The effects of glucose, insulin and metformin on the order parameters of isolated red cell membranes. An electron paramagnetic resonance spectroscopic study.
Human red blood cell (RBC) membranes (RBC ghosts) were treated with glucose, insulin and metformin. The order parameters of RBC membranes were determined by 5- and 16-doxyl-stearic acid spin labels. Metabolic effects were excluded using an isolated system of RBC membranes. The membranes were incubated with glucose in physiological (5 mM), renal threshold (10 mM) and manifested diabetic (20 mM) concentrations for limited times. High concentrations of glucose (10, 20, 100 mM) increase the order parameters of RBC membranes significantly. Insulin by itself has a similar effect which is, however, not strictly concentration-dependent. By contrast, metformin at therapeutic concentrations (0.5 and 5.0 microM) decreases the order parameters. At 50 microM concentration the metformin effect is expressed less and recurs at 100 microM concentration. The effects are significant with 5-doxyl-stearic acid, but are not significant with the 16-doxyl derivative. When RBC membranes are co-incubated with 20 mM glucose and metformin at 0.5 and 5.0 microM concentrations the order parameters as determined by 5-doxyl-stearic acid remain normal (= control values). Higher concentrations of metformin (50 and 100 microM) cause an overshoot to very low order parameters. Insulin at 10, 100 and 200 mU/L does not influence significantly the effects of metformin. Addition of physiological amounts of bovine serum albumin does not abolish the effects of metformin. Metformin, at therapeutic concentrations (0.5 and 5.0 microM), maintains the normal fluidity at the polar interface of isolated RBC membranes by counterbalancing non-enzymatic glycosylation with 20 mM glucose in vitro.


Postoperative pain control with intrathecal morphine.
A clinical study of the use of intrathecal morphine in two groups of surgical patients, 32 in all, showed that the morphine provided very powerful and prolonged analgesia with little disturbance of cerebral function. When combined with a spinal block it did not interfere with the action of the spinal anaesthetic. When combined with a relaxant technique of anaesthesia some persistent curarisation was seen. The only complication to emerge from the study was respiratory depression which could be very delayed in its offset. The depression was sufficient to induce carbon dioxide narcosis in two patients. It is suggested that the dose of intrathecal morphine in the very elderly should be very severely restricted as they appeared to be unduly sensitive to the respiratory depressant effect of morphine when given intrathecally.


Occipital Donor Area Grading and Profile in Indian Population.
Safe donor area (SDA) in hair transplant surgery had been categorized by various studies. We designed a study to profile the occipital donor area in our population and devise a grading scale the donor area. To profile and grade the pattern of receding hair over the occipital donor area among men in the age group of 50-55 years with androgenetic alopecia (AGA). A total of 681 men with AGA (grade 3 and above Norwood scale, diffuse unpatterned AGA, and retrograde AGA) in the age group between 50 and 55 were included in the study group. Their occipital donor area was analyzed and photographed with the head in the sagittal plane. A team of two dermatologists graded the hair loss and the pattern of the receding hair over the occipital donor area and devised a grading scale and profiled the donor area. Grades 1, 2, and 3 occipital donor area constituting 76.05% of the subjects analyzed, fulfilled the standard SDA criteria and 22.31% of the subjects did not fit well into the standard SDA widely followed. Diffuse thinning and reverse thinning of the occipital donor area was observed among the subjects. There is no clear cut defined SDA. There are lot of individual variations in SDA. SDA selection should be always conservative and over harvesting of the occipital donor region should be avoided.


Enterogastric reflux in normal subjects and patients with Bilroth II gastroenterostomy. Measurement of enterogastric reflux.
Initially, scintigraphy was established as a valid method for detecting and quantitating enterogastric reflux. A new, tubeless technique for the measurement of enterogastric reflux was developed. 99mTc bound to [(2,6 dimethylphenylcarbamoylmethyl) iminodiacetic acid] (5 mCi) was administered intravenously to visualize the liver and biliary tract. One hour later, a standard liquid meal labeled with 111In bound to diethylene-triamine penta-acetic acid (250 microCi) was given. The 99mTc and 111In activities were recorded simultaneously for 1-min periods at 15-min intervals for 2 hr over liver, gallbladder, and gastric areas of interest. Enterogastric reflux indices were determined. Ten normal subjects and 13 patients with vagotomy, hemigastrectomy, and Bilroth II gastrojejunostomy were evaluated. The enterogastric reflux index in asymptomatic postsurgical patients was increased significantly to 24.6 +/- 4.7 compared with 8.2 +/- 6.0 (P less than 0.01) in normal subjects. In postsurgical patients with the syndrome of alkaline gastritis, the enterogastric reflux index was increased significantly to 86.3 +/- 7.1 (P less than 0.01) compared with asymptomatic postsurgical patients.


Closure of palatal defect with full-thickness skin graft via Le Fort 1 maxillary access osteotomy.
A technique for resection of a palatal tumour via a Le Fort 1 maxillary access osteotomy is described. Access via the osteotomy allows intra-operative examination of the superior aspect of the palate and resection of the tumour without gross destruction of the nasal mucosa. The nasal mucosa provides a bed for a full-thickness skin graft to effect closure of the palatal defect.


