as intra and extracellular pH sensors.
A series of new naphthalimide derivatives were synthesized and studied. Three of the materials (SM1, SM2, and SM3) possess methacrylate(s) moieties as pH sensor monomers, enabling these compounds to be polymerized with other monomers for thin film preparation for extracellular pH sensing. Herein, poly(2-hydroxyethyl methacrylate)-co-poly(acrylamide) (PHEMA-co-PAM) was chosen as the polymer matrix. Structure influences on pH responses and pK(a) values were studied. The film P3 composed of the sensing moiety SM3 has a pK(a) close to the usual biological environmental pH of approximately 7. It was used as an extracellular pH sensor to monitor pH change during the metabolism of prokaryotic Escherichia coli (E. coil). On the other hand, the three sensor monomers are new intracellular biomarkers to sense lysosomes of eukaryotic cells since (1) their pK(a) values are in a range of 5.9-6.8; (2) their emission intensities at acidic conditions (such as at pH 5) are much stronger than those at a neutral condition of pH 7; (3) lysosomes range in size from 0.1 to 1.2 mum in diameter with pH ranging from 4.5 to 5.0, which is much more acidic than the pH value of the cytoplasm (usually with a pH value of approximately 7.2); and (4) the acidity of lysosomes enables a protonation of the amino groups of the pH probes making the sensors emit brightly in acidic organelles by inhibiting the photo-induced electron transfer from the amino groups to the fluorophores. Lysosome sensing was demonstrated using live human brain glioblastoma U87MG cell line, human cervical cancer HeLa cell line, and human esophagus premalignant CP-A and CP-D cell lines by observations of small acidic spherical organelles (lysosomes) and significant colocalizations (82-95%) of the sensors with a commercially available lysosome-selective staining probe LysoTracker Red under confocal fluorescence microscopy.


Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells.
Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.


Silicon-Based 3D Microfluidics for Parallelization of Droplet Generation.
Both the diversity and complexity of microfluidic systems have experienced a tremendous progress over the last decades, enabled by new materials, novel device concepts and innovative fabrication routes. In particular the subfield of high-throughput screening, used for biochemical, genetic and pharmacological samples, has extensively emerged from developments in droplet microfluidics. More recently, new 3D device architectures enabled either by stacking layers of PDMS or by direct 3D-printing have gained enormous attention for applications in chemical synthesis or biomedical assays. While the first microfluidic devices were based on silicon and glass structures, those materials have not yet been significantly expanded towards 3D despite their high chemical compatibility, mechanical strength or mass-production potential. In our work, we present a generic fabrication route based on the implementation of vertical vias and a redistribution layer to create glass-silicon-glass 3D microfluidic structures. It is used to build different droplet-generating devices with several flow-focusing junctions in parallel, all fed from a single source. We study the effect of having several of these junctions in parallel by varying the flow conditions of both the continuous and the dispersed phases. We demonstrate that the generic concept enables an upscaling in the production rate by increasing the number of droplet generators per device without sacrificing the monodispersity of the droplets.


Fungal Deoxynivalenol-Induced Enterocyte Distress Is Attenuated by Adulterated Adlay: In Vitro Evidences for Mucoactive Counteraction.
Adlay is a cereal crop that has long been used as traditional herbal medicine and as a highly nourishing food. However, deoxynivalenol (DON), the most prevalent trichothecene mycotoxin worldwide, frequently spoils grains, including adlay, via fungal infection. On the basis of an assumption that the actions of DON in the gut could be modified by adlay consumption, we simulated the impacts of co-exposure in enterocytes and investigated the effectiveness of treatment with adlay for reducing the risk of DON-induced inflammation and epithelia barrier injury. In particular, adlay suppressed DON-induced pro-inflammatory signals such as mitogen-activated kinase transduction and the epidermal growth factor receptor-linked pathway. In addition to regulation of pro-inflammatory responses, adlay treatment interfered with DON-induced disruption of the epithelial barrier. Mechanistically, adlay could boost the activation of protein kinase C (PKC) and cytosolic translocation of human antigen R (HuR) protein, which played critical roles in the epithelial restitution, resulting in protection against disruption of enterocyte barrier integrity. Notably, DON abrogated the Ras homolog gene family member A GTPase-mediated actin cytoskeletal network, which was diminished by adlay treatment in PKC and HuR-dependent ways. Taken together, this study provides evidences for adlay-based attenuation of trichothecene-induced gut distress, implicating potential use of a new gut protector against enteropathogenic insults in diets.


Design, Synthesis and Catalytic Activity of (Cyclopentadienone)iron Complexes Containing a Stereogenic Plane and a Stereogenic Axis.
Herein, we report the synthesis and characterization of several chiral (cyclopentadienone)iron complexes (CICs) featuring either two (R)-BINOL-derived stereoaxes or a combination of one (R)-BINOL-derived stereoaxis and a stereogenic plane. The stereoplane-containing CICs were obtained as epimer mixtures, which were separated by flash column chromatography and assigned an absolute configuration based on XRD analysis, NMR and order of elution. The library was tested in the asymmetric hydrogenation of ketones showing good catalytic activity and a moderate stereoselectivity which, notably, is mostly imparted by the stereogenic plane. Indeed, the two epimers of each CIC possessing a stereoplane show opposite and equally strong stereochemical preference.


