A prospective, randomized, controlled study assessing vagus nerve stimulation using the gammaCore®-Sapphire device for patients with moderate to severe CoViD-19 Respiratory Symptoms (SAVIOR): A structured summary of a study protocol for a randomised controlled trial".
Primary Objective: The primary objective is to reduce initiation of mechanical ventilator dependency in patients with moderate to severe CoViD- 19. This will be measured as the difference between the control group and active group for subjects admitted to the hospital for CoViD-19. Secondary Objectives: • To evaluate cytokine trends / Prevent cytokine storms • To evaluate supplemental oxygen requirements • To decrease mortality of CoViD-19 patients • Delay onset of ventilation TRIAL DESIGN: The study is a single centre, 2-arm, prospective, randomized (ratio 1:1), controlled trial with parallel groups design to compare the reduction of respiratory distress in a CoViD-19 population, using the intervention of the gammaCore®-Sapphire device plus standard of care (active) vs. standard of care alone (SoC) - the control group. The gammaCore® treatments will be used acutely and prophylactically. The active and control groups will be matched for disease and severity. i. Inclusion Criteria The subjects have to meet all of the following criteria to be eligible to enter the trial: 1.Patient older than 18 years2.Been tested positive or suspected/presumed positive for CoViD-19 Has a cough, shortness of breath or respiratory O2 Saturation less than or equal to 92% without need for mechanical ventilation or acute respiratory failure 3.Agree to use the gammaCore®-Sapphire device as intended and to follow all of the requirements of the study including recording required study data4.Patient is able to provide signed and witnessed Informed Consent ii. Exclusion Criteria Subjects meeting any of the following criteria cannot be included in this research study: 1.Pregnant women2.On home/therapy oxygen (i.e. for patients with Chronic Obstructive Pulmonary Disease) at baseline prior to development of CoViD-193.Patient already enrolled in a clinical trial using immunotherapeutic regimen for CoViD-194.History of aneurysm, intracranial hemorrhage, brain tumors, or significant head trauma5.Known or suspected severe atherosclerotic cardiovascular disease, severe carotid artery disease (eg, bruits or history of transient ischemic attack or cerebrovascular accident), congestive heart failure, known severe coronary artery disease, or recent myocardial infarction6.Uncontrolled high blood pressure (>140/90)7.Current implantation of an electrical and/or neurostimulator device, including but not limited to a cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant8.Current implantation of metal cervical spine hardware or a metallic implant near the gammaCore stimulation site9.Belongs to a vulnerable population or has any condition such that his or her ability to provide informed consent, comply with the follow-up requirements, or provide self-assessments is compromised (e.g. homeless, developmentally disabled and prisoner) Participants will be recruited from Hospital Clínico Universitario de Valencia in Spain. Intervention: Prophylactic: Administer 2 doses (at 2 minutes each) of gammaCore®-Sapphire, one dose on each side of the neck scheduled three times a day (morning, mid-day and 1 hour before bed at night).Acute respiratory failure or shortness of breath: Administer 2 doses (at 2 minutes each) of gammaCore®-Sapphire, one on each side of the neck. If shortness of breath (SOB) persists 20 minutes after the start of the first treatment, a second dose will be administered. Max doses per day is 9 or 18 stimulations.Plus standard of care Control: Standard of care: oxygen therapy, antibiotics and ventilatory support if necessary depending on the clinic MAIN OUTCOMES: Primary Endpoint: Initiation of mechanical ventilation, from randomization until ICU admission or hospital discharge, whatever occurs first Secondary Endpoints: Safety; ascertainment of Adverse Effects/Serious Adverse Events, from randomisation to ICU admission or hospital discharge, whatever occurs firstCytokine Storm measured by: Tumor necrosis factor α, Interleukin 6, Interleukin 1β. Days 1,3,5,10,15 and/or at hospital dischargeMortality and/or need for Critical Care admission, from randomisation until ICU admission or hospital discharge, whatever occurs first,O2 saturation levels , from randomization until ICU admission or hospital discharge, whatever occurs firstNeed for supplemental oxygen, from randomisation until ICU admission or hospital discharge, whatever occurs first RANDOMISATION: The patients are classified according to their oxygen levels as mild, moderate and severe and randomized according to their classification to the intervention and control in a ratio of 1:1. The randomization will be stratified for gender and age. This is an open label study, it is not possible to blind the participants and healthcare providers to the intervention. The total number of patients to be included in the study is 90, with 45 in each study group TRIAL STATUS: The protocol version is 8.0 from 07th April 2020. The recruitment began 20th April 2020 and is expected to be complete 31st July 2020. The study is registered in clinicaltrials.gov on 29th April 2020 with the identification number: NCT04368156 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Stability of dopamine in an in vitro incubation system using Medium 199.
This study investigated the stability of exogenous dopamine (DA) in vitro in a commercially available medium (Medium 199), with and without additional ascorbic acid, during incubation with pituitary halves in prolactin secretion experiments. After a 3-h incubation period, 26 and 15% of the starting concentrations of DA were degraded in the absence and presence of 1 mM ascorbic acid, respectively; in the absence of pituitary tissue, these reductions in DA concentration were 19% and 0%, respectively. In contrast, 98% of DA was degraded after 3 h of incubation in Krebs-Henseleit bicarbonate buffer which contained no tissue or no antioxidants. A number of antioxidants (including a low concentration of ascorbic acid) which are already present in Medium 199 are most likely responsible for the relative stability of DA in this medium. The loss of DA during incubation in Medium 199 is considered small for this type of study, and additional ascorbic acid only marginally improves DA stability in this medium. We have concluded that there is no need to be overly concerned about the degradation of exogenous DA in vitro for some incubation experiments using Medium 199, and the addition of extra ascorbic acid (which may be deleterious) is not necessary.


Initiation of translation at AUC, AUA and AUU codons in Escherichia coli.
A truncated form of the HBL murein hydrolase, encoded by the temperate bacteriophage HB-3, was cloned in a pUC-derivative and translated in Escherichia coli using AUC as start codon, as confirmed by biochemical, immunological, and N-terminal analyses. Using site-directed mutagenesis, we have changed this AUC codon into AUA, AUU and AUG codons. The relative translation efficiencies for these triplets were about 5% for AUC and AUU and 7.5% for AUA compared to that of AUG codon. In the same gene arrangement E. coli beta-galactosidase was also translated at moderate efficiency using AUC as initiator.


Plasma N-Acetylaspartate Is Related to Age, Obesity, and Glucose Metabolism: Effects of Antidiabetic Treatment and Bariatric Surgery.
Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = -0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = -0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function.


[Labor induction with prostaglandin in post-cesarean section status].
60 pregnant women with previous cesarean section and induction of labour with prostaglandins (PGE2) in the following pregnancy were compared to a collective of 1412 patients with PGE2 induction without any previous uterine surgery, and to a collective of 82 patients with previous cesarean section, but an uncomplicated course of pregnancy and therefore no indication for an induction of labour. Uterine hyperstimulation was more frequent in both collectives with previous cesarean section than in the collective without that risk. In the case of previous cesarean section induction of labour with prostaglandins did not lead to an increased number of uterine ruptures compared to cases with a previous cesarean section. Therefore the induction of labour itself in the case of a previous cesarean section doesn't lead to an increased maternal risk during delivery. Uterine hyperstimulation being rare, the increased number of fetal acidosis and vaginal-operative delivery in the group with previous cesarean section and consecutive PGE2 induction of labour seems to originate rather from the risk which was the indication for labour induction than from the PGE2 application itself. The information of a patient with previous cesarean section and planed induction of labour with PGE2 should therefore put the stress in the necessity of an intensive surveillance during delivery because of the basic risk "previous cesarean section" and the secondary risk resulting from the induction of labour.


Selective coronary arteriography. Risk in a community hospital.
Over a 33-month period, selective coronary arteriography was performed in 627 consecutive patients in a 385-bed, non-university-affiliated community hospital. Mortality was 0.16% (one death); there was also one nonfatal myocardial infarction. No deaths or myocardial infarctions occurred in the last 369 consecutive patients in this series when routine systemic heparinization was introduced. Substantially greater risk of mortality (2.6%) and nonfatal myocardial infarction (2.6%) was encountered in an earlier series of 78 consecutive patients for whom a different protocol was used. It included extensive exercise hemodynamic studies with the use of percutaneous arterial angiographic catheters, without systemic heparinization. This indicates that coronary arteriography can be carried out with acceptable risk in a community hospital. Protocols should be designed to minimize the time that catheters are in the arterial system. Systemic heparinization may reduce the risk of procedure-related death and myocardial infarction.


The Prevalence of Helicobacter pylori in Estonian Bariatric Surgery Patients.
Helicobacter pylori (Hp) is one of the most important human pathogens that can cause duodenal and gastric ulcers, gastritis and stomach cancer. Hp infection is considered to be a cause of limiting access to bariatric surgery. The aim of this study was to determine the prevalence of Hp in patients with obesity going into bariatric surgery and to reveal the relationship between Hp and clinical data. The study group was formed of 68 preoperative bariatric surgery patients (body mass index (BMI) 44.7 ± 4.8). Gastric biopsies (antrum and corpus) were used for histological and molecular (caqA and glmM genes) examinations. The PCR method revealed Hp infection in 64.7% of obese patients that is higher in comparison with histological analysis (55.9%). The prevalence of cagA and glmM genes in antrum mucosa was 45.6% and 47.0% while in the corpus it was 41.2% and 38.3%, respectively. The coincidence of both cagA and glmM virulence genes in the antrum and corpus mucosa was 33.8% and 22.1%, respectively. Either of the genes was found in 58.8% of antrum and 57.3% of corpus mucosa. Presence of caqA and glmM genes was in association with active and atrophic chronic gastritis. In conclusion, our study demonstrated that two thirds of morbidly obese patients undergoing bariatric surgery are infected with Hp and have a high prevalence of cagA and glmM virulence genes that points out the necessity for diagnostics and treatment of this infection before surgery.