Development and application of a metabolomic tool to assess exposure of an estuarine amphipod to pollutants in the environment.
Identifying major adverse effects on aquatic organisms in environmental samples is still challenging, and metabolomic approaches have been utilized as non-target screening techniques in the context of ecotoxicology. While existing methods have focused on statistical tests or univariate analysis, there is the need to further explore a multivariate analytical method that captures synergetic effects and associations among metabolites and toxicants. Here we show a new tool for screening sediment toxicity in the environment. First, we constructed predictive models using the metabolomic profiles and the result of exposure tests, to discriminate the toxic effects of target substances. The developed models were then applied to sediment samples collected from an actual urban area that contain chromium, nickel, copper, zinc, cadmium, fluoranthene, nicotine, and osmotic stress, incorporated with exposure tests of the benthic amphipod Grandidierella japonica. As a result, the fitted models showed high predictive power (Q2 > 0.71) and could detect toxicants from mixed chemical samples across a wide range of concentrations in test datasets. The application of the constructed models to river sediment and road dust samples indicated that almost all target substances were less toxic compared with the effects at LC50 levels. Only zinc showed slight increasing trends among samples, suggesting that the proposed method can be used for prioritization of toxicants. The present work made a direct connection between chemical exposures and metabolomic responses, and draws attention to the need for further studies on interactive mechanisms of metabolites in toxicological assessments.


All cut up! The consequences of calpain activation on platelet function.
The Ca(2+)-activated proteases or calpains, play a crucial role in a spectrum of physiological processes such as cytoskeletal remodeling, cellular signaling, cell migration, apoptosis, cell survival and platelet activation, by the proteolytic cleavage of target proteins. Rather than eliciting protein degradation the calpains are responsible for their modification (e.g. activation, inhibition or altered sensitivity to intracellular signals) and therefore make a significant impact on intracellular signaling. Maintained calpain activation is known to be associated with disease development and in platelet calpains are involved in both physiological platelet activation as well as pathological platelet hyper-activation.


Assay of the Ca pump ATPase activity of intact red blood cells.
An assay for the Ca pump ATPase of intact human red blood cells (RBCs) was developed. The assay utilized a small volume (typically 10 microliters) of packed RBCs in 1 ml of a buffer of known composition. The assay was based on the exposure of intact RBCs to the ionophore, A23187, in the presence of Ca. Such exposure caused a rapid degradation of ATP in RBCs. This degradation process is modeled in a numerical simulation in a companion paper (Vincenzi, F. F. and Hinds, T. R. (1992) Biochim. Biophys. Acta 1105, 63-70). The loss of ATP followed pseudo-first-order kinetics, and the rate constants for ATP degradation was taken as a measure of the capacity of the Ca pump ATPase. A number of variables were examined to optimize the activity of the ATPase. These variables included the concentrations of Ca and A23187. Because A23187 can promote loss of cellular Mg, it was necessary to include MgCl2 in the incubation medium to optimize ATPase activity. Likewise, it was determined that inclusion of iodoacetic acid optimized the rate of ATP loss, presumably by preventing the resynthesis of ATP from ADP and inorganic phosphate. Cobalt inhibited the ionophore-dependent loss of ATP by apparent competition with Ca for binding to A23187. Results of many assays demonstrated substantial differences in the rate constant for ATP loss in RBCs from different individuals. RBCs were selected according to density. Density associated loss of Ca pump ATPase activity was observed both by the intact RBC assay, and by assay of Ca pump ATPase activity in saponin lysates of RBCs. The correlation coefficient between the two assays was 0.93. It is suggested that the rate constant for ATP loss in intact RBCs exposed to A23187 and Ca can be taken as a measure of the Ca pump ATPase activity. This may be useful when isolated membrane ATPase assays fail (e.g., dog RBCs). The intact cell assay can also be carried out on very small volumes of cells and may be of particular value when RBC volumes are limited.


Anti-proliferative effect of RCE-4 from Reineckia carnea on human cervical cancer HeLa cells by inhibiting the PI3K/Akt/mTOR signaling pathway and NF-κB activation.
Cervical cancer is the second leading cause of cancer deaths in women worldwide. In recent years, the studies find that inflammation is a critical component of tumor progression, and the ideal therapeutic methods should be aimed at the inflammation reaction triggers. (1β,3β,5β,25S)-spirostan-1,3-diol1-[α-L-rhamnopyranosyl-(1 → 2)-β-D-xylopyranoside] (RCE-4) was the main active composition of Reineckia carnea (Andr.) Kunth. It significantly induced apoptosis in cervical cancer Caski cells through the mitochondrial pathway in our previous studies; however, its underlying mechanism remains poorly understood. This study aimed to further evaluate the effect of RCE-4 on human cervical cancer HeLa cells. Based on this observation, we investigated the anti-cervical cancer effect of RCE-4 by modulating phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, nuclear factor-kappa B (NF-κB) activation, and inflammation-related key factors in HeLa cells. The results indicated that the HeLa cell was the most sensitive with an IC50 of 7.01 μM; RCE-4 significantly promoted the release of cellular lactate dehydrogenase (LDH); increased DNA fragmentation and apoptosis; reduced PI3K, Akt, mTOR, and NF-κBp65 phosphorylation levels; increased the Bax and cleaved poly (ADP-ribose) polymerase (PARP) protein levels; suppressed Bcl-2 protein expression; elevated the Bax/Bcl-2 expression ratio; and decreased the interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) mRNA expressions in HeLa cells in a concentration-dependent manner. These findings suggest that RCE-4 exerted beneficially anti-cervical cancer effect on HeLa cells, mainly inhibiting PI3K/Akt/mTOR signaling pathway phosphorylation and NF-κB activation, promoting HeLa cell apoptosis. Graphical abstract Anti-tumor effect of RCE-4 on HeLa cells.