Management of life threatening hemorrhage from facial fracture.
Persisted bleeding from facial fractures after nasal packing or direct pressure is not common, however if it happens, the mortality rate is very high. The study of the treatment for this group of surviving patients was made to find the guideline for management of these patients. From the period of 1 January 1993 to 31 December 2002, 3756 cases of facial fractures were treated at the Trauma Center, Faculty of Medicine, Siriraj Hospital. There were 14 life-threatening hemorrhage cases and 9 patients survived. They were 3 Le Fort fracture, 2 nasal fracture, 1 mandibular fracture and 3 multiple facial fractures. Repacking of nasal cavities was performed and was able to stop bleeding successfully in 2 cases. Three cases required operation and 3 cases had angiography and embolization. One case still bled after operation and needed angiography and embolization. The present study shows that the adequacy of nasal packing or wound compression should be evaluated first. Early operation could stop bleeding in nearly half of the cases. Angiography and embolization can be used alone or adjunct to the operation to control bleeding with good result.


Hip resurfacing through an anterolateral approach. Surgical description and early review.
Recently, metal-on-metal hip resurfacing has enjoyed a resurgence as an alternative to hip arthroplasty in properly selected patients. The purpose of the present study was to report the early results of hip resurfacing through an anterolateral approach and to describe the technique with modifications that have been made as experience with the procedure has increased. A total of fifty-seven hip resurfacing procedures in fifty-three patients were performed by a single surgeon with use of the Cormet Hip Resurfacing system through an anterolateral approach. The results were assessed on the basis of Harris hip scores, a radiographic analysis, and an analysis of failures. After a mean duration of follow-up of thirty-eight months, the mean Harris hip score was 99 points. Fifty-five hips were in patients with normal function scores, and two were in patients who reported mild dysfunction. Fifty hips had no pain, five had slight pain, one had mild pain, and one had moderate pain. Three hips had a failure of resurfacing and required revision. Two failures were secondary to femoral neck fractures, and one was the result of debonding of the surface coating of the acetabular component. The early results associated with a new generation of hip resurfacing devices are promising. The anterolateral approach affords the surgeon excellent exposure with the advantage of increased hip stability and potentially improved vascular supply of the femoral head as compared with the posterior approach.


Synthesis of pelargonoyl-cyclic decapeptide analog of the antibiotic polymyxin B.1.
The synthesis of pelargonoyl-cyclic decapeptide, analog of polymycin B1, is described. The open-chain protected decapeptide was synthesized on a polymer support, starting with threonine as the C-terminal amino acid residue, and was cleaved satisfactorily by hydrazinolysis. The alpha-amino protecting Boc-group was removed with HCl (1 mol/l) acetic acid and the resulting decapeptide hydrazide was converted to the azide with nitrous acid. Cyclization of the azide in pyridine at peptide concentration 2.5.10(-5) mol/l gave the penta-benzyloxycarbonyl-substituted decapeptide in 65% yield. Catalytic hydrogenation afforded the pelargonoyl cyclic decapeptide pentahydrochloride (6) in 75% yield. The synthetic product (6) exhibited an activity comparable to that of the natural polymyxin B1 against Bacillus subtilis and Staphylococcus aureus, whereas it showed only 2% of the activity to Escherichia coli2.


Fish and fish oil intake in relation to risk of asthma: a systematic review and meta-analysis.
Although laboratory studies suggest that long-chain n-3 polyunsaturated fatty acids (LCn3PUFAs) may reduce risk of asthma, epidemiological data remain controversial and inconclusive. We quantitatively reviewed the epidemiological studies published through December 2012 in PubMed and EMBASE by using a fixed-effects or random-effects model. Eleven studies, comprised of 99,093 individuals (3,226 cases), were included in the final dataset. Of them, 7 studies examined associations between intake of fish or LCn3PUFA and risk of asthma: 4 studies in children (996 cases from 12,481 children) and 3 in adults (1,311 cases from 82,553 individuals). Two studies (69 cases from 276 infants) investigated LCn3PUFA levels in mothers' milk, and two studies assessed maternal fish consumption (786 cases from 2,832 individuals) during lactation and/or plasma LCn3PUFA levels during pregnancy (64 cases from 951 infants) in relation to offspring's asthma. The pooled relative risk of child asthma were 0.76 (95% CI, 0.61-0.94) for fish consumption and 0.71 (95% CI, 0.52-0.96) for LCn3PUFA intake. No statistically significant association was found in studies among adults. Epidemiological data to date indicate that fish or LCn3PUFA intake may be beneficial to prevent asthma in children. Further studies are needed to establish causal inference and to elucidate the potential mechanisms.


Serum prolactin and macroprolactin levels among outpatients with major depressive disorder following the administration of selective serotonin-reuptake inhibitors: a cross-sectional pilot study.
Clinical trials evaluating the rate of short-term selective serotonin-reuptake inhibitor (SSRI)-induced hyperprolactinemia have produced conflicting results. Thus, the aim of this study was to clarify whether SSRI therapy can induce hyperprolactinemia and macroprolactinemia. Fifty-five patients with major depressive disorder (MDD) were enrolled in this study. Serum prolactin and macroprolactin levels were measured at a single time point (i.e., in a cross-sectional design). All patients had received SSRI monotherapy (escitalopram, paroxetine, or sertraline) for a mean of 14.75 months. Their mean prolactin level was 15.26 ng/ml. The prevalence of patients with hyperprolactinemia was 10.9% for 6/55, while that of patients with macroprolactinemia was 3.6% for 2/55. The mean prolactin levels were 51.36 and 10.84 ng/ml among those with hyperprolactinemia and a normal prolactin level, respectively. The prolactin level and prevalence of hyperprolactinemia did not differ significantly within each SSRI group. Correlation analysis revealed that there was no correlation between the dosage of each SSRI and prolactin level. These findings suggest that SSRI therapy can induce hyperprolactinemia in patients with MDD. Clinicians should measure and monitor serum prolactin levels, even when both SSRIs and antipsychotics are administered.