Fatal aplastic anemia caused by Epstein-Barr virus infection after autologous bone marrow transplantation for non-Hodgkin malignant lymphoma.
We report a case of severe and fatal aplastic anemia during an episode of infectious mononucleosis caused by Epstein-Barr (EB) virus infection. The 13-year-old female patient had shown normal hematological findings and had previously undergone repeated chemotherapy and autologous bone marrow transplantation for refractory non-Hodgkin malignant lymphoma (NHL). She was probably in an immuno-suppressed condition prior to this episode of infection. The possible causal relationship of the EB virus infection in the pathogenesis of aplastic anemia was documented by the clinical course, demonstration of EB virus genome in the bone marrow cells, and an elevated plasma interferon (IFN)-gamma level.


Trends in Evaluation Research 1982 - 2002: A Study on how the Quality of IT Evaluation Studies Develop.
During the last years the significance of evaluation studies as well as the interest in adequate methods and approaches for evaluation has grown in medical informatics. In order to put this discussion into historical perspective of evaluation research, we conducted a systematic review on trends in evaluation research of information technology in health care from 1982 to 2002. The inventory is based on a systematic literature search in PubMed.In the first step of our inventory, we concentrated on describing long-term developments in questions, approaches, setting, methods and criteria of IT evaluation studies as described in the abstracts of the identified 1.035 publications. We found some signs of a maturation of evaluation research in medical informatics. However, these findings are only based on study abstracts that do not give sufficient information to assess the quality of studies in more detail.In a second step of our inventory, we are now looking at the quality of IT evaluation studies in health care, describing in more detail study design and assessing 10 quality indicators. For this second step, we analyse a randomized sample of 105 evaluation full papers in more detail. Besides more descriptive details on study design, the results will show whether IT evaluation studies are credible, and how their quality changed in the last 20 years. An interim analysis of the first 64 papers shows a stable quality of IT evaluation studies over the last 20 years.


Nuclear Magnetic Shieldings of Stacked Aromatic and Antiaromatic Molecules.
Nuclear magnetic shieldings have been calculated at the density functional theory (DFT) level for stacks of benzene, hexadehydro[12]annulene, dodecadehydro[18]annulene, and hexabenzocoronene. The magnetic shieldings due to the ring currents in the adjacent molecules have been estimated by calculating nucleus independent molecular shieldings for the monomer in the atomic positions of neighbor molecules. The calculations show that the independent shielding model works reasonably well for the 1H NMR shieldings of benzene and hexadehydro[12]annulene, whereas for the larger molecules and for the 13C NMR shieldings the interaction between the molecules leads to shielding effects that are at least of the same size as the ring current contributions from the adjacent molecules. A better agreement is obtained when the nearest neighbors are also considered at full quantum mechanical (QM) level. The calculations suggest that the nearest solvent molecules must be included in the quantum mechanical system, at least when estimating solvent shifts at the molecular mechanics (MM) level. Current density calculations show that the stacking does not significantly affect the ring current strengths of the individual molecules, whereas the shape of the ring current for a single molecule differs from that of the stacked molecules.


Activation of lignocellulosic biomass for higher sugar yields using aqueous ionic liquid at low severity process conditions.
Concerns around greenhouse gas emissions necessitate the development of sustainable processes for the production of chemicals, materials, and fuels from alternative renewable sources. The lignocellulosic plant cell walls are one of the most abundant sources of carbon for renewable bioenergy production. Certain ionic liquids (ILs) are very effective at disrupting the plant cell walls of lignocellulose, and generate a substrate that is effectively hydrolyzed into fermentable sugars. Conventional ILs are relatively expensive in terms of purchase price, and the most effective imidazolium-based ILs also require energy intensive processing conditions (>140 °C, 3 h) to release >90 % fermentable sugar yields after saccharification. We have developed a highly effective pretreatment technology utilizing the relatively inexpensive IL comprised tetrabutylammonium [TBA](+) and hydroxide [OH](-) ions that generate high glucose yields (~95 %) after pretreatment at very mild processing conditions (50 °C). The efficiency of [TBA][OH] pretreatment of lignocellulose was further studied by analyzing chemical composition, powder X-ray diffraction for cellulose structure, NMR and SEC for lignin dissolution/depolymerization, and glycome profiling for cell wall modifications. Glycome profiling experiments and computational results indicate that removal of the noncellulosic polysaccharides occurs due to the ionic mobility of [TBA][OH] and is the key factor in determining pretreatment efficiency. Process modeling and energy demand analysis suggests that this [TBA][OH] pretreatment could potentially reduce the energy required in the pretreatment unit operation by more than 75 %. By leveraging the benefits of ILs that are effective at very mild processing conditions, such as [TBA][OH], lignocellulosic biomass can be pretreated at similar efficiency as top performing conventional ILs, such as 1-ethyl-3-methylimidazolium acetate [C2C1Im][OAc], but at much lower temperatures, and with less than half the IL normally required to be effective. [TBA][OH] IL is more reactive in terms of ionic mobility which extends removal of lignin and noncellulosic components of biomass at the lower temperature pretreatment. This approach to biomass pretreatment at lower temperatures could be transformative in the affordability and energy efficiency of lignocellulosic biorefineries.


Abnormal melt curve profile during prothrombin 20210G --> A analysis due to the 20209C --> T variant.
The common factor II 20210G --> A mutation, located in the 3'-untranslated region, is an important risk factor for the development of thromboembolic disorders, especially in Caucasians. A number of methods are employed for clinical laboratory diagnosis of this mutation, some of which are capable of detecting adjacent 3'-end sequence variations. We present results from an African deep vein thrombosis patient tested for the 20210G --> A mutation by real-time polymerase chain reaction and melt-curve analysis using hybridization probes that incidentally detected an adjacent 3'-untranslated region variant. The patient sample was tested using the Factor II (Prothromobin) G20210A Kit (Roche Diagnostics, Indianapolis, Indiana, USA), in conjunction with the Roche LightCycler. A polymerase chain reaction fragment from the 3'-end of the F2 gene was subsequently sequenced for identification of the variant. Melt-curve analysis revealed a normal 20210*G peak and an unknown aberrant allelic peak. Following sequence analysis, the patient was determined to be heterozygous for 20209C --> T. The presence of the 20209C --> T variant in the current patient and in eight other reported individuals of African descent, most with thrombosis-associated complaints, suggests that this rare variant poses a potential increased risk for thromboembolic disease in this ethnic group.


Seroprevalence survey of selective anti-neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia.
Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies on the detection of specific autoantibodies in the blood or cerebral spinal fluid in addition to the clinical presentations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our patients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample collected from patients with the first-episode schizophrenia. The six autoantibodies including antibodies against N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, γ-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 females) were investigated; however, no positive case was identified. In this second study, we screened anti-NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and 101 males) including 48 patients defined as treatment resistance. None of this sample was detected as positive. The negative findings in this study suggest that the seroprevalence of autoantibodies against neuronal surface proteins might be low in patients diagnosed with schizophrenia.


Borrelia burgdorferi-associated primary cutaneous marginal-zone B-cell lymphoma: a case report.
An association between Borrelia burgdorferi with primary cutaneous B-cell lymphoma (PCBCL) has long been suspected but just recently, thanks to a polymerase chain reaction technique, it had been possible to demonstrate B. burgdorferi-specific DNA in skin lesions of patients with different PCBCL subtypes. Locating cases of PCBCL that are related to B. burgdorferi infection could be really important for therapeutic implications; in fact, there are several reports of PCBCL responding to antibiotic therapy against B. burgdorferi. We report a case of B. burgdorferi-associated primary cutaneous marginal-zone B-cell lymphoma that, after specific antimicrobial therapy, did not show any clinical regression. We can conclude that additional studies are necessary in order to establish the use of antimicrobial therapy in B. burgdorferi-associated PCBCL.


Physiological studies on Phymatotrichum omnivorum. XII Influence of cultural conditions on amylase synthesis.
The production of extracellular amylase by P. omnivorum has been studied under different cultural conditions. Maximum mycelial growth and amylase synthesis were found in basal synthetic medium containing 2% glycogen as the carbon source. Significant amounts of amylase and growth were obtained in medium containing other carbon compounds with alpha-1, 4-linkages. Optimum temperatures for mycelial growth and amylase synthesis were found at 28 degree and 30 degree C, respectively. Of all the nitrogenous compounds tested, ammonium nitrate supported the maximum mycelial growth and amylase production. Increasing the concentration of starch in the basal medium increased the growth as well as the enzyme synthesis.


Detection of spoilage-causing yeasts and bacteria in tchapalo, the Ivorian traditional sorghum beer.
In this study, we aimed to analyse the spoilage potential of the isolated yeast, LAB and AAB species. Thus, 11 strains were inoculated at 0·3% (v/v) into a sterile filtered tchapalo and stored for 3 days at ambient temperature (27-30°C). All the tested strains grew well or remained stable except for Limosilactobacillus fermentum and Pediococcus acidilactici, which decreased throughout the storage time. A significant decrease of total soluble solids was observed only for Saccharomyces cerevisiae (from 7·8 to 5·8 °Brix) and Meyerozyma guilliermondii (from 7·8 to 5·5 °Brix). The tchapalo samples inoculated with the LAB strains Weissella paramesenteroides, P. acidilactici, L. fermentum and the yeast strain Candida tropicalis were judged similar to the control by the panellists. However, the strains of Lacticaseibacillus paracasei and Latilactobacillus curvatus (LAB), S. cerevisiae, M. guilliermondii and Kluyveromyces marxianus (yeasts) and Acetobacter pasteurianus and A. cerevisiae (AAB) induced the spoilage of the tchapalo appearance, smell and/or taste. In the spoiled tchapalo quantitative and qualitative modification of some volatile compounds (VOCs), such as lilac aldehyde, ethyl acetate, ethyl hexanoate, ethyl octanoate and phenethyl acetate, were observed. These results provide information about the microorganisms that need to be removed to extend the shelf life of tchapalo.


Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic therapy of autoimmune skin disorders.
Existing therapeutics for autoimmune diseases remain problematic due to low efficacy, severe side effects, and difficulties to reach target tissues. Herein, we design multifunctional fusion nanovesicles that can target lesions for the treatment of autoimmune skin diseases. The grapefruit-derived exosome-like nanovesicles (GEVs) with anti-inflammatory and antioxidant effects are first encapsulated with CX5461, an immunosuppressant with anti-proliferative properties to form GEV@CX5461. In order to enhance therapeutic efficiency and safety, GEV@CX5461 are then fused with CCR6+ nanovesicles derived from membranes of engineered gingiva-derived mesenchymal stem cells (GMSCs). The resulting FV@CX5461 not only maintain the bioactivity of GEVs, CX5461, and GMSC membranes but also home to inflamed tissues rich in chemokine CCL20 through the chemotaxis function of CCR6 on FVs. Moreover, FV@CX5461 reduce the secretion of inflammatory factors, calm down Th17 cell activation, and induce Treg cell infiltration. Finally, impressive therapeutic efficiency in both psoriasis and atopic dermatitis disease models is demonstrated using FV@CX5461 to reshape the unbalanced immune microenvironment. A nanotherapeutic drug delivery strategy is developed using fusion nanovesicles derived from plant and animal cells with high clinical potential.


Quadratic solitons as nonlocal solitons.
We show that quadratic solitons are equivalent to solitons of a nonlocal Kerr medium. This provides new physical insight into the properties of quadratic solitons, often believed to be equivalent to solitons of an effective saturable Kerr medium. The nonlocal analogy also allows for analytical solutions and the prediction of bound states of quadratic solitons.


Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models.
Targeting tumor endothelium is an important strategy for cancer therapy. We evaluated the effectiveness of gene therapy, that is, intramuscular delivery of plasmid DNA encoding tumstatin (pSecTag2B-tum), combined with gemcitabine administration in vitro and in vivo, using colon carcinoma (CT26) and Lewis lung carcinoma (LLC) murine models. The in vitro growth-inhibitory and proapoptotic effects of gemcitabine and/or tumstatin on human umbilical vein endothelial cells (HUVECs) and mouse endothelial cells (SVEC4-10), respectively, were assessed. in vitro, conditioned medium from pSecTag2B-tum-transfected COS cells inhibited the growth of endothelial cells but not of CT26 or LLC cells, whereas gemcitabine inhibited the growth of both endothelial cells and CT26 and LLC cells. Mice bearing subcutaneously established CT26 or LLC tumors received pSecTag2B-tum alone or in combination with gemcitabine to assess tumor growth inhibition. in vivo, combined treatment with pSecTag2B-tum and gemcitabine significantly decreased tumor growth through increased inhibition of tumor angiogenesis and increased tumor cell apoptosis compared with either agent alone. Enhanced antiproliferative and proapoptotic activity of the combination therapy on tumor-associated endothelial cells was calculated to be significant. This study suggests that combined treatment by the intramuscular delivery of plasmid DNA encoding tumstatin and gemcitabine augments tumor growth inhibition by suppressing angiogenesis and enhancing apoptosis in murine models. A combination of these agents could be used in future studies and translated into the clinical setting.


A comparison of the effects of converting-enzyme inhibition and protein restriction in experimental nephrosis.
We compared the effects of protein restriction and converting-enzyme inhibition by captopril (CAP) on urinary protein excretion (UP) and progressive glomerular sclerosis (GS) in an experimental model of nephrosis induced in rats by a single injection of Adriamycin (ADR) at a dose of 3 mg/kg. Two isocaloric diets with a 6% and 22% (NP) protein content were used. Experimental groups were started on NP, on NP plus CAP (500 mg/liter) or on an isocaloric diet with a 6% protein content at day 2 after ADR injection and followed for 38 days. According to a cross-over design, groups were then switched to the alternative diet or maintained on the original diet, whereas in one CAP-treated group CAP treatment was stopped. All groups were followed for another 34 to 42 days and then sacrificed. Results showed that UP and the incidence of GS were significantly reduced in groups on the isocaloric diet with a 6% protein content during the full length or the second half of the observation period. In contrast, CAP had no effect on UP or on the incidence of GS, although systolic blood pressure was significantly reduced. Renal function studies performed in separate groups on the same regimes at 5 weeks after induction of ADR nephrosis, showed that LP had lowered glomerular filtration rate numerically and renal plasma flow significantly, whereas CAP was found to have no effect on glomerular filtration rate and renal plasma flow. Glomerular volumes were increased in proteinuric rats on both NP diet and NP diet with CAP treatment. The present study confirms earlier reports that in ADR-nephrotic rats, protein restriction attenuates UP and GS without affecting systolic blood pressure, whereas converting-enzyme inhibition does not have this beneficial effect although systolic blood pressure is lowered. GS seems to be related to glomerular extension and hypertrophy. The effect of protein restriction may be partially hemodynamically mediated by afferent vasoconstriction, resulting in a decrease in glomerular filtration rate and a reduction in protein flux across the ADR-induced large pore defects.


Missed opportunity to diagnose HIV with Pneumocystis carinii pneumonia as its sequela.
Pneumocystis carinii pneumonia (PCP) is an opportunistic infection of the lung occurring primarily in patients with HIV infection with a CD4 cell count <200 mm3, solid organ transplant recipients and those taking immunosuppressive therapy. The 1980s heralded the HIV pandemic, turning PCP into a major medical and public health problem worldwide. Manifestations of unusual infections such as pneumocystis and Kaposi's sarcoma, were, after all, the first signs of the emerging pandemic to be recognised and may indeed, be the presenting feature of a previously undiagnosed HIV infection. With the advent of pneumocystis chemoprophylaxis and the initiation of highly active antiretroviral therapy, there has been a decreased incidence in developed countries, but it remains high in developing countries. Unfortunately, late presentation of HIV remains a problem resulting in significant morbidity and mortality. The authors report the case of a new diagnosis of HIV infection in a 45-year-old woman, presenting with a dry cough, dyspnoea, unintentional weight loss and PCP. Two weeks after commencing highly active antiretroviral therapy, she was diagnosed with immune reconstitution inflammatory syndrome. Research shows that stigma and discrimination in the healthcare setting contributes to keeping individuals from accessing HIV prevention, care and treatment services and adopting key preventive behaviours. The barriers to HIV testing and stigma eradication in primary care will be explored as well as missed opportunities to diagnosis HIV in primary care in individuals presenting with signs and symptoms of immunosuppression, in this case shingles.


Multicenter prospective study on the prevalence of colistin resistance in Escherichia coli: relevance of mcr-1-positive clinical isolates in Lombardy, Northern Italy.
The emergence of the plasmid-mediated colistin resistance mechanism in Escherichia coli has raised concern among public health experts as colistin is a last-line antimicrobial resort. The primary aim of the study was to investigate the prevalence of this resistance trait in E. coli isolates circulating in the Lombardy region, Northern Italy. The presence of mcr-type genes and their genetic relationship were also studied. A prospective study was performed during a 4-month period (May to August, 2016) in six acute care Hospitals. Consecutive nonduplicate clinical isolates of E. coli from any type of clinical specimen, with the exception of rectal swabs, were included in the study. Isolates that exhibited MIC values for colistin >2 mg/L were further investigated. Bacterial identification was obtained by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Amplification of mcr-type genes (-1 to -5 variants) and microarray analysis were accomplished. Repetitive sequence-based PCR (Rep-PCR) and multilocus sequence typing (MLST) analysis were used for genotyping. Overall, 3,902 consecutive E. coli isolates (2,342 from outpatients, 1,560 from inpatients) were evaluated during the study period. Of them, 18/3,902 (0.5%), collected from 4/6 centers, showed resistance to colistin. These isolates were mostly obtained from urine of both outpatients (n=12) and inpatients (n=6). Colistin MIC values ranged from 4 to 8 mg/L. The mcr-1 gene was detected in 10/18 isolates (7 from outpatients, 3 from inpatients). Rep-PCR and MLST analysis revealed the presence of nine different clusters. Further mcr-type genes were not detected. Resistance to colistin in E. coli clinical isolates appears low in our geographic area. With regard to mcr-1-positive isolates, they accounted for approximately 50% of colistin-resistant E. coli isolates, thus representing a relevant resistance mechanism in this context. Although overall limited, the presence of mcr-1 determinant in our region should not be ignored and great concern should be given to the continuous surveillance.


Environmental, scanning electron and optical microscope image analysis software for determining volume and occupied area of solid-state fermentation fungal cultures.
Here we propose a software for the estimation of the occupied area and volume of fungal cultures. This software was developed using a Matlab platform and allows analysis of high-definition images from optical, electronic or atomic force microscopes. In a first step, a single hypha grown on potato dextrose agar was monitored using optical microscopy to estimate the change in occupied area and volume. Weight measurements were carried out to compare them with the estimated volume, revealing a slight difference of less than 1.5%. Similarly, samples from two different solid-state fermentation cultures were analyzed using images from a scanning electron microscope (SEM) and an environmental SEM (ESEM). Occupied area and volume were calculated for both samples, and the results obtained were correlated with the dry weight of the cultures. The difference between the estimated volume ratio and the dry weight ratio of the two cultures showed a difference of 10%. Therefore, this software is a promising non-invasive technique to determine fungal biomass in solid-state cultures.