Q10-triggered facial vitiligo.
Generation and accumulation of reactive oxygen/nitrogen species in the epidermis of patients with vitiligo has been widely documented. Moreover, semiquinone radical-mediated sensitivity has been shown in blood lymphocytes of these patients. To determine the possible mechanism behind Q10-induced facial vitiligo. This was a clinical assessment supported by in vivo Fourier transform-Raman spectroscopy and repigmentation. Topical Q10 application generated hydrogen peroxide (H2 O2 ) leading in turn to facial vitiligo in susceptible individuals. Proof of the basic result stemmed from reduction of epidermal H2 O2 by using narrowband ultraviolet B-activated propseudocatalase PC-KUS in association with cessation of depigmentation and repigmentation of the lost skin colour. Over-the-counter availability of Q10-containing topical formulations can be harmful to individuals susceptible to vitiligo.


In vivo brain viscoelastic properties measured by magnetic resonance elastography.
Magnetic resonance elastography (MRE) is a non-invasive imaging technique used to visualise and quantify mechanical properties of tissue, providing information beyond what can be currently achieved with standard MR sequences and could, for instance, provide new insight into pathological processes in the brain. This study uses the MRE technique at 3 T to extract the complex shear modulus for in vivo brain tissue utilizing a full three-dimensional approach to reconstruction, removing contributions of the dilatational wave by application of the curl operator. A calibrated phantom is used to benchmark the MRE measurements, and in vivo results are presented for healthy volunteers. The results provide data for in vivo brain storage modulus (G'), finding grey matter (3.1 kPa) to be significantly stiffer than white matter (2.7 kPa). The first in vivo loss modulus (G'') measurements show no significant difference between grey matter (2.5 kPa) and white matter (2.5 kPa).


The effect of exogenous L-carnitine on biochemical parameters in serum and in heart of the hyperlipidaemic rat.
In previous experiments we have demonstrated that L-carnitine administration is capable of reducing olive oil-induced lipidaemia in the rat. In the present study we determined the effect of L-carnitine on the levels of (acyl)carnitines in heart and serum in addition to its effect on serum levels of lipids and ketone bodies after olive oil gavage feeding. L-carnitine was found to reduce the level of myocardial long-chain acylcarnitine which was increased by the olive oil treatment. It also increased the levels of carnitine and acid soluble acylarnitines in both heart and serum. L-carnitine administration caused a clearcut decrease of olive oil-induced lipidaemia and ketonaemia. These effects of added L-carnitine strongly suggest that the stimulation of the beta-oxidation in the mitochondria (at the expense of extra mitochondrial triglycerceride synthesis) is suboptimal after fat loading.


Benchmarking Ground-State Geometries and Vertical Excitation Energies of a Selection of P-Type Semiconducting Molecules with Different Polarity.
A benchmark of TD-DFT, wave function-based and semiempiric methods was performed for the geometries and excitation energies of diverse molecular organic semiconductors with varying polarity. Geometries were benchmarked by means of RMSD (root-mean-square deviation) values and MAE (maximum absolute error) values of geometric parameters specific for the electronic structure of the respective molecule. MS-CASPT2 calculations were used to benchmark excitation energies with respect to a confidence interval around the values obtained with CASPT2. The effect of spin-component scaling (SCS) on several wave function-based methods was thoroughly evaluated.


The novel KIR3DL3*117 allele identified by sequencing-based typing in a Chinese Han individual.
The novel KIR3DL3*117 allele differs from the closest allele KIR3DL3*01002 by two mutations in exon 3.