[Eyelid neurofibroma affecting a young woman].
A 43-year-old female patient had an amelanotic single tumor thickening the upper right eyelid and observed since early childhood. Clinically, it appeared as a firm mass, without sharp margins, giving a thickened appearance to the superior eyelid. The ophthalmic clinical examination was normal but some subcutaneous nodules attested to the diffusion of the disease recognized as a limited form of neurofibromatosis 1. Although well tolerated, it gave rise to a cosmetic disturbance and the patient was willing to undergo an excision. A complete surgical excision was performed on the lesions and the pathological study disclosed a typical neurofibroma. Regular observation of the different cutaneous nodules was recommended.


The effect of oxytocin and oestradiol on the action of conceptus secretory protein in progesterone-treated ovariectomized ewes.
In intact cyclic ewes intrauterine infusion of conceptus secretory proteins results in the suppression of both endometrial oxytocin receptor concentrations and oxytocin-induced prostaglandin F2 alpha release. However, similar infusion in progesterone-treated ovariectomized ewes, while suppressing endometrial oxytocin receptors, does not fully inhibit oxytocin-induced prostaglandin F2 alpha release. To examine whether this anomaly resulted from an inadequate simulation of the luteal phase in the ovariectomized ewe treated with progesterone alone, the effects of additional treatment with two other ovarian hormones, oestradiol-17 beta and oxytocin, was investigated. Rather than permitting conceptus secretory protein to successfully inhibit oxytocin-induced prostaglandin F2 alpha release, treatment with oestradiol-17 beta in addition to progesterone actually resulted in an advancement in the timing of release. However, treatment with oxytocin, alone or in combination with oestradiol, permitted the full inhibition of oxytocin-induced prostaglandin F2 alpha release. To confirm that this effect did not result from the action of oxytocin alone, independently of the action of conceptus secretory protein, a second experiment was undertaken using a similar protocol but without the infusion of conceptus secretory protein. In this situation, oxytocin-induced prostaglandin F2 alpha release was only partially inhibited suggesting that both luteal oxytocin and conceptus secretory proteins are necessary to facilitate the full inhibition of luteolysis during early pregnancy in the ewe.


Postnatal development of dendritic structure of layer III pyramidal neurons in the medial prefrontal cortex of marmoset.
In the primate cerebral cortex, dendritic spines rapidly increase in number after birth up to infancy or mid-childhood, and then decrease towards adulthood. Abnormalities in these processes accompany several psychiatric disorders. In this study, we examined developmental changes of basal dendrites and spines of layer III pyramidal cells in the medial prefrontal cortex (mPFC) of the common marmoset. The mPFC consists of several areas with distinct features in layer organization, histochemistry, connections, and, in humans, vulnerability to psychiatric disorders. We selected three areas for examination: granular dorsomedial prefrontal (area 8B/9), dysgranular ventromedial prefrontal (area 14r), and agranular anterior cingulate (area 24) cortices. Dendritic field areas, lengths, number of branching points, and total spine number reached a peak at 2-3 postnatal months in all three areas. However, the profiles of spine formation and pruning differed across the three areas with different degrees of granularity; the amount of spine loss from the peak to adulthood was less in areas 24 (33%) and 14r (29%) than in area 8B/9 (43%). Disturbance of this modest spine pruning in the less granular cortical areas may lead to an excessive loss of spines reported for areas 24 and 14r of schizophrenic patients.


Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation-A protocol for a randomized controlled pilot study.
Coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, is spreading rapidly across the globe, with little proven effective therapy. Fever is seen in most cases of COVID-19, at least at the initial stages of illness. Although fever is typically treated (with antipyretics or directly with ice or other mechanical means), increasing data suggest that fever is a protective adaptive response that facilitates recovery from infectious illness. To describe a randomized controlled pilot study of core warming patients with COVID-19 undergoing mechanical ventilation. This prospective single-site randomized controlled pilot study will enroll 20 patients undergoing mechanical ventilation for respiratory failure due to COVID-19. Patients will be randomized 1:1 to standard-of-care or to receive core warming via an esophageal heat exchanger commonly utilized in critical care and surgical patients. The primary outcome is patient viral load measured by lower respiratory tract sample. Secondary outcomes include severity of acute respiratory distress syndrome (as measured by PaO2/FiO2 ratio) 24, 48, and 72 hours after initiation of treatment, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. Resulting data will provide effect size estimates to guide a definitive multi-center randomized clinical trial. ClinicalTrials.gov registration number: NCT04426344. With growing data to support clinical benefits of elevated temperature in infectious illness, this study will provide data to guide further understanding of the role of active temperature management in COVID-19 treatment and provide effect size estimates to power larger studies.