Fluorescent labeling of peptides on solid phase.
N(alpha)-Fmoc-N(epsilon)-[(7-methoxycoumarin-4-yl)acetyl]-L-lysine (N(alpha)-Fmoc-L-Lys(Mca)-OH) 3 is conveniently prepared by benzotriazole methodology (52% over two steps). N-Acylbenzotriazoles Mca-Bt 2, N(alpha)-Fmoc-L-Lys(Mca)-Bt 4, coumarin-3-ylcarbonyl (Cc)-Bt 5, N(alpha)-Fmoc-L-Lys(Cc)-Bt 7 and N(alpha)-(Cc)-L-Lys(Fmoc)-Bt 9 enable the efficient microwave enhanced solid-phase fluorescent labeling of peptides.


Netrin-1 Overexpression Induces Polycystic Kidney Disease: A Novel Mechanism Contributing to Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
Despite recent advances in understanding the pathogenesis of polycystic kidney disease (PKD), the underlying molecular mechanisms involved in cystogenesis are not fully understood. This study describes a novel pathway involved in cyst formation. Transgenic mice overexpressing netrin-1 in proximal tubular cells showed increased production and urinary excretion of netrin-1. Although no cysts were detectable immediately after birth, numerous small cysts were evident by the age of 4 weeks, and disease was accelerated along with age. Surprisingly, cyst formation in the kidney was restricted to male mice, with 80% penetrance. However, ovariectomy induced kidney cyst growth in netrin-1-overexpressing female mice. Cyst development in males was associated with albuminuria and polyuria and increased cAMP excretion in netrin-1 transgenic mice. Netrin-1 overexpression significantly increased extracellular signal-regulated kinase and focal adhesion kinase phosphorylation and vimentin expression. Interestingly, p53 expression was increased but in an inactive form. Furthermore, netrin-1 expression was increased in cystic epithelia and urine of various rodent models of PKD. siRNA-mediated suppression of netrin-1 significantly reduced cyst growth and improved kidney function in netrin-1 transgenic mice and in two genetic animal models of PKD. Together, these data demonstrate that netrin-1 up-regulation induced cyst formation in autosomal dominant PKD.


Provider and community stakeholder perspectives of expanding Medicaid coverage of abortion in Illinois.
Many people seeking abortion encounter financial difficulties that delay or prevent them from accessing care. Although some patients qualify for Medicaid (a public program that can help cover health care costs), laws in some states restrict the use of Medicaid for abortion care. In 2017, Illinois passed House Bill 40 (HB-40), which allowed patients with Medicaid to receive coverage for their abortion. This study aimed to understand how HB-40 affected abortion affordability from the perspectives of individuals that work directly or indirectly with abortion patients or facilities providing abortion care. We conducted interviews with clinicians and administrators from facilities that provided abortion services; staff from organizations that provided resources to abortion providers or patients; and individuals at organizations involved in the passage and/or implementation of HB-40. Interviews were audio-recorded and transcribed. We created codes based on the interview guides, coded each transcript using the web application Dedoose, and summarized findings by code. Interviews were conducted with 38 participants. Participants reflected that HB-40 seemed to remove a significant financial barrier for Medicaid recipients and improve the experience for patients seeking abortion care. Participants also described how the law led to a shift in resource allocation, allowing financial support to be directed towards uninsured patients. Some participants thought HB-40 might contribute to a reduction in abortion stigma. Despite the perceived positive impacts of the law, participants noted a lack of public knowledge about HB-40, as well as confusing or cumbersome insurance-related processes, could diminish the law's impact. Participants also highlighted persisting barriers to abortion utilization for minors, recent and undocumented immigrants, and people residing in rural areas, even after the passage of HB-40. HB-40 was perceived to improve the affordability of abortion. However, participants identified additional obstacles to abortion care in Illinois that weakened the impact of HB-40 for patients and required further action, Findings suggest that policymakers must also consider how insurance coverage can be disrupted by other legal barriers for historically excluded populations and ensure clear information on Medicaid enrollment and abortion coverage is widely disseminated.


QM/MM (ONIOM) study of glycerol binding and hydrogen abstraction by the coenzyme B12-independent dehydratase.
Glycerol binding and the radical-initiated hydrogen transfer by the coenzyme B(12)-independent glycerol dehydratase from Clostridium butyricum were investigated by using quantum mechanical/molecular mechanical (QM/MM) calculations based on the high-resolution crystal structure (PDB code: 1r9d). Our QM/MM calculations of enzyme catalysis considered the electrostatic coupling between the quantum-mechanical and molecular-mechanical subsystems and two alternative mechanisms. In addition to performing QM/MM calculations in the enzyme, we evaluated energetics along the same reaction pathway in aqueous solution modeled by the polarized dielectric and in the virtual enzyme site that included full steric component from the enzyme residues described by molecular mechanics but lacked the electrostatic contribution of these residues. In this way, we established significant enzyme catalytic effect with respect to reference reactions in both an aqueous solution and a nonpolar cavity. Structurally, four hydrogen bonds formed between glycerol and H164, S282, E435, and D447 anchor glycerol for hydrogen abstraction by thiyl radical on C433. These hydrogen-bond partners orient glycerol molecule to facilitate the formation of the transition state for hydrogen abstraction from carbon C1. This reaction then proceeds with the activation free energy of 6.3 kcal/mol and the reaction free energy of 6.1 kcal/mol. The polarization effects imposed by these hydrogen bonds represent a predominant contribution to a 7.5 kcal/mol enzyme catalytic effect. These results demonstrate the importance of electrostatic catalysis and hydrogen-bonding in enzyme-catalyzed radical reactions and advance our understanding of the catalytic mechanism of B(12)-independent glycerol dehydratases.


Prevalence and Extrinsic Risk Factors for Dental Erosion in Adolescents.
This manuscript examined the prevalence and extrinsic risk factors for dental erosion (DE) in early and middle adolescents in Pasto, Colombia. Dental erosion was evaluated in a random sample of 384 individuals aged 10-15 years attending three primary and high schools in this cross-sectional study. Clinical dental assessment for DE was done using O'Sullivan index. Data on general sociodemographic variables and extrinsic risks factors were obtained. Descriptive and univariate binary logistic regression analyses were performed. Dental erosion was observed in 57.3% of individuals. The univariate binary logistic regression analysis showed that frequency of drinking natural fruit juices (OR 2.670, 95% CI 1.346 - 5.295, P=0.004) and their pH (OR 2.303, 95% CI 1.292 - 4.107, P=0.004) were more associated with the odd of DE in early adolescence. However, a high SES (OR 10.360, 95% CI 3.700 - 29.010, P<0.001) and frequency of snacks with artificial lemon taste (OR 3.659, 95% CI 1.506 - 8.891, P=0.003) were highly associated with the risk of DE in middle adolescence. The results suggest that DE is a prevalent condition in adolescents living in a city in southern Colombia. The transition from early to middle adolescence implies new bio-psychosocial changes, which increase the risk for DE.


Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis.
Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing-remitting multiple sclerosis (RRMS). The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = -0.275, p = 0.009) and SDMT (r = -0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed. Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing-remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter.


Conservatism of lizard thermal tolerances and body temperatures across evolutionary history and geography.
Species may exhibit similar thermal tolerances via either common ancestry or environmental filtering and local adaptation, if the species inhabit similar environments. We ask whether upper and lower thermal limits (critical thermal maxima and minima) and body temperatures are more strongly conserved across evolutionary history or geography for lizard populations distributed globally. We find that critical thermal maxima are highly conserved with location accounting for a higher proportion of the variation than phylogeny. Notably, thermal tolerance breadth is conserved across the phylogeny despite critical thermal minima showing little niche conservatism. Body temperatures observed during activity in the field show the greatest degree of conservatism, with phylogeny accounting for most of the variation. This suggests that propensities for thermoregulatory behaviour, which can buffer body temperatures from environmental variation, are similar within lineages. Phylogeny and geography constrain thermal tolerances similarly within continents, but variably within clades. Conservatism of thermal tolerances across lineages suggests that the potential for local adaptation to alleviate the impacts of climate change on lizards may be limited.


Styryl ether formation from benzyl alcohols under transition-metal-free basic DMSO conditions.
A phenol-catalyzed aerobic oxidative styryl ether formation method was developed with benzyl alcohol under basic DMSO. Styryl ether was obtained after 12 hours of heating at 60-80 °C where DMSO was involved in the reaction as the extra carbon source. Control experiments indicated that both phenol and DMSO are crucial for the success of the reaction. A variety of styryl ethers were prepared smoothly from benzyl alcohols in good to excellent yields in an environmentally friendly way.


Regulation of Helicobacter pylori Virulence Within the Context of Iron Deficiency.
Helicobacter pylori strains that harbor the oncoprotein CagA increase gastric cancer risk, and this risk is augmented under iron-deficient conditions. We demonstrate here that iron depletion induces coccoid morphology in strains lacking cagA. To evaluate the stability of augmented H. pylori virulence phenotypes stimulated by low-iron conditions, H. pylori isolated from iron-depleted conditions in vivo were serially passaged in vitro. Long-term passage decreased the ability of hypervirulent strains to translocate CagA or induce interleukin 8, indicating that hypervirulent phenotypes stimulated by low-level iron conditions are reversible. Therefore, rectifying iron deficiency may attenuate disease among H. pylori-infected persons with no response to antibiotics.