Impact of hospital teaching intensity on quality of care and patient outcomes.
Proposed changes to financing of teaching hospitals and new quality-based performance incentives may differentially impact the financial health of teaching and safety-net institutions. Few data have examined the potential impact of these financial changes on teaching institutions. To determine the association of hospital teaching intensity with processes and outcomes of care for the most common inpatient diagnoses in the United States. Cross-sectional analysis of the 2008 Hospital Quality Alliance and 2007 American Hospital Association databases, adjusted for hospital characteristics. A total of 2418 hospitals distributed across the country with available data on teaching intensity (resident-to-bed ratio), quality-of-care process measures, and risk-adjusted readmission and mortality rates for acute myocardial infarction (AMI), congestive heart failure (CHF), and pneumonia. Hospital-level quality-of-care process indicators and 30-day risk-adjusted readmission and mortality rates for AMI, CHF, and pneumonia. Multivariable analysis demonstrates that all hospitals perform uniformly well on quality-of-care process measures for AMI, CHF, and pneumonia. However, when compared with nonteaching hospitals, increasing hospital teaching intensity is significantly associated with improved risk-adjusted mortality for AMI and CHF, but higher risk-adjusted readmission rates for all 3 conditions. Among high teaching intensity hospitals, those with larger Medicaid populations (safety-net institutions) had particularly high readmission rates for AMI and CHF. In this nationally representative evaluation, we found significant variation in performance on risk-adjusted mortality and readmission rates, and differences in readmission rates based on safety-net status. Our findings suggest that high teaching intensity and safety-net institutions may be disproportionately affected by upcoming changes in hospital payment models.


Pericardial tamponade following CT-guided lung biopsy.
While not free from hazards, CT-guided biopsy of the lung is a safe procedure, with few major complications. Despite its safety record, however, potentially fatal complications do rarely occur. We report a case of pericardial tamponade following CT-guided lung biopsy. Rapid diagnosis and therapy allowed for complete patient recovery. Physicians who perform this procedure should be aware of the known complications and be prepared to treat them appropriately.


Single-molecule fluorescence experiments determine protein folding transition path times.
The transition path is the tiny fraction of an equilibrium molecular trajectory when a transition occurs as the free-energy barrier between two states is crossed. It is a single-molecule property that contains all the mechanistic information on how a process occurs. As a step toward observing transition paths in protein folding, we determined the average transition-path time for a fast- and a slow-folding protein from a photon-by-photon analysis of fluorescence trajectories in single-molecule Förster resonance energy transfer experiments. Whereas the folding rate coefficients differ by a factor of 10,000, the transition-path times differ by a factor of less than 5, which shows that a fast- and a slow-folding protein take almost the same time to fold when folding actually happens. A very simple model based on energy landscape theory can explain this result.


Novel prognostic nomograms in cervical cancer based on analysis of 1075 patients.
To explore the factors affecting the prognosis of cervical cancer (CC), and to construct and evaluate predictive nomograms to guide individualized clinical treatment. The clinicopathological and follow-up data of CC patients from June 2013 to December 2019 in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively analyzed. Log-rank test was used for univariate survival analysis, and Cox multivariate regression was used to identify independent prognostic factors, based on which nomogram models were established and evaluated in multiple aspects. Patients were randomly assigned into the training (n = 746) and validation sets (n = 329). Survival analysis of the training set identified cervical myometrial invasion, parametrial involvement, and malignant tumor history as prognosticators of postoperative DFS and pathological type, cervical myometrial invasion, and history of STD for OS. C-index was 0.799 and 0.839 for the nomograms for DFS and OS, respectively. Calibration curves and Brier scores also indicated high performance. Importantly, decision curve analysis suggested great clinical applicability of these nomograms. In this study, we analyzed a cohort of 1075 CC patients and identified DFS- or OS-associated clinicohistologic characteristics. Two nomograms were subsequently constructed for DFS and OS prognostication, respectively, and showed high performance in terms of discrimination, calibration, and clinical applicability. These models may facilitate individualized treatment and patient selection for clinical trials. Future investigations with larger cohorts and prospective designs are warranted for validating these prognostic models.


Secondary school teachers psychological status and competencies in e-teaching during Covid-19.
The Covid-19 outbreak has had a staggering impact on the global economy, public health and safety, trade and education. In Malaysia, the government implemented the Movement Control Order (MCO) as a preventive measure against Covid-19. In education, the learning process has been transferred to online teaching. However, pandemic pedagogy is making learning into completely online either synchronous or asynchronous. Therefore, the current research aims to determine the secondary school teachers' psychological status, competencies in e-teaching and teachers work motivation as well as determine the relationship between secondary school teachers' psychological status and competencies in e-teaching during the Covid-19 outbreak. Current research is a descriptive-correlational quantitative survey to determine teachers' psychological status, e-teaching competencies and working motivation during Movement Control Order (MCO) to contain the Covid-19 pandemic. The study sample consists of 595 secondary school teachers selected via convenient sampling. Quantitative data are collected from an online survey through the questionnaires with demographic, psychological status (stress, anxiety and depression), e-teaching competencies (teaching, monitoring and evaluation) and teaching motivation developed by the researchers were distributed during the MCO period. SPSS 25 is applied, Statistical measures such as Cronbach's alpha, means, percentage and standard deviation were employed to analyze the data to obtain the value of the school teachers' psychological status, e-teaching competencies and teaching motivation. Consequently, a Pearson correlation table was created to show the analysis of the school teachers' psychological status and competencies in e-teaching. This finding indicated that the teachers' psychological factors in stress, anxiety and depressed are moderate, the teachers' competencies in e-teaching is moderate as well as teachers' working motivations is also the moderate level. However, the highest mean value was found among the variables, this is revealed that despite the challenges during the Covid-19 outbreak, teachers showed positive and strong motivation in conducting e-teaching. Additionally, the result showed a negative relationship between psychological status and e-teaching competencies (-0.286, p < 0.01), as well as reported a negative relationship between dimension of psychological status and competencies in e-teaching. This study has its limitations. This study is included only Selangor teachers and given that the information obtained from the study was gather from secondary schools, the generalizability might be limited. future research may consider expanding the scope from secondary schools to primary schools' teachers and then to university lecturers. Perhaps the scope is expanding, so more information could be obtaining and help researchers understand the teachers' competencies in e-teaching, psychological status and work motivation.