Sleep apnoea among Australian Aboriginal and non-Aboriginal patients in the Northern Territory of Australia-a comparative study.
Australian Aboriginal and Torres Straight Islanders (ATSI) are noted to have a higher burden of chronic health conditions. However, there is a paucity of data on obstructive sleep apnoea (OSA) in this population. In this retrospective study, we evaluated the clinical and polysomnographic (PSG) characteristics of ATSI and non-ATSI adult patients who underwent diagnostic PSG between 2011 and 2015. There were a total of 3078 patients. Of the total, 403 (13%) were of ATSI origin. Among those of ATSI origin, 61% were male and 39% females, while among the non-ATSI cohort, 66% were males. The median age was 47.8 years in ATSI and 51.5 years in the non-ATSI cohort. In the combined cohort, body mass index was more than 30 kg/m2 (61%), hypertension (14.4%), diabetes (17.8%), and heart disease (23.3%). The ATSI patients had higher rates of class III obesity (27 vs. 15%), hypertension (26 vs. 14%), cardiac disease (34 vs. 23%), and diabetes (37 vs. 17%). Among all the study participants, the PSG confirmed 83.7% of the patients had an apnoea-hypopnea index (AHI) more than 5/h, mild (AHI 5-15/h) in 28.4%, moderate (AHI 15-30/h) in 22.3%, and severe (AHI > 30/h) in 33.0%. Among the ATSI patients, 46% had severe OSA. The median total AHI value was higher in the ATSI population (25, interquartile range [IQR]: 11-58) compared to the non-ATSI (17, IQR: 7-36), and in rural/remote population (19, IQR: 8-42) compared to urban (17, IQR: 7-37). This trend was similar for NREM (non-rapid eye movement)-AHI and REM (rapid eye movement)-AHI scores, although statistically significant difference was found only with ATSI status. In the combined cohort the probability of (OR = 1.62, 95% CI: 1.32-2.00, p < 0.001) of severe OSA was 62% higher in individual with hypertension, however, when stratified by ATSI status, the association was only significant in the non-ATSI population (OR = 1.53 95% CI: 1.21-1.94, p < 0.001). The odds of severe AHI was also significantly associated with heart disease (1.37; 95% CI: 1.14,1.63, p < 0.001), diabetes (1.74; 95% CI: 1.43,2.10; p < 0.001) and smoking (1.28; 95% CI: 1.09,1.50, p = 0.0023) in the overall study cohort. In both ATSI and non-ATSI patients, body mass index, neck circumference, sleep efficiency, wake after sleep onset, and respiratory arousal index were significantly higher and independently associated with severe AHI.


Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.
We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.


STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b.
The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy.


IRF8 regulates myeloid and B lymphoid lineage diversification.
Interferon regulatory factor 8 (IRF8) is a member of the IRF family of transcription factors whose members play critical roles in interferon (IFN) signaling pathways governing the establishment of innate immune responses by myeloid and dendritic cells. IRF8 is also expressed in lymphoid cells and recent studies have documented its involvement in B cell lineage specification, immunoglobulin light chain gene rearrangement, the distribution of mature B cells into the marginal zone and follicular B cell compartment, and the transcriptional regulation of critical elements of the germinal center reaction. Here we review the contributions of IRF8 to B cell development from hematopoietic stem cells in the bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B cell fate.


Gestational Diabetes Mellitus and the Risks of Overall and Type-Specific Cardiovascular Diseases: A Population- and Sibling-Matched Cohort Study.
To evaluate associations between gestational diabetes mellitus (GDM) and various incident cardiovascular disease (CVD) end points, considering the effects of the mediating role of type 2 diabetes and shared environmental/familial factors. This population-based cohort study included 10,02,486 parous women in Denmark during 1978-2016. We used Cox regression to 1) examine the associations of GDM with overall and type-specific CVDs using full-cohort and sibling-matched analysis, 2) quantify the impact of type 2 diabetes after GDM using mediation analysis, and 3) assess whether these associations were modified by prepregnancy obesity or maternal history of CVD. Women with a history of GDM had a 40% increased overall CVD risk (hazard ratio [HR] 1.40, 95% CI 1.35-1.45). Sibling-matched analyses yielded similar results (HR 1.44, 95% CI 1.28-1.62). The proportion of association between GDM and overall CVD explained by subsequent type 2 diabetes was 23.3% (15.4-32.8%). We observed increased risks of specific CVDs, including 65% increased stroke risk and more than twofold risks for myocardial infarction, heart failure, and peripheral artery disease. The elevated overall risks were more pronounced among women with GDM and prepregnancy obesity or maternal history of CVD. A history of GDM was associated with increased risks of overall and specific CVDs. Increased risks were partly explained by subsequent type 2 diabetes, and the need to identify other pathways remains important. Continuous monitoring of women with a history of GDM, especially those with prepregnancy obesity or maternal history of CVD, may provide better opportunities to reduce their cardiovascular risk.


The efficacy of Prrrikweg gel in the treatment of insect bites: a double-blind, placebo-controlled clinical trial.
This study was conducted to examine the efficacy of Prrikweg gel, a homeopathic after-bite gel, in relieving the effects of mosquito bites, in particular itching and erythema. A double-blind, randomized, placebo-controlled clinical trial. London School of Hygiene and Tropical Medicine. 100 healthy volunteers. All subjects were bitten under laboratory conditions by Aedes aegypti mosquitoes at one spot on the ventral aspect of the left forearm and another on a corresponding position on the right forearm. One spot was treated with the homeopathic after-bite gel and the other with a placebo gel. Itching was assessed on a 5-point discrete rating scale at 0, 0.5, 1, 26.5, and 48 h post-bite to compare the itch-relieving efficacy of the two treatments. Erythema development was assessed by photographing the bite sites, measuring length and width of the erythema with a calliper, and comparing the ratio of the erythema surface at baseline T(0) to the mean erythema surface at 0.5, 1, 26.5, and 48 h post-bite (T mean) for the two treatments. Testing erythema development by comparing the ratio T(0)/T (mean, after-bite gel) and the ratio T(0)/T (mean, placebo gel) gave a two-tailed p = 0.098(95% Cl, -0.031-0.361) in favour of the after-bite gel. There was not a statistically significant difference between the itch relief provided by the two treatments (two-tailed p = 0.424; 95 percent Cl, -0.541-0.191). The correlation between itching and erythema was significant (r = 0.46; p < 0.001). CONCLUSIONS. There are strong indications that the homeopathic after-bite gel reduces erythema development following mosquito bites. The homeopathic mother tinctures of Echinacea angustifolia DC., Ledum palustre L., Urtica urens L. as well as the Hamamelis extract in this gel, whether alone or in combination, are the biologically active ingredients. The homeopathic after-bite gel was not demonstrated to relieve itching; however, based on the correlation between erythema and itching, an effect on itching is not inconceivable.