Organizational and cultural entry: a new type of orientation program for multiple boundary crossings.
A longitudinal field experiment was designed to test the efficacy of a new type of orientation program in facilitating sojourners' organizational and cultural entry. Focused on stress coping, this new approach to orientation has the following features: (a) a thorough needs assessment identified the major stressors from both organizational and cultural entry, (b) sojourners were provided with realistic information regarding their future tasks and environment, and (c) sojourners were taught various coping skills to handle the major stressors. Seventy-two new graduate students from Asia entering a large midwestern public university in the United States were randomly assigned to either a traditional orientation program or the new program. The participants were assessed immediately after the orientation, as well as at 1, 3, 6, and 9 months post-entry. Results show that participants in the new orientation program had lower pre-entry expectations, felt less stressed, and reported higher levels of academic and interaction adjustment at 6 and 9 months post-entry than participants in the traditional orientation program. Many of the beneficial effects from the new orientation experience were not immediately apparent; rather, they emerged over time. Sojourner stress was found to mediate some of the treatment effects, as predicted.


Template based rodent brain extraction and atlas mapping.
Accurate rodent brain extraction is the basic step for many translational studies using MR imaging. This paper presents a template based approach with multi-expert refinement to automatic rodent brain extraction. We first build the brain appearance model based on the learning exemplars. Together with the template matching, we encode the rodent brain position into the search space to reliably locate the rodent brain and estimate the rough segmentation. With the initial mask, a level-set segmentation and a mask-based template learning are implemented further to the brain region. The multi-expert fusion is used to generate a new mask. We finally combine the region growing based on the histogram distribution learning to delineate the final brain mask. A high-resolution rodent atlas is used to illustrate that the segmented low resolution anatomic image can be well mapped to the atlas. Tested on a public data set, all brains are located reliably and we achieve the mean Jaccard similarity score at 94.99% for brain segmentation, which is a statistically significant improvement compared to two other rodent brain extraction methods.


[Several Issues before and after the Recognition of "Anesthesiology" as "Specially Approved Specialty"].
A movement occurred at the end of 1940's among members of the Japan Medical Association (JMA) to recognize "specially approved specialty" in the practice of medicine, but their petition was rejected by the Medical Ethics Committee. Thus, the JMA expanded an energetic campaign for the recognition, by the support from four diet members. Consequently, six specialties including neurology and venereology were eventually accredited as "generally approved specialty" in 1950. About 1960, several years after anesthesiology having been recognized as a "specially approved medical specialty", some elder members of the Japan Society of Anesthesiology (JSA) discussed to change the term "specially approved specialty" to "generally approved medical specialty"in the Medical Service Law, but their motion could not gain majority support at the Councils of Elders of the JSA. The council also presented to the Ministry of Health and Welfare (MHW), a written request to alter the eligibility criteria of a registered anesthesiologist; however, the request was declined because of a strong opposition of the MHW which was under the strong influence of the JMA. The JSA did never show interest to these issues since then, and the situation remains unchanged to the present.


Response of dung beetle diversity to remediation of soil ecosystems in the Ecuadorian Amazon.
Efforts to alleviate the negative effects of oil spills in the Ecuadorian Amazon include remediation activities such as cleaning, reshaping, and revegetation of polluted areas. However, studies of the diversity of biological communities in these hydrocarbon-degraded ecosystems have never been carried out. Here, we evaluated the diversity of dung beetles on remediated soil ecosystems (Agricultural Soils and Sensitive Ecosystems) and on non-contaminated soils (Natural Forests and Palm Plantations). The study was conducted in Sucumbíos and Orellana provinces, in the Ecuadorian Amazon at four sampling sites per ecosystem type (a total of 16 sites). At each sampling site, six pitfall traps remained active for 120 consecutive h per month for 1 year. We collected 37 species and 7,506 individuals of dung beetles. We observed significant differences in mean species abundance, richness, and diversity between non-contaminated soil ecosystems and remediated soil ecosystems, with Natural Forests presenting the highest values, and Agricultural Soils the lowest values. Regarding sampling month, we also found significant differences among ecosystems, which were also higher in Natural Forests. The results suggest that hydrocarbon-degraded ecosystems tend to conserve lower beetle diversity one year after remediation highlighting the importance of Natural Forests for the conservation of tropical biodiversity. Therefore, dung beetle diversity could be used for future landscape management of these hydrocarbon-degraded ecosystems.


Peripheral arterial disease affects kinematics during walking.
Claudication is the most common manifestation of peripheral arterial disease (PAD) producing significant ambulatory compromise. The purpose of this study was to use advanced biomechanical analysis to characterize the kinematic ambulatory pattern of claudicating patients. We hypothesized that compared with control subjects, claudicating patients have altered kinematic gait patterns that can be fully characterized utilizing advanced biomechanical analysis. The study examined fourteen PAD patients (age: 58 +/- 3.4 years; weight: 80.99 +/- 15.64 kg) with clinically diagnosed femoro-popliteal occlusive disease (Ankle Brachial Index (ABI): 0.56 +/- 0.03, range 0.45 to 0.65) and five healthy controls (age: 53 +/- 3.4 years; weight: 87.38 +/- 12.75 kg; ABI >or= 1). Kinematic parameters (hip, knee, and ankle joint angles in the sagittal plane) were evaluated during gait in patients before and after the onset of claudication pain and compared with healthy controls. Joint angles were calculated during stance time. Dependent variables were assessed (maximum and minimum flexion and extension angles and ranges of motion) and mean ensemble curves were generated. Time to occurrence of the discrete variables was also identified. Significantly greater ankle plantar flexion in early stance and ankle range of motion during stance was observed in PAD patients (P < .05). Time to maximum ankle plantar flexion was shorter and time to maximum ankle dorsiflexion was longer in PAD patients (P < .05). These differences were noted when comparing PAD patients prior to and after the onset of claudication with healthy controls. The analysis of the kinematic parameters of the knee and the hip joints revealed no significant differences between PAD patients and controls. PAD patients with claudication demonstrate significant gait alterations in the ankle joint that are present prior to the onset of claudication pain. In contrast, the joint motion of the hip and knee did not differ in PAD patients when compared with controls. Further research is needed to verify our findings and assess the impact of more proximal disease in PAD patients as well as the effect of revascularization on joint kinematics.


The disease activity of ulcerative colitis and Crohn's disease.
The disease activity in ulcerative colitis and Crohn's disease was studied. Parameters found to reflect the disease activity were given scores from 1 to 4. The score obtained by a patient compared with the maximum scores gives the percentage disease activity. The regressions between the percentage disease activity and the ESR in ulcerative colitis and Crohn's disease were r=0.68 (p less than 0.001) and r=0.48 (p less than 0.001), respectively. The different activity parameters have different time response curves explaining the occasional slight correlation. The percentage disease activity represents the mean activity of the different parameters at a given time. It is proposed to define slight, moderate, and severe ulcerative colitis or Crohn's disease as percentage disease activity of less than 30, 30-70 and greater than 70 per cent, respectively.


Mitochondrial Ca2+ antagonist binding sites are associated with an inner mitochondrial membrane anion channel.
The inner mitochondrial membrane contains specific Ca2+ antagonist binding sites unrelated to the L-type Ca2+ channel. The mitochondrial 1,4-dihydropyridine (DHP) and phenylalkylamine sites are reciprocally allosterically coupled, require anions (e.g., Cl-, No3-) for optimal binding, and are inhibited by purine and pyrimidine nucleotides in a noncompetitive manner. In mitochondrial swelling experiments, a concentration-dependent inhibition of an inner mitochondrial membrane anion channel (IMAC) by Ca2+ antagonists from different chemical classes can be demonstrated. Under the conditions of the swelling experiments, affinity of different Ca2+ antagonists and amiodarone, a known IMAC inhibitor, for the mitochondrial (+/-)-[3H]nitrendipine binding site (Kd, 7.2 +/- 2.0 microM; Bmax, 1.03 +/- 0.37 nmol/mg of protein) strongly correlated with their inhibitory potency for the IMAC. Linear regression of pIC50 values for IMAC-induced swelling versus pIC50 values for (+/-)-[3H]nitrendipine binding inhibition yielded a correlation coefficient of 0.91 for all tested DHPs (n = 12, p less than 0.001). Amiodarone inhibited (+/-)-[3H]nitrendipine binding and IMAC-induced swelling with pIC50 values of 6.11 and 5.93, respectively. The correlation coefficient between binding and inhibition of IMAC-induced swelling for amiodarone and all tested Ca2+ antagonists (including non-DHP compounds) was 0.76 (n = 20, p less than 0.001), with the slopes approaching unity. These results suggest the association of the mitochondrial Ca2+ antagonist binding sites with an IMAC.


Synthesis and structural characterization of 1-mesityl-1,3-dihydro-imidazole-2-selone and bis(1-mesitylimidazol-2-yl)diselenide: experimental evidence that the selone is more stable than the selenol tautomer.
1-Mesityl-1,3-dihydro-imidazole-2-selone, (seim(Mes))H, may be obtained from 1-mesitylimidazole via (i) deprotonation with Bu(n)Li, (ii) treatment with elemental selenium, and (iii) addition of HCl(aq). Structural characterization of (seim(Mes))H by X-ray diffraction demonstrates that the compound exists as the selone rather than selenol tautomer, a result that is in accord with DFT calculations. Solutions of (seim(Mes))H are oxidized by air to give bis(1-mesitylimidazol-2-yl)diselenide, (seim(Mes))(2). A corresponding investigation of (seim(Me))H demonstrates that, in contrast to a previous report, the selenium analogue of methimazole exists in the selone form with a structure analogous to that of methimazole. (1)H and (77)Se NMR studies demonstrate that the (seim(R)) groups of the selone (seim(R))H and diselenide (seim(R))(2) undergo facile exchange on the NMR time scale.