Early serum infliximab trough level and mucosal healing could be predictors for one-year outcome after initiating therapy in Crohn's disease.
Serum infliximab trough level(S-IFX) and antibody were documented to correlate with clinical response. The aim of this study was to identify the relationship between early S-IFX, early mucosal healing (MH) and one-year outcome in a cohort on maintenance IFX therapy in Crohn's disease (CD). The study group comprised of retrospectively enrolled patients diagnosed for Crohn's disease (n = 108). Patients received scheduled maintenance therapy after response to IFX induction, and had undergone the early S-IFX test and endoscopic examination at week 14. Clinical outcomes were evaluated during maintenance therapy until week 52. Early S-IFX was 4.78 ± 6.16 ug/ml in all the patients and 19% (21/108) of them developed antibodies, and 52 patients reached early MH. During 52 weeks' follow-up. Twenty-eight percent (30/108) of patients showed loss of response to IFX. Patients who lost response had lower early S-IFX than those who had sustained response (3.01 ± 3.66 vs. 5.47 ± 6.79 ug/ml, p = .02; 48 vs. 23%, p = .02). At week 52, 73 patients had repeated endoscopy and 42% of them reached MH. Early S-IFX had a predictive value on MH at week 52. When early S-IFX > 2.5 ug/ml, the sensitivity for predicting MH at week 52 was 87%, and the specificity were 61% (AUC = 0.73, p < .01). The combined predictive value of early S-IFX and early MH became stronger. Only 6% (1/18) of those patients who had low early S-IFX and had not reached early MH could reach MH at week 52. Early S-IFX and early MH could predict one-year response after initiating IFX therapy in Crohn's disease.


From Model Organisms to Humans, the Opportunity for More Rigor in Methodologic and Statistical Analysis, Design, and Interpretation of Aging and Senescence Research.
This review identifies frequent design and analysis errors in aging and senescence research and discusses best practices in study design, statistical methods, analyses, and interpretation. Recommendations are offered for how to avoid these problems. The following issues are addressed: (a) errors in randomization, (b) errors related to testing within-group instead of between-group differences, (c) failing to account for clustering, (d) failing to consider interference effects, (e) standardizing metrics of effect size, (f) maximum life-span testing, (g) testing for effects beyond the mean, (h) tests for power and sample size, (i) compression of morbidity versus survival curve squaring, and (j) other hot topics, including modeling high-dimensional data and complex relationships and assessing model assumptions and biases. We hope that bringing increased awareness of these topics to the scientific community will emphasize the importance of employing sound statistical practices in all aspects of aging and senescence research.


Genotoxicity, DNA damage and sperm defects induced by vinblastine.
The treatment with chemotherapy may develop secondary tumors as a result of chemo genotoxicity. Sperm defects is another complication associated with chemo treatment. In this study the genotoxicity of vinblastine (VB) was estimated in both somatic and germ cells. 85 mice were taken. Four single doses of VB at 3, 4.5, 6 and 10 mg/kg and three successive doses at 3, 4.5 and 6 mg/kg were taken for estimation of chromosomal aberrations (CAs). Four single doses of VB were involved in estimating the DNA fragmentation, and comet assay. For sperm abnormalities mice were injected with three successive doses of VB at 3, 4.5, and 6 mg/kg. The results demonstrated a significant frequency of DNA fragmentation in spleen cells and in the percentage of CAs in bone marrow. Numerical and structural aberrations were recorded with a pronounced number of polyploidy metaphases which reached (11.60%) after treatment with 6 mg/kg for three successive days vs zero for control. VB also induced a significant percentage of CAs in spermatocytes in the form of univalent. Sperm defects in the form of coiled tail, absence of acrosome and shapeless head and a significant DNA damage in the testes were recorded. The frequency of sperm abnormalities reached 11.06 ± 0.14 after treatment with highest tested dose (6 mg/kg) vs 3.04 ± 0.19 for control. VB is genotoxic in somatic and germ cells. Sperm defects induced by VB are of serious concern to future generations and may affect the fertility of cancer survivors.