[Effect on cell genotype on thermal radiosensitization of yeast].
The combined action of hyperthermia and ionizing radiation on the arrival of isogenic haploid and diploid yeast cells of wild type and rad51 mutant was studied. The experiments demonstrated the essential enhancement of radiosensitivity of diploid wild type cells is hyperthermic conditions. For haploid wild type cells and rad51 mutant cells the enhancement was smaller and negligible respectively. The action of both factors on rad51 homozygous diploid cells was additive. It is established that diploid cells were less thermosensitive than haploid ones. Rad51 mutation does not change these properties. It was concluded that the enhancement of radiosensitivity of cells under hyperthermic conditions depends on cell genotype and may be caused by the reduced capacity of cells to recover the radiation damages inflicted by the both modalities.


[Acute promyelocytic leukemia with asymptomatic cerebral hemorrhage].
A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.


[Optimization of directed training loads on the respiratory system].
Potentiality of an increased elastic resistance to respiratory movements in improving the functional conditioning of young athletes was evaluated. Training with increased elastic resistance to respiration brought about gains in strength and endurance of the respiratory muscles, growth of the maximal oxygen consumption, work ability, and special physical fitness of athletes.


The TgsGP gene is essential for resistance to human serum in Trypanosoma brucei gambiense.
Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense.


Challenges of using in vitro data for modeling P-glycoprotein efflux in the blood-brain barrier.
The efficacy of central nervous system (CNS) drugs may be limited by their poor ability to cross the bloodbrain barrier (BBB). Transporters, such as p-glycoprotein, may affect the distribution of many drugs into the CNS in conjunction with the restricted paracellular pathway of the BBB. It is therefore important to gain information on unbound drug concentrations in the brain in drug development to ensure sufficient drug exposure from plasma at the target site in the CNS. In vitro methods are routinely used in drug development to study passive permeability and p-glycoprotein efflux of new drugs. This review discusses the challenges in the use of in vitro data as input parameters in physiologically based pharmacokinetic (PBPK) models of CNS drug disposition of p-glycoprotein substrates. Experience with quinidine demonstrates the variability in in vitro parameters of passive permeability and active pglycoprotein efflux. Further work is needed to generate parameter values that are independent of the model and assay. This is a prerequisite for reliable predictions of drug concentrations in the brain in vivo.


Dual roles of c-Myc in the regulation of hTERT gene.
Human telomerase gene hTERT is important for cancer and aging. hTERT promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment. However, it remains unsolved how the interplay between TFs and chromatin environment controls hTERT transcription. In this study, we employed the recombinase-mediated BAC targeting and BAC recombineering techniques to dissect the functions of two proximal E-box sites at -165 and +44 nt in regulating the hTERT promoter in the native genomic contexts. Our data showed that mutations of these sites abolished promoter binding by c-Myc/Max, USF1 and USF2, decreased hTERT promoter activity, and prevented its activation by overexpressed c-Myc. Upon inhibition of histone deacetylases, mutant and wildtype promoters were induced to the same level, indicating that the E-boxes functioned to de-repress the hTERT promoter and allowed its transcription in a repressive chromatin environment. Unexpectedly, knockdown of endogenous c-Myc/Max proteins activated hTERT promoter. This activation did not require the proximal E-boxes but was accompanied by increased promoter accessibility, as indicated by augmented active histone marks and binding of multiple TFs at the promoter. Our studies demonstrated that c-Myc/Max functioned in maintaining chromatin-dependent repression of the hTERT gene in addition to activating its promoter.


Brolucizumab in Neovascular Age-Related Macular Degeneration - Indian Real-World Experience: The BRAILLE Study.
To assess the short-term efficacy and safety profile of intravitreal brolucizumab injection in Indian eyes with neovascular age-related macular degeneration (nAMD) under real-world conditions. This was a multicenter, retrospective chart review of 94 eyes of 94 patients with nAMD (treatment-naïve and switch-therapy) undergoing brolucizumab therapy. Re-treatment as per pro-re-nata protocol was performed based on fixed visual and tomographic criteria. The main outcome measures were changes in the best-corrected visual acuity (BCVA), intraretinal fluid (IRF), subretinal fluid (SRF), central subfield thickness (CST), and pigment epithelial detachment (PED) along with safety analysis. Of the 94 eyes, 20 eyes (21.3%) were treatment-naïve, whereas the rest 74 eyes (78.7%) underwent switch therapy. One hundred and twenty-six injections were given over a mean follow-up of 7.3 ± 2.2 (range 5-30) weeks. The BCVA improved significantly from 0.82 ± 0.5 LogMAR at baseline to 0.66 ± 0.5 LogMAR at the final visit (p < 0.0001). Significant reduction in CST was simultaneously noted (Baseline: 408.45 ± 65.63 µm; Final: 281.14 ± 37.74 µm; p < 0.0001). On qualitative analysis, resolution of subretinal fluid (SRF), intraretinal fluid (IRF), and pigment epithelial detachment (PED) was observed in 15.5%, 39.29%, and 23.81% of the eyes, respectively. The mean interval of repeat injection was 10.2 ± 2.1 weeks. Three episodes of ocular adverse drug reaction were reported, including two patients developing subretinal hemorrhage while one having a retinal pigment epithelial (RPE) tear. Notably, no intraocular inflammation (IOI) was seen in any of the eyes, and no systemic side effects were identified. In a real-world scenario, brolucizumab therapy is efficacious and safe in the management of nAMD over the short term. Further long-term studies are warranted to validate these findings. Additionally, lack of ocular inflammation after 126 brolucizumab injections in our Indian data is peculiar and underlines the necessity to explore the role of race and genetics in predisposing to/safeguarding against brolucizumab-related IOIs.