Specific overexpression of SIRT1 in mesenchymal stem cells rescues hematopoiesis niche in BMI1 knockout mice through promoting CXCL12 expression.
Osteoblastic lineage cells (OBCs) are bone-building cells and essential component of hematopoietic niche, but mechanisms whereby bone-building and hematopoiesis-supportive activities of OBCs could be regulated simultaneously remain largely unknown. Here we found that B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) was involved in such a co-regulatory mechanism. In this study, we first found that, accompanied with marked decline of osteogenic activity, the hematopoietic niche in Bmi1 knockout (KO) mice was severely impaired and manifested as CXCL12 expression falls and LSK homing failure; however, intratibial injection with CXCL12 effectively facilitated LSK accumulation in bone marrow of Bmi1 KO mice. To try to rescue these defects in Bmi1 KO mice, we generated Bmi1KO/Sirt1Tg (KO-TG) double mutant mice with Sirt1 specific overexpression in mesenchymal progenitor cells (MPCs) in Bmi1 KO mice, and our data showed that KO-TG mice had significantly increased bone-building activity, elevated Cxcl12 expression by MPCs, increased LSK homing and expanded LSK pool in bone marrow compared to Bmi1 KO mice. Of note, similar improvements in KO-TG mice were observed in Bmi1 KO mice fed with dietary resveratrol, an established Sirt1 activator, comparing with KO control mice. Therefore, pharmacologic activation of Bmi1/Sirt1 signaling pathway could simultaneously promote bone-building and hematopoiesis-supportive activities of OBCs.


Neuronal activity determines distinct gliotransmitter release from a single astrocyte.
Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses.


Human health effects of air pollution.
Over the past three or four decades, there have been important advances in the understanding of the actions, exposure-response characteristics, and mechanisms of action of many common air pollutants. A multidisciplinary approach using epidemiology, animal toxicology, and controlled human exposure studies has contributed to the database. This review will emphasize studies of humans but will also draw on findings from the other disciplines. Air pollutants have been shown to cause responses ranging from reversible changes in respiratory symptoms and lung function, changes in airway reactivity and inflammation, structural remodeling of pulmonary airways, and impairment of pulmonary host defenses, to increased respiratory morbidity and mortality. Quantitative and qualitative understanding of the effects of a small group of air pollutants has advanced considerably, but the understanding is by no means complete, and the breadth of effects of all air pollutants is only partially understood.


Regulator of G protein signaling-1 modulates paraquat-induced oxidative stress and longevity via the insulin like signaling pathway in Caenorhabditis elegans.
Insulin or insulin like signaling (IIS) pathway is a crucial pathway in Caenorhabditis elegans associated with mediating longevity, and stress resistance. Regulators of G protein signaling (RGS) also modulate stress resistance and longevity in multiple in vitro and in vivo models. However, the mechanism underlying RGS mediating stress resistance and longevity remains largely unclear. Here we report that rgs-1, an important member of rgs family, is a novel modulator of IIS pathway in C. elegans. We found that the loss of rgs-1 dramatically promoted paraquat resistance in C. elegans. Further genetic analyses demonstrated that rgs-1 acted downstream of daf-2 and upstream of age-1, pdk-1, daf-16. Instead of affecting those IIS-associated genes in transcriptional process, loss of rgs-1 promoted DAF-16's nucleus translocation and subset genes' expression in paraquat-induced oxidative status. By this way, rgs-1 mutant worms exhibited lower ROS damage and longer survival time than wild type worms when both exposed to paraquat. Other than paraquat exposure, rgs-1 mutant also promoted lifespan and cadmium resistance relying on daf-16. As rgs is evolutionarily conserved, our findings open a new insight into rgs family and its role in paraquat-induced oxidative stress and longevity in C. elegans or even mammals.


From O2- to HO2- : Reducing By-Products and Overpotential in Li-O2 Batteries by Water Addition.
The development of aprotic Li-O2 batteries, which are promising candidates for high gravimetric energy storage devices, is severely limited by superoxide-related parasitic reactions and large voltage hysteresis. The fundamental reaction pathway of the aprotic Li-O2 battery can be altered by the addition of water, which changes the discharge intermediate from superoxide (O2- ) to hydroperoxide (HO2- ). The new mechanism involving HO2- intermediate realizes the two-electron transfer through a single step, which significantly suppresses the superoxide-related side reactions. Moreover, addition of water also triggers a solution-based pathway that effectively reduces the voltage hysteresis. These discoveries offer a possible solution for desirable Li-O2 batteries free of aggressive superoxide species, highlighting the design strategy of modifying the reaction pathway for Li-O2 electrochemistry.


Creation of state basic health programs would lead to 4 percent fewer people churning between Medicaid and exchanges.
The Affordable Care Act gives states the option of creating a so-called Basic Health Program to provide health insurance coverage for individuals and families whose incomes are low but who do not qualify for Medicaid. The Basic Health Program is intended, in part, to decrease churning, or frequent movement between Medicaid and state-run health insurance exchanges, by increasing the income-based eligibility transition point between the two programs to 200 percent of the federal poverty level. We analyzed data from the 2008 panel of the Survey of Income and Program Participation and found that among adults likely to participate in Medicaid and exchanges, only somewhat fewer experienced a change in eligibility with a 200 percent federal poverty level eligibility threshold compared with the previous threshold of 138 percent. As a result, we found that a Basic Health Program would prevent churning for 1.8 million adults nationally each year-reducing by about 4 percent the expected churning of low-income Americans between Medicaid and exchanges within a year. Such programs would also decrease the risk that lower-income families would be subject to recouping of premium tax credits. But churning rates would remain very high, and additional policy steps would be required to minimize the effect of coverage disruptions.


Stress and infections.
Neurotransmitters and neuroendocrine hormones can modify the functioning of immune cells and conversely cytokines produced by immune cells can alter brain homeostasis. This connection is further manifested by experimental studies showing a relationship between stress and resistance to infection. Human subjects with a high stress index were shown to be more susceptible to infection with common cold viruses. Furthermore, a diversity of experimental animal paradigms show that laboratory stressors such as forced exercise, avoidance learning, restraint, isolation, and cold exposure make animals more susceptible to primary infection with a variety of viruses and bacteria. The cellular and molecular basis for the observed modulation of host resistance is not fully understood but involves altered functioning of both T lymphocytes and cells of the hypothalamic-pituitary adrenal axis. Also involved is the altered production of cytokines and hormones produced by the immune system and brain.


Risk factors for perioperative stroke after thoracic endovascular aortic repair.
Stroke has emerged as an important complication of thoracic endovascular aortic repair (TEVAR). Identifying risk factors for stroke is important to define the risks of this procedure. All neurologic complications were analyzed in a prospective database of patients in thoracic aortic stent graft trials from 1999 to 2006. Serial neurological examination was performed. Stroke was defined as any new onset focal neurologic deficit. The TEVAR was performed on 171 patients; 52 had lesions requiring coverage of the proximal descending thoracic aorta (extent A), 50 requiring coverage of the distal descending aorta (extent B), and 69 requiring coverage of the entire descending thoracic aorta (extent C). The incidence of stroke was 5.8%. Eighty-nine percent (8 of 9) of strokes occurred within 24 hours of operation. Stroke was associated with a 33% in-hospital mortality rate. Risk factors identified for stroke included prior stroke (odds ratio [OR] 9.4, confidence interval [CI] 2.3 to 38.1, p = 0.002) and extent A or C coverage (OR 5.5, CI 1.7-12.5, p = 0.001). The stroke rate in patients with both prior stroke and extent A or C coverage was 27.7%. Severe atheromatous disease involving the aortic arch by computed tomographic scan was strongly associated with perioperative stroke (OR = 14.8, CI 1.7 to 675.6, p = 0.0016). Transesophageal echocardiography demonstrated mobile atheroma in two patients with stroke. Stroke after TEVAR was associated with a high mortality. The TEVAR of the proximal descending aorta (extent A or C) in patients with a history of stroke had the highest perioperative stroke rate. These risk factors, together with high grade aortic atheroma of the aortic arch, predicted a high probability for cerebral embolization and can be used to identify patients at high risk for stroke as a consequence of TEVAR.


Endothelial molecular changes in a rodent model of arteriovenous malformation.
The cellular and molecular processes underlying arteriovenous malformation (AVM) development and response to radiosurgery are largely unknown. An animal model mimicking the molecular properties of AVMs is required to examine these processses. This study was performed to determine whether the endothelial molecular changes in an animal model of arteriovenous fistula (AVF) are similar to those in human AVMs. Arteriovenous fistulas were created in 18 Sprague-Dawley rats by end-to-side anastomosis of the left jugular vein to the common carotid artery creating a model "nidus" of arterialized branching veins that coalesce into a "draining vein" (sigmoid sinus). Six control animals underwent sham operations. After 1 or 3 days, or 1, 3, 6, or 12 weeks, fresh-frozen sections of the fistula, nidus vessels, and contralateral vessels were studied immunohistochemically for thrombomodulin, von Willebrand factor, E-selectin, P-selectin, and vascular endothelial growth factor. The AVF model has a "nidus" with endothelial molecular changes similar to those observed in human AVMs, supporting its use as a model for studying the effects of radiosurgery on AVMs.


Near-infrared Fourier transform Raman spectroscopic study of cornea and sclera.
Near-infrared excited Fourier transform Raman spectroscopy was applied in situ on intact rabbit cornea and sclera. High quality Raman spectra were obtained noninvasively from these tissues. The characteristic bands assigned to proline and hydroxyproline appeared in the region of 800-1000 cm-1. Raman spectra of purified type I collagen and other components of the cornea and sclera were also determined. The main elements of the spectra of the cornea and sclera originated from the collagen proteins, and other components such as proteoglycan contributed little. Near-infrared excited Fourier transform Raman spectroscopy can be used for biophysical study of the cornea and sclera in situ or in vivo.