Preparation, characterization and antifungal activity of pyraclostrobin solid nanodispersion by self-emulsifying technique.
Pathogenic fungi are the causal agents of 70-80% of plant diseases. Therefore, it is imperative to explore new and high effective fungicides. Constructing nanoscale fungicides using nanomaterial and nanotechnology has attracted wide attention in recent years. In this research, a pyraclostrobin solid nanodispersion (PSND) was prepared using the self-emulsifying method. The solid nanodispersion had a mean particle size of 20 nm and a zeta potential of -29.3 mV. The solubility and dissolution rate of the PSND increased owing to the decrease in particle size and the actions of the surfactants. The contact angle and retention volumes of the PSND on cucumber and cabbage leaf surfaces were greater than those of the commercial water dispersible granule. In addition, the median lethal concentration against Fusarium oxysporum was 0.7 43 µg mL-1 . The toxicity of the nanoparticles was 4.5 times that of the water dispersible granule (WDG). The high fungicidal activity of PSND promoted the production of excess reactive oxygen species (ROS). The activity levels of the antioxidant enzymes containing superoxide dismutase (SOD) and catalase (CAT) decreased in F. oxysporum. The research introduced a new method for preparing insoluble pyraclostrobin solid nanoformulation for fungicides to enhance the fungicidal activity and reduce environmental pollution. © 2019 Society of Chemical Industry.


The Fitness and Economic Benefits of Rearing the Parasitoid Telenomus podisi Under Fluctuating Temperature Regime.
Successful biological control requires detailed knowledge about the mass rearing conditions of the control agents in order to ensure higher quality of field-released insects. Thus, we investigated whether rearing fluctuating thermal condition would affect the fitness and costs of the parasitoid wasp Telenomus podisi Ashmead (a biocontrol agent used for controlling the Neotropical brown stink bug Euschistus heros (Fabricius)) when compared with parasitoid reared at constant temperature condition, which is commonly used in insect facilities. Parasitoids were reared under either constant (continuous exposure at 25 ± 2°C) or fluctuating temperature conditions (i.e., 30 ± 2°C during day and 20 ± 2°C at night) during four consecutive generations. Our results indicated that tested fluctuating temperature is more suitable for rearing of T. podisi as such temperature condition not only resulted in fitness benefits (e.g., shorter developmental time, longer female longevity, higher fecundity/fertility) but also reduced (approximately 23.5%) the estimated costs for producing the parasitoids. Furthermore, rearing T. podisi under fluctuating temperatures improved tolerance to low constant temperatures (i.e., 20°C) without changing the tolerance to constant high temperatures (30°C) in the fourth generation. Surprisingly, even parasitoids that developed under fluctuating thermal conditions performed better than those reared at constant temperature of 25°C. Collectively, our findings suggest that T. podisi reared under fluctuating thermal condition can tolerate better fluctuating temperatures that normally occur both during long periods of transport and in agricultural ecosystems, which will increase the quality and productivity of mass-reared T. podisi for inundative releases.


Special issues in fertility preservation for gynecologic malignancies.
Gynecologic malignancies account for 1,09 million new cancer cases worldwide consisting of about 12% of tumors affecting female population. About 10% of all female cancer survivors are younger than 40 years of age. Since cancers affecting female genital organs are usually treated by radical surgery, chemotherapy or chemoradiation approaches that induce permanent damage of reproductive functions, the development of strategies for fertility preservation represent one of the most important goals for gynecologic oncology. In this scenario, the newly defined oncofertility discipline acquires increasing interest, offering patients maximal chances to make an adequate decision about future fertility, based on their oncologic diagnosis and prognosis. However, the majority of physicians do not pay particular attention to these issues, even if impressive progresses have been made in this field in the last decades. Possibly, it is due to the lack of strong evidences from clinical trials without an adequate number of cases to establish safety and efficacy of these procedures. In this review we will discuss the most recently debated options for fertility preservation in gynecologic oncology, highlighting issues and controversies related to oncofertility.


Domain-swapped structure of the potent antiviral protein griffithsin and its mode of carbohydrate binding.
The crystal structure of griffithsin, an antiviral lectin from the red alga Griffithsia sp., was solved and refined at 1.3 A resolution for the free protein and 0.94 A for a complex with mannose. Griffithsin molecules form a domain-swapped dimer, in which two beta strands of one molecule complete a beta prism consisting of three four-stranded sheets, with an approximate 3-fold axis, of another molecule. The structure of each monomer bears close resemblance to jacalin-related lectins, but its dimeric structure is unique. The structures of complexes of griffithsin with mannose and N-acetylglucosamine defined the locations of three almost identical carbohydrate binding sites on each monomer. We have also shown that griffithsin is a potent inhibitor of the coronavirus responsible for severe acute respiratory syndrome (SARS). Antiviral potency of griffithsin is likely due to the presence of multiple, similar sugar binding sites that provide redundant attachment points for complex carbohydrate molecules present on viral envelopes.