Membrane trafficking in breast cancer progression: protein kinase D comes into play.
Protein kinase D (PKD) is a serine/threonine kinase family that controls important cellular functions, most notably playing a key role in the secretory pathway at the trans-Golgi network. Aberrant expression of PKD isoforms has been found mainly in breast cancer, where it promotes various cellular processes such as growth, invasion, survival and stem cell maintenance. In this review, we discuss the isoform-specific functions of PKD in breast cancer progression, with a particular focus on how the PKD controlled cellular processes might be linked to deregulated membrane trafficking and secretion. We further highlight the challenges of a therapeutic approach targeting PKD to prevent breast cancer progression.


Nitrergic and cholinergic vagal pathways involved in the regulation of canine proximal gastric tone: an in vivo study.
To better understand the relationship between cholinergic and nitrergic (NO) innervation in the regulation of proximal gastric (fundic) tone in vivo, the effects of nitric oxide synthase blockade on fundic tone were studied in conscious dogs using vagal cooling and an electronic barostat. Vagal cooling, atropine (0.05 mg kg-1 i. v. bolus) and hexamethonium (1 mg kg-1 i.v. bolus) all markedly decreased fundic tone as reflected by increased intragastric volume, indicating a significant contribution of vagal and enteric cholinergic pathways to the maintenance of canine fundic tone. Administration of L-NNA (10 mg kg-1 i.v. bolus) increased fundic tone and the effects of L-NNA were completely prevented by prior vagal cooling or atropine administration, but not by pretreatment with hexamethonium. The relaxation effects of neurally derived NO appear primarily related to inhibition of ongoing vagal cholinergic activity. The data are consistent with the primary site of action of nitrergic mechanisms on gastric fundic tone in conscious dogs being at a presynaptic site on vagal cholinergic efferent nerves.


Oil pollution in the Eastern Arabian Sea from invisible sources: A multi-technique approach.
The Eastern Arabian Sea (EAS) is affected by oil pollution, as often evidenced by the presence of tarballs along the West Coast of India (WCI). Tarball samples collected during May 2017 along the Goa coast were subject to biomarker fingerprints, and the results matched with Bombay High (BH) oil fingerprints. The present study primarily aims at identifying the potential minor spill areas using Sentinel-imagery. Interestingly, repeated occurrence of oil spills detected at two locations, perfectly matched with BH platforms. The simulated Lagrangian trajectories also depict that tarball particles have originated from those detected locations. In 2017 alone, the quantity of spilled oil was estimated to be 129,392 l. However, spills detected offshore regions of Kachchh and Mangalore were found to be caused by ships. This is the first comprehensive study, tracking the oil pollution sources in the EAS through multi-technique approach - chemical, remote sensing and numerical modeling.


Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs.
Recruitment of cytoplasmic signaling proteins into the nucleus is an essential step in the activation of gene expression in response to an extracellular signal. Nucleo-cytoplasmic transport of macromolecules is mediated by the transport receptors of an importin beta family. Post-translational modifications and masking/unmasking of specific signal sequences responsible for nuclear import and export are important for the coordinated control of the nucleo-cytoplasmic transport. Malfunctioning of the nucleo-cytoplasmic transport is profoundly involved in a number of diseases including cancer. Leptomycin B (LMB) is a Streptomyces metabolite that causes specific inhibition of the cell cycle of fission yeast and mammalian cells. The target molecule of LMB has been shown by genetic and biochemical analyses to be CRM1, a highly conserved protein in eukaryotes. CRM1 was shown to be a member of the importin beta family and a receptor for the nuclear export signal (NES) of proteins in both yeast and mammalian cells. LMB binds directly to CRM1, which results in dissociation of the NES from the nuclear export machinery containing CRM1. Thus, LMB serves as a potent tool for understanding the molecular mechanisms of nucleo-cytoplasmic transport of proteins and a potential therapeutic drug for diseases caused by mislocalization of regulatory proteins.


Positive correlation between lipid accumulation product index and arterial stiffness in Chinese patients with type 2 diabetes.
Many studies have confirmed that lipid accumulation products (LAP) predict arterial stiffness (AS) in hypertensive patients. But there is little research on the use of LAP in identifying early atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to determine the relationship between the LAP index and brachial-ankle pulse wave velocity (baPWV) in Chinese patients with T2DM. A total of 1471 Chinese participants with T2DM, ranging in age from 18 to 80, were included in this cross-sectional study. BaPWV measurements were used to calculate the AS. A baPWV greater than the 75th percentile (1700 cm/s) was defined as indicating increased AS. The LAP index was calculated from the combination of waist circumference (WC) and triglycerides (TG). According to the quartiles of the LAP index, baPWV tended to increase after adjusting for sex and age. Multiple linear regression analysis showed that the beta coefficient (β) of baPWV increased by 31.0 cm/s for each unit of lnLAP that was increased, and the 95% confidence interval (CI) was (6.5, 55.5) cm/s. In multivariate logistic regression analyses, after fully adjusting for confounders, the risk of elevated baPWV increased with each unit increase in lnLAP, with an odds ratio (OR) of 1.3 (95% CI: 1.0, 1.8). According to the generalized additive model (GAM), we found that lnLAP was positively correlated with baPWV and baPWV elevation. The results were the same for males and females. Subgroup analyses showed that the positive correlation between lnLAP and elevated baPWV did not interact across all subgroups. In Chinese patients with T2DM, LAP was strongly and positively correlated with baPWV and elevated baPWV.