Thrombus formation in a dilated torcula following aneurysmal subarachnoid haemorrhage.
A case of thrombus formation occurring within a dilation of the dural venous sinuses following aneurysmal sub-arachnoid haemorrhage is presented. Acute neurological deterioration accompanied propagation of the thrombus. The patient was anticoagulated on day 5 post-SAH with no haemorrhagic complications and made a full recovery. The optimum time to commence anticoagulation is not clear and is discussed.


[Bacteriological evaluation of netilmicin].
The following results were obtained from the bacteriological evaluations of netilmicin (NTL), a newly developed antibiotic agent, with gentamicin (GM), dibekacin (DKB) and amikacin (AMK) as the controls. (1) NTL demonstrated broad antibacterial spectra against both Gram-positive and Gram-negative bacteria, but its antibacterial potency against streptococci was not very strong among other Gram-positive bacteria. (2) In terms of distribution of sensitivity of clinically isolated bacterial strains, NTL proved to have antibacterial potency comparable to that of GM and higher potency than that of DKB of AMK against E. coli K. pneumonia, Enterobacter sp., or H. influenzae. However, its efficacy was inferior to GM against Proteus sp., S. marcescens and P. aeruginosa. (3) In conjunction with the influences of pH of culture media or of addition of horse sera upon the antibacterial efficacy, NTL showed an inclination similar to that of GM, DKB and AKM. Its antibacterial efficacy was fortified on the alkaline side or by addition of sera. In connection with the influences of the amounts of inoculated bacteria upon antibacterial efficacy, there were hardly any appreciable influences on it by any of the tested bacterial strains. (4) The interactions of NTL with carbenicillin were evaluated with the chequerboard titration method to find remarkable cooperative actions in any of E. coli, K. pneumoniae, S. marcescens, A. calcoaceticus and P. aeruginosa. (5) The results of evaluation on the patterns of its antibacterial effects revealed that it acted bactericidal in any tested bacterial strains. (6) As to the therapeutic effects against experimental infections in mice, it was found out that NTL = GM greater than DKB and AMK against E. coli, GM greater than NTL = DKB and AMK against K. pneumoniae and GM and DKB greater than NTL greater than or equal to AMK against A. calcoaceticus and P. aeruginosa in the decreasing order of efficacy.


Detection of insulin receptors in newt liver and forelimb regenerates and the effects of local insulin deprivation on epimorphic regeneration.
Previous in vivo and in vitro studies indicate that insulin is required in adult newt forelimb regeneration. The objectives of the current study were 1) to detect insulin receptors in the liver (a classical target organ for insulin) and once verified, detection of insulin receptors in the adult newt forelimb regenerate; and 2) to determine whether locally implanting insulin antibody-soaked hydrolyzed polyacrylamide beads (hypa beads) into a regenerating forelimb blastema would affect its growth and/or differentiation. The results show that insulin receptors are detectable in the plasma membranes of newt liver and forelimb regenerates. Radioiodinated bovine insulin binding is time-dependent and specific; unlabeled bovine insulin competes with labeled insulin for binding to NLPM more effectively than does insulin-like growth factor-I, guinea pig insulin, and glucagon. The newt hepatic insulin receptor binds insulin with high affinity (1.1 nM-1) and low capacity (63 +/- 8 fmoles/mg). The size of the alpha subunit of the newt insulin receptor is 130 kDA and that of the beta subunit is 95 kDa. The beta subunits undergo insulin-stimulated phosphorylation in response to insulin. An autoantibody against the human insulin receptor recognizes the newt receptor protein. Insulin receptors are also detectable in 15 and 20 day newt forelimb regenerates. Specific immunogold labelling of the receptor-bound antibody appears to be restricted to the cellular processes of the regenerate. Implanting hypa beads soaked with purified insulin antibody into regenerating adult newt forelimbs results in abnormal growth and differentiation of the regenerates, confirming that insulin plays an essential role in adult newt forelimb regeneration.


The problem with breaks.
It is interesting to read about the new break initiative at Guy's and St Thomas's hospital (news online, 20 March). I would have been happy with a quick slurp of a coffee between tasks. It's almost impossible to stop what you are doing, make a cuppa and finish it uninterrupted.


Effect of probiotic administration in the therapy of pediatric thermal burn.
Oral probiotic administration has been advocated for treatment and prevention of a diverse range of disorders. This study was undertaken to evaluate the effect of probiotic supplementation on outcome of pediatric post-burn patients. Forty thermally-injured pediatric patients with total body surface burns between 20-50% and depth between 5-10% were randomized in a prospective, double-blind, controlled clinical trial into two even groups: probiotic group (n=20), who received probiotic preparations, and placebo control group (n=20). Clinical outcomes, including GIT tolerance, incidence of infection, need for grafting, length of hospital stay and mortality were recorded. Laboratory measurements of serum CRP, serum albumin, serum IgA and total lymphocyte count were done upon admission and on days 4, 7 and 14. There were no significant differences between the groups regarding age (3.67 ± 0.67 vs. 3.56 ± 0.73), sex, %BSA (34.5 ± 1.96 vs. 33.9 ± 1.82) and %deep burns (6.95 ± 0.34 vs. 7.25 ± 0.39). Frequency of diarrhea (3 vs. 9), need for grafting (2 vs. 8) and length of hospital stay (17.25 ± 0.5 days vs. 21.9 ± 2.2 days) were significantly lower in the probiotic group (p=0.038, p=0.028 and p=0.044, respectively). A trend towards a decrease in incidence of infections (7 vs. 12) was noted in the probiotic group (p=0.113). There was no mortality in our series. There was improvement in the patients' overall outcome related to wound healing and length of hospital stay following the use of probiotics. However, their effects on infectious morbidity and mortality remain unclear and require further investigation.


[A case of meconium peritonitis].
A case of meconium peritonitis that was diagnosed ultrasonographically in the second trimester is presented. Fetal ascites, intra-abdominal calcification and polyhydramnios were detected on antenatal ultrasonography.


Mpox Infection and Sexually Transmitted Infections: A Cross-Sectional Study from a Secondary Hospital in the May-September 2022 International Outbreak.
The aims of this study were to describe the characteristics of patients infected by mpox in our setting, to determine the prevalence of mpox in samples that are classically used for diagnosing sexually transmitted infections (STIs) such as anal, urethral, pharyngeal, and urine, and to assess the prevalence of coinfection with STIs in the same samples. A cross-sectional study was conducted, collecting all confirmed cases of mpox between June and July 2022 using polymerase chain reaction. Sociodemographic data, HIV and other STI status, and prevalence of mpox and STIs in urethral, anal, pharyngeal, or urine samples were collected. Data from 22 patients were extracted, all of whom were men who have sex with men (MSM) and 54.5% were previously HIV positive. The median age was 43 years. All the skin samples were positive for mpox, followed by anal samples (n = 10, 45.5%). Mpox was isolated in 2 or more samples simultaneously in 12 (54%) cases. Nine (41%) patients were positive for an STI and four of them had more than one STIs (18.2%). Human mpox has been epidemiologically significant among MSM. Mpox should be investigated not only in skin lesions but also in samples classically used for STIs. Mpox, such as other STIs, shares ways of transmission and coinfection may be underdiagnosed.


Kinetic adsorption energy distributions of rough surfaces: a computational study.
The adsorption energy distribution usually refers to localized monolayers of adsorbate at thermodynamic equilibrium. Many papers have been published that analyze its influence on adsorption isotherms, heats of adsorption, and adsorption kinetics. However, the adsorption energy distribution, in its classical thermodynamic equilibrium sense, may be not as useful as expected. This is because many important processes involving adsorption have dynamic character and reactant particles have a finite time for penetration of the adsorbent. The above suggests that some adsorption centers located in less accessible fragments of the surface can be invisible in a dynamic process. However, under conditions allowing the thermodynamic equilibrium such adsorption centers could noticeably contribute to the adsorption energy distribution. The aim of this work is to measure the adsorption energy distributions of special rough surfaces using a dynamic method. This method is based on the molecular dynamics simulation of an ideal gas flowing over a sample surface. The ideal gas particles penetrate the surface, and at the moment of collision of a gas particle with the surface the Lennard-Jones potential energy is calculated. This energy can be identified with the adsorption energy at a given point on the surface. The surfaces used in the calculations have been created using two surface growth models (i.e., random deposition and ballistic deposition). The application of these highly disordered surfaces enables us to draw some general conclusions about the properties of real surfaces that are usually far from any deterministic geometry.


Association between polymorphisms and haplotypes of the beta-2 adrenergic receptor gene and asthma in a Chinese Han population.
Conflicting data have been reported on the association of variants of the beta-2 adrenergic receptor (ADRB2) gene with asthma etiology. To provide a scientific basis for the prevention and treatment of asthma, the relationship between single nucleotide polymorphisms and haplotypes of ADRB2 and asthma was examined in a Chinese Han population. Six loci (base positions -2387, -47, 46, 79, 491, and 523) of ADRB2 were examined in a group of individuals with asthma (n = 429) and a control group of individuals who do not have the disease (n = 483). Polymorphisms at the -47 locus [odds ratio (OR) = 0.789, 95% confidence interval (CI): 0.398~0.961, P < 0.05) and the 79 locus (OR = 0.788, 95% CI: 0.394~0.948, P < 0.05) and haplotype III (CCGGC; OR = 0.705, 95% CI: 0.412~0.973, P < 0.05) were correlated with asthma susceptibility and may affect the incidence of asthma in a Chinese Han population by conferring a protective effect. By examining several polymorphisms and haplotypes, this study yields a more comprehensive examination of the role of the ADRB2 gene in the pathogenesis of asthma.