Diagnostic Value of Contrast-Enhanced Ultrasound for Differential Diagnosis of Malignant and Benign Soft Tissue Masses: A Meta-Analysis.
This meta-analysis was aimed at investigating the value of using contrast-enhanced ultrasound (CEUS) in the differential diagnosis of benign and malignant soft tissue masses (STMs). Relevant studies published before March 24, 2020 were identified through a comprehensive search of PubMed, Ovid, Cochrane and Web of Science. According to the inclusion criteria, five studies were selected comprising 746 patients. In the differential diagnosis of benign and malignant STMs, the pooled sensitivity and specificity of CEUS were 76% (95% confidence interval [CI]: 71%-81%; heterogeneity [I2] = 74.5%) and 67% (95% CI: 62%-71%; I2 = 36.5%), respectively. The diagnostic odds ratio was 7.37 (95% CI: 3.78%-14.35; I2 = 66.6%). The overall area under the curve was 0.77 (standard error: 0.0392). Subgroup analysis revealed that different index tests of CEUS resulted in different diagnostic performance. Importantly, CEUS is an effective method for the differential diagnosis between benign and malignant STMs.


The dual task paradigm: speech dominance or manual dominance?
Two hundred and sixty monolinguals divided into subgroups based on gender, handedness, and familial left-handedness, were given a concurrent task, verbal-manual interference paradigm. The primary purpose of the study was to test whether the dual task interference effects were more related to hemispheric speech or manual dominance factors. The dominant hand, regardless of handedness, underwent relatively more tapping interference than the nondominant hand. The obtained results seriously question the basic assumptions underlying the interpretation of the dual task paradigm as an assessment index for hemispheric language lateralization. A possible explanation of this result that is in keeping with known hemispheric language representation proportions in left-handers is offered based on left hemisphere ipsilateral control of the left hand.


The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.
The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger. The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.


Hemorrhagic disease in bighorn sheep in Arizona.
Two bighorn sheep from Arizona (USA) were submitted for necropsy. One was a Rocky Mountain bighorn (Ovis canadensis canadensis) and the other was a desert bighorn (Ovis canadensis mexicana). Both had lesions consistent with those of hemorrhagic disease (HD). Epizootic hemorrhagic disease virus (EHDV) type-2 and bluetongue virus (BTV) type-17, respectively, were isolated from the sheep tissues. To our knowledge, HD caused by either EHDV or BTV infection has not been documented previously in Arizona bighorn sheep.


Brucella abortusΔcydCΔcydD and ΔcydCΔpurD double-mutants are highly attenuated and confer long-term protective immunity against virulent Brucella abortus.
We constructed double deletion (ΔcydCΔcydD and ΔcydCΔpurD) mutants from virulent Brucella abortus biovar 1 field isolate (BA15) by deleting the genes encoding an ATP-binding cassette-type transporter (cydC and cydD genes) and a phosphoribosylamine-glycine ligase (purD). Both BA15ΔcydCΔcydD and BA15ΔcydCΔpurD double-mutants exhibited significant attenuation of virulence when assayed in murine macrophages or in BALB/c mice. Both double-mutants were readily cleared from spleens by 4 weeks post-inoculation even when inoculated at the dose of 10(8) CFU per mouse. Moreover, the inoculated mice showed no splenomegaly, which indicates that the mutants are highly attenuated. Importantly, the attenuation of in vitro and in vivo growth did not impair the ability of these mutants to confer long-term protective immunity in mice against challenge with B. abortus strain 2308. Vaccination of mice with either mutant induced humoral and cell-mediated immune responses, and provided significantly better protection than commercial B. abortus strain RB51 vaccine. These results suggest that highly attenuated BA15ΔcydCΔcydD and BA15ΔcydCΔpurD mutants can be used effectively as potential live vaccine candidates against bovine brucellosis.


Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 2. Oligodendroglial cytoplasmic inclusions.
Oligodendroglial cytoplasmic inclusions (OCI) in multiple system atrophy were investigated immunocytochemically and ultrastructurally. Among the 17 cases examined, 16 had OCIs. Almost all OCIs were positive for both alpha B-crystallin and ubiquitin. The antibodies against tubulin, paired helical filament and tau stained OCIs to various extents. Ultrastructurally OCIs consisted of meshworks of granule-associated filaments about 25 nm in diameter that sometimes formed flame-shaped tangle-like structures. Immunoelectron microscopy showed that an epitope of alpha B-crystallin was located on the granule-associated filaments composing OCIs. Our studies further support a cooperative role of alpha B-crystallin, ubiquitin and cytoskeletal protein in the formation of some types of intracytoplasmic inclusions.