Knowledge, attitude and practice of medical students towards HIV patients in their pre-clinical and post-clinical years in Karachi, Pakistan: a dual-center cross-sectional study.
The human immunodeficiency virus (HIV) is currently a global threat with an estimated 38.6 million people affected with HIV worldwide. According to the Joint United Nations Program on HIV/AIDS (UNAIDS), since 2004 the total number of cases of HIV in Pakistan has risen from 2700 to 130,000. In light of the rising burden of HIV/AIDS across the country, it is essential that medical students possess appropriate knowledge regarding the subject. Therefore, we aimed to assess the knowledge, attitude and practice of medical students towards HIV patients in their pre-clinical and post-clinical years in Karachi, Pakistan. A cross-sectional study was conducted among 518 pre-clinical (year 1 and 2) and post-clinical (year 3, 4, and 5) medical students from two medical schools in Karachi during the months of October - December 2019. Similar numbers of participants were taken from each year. Data were analyzed using SPSS. Descriptive statistics were used to report frequencies and proportions for categorical responses. Chi-square and Kruskal-Wallis tests were used as the primary statistical tests. About 55% of participants were female, and most belonged to the Islamic faith. More than half of the participants learned about HIV from books (315/518), followed by medical personnel (287/518). A quarter (134/518) of the participants believed HIV could be transmitted by sharing saliva, more than half of whom consisted of pre-clinical year students. Over half the participants (60.4%) knew that there was a difference between HIV and AIDs, most of whom belonged to the 5th year group. When detecting HIV, only about 30% of participants knew about indirect fluorescent antibody. Regarding attitudes, one-third would not be friends with a person diagnosed with HIV/AIDS. As a medical officer, a large majority (76.6%; n=397/518) of the participants would be anxious or somewhat anxious. Two-thirds believed that treating an HIV patient can make them contract HIV, and a majority of participants (333/518) did not feel adequately prepared to deal with the psycho-social problems of an HIV/AIDS patient. Finally, regarding practice, only one-third of the participants were willing to treat an HIV/AIDS patient, most of whom belonged to the pre-clinical 2nd year group and fewer to the post-clinical 3rd year group. Knowledge amongst medical students regarding HIV/AIDS was generally high, although there are some knowledge inadequacies which require more emphasis in the medical school curriculum. However, contrasting with the level of knowledge, in terms of attitude the majority were anxious or somewhat anxious when treating an HIV patient, and only one-third were willing to treat a patient with HIV.


Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy.
The urokinase plasminogen activator receptor (uPAR) has been implicated in the growth, metastasis, and angiogenesis of several solid and hemotologic malignancies. uPAR is part of a cell surface system that also consists of the serine protease uPA and several specific inhibitors (plasminogen activator inhibitors 1 and 2). This system has classically been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells, and intervening with this proteolysis by targeting uPAR has been proposed to represent a novel approach for inhibiting tumor progression. However, despite abundant evidence suggesting the utility of targeting uPAR for the treatment of cancer, there are currently no uPAR-targeted therapies being evaluated in clinical trials. Recent data have provided new insights into the role of uPAR in tumor progression. In addition to mediating proteolysis, this receptor appears to also mediate cell signaling, proliferation, and survival, and these observations have revealed novel ways to target uPAR. How these data have led to a paradigm shift in how the role of uPAR in tumor progression is perceived as well as past and present attempts to therapeutically target a molecule that is generating renewed interest as a cancer target will be discussed in this article.


Ex Vivo Evaluation of Thymus daenensis as an Antioxidant and Antibacterial Medicinal Herb.
Herbal medicines are defined as traditionally used natural products. The current study in an attempt try to investigate the antibacterial activity on extended spectrum beta-lactamases (ESBL), methalo beta-lactamases (MBL) producing gram negative bacteria and methicillin resistant Staphylococcus aureus (MRSA) and subsequently, to determine the antioxidant activity of Thymus daenensis. For this reasons, firstly cytotoxicity of T. daenensis was determined by MTT assay. Then, essential oil was subjected for antibacterial and antioxidant activity. Our results demonstrated that 15 mg/ml concentration of T. daenensis inhibited both P. aeruginosa producing MBL and E.coli producing ESBL, while this value was 25 mg/ml concentration for MRSA inhibition. The association between phenolic compound and antioxidant activity was found for the ABTS•+ method (43.52%) in the lowest level, while, for FRAD and DPPH• methods the opposite story occurred (70.5% correlation for DPPH• and 50.9% for FRAD). Our findings suggested that T. daenensis has a potential herbal medicine that should be considered as an antibacterial and antioxidant with very low toxicity.


Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line.
Sonodynamic therapy (SDT) is expected to be a new method to solve the clinical problems caused by advanced metastasis in patients with lung cancer. The use of ultrasound has the advantage of being noninvasive, with deep-penetration properties. This study explored the anti-tumor effect of SDT with a new sonosensitizer, sinoporphyrin sodium (DVDMS), on the human small cell lung cancer H446 cell line in vitro and in vivo. Absorption of DVDMS was detected by a fluorescence spectrophotometer, and DVDMS toxicity was determined using a Cell Counting Kit-8. Mitochondrial membrane potential (MMP) was assessed using the JC-1 fluorescent probe. Cell apoptosis was measured by flow cytometry, and apoptosis-related proteins were detected by western blotting. The expression of cytokines was measured using an enzyme-linked immunosorbent assay and quantitative real-time PCR. To verify the in vitro results, we detected tumor volumes and weight changes in a xenograft nude mouse model after DVDMS-SDT. Hematoxylin and eosin staining was used to observe changes to the tumor, heart, liver, spleen, lung, and kidney of the mice, and immunohistochemistry was used to examine changes in the expression of tumor CD34 and receptor-interacting protein kinase-3 (RIP3), while terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to observe apoptosis in tumor tissues. DVDMS-SDT-treated H446 cells increased the rate of cellular apoptosis and the levels of reactive oxygen species (ROS), cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and caspase-10, and decreased the levels of MMP, RIP3, B-cell lymphoma 2, vascular endothelial growth factor, and tumor necrosis factor-α. The sonotoxic effect was mediated by ROS and was reduced by a ROS scavenger (N-acetyl-L-cysteine). In the in vivo mouse xenograft model, DVDMS-SDT showed efficient anti-cancer effects with no visible side effects. DVDMS-SDT induced apoptosis in H446 cells, in part by targeting mitochondria through the mitochondria-mediated apoptosis signaling pathway, and the extrinsic apoptosis pathway was also shown to be involved. Both apoptosis and changes in RIP3 expression were closely related to the generation of ROS. DVDMS-SDT will be advantageous for the management of small cell lung cancer due to its noninvasive characteristics.


Glutamate metabolism and transport in rat brain mitochondria.
1. The metabolism and transport of glutamate and glutamine in rat brain mitochondria of non-synaptic origin has been studied in various states. 2. These mitochondria exhibited glutamate uptake and swelling in iso-osmotic ammonium glutamate, both of which were inhibited by N-ethylmaleimide. 3. The oxidation of glutamate was inhibited by 20% by avenaciolide, but glutamine oxidation was not affected. 4. These mitochondria, when metabolizing glutamine, allowed glutamate, but very little aspartate, to efflux at considerable rates. 5. These results suggests that brain mitochondria of non-synaptic origin possess in addition to a relatively rapid glutamate-aspartate translocase, a relatively slow aspartate-independent glutamate-OH-translocase (cf. liver mitochondria).


Studies on the mechanism of captopril induced hypotension in rats.
The mechanism of the hypotensive response to captopril was investigated in pithed and urethane anesthetized rats. Cumulative intravenous doses of captopril produced dose-dependent hypotensive responses which were correlated with blockade of the pressor response to angiotensin I. Angiotensin II responses were unaffected. Infusions of saralasin, an angiotensin receptor antagonist, inhibited the hypotensive action of captopril, the degree of antagonism being correlated with inhibition of angiotensin II pressor responses. Bilateral nephrectomy lowered blood pressure to approximately the same level as captopril and completely abolished the hypotensive effect of captopril. No evidence was obtained for the involvement of endogenous bradykinin or prostaglandins in the hypotensive action of captopril. It is concluded that in pithed and urethane anesthetized rats, captopril mediates its hypotensive response by removing the renal renin-angiotensin system, most probably via inhibition of angiotensin I - converting enzyme. The results contrast with similar studies conducted in anesthetized dogs. In this species, the mechanism of action of captopril remains for further resolution.


Spontaneous Subdural Haemorrhage: A Rare Association with Plasmodium Vivax Malaria.
Malaria is an endemic disease in tropical countries and disease of universal importance. Central Nervous System (CNS) complications of malaria are severe and associated with significant mortality. Thrombocytopaenia in malaria causing haemorrhagic CNS complications is rare. We report a case of 35-year-old male patient presented with headache, vomiting and was diagnosed to have subdural haemorrhage (SDH). On examination patient was found to be febrile with peripheral smear showing evidence of Plasmodium vivax (P.vivax) infection with severe thrombocytopaenia. In endemic regions with malaria, SDH being rare presentation of malaria should be considered as a differential diagnosis in febrile patients with neurological manifestations. Rarity of spontaneous SDH in malaria and raising awareness amongst treating physicians about the same is the driving factor for reporting this case.


[Comparative study of the analgesic, sedative and myorelaxant effects of GABA-positive preparations].
It was shown in experiments on rats that the analgesic effect of GABA-positive drugs is followed by sedative and myorelaxant manifestations, however there is no direct relationship between the effects. Bicuculline significantly attenuates analgesia induced by THIP, gamma-acetylenic-GABA and depakin in the test of vocalization but enhances their analgesic activity in the tail-flick test. The involvement of individual subtypes of GABA receptors in mediation of analgesic and general depressant effects of GABA-positive drugs was discussed.


Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A.
OKT4A, a murine mAb that recognizes an epitope on the CD4 receptor, is a potent immunosuppressive agent in vitro and in a variety of nonhuman primate models of graft rejection and autoimmune disease. Initial human cardiac transplant trials suggest that OKT4A does not cause either cytokine release syndrome or CD4+ cell depletion, but does induce a human anti-mouse Ab (HAMA) response despite strong concurrent immunosuppression. To further investigate the potential of OKT4A as an immunomodulator, it was necessary to decrease its immunogenicity. Therefore, we developed a humanized version of this Ab (gOKT4A-4), which has the same binding affinity and in vitro immunosuppressive properties of OKT4A, but retains only three murine sequence-derived amino acid residues outside of the complementarity-determining regions (CDRs). Detailed computer modeling of both OKT4A and gOKT4A-4 provided a computational rationale for the changes necessary to regain activity after humanization. This has also provided a plausible representation of the Ag binding site. Preliminary clinical results with gOKT4A-4 suggest that we have eliminated the immunogenicity observed in the parent murine Ab.