Optimizing moderator dimensions for neutron scattering at the spallation neutron source.
In this work, we investigate the effect of neutron moderator dimensions on the performance of neutron scattering instruments at the Spallation Neutron Source (SNS). In a recent study of the planned second target station at the SNS facility, we have found that the dimensions of a moderator play a significant role in determining its surface brightness. A smaller moderator may be significantly brighter over a smaller viewing area. One of the immediate implications of this finding is that for modern neutron scattering instrument designs, moderator dimensions and brightness have to be incorporated as an integrated optimization parameter. Here, we establish a strategy of matching neutron scattering instruments with moderators using analytical and Monte Carlo techniques. In order to simplify our treatment, we group the instruments into two broad categories: those with natural collimation and those that use neutron guide systems. For instruments using natural collimation, the optimal moderator selection depends on the size of the moderator, the sample, and the moderator brightness. The desired beam divergence only plays a role in determining the distance between sample and moderator. For instruments using neutron optical systems, the smallest moderator available that is larger than the entrance dimension of the closest optical element will perform the best (assuming, as is the case here that smaller moderators are brighter).


On-line and memory-based aspects of individual and group target judgments.
Ss were given instruction sets to induce either on-line or memory-based processing while reading behavioral statements about individual and group targets. Impression-set instructions induced online judgments, and comprehensibility-set (comp) instructions induced memory-based judgments regardless of target type. More important, with nondirective instructions (memory set), natural differences in processing information about individuals and groups were observed, with more online judgments for individuals. As expected, illusory correlations between minority targets and infrequent behaviors (a memory-based product) emerged with comp instructions (which induced memory-based judgments for both target types) and in the memory-set condition for group targets only. These data provide insights into the differences in impression formation for groups and individuals and furnish direct evidence of the processes responsible for illusory correlations.


[Effect of combined application of external cyclosporine A and CTLA4Ig on the survival of rat auricle allograft].
To study the effect of combined application of external cyclosporine A (CsA) and CTLA4Ig in inhibiting rejection and inducing immune tolerance in composite tissue allograft. The auricles with vessel pedicle were transplanted from Lewis rats to BN rats under microsurgery. CsA was spreaded on the surface of grafts in combination with administration of CTLA4Ig intraperitoneally after transplantation. The rejection response and survival time of grafts were observed, and the IL-2 level in serum was measured. The mean survival time was (7.8 +/- 1.7) days in control group. It was (15.2 +/- 1.9) days when recipients treated by CsA and (16.6 +/- 2.1) days by CTLA4Ig. Under the combination of CsA and CTLA4Ig, the mean survival time was significantly prolonged to (28.8 +/- 3.5) days (P < 0.05) with the lowest level of IL-2 in serum of recipients. The combined application of external CsA and CTLA4Ig inhibits rejection of allograft effectively, which can be a favorable therapy on composite tissue allo-transplantation.


Characterization of Noise Level Inside a Vehicle under Different Conditions.
Vehicular acoustic noise evaluations are a concern of researchers due to health and comfort effects on humans and are fundamental for anyone interested in mitigating audio noise. This paper focuses on the evaluation of the noise level inside a vehicle by using statistical tools. First, an experimental setup was developed with microphones and a microcomputer located strategically on the car's panel, and measurements were carried out with different conditions such as car window position, rain, traffic, and car speed. Regression analysis was performed to evaluate the similarity of the noise level from those conditions. Thus, we were able to discuss the relevance of the variables that contribute to the noise level inside a car. Finally, our results revealed that the car speed is strongly correlated to interior noise levels, suggesting the most relevant noise sources are in the vehicle itself.


pp32r1 controls the decay of the RNA-binding protein HuR.
pp32 is a tumor suppressor and is one of the associated proteins of the RNA-binding protein HuR. The pp32-HuR complex is exported to the cytoplasm of cells under stress conditions, and HuR is degraded by caspases in the cytoplasm. In the present study, we examined the role of pp32r1, a member of the pp32 family that has oncogenic properties, in the decay of HuR. pp32r1 was found to be abundantly expressed in cancer cells, and overexpression of pp32r1 induced colony formation in soft-agar. pp32r1 was expressed in both the nucleus and cytoplasm, whereas pp32 was predominantly localized in the nucleus. Even with lethal stress such as staurosporine (STS), HuR in the cytoplasm was never downregulated, and caspase-3 activity was inhibited when cells expressed pp32r1. pp32r1 bound to HuR without interacting with pp32. In cancer cells, HuR survived in the cytoplasm of cells overexpressing pp32r1, although HuR was not expressed in the cytoplasm of pp32-expressing cells, similar to lethal stress conditions. Taken together, these results indicate that pp32r1 binds to HuR to avoid the caspase-mediated decay of HuR in the cytoplasm of cells. We suggest that this function contributes to the oncogenic activity of pp32r1.


Adhesive properties of metastasizing tumour cells.
Cancer metastasis depends on a functional property which enables tumour cells to depart from the primary site of growth, to disseminate to distant organs and to establish secondary growth. The acquisition of a metastatic phenotype by neoplastic cells most probably involves alterations in their adhesive properties as the migrating cells continuously break and establish cellular contacts throughout the process. In vitro, normal cells of either mesenchymal or epithelial origin usually depend on adhesion to and spreading on a solid substratum (anchoring) for cell division. Neoplastic cells, however, are free of dependence on the support of solid substrata for cell proliferation (anchorage independent). The search for the characteristic alterations in cell adhesion, spreading and morphology which may accompany neoplastic transformation in general and cancer metastasis in particular has engendered a wide range of research activities. These studies have led to the identification of various membrane receptors that mediate cell-cell and cell-extracellular matrix recognition and adhesion on normal and tumour cells. Central to this is the effect of cell adhesion on cell shape and cytoskeleton organization in relation to metastasis. The use of specific antibodies, ligands, drugs and culture conditions permits exploration and identification of some of the macromolecules involved in tumour cell adhesion in vitro and metastasis in vivo. Nevertheless the specificity of the interactions which might determine organ-specific metastasis remains to be elucidated. This paper discusses the interrelation between cell adhesion, cell shape, cytoskeleton and metastasis.


The pharmacological treatment of anxiety disorders in children and adolescents.
As the recognition of paediatric and adolescent anxiety disorders improves, so does the number of recommended treatments. Newer medications (chiefly serotonergic antidepressants) have emerged as the pharmacological treatment of choice and have largely replaced benzodiazepines and tricyclic antidepressants (TCAs) for these disorders. This review will focus on placebo-controlled and open-label studies concerning the treatment of anxiety in children and adolescents, comparing data from newer antidepressant medications (plus buspirone) with data on TCAs and benzodiazepines in this population. There are few randomised, placebo-controlled trials of medications for anxiety in children and adolescents, with most data coming from open-label trials and case series. Moreover, there are no studies comparing pharmacological versus behavioural treatments. Most recent data concerning the efficacy of selective serotonin reuptake inhibitors suggests that these agents will be effective and safe in the treatment of paediatric anxiety disorders. The potential side effect profiles of these newer agents also makes them an attractive first choice for anxiety when compared to the benzodiazepines or TCAs, each of which poses its own potentially serious adverse effects. More research is needed in the area of psychopharmacological treatments for paediatric and adolescent anxiety, not only to substantiate the current beliefs that serotonergic agents are effective and safe but to pinpoint the factors that might predict responses to particular agents or classes of medications. Future investigations should focus on treatments which have already proven effective for adult anxiety disorders (both medications and psychotherapies), given the apparent links between paediatric and adult anxiety disorders.


An efficient method of early caponization in slow-growing meat-type chickens.
We developed a new tool for testectomy and investigated the efficiency with regard to caponizing time and growth performance in Hinai-jidori chickens, a popular breed of chicken in Japan. Hinai-jidori chicks were divided into 2-, 4-, and 8-wk caponized groups and an intact male group (20 birds/group) at 2 wk of age and were raised until 26 wk of age. The testes of the male chicks caponized at 8 wk of age were surgically removed from both sides using a Japanese traditional tool, whereas those of male chicks caponized at 2 and 4 wk of age were surgically removed from only one side using the new tool. Using the traditional method, caponization of an 8-wk-old chick was achieved in 324.6 s (5 min 24 s), whereas using the new method, caponization of 2- and 4-wk-old chicks was achieved in only 35.9 and 28.4 s, respectively. Moreover, at 10 and 18 wk of age, the chicks caponized at 4 wk of age were significantly heavier than the chicks caponized at 8 wk of age. The data suggest that the decrease in the daily weight gain caused by caponization at a younger age was less than that at an older age. We concluded that early caponization shortens the caponizing time significantly and improves the decrease in the daily weight gain after caponization, thereby enabling efficient capon production from slow-growing meat-type chickens at early stages of development.


The effect of changes in group composition on social dynamics in marabou storks (Leptoptilos crumeniferus).
The reduction of aggressive behaviors can be a concern whenever animals are socially housed, but for some species, such as marabou storks, zoos are still unsure of the best management strategies. To learn more about marabou behavior and how dynamics change as group composition changes, we monitored a total of 3.5 marabous as individuals were added and removed over 2 years. We found that, in mixed-sex groups, males were more likely to be the initiators of displacements and females were more likely to be the recipients. Most contact aggression was intra-sexual, and females engaged in contact aggression more often than males. The highest levels of aggression were seen in our all-female groups, which was unexpected given the high number of male attacks on females reported in zoos. Because females were being added and removed but our males remained the same throughout the study, we are unsure whether this was due to a higher level of instability among females or a true sex difference; regardless, these data highlight the need to monitor aggression even within all female stork groups. Overall, we observed low levels of inter-sexual aggression, suggesting that some fatal attacks may be due, in part, to non-social factors, such as enclosure design. Social birds like marabous may benefit from the same type of group management approach that is commonly utilized with other social taxa. A two-pronged approach of observation and management of marabou social dynamics and some modification of their enclosure structure may limit injurious aggression in the future.