Predictions of a network thermodynamics computer model relating to the mechanism of methotrexate rescue by 5-formyltetrahydrofolate and to the importance of inhibition of thymidylate synthase by methotrexate-polyglutamates.
Computer modeling has been a valuable tool for clarifying the mechanism of action of antifolates. Some consequences of folyl and antifolyl polyglutamate synthesis can be addressed by adaptation of a network thermodynamic computer model of methotrexate action. Reversal or prevention of methotrexate cytotoxicity by 5-formyltetrahydrofolate has widely been assumed to occur through the delivery of reduced folate in substrate amounts for thymidylate synthesis, by-passing the effects of methotrexate at dihydrofolate reductase. This mechanism is inconsistent with experimental data which shows that "rescue" is a competitive phenomenon and that the transport process is incapable of delivering reduced folate at an adequate rate. Computer modeling studies are presented which predict that expansion of the total folate pool as folylpolyglutamates with "rescue" would reduce the inhibitory effect of MTX on thymidylate synthesis. Dihydrofolate polyglutamates could then accumulate to the high level needed to displace methotrexate from the small fraction of sites on dihydrofolate reductase that are sufficient to sustain tetrahydrofolate synthesis. Experimental studies with Ehrlich ascites tumor cells support this prediction. It is likely that a critical step in the protection of normal host tissues in high dose-rescue treatment regimens is the conversion of exogenously supplied 5-formyltetrahydrofolate to polyglutamyl derivatives and accumulation of total intracellular folate to higher than normal levels. Other computer simulations are presented which examine the potential significance of direct inhibition of thymidylate synthase by polyglutamyl forms of methotrexate. The model predicts that in cells with biochemical properties similar to methotrexate sensitive L1210 cells, inhibition of dihydrofolate reductase would still be the predominant site of action unless the thymidylate synthase Ki for a methotrexate polyglutamate is below about 0.1 microM. However, in methotrexate-resistant cells with elevated dihydrofolate reductase but normal membrane transport and polyglutamylation, thymidylate synthase may be the more important target enzyme.


Characterization of the novel HLA-A*31:11:02 allele by next generation sequencing.
HLA-A*31:11:02 differs from A*31:01:02 by one nucleotide substitution at position 565 in exon 3.


Major impacts of caving activities on cave microbial diversity: case study of Morca Cave, Turkey.
Some of microorganisms identified in cave ecosystems have been reported to play a permanent and strategic role for maintaining life of these environments. Human entrance into caves can induce some changes of cave physicochemical parameters which ultimately impacts the living organisms. In these facts, for the first time, Morca Cave was explored in a purpose to evaluate the impacts that can be caused by the human activities on microbial diversity in a limited period of time. Morca is a karts cave located in the Taşeli Plateau in the Middle Taurus mountains in Turkey. The first entrance into this cave was in 2018, and expeditors reached to - 500 m. During the second expedition in 2019, a camp was established at the - 1040-m depth during 4 days. In order to evaluate the human impacts in a new explored cave, this camping depth is chosen to be our studied area because it was its first entrance. Before the installation and at the end of the camp, sediments and surface samples were taken from different points of the camp area and around. Sequencing of 16 s rRNA of each sample to isolate DNA by using the next-generation sequencing (NGS) method was performed. The profile of the microbial diversity before the camping revealed that the class Thermoplasmata was dominated the archaea group and Gammaproteobacteria and Alphaproteobacteria were the most dominant bacterial classes. After the camp, most studied sites were noted with a decrease of microbial diversity especially the previous cited classes strains. Bacteria belonging to Bacilli class have increased after the camp. Increase of bacteria that are belonging to Bacteroidia has also observed in the most active areas. This present study highlight how cave microbial diversity can respond to the human activities within a short period inside a closed cave. Furthermore, it may constitute a solid basis and support on the improvement of techniques for cave management and expedition planning for the conservation of cave nature.


Comparing the Analysis and Results of a Modified Social Accounting Matrix Framework with Conventional Methods of Reporting Indirect Non-Medical Costs.
Assessing the societal perspective in economic evaluations of new interventions requires estimates of indirect non-medical costs caused by the disease. Different methods exist for measuring the labor input function as a surrogate for these costs. They rarely specify the effect of health on labor and who gains and who loses money. Social accounting matrix (SAM) is an established framework that evaluates public policies with multiple perspectives that could help. We evaluated the use of a modified SAM to assess money flows between different economic agents resulting in economic transactions following policy changes of medical interventions. We compared conventional methods of measuring indirect non-medical costs related to rotavirus vaccination in the Netherlands with a modified SAM framework. To compare the outcome of each method, we calculated returns on investment (ROI) as the net amount of money per euro invested in the vaccine. One-way and probabilistic sensitivity analyses were carried out for each method, focusing on critical variables with the largest impact on indirect cost estimates. The ROI was higher for the modified SAM (1.33) than for the conventional methods assessing income calculations (range - 0.178 to 1.22). Probabilistic sensitivity analyses showed wide distributions in the ROI estimates, with variation in the variable impact on the indirect cost results per method selected. In contrast to conventional methods, the SAM approach provides detailed and comprehensive assessments of the impact of new interventions on the indirect non-medical costs and the financial interactions between agents, disclosing useful information for different stakeholders.


Acetylation increases the alpha-helical content of the histone tails of the nucleosome.
The nature of the structural changes induced by histone acetylation at the different levels of chromatin organization has been very elusive. At the histone level, it has been proposed on several occasions that acetylation may induce an alpha-helical conformation of their acetylated N-terminal domains (tails). In an attempt to provide experimental support for this hypothesis, we have purified and characterized the tail of histone H4 in its native and mono-, di-, tri-, and tetra- acetylated form. The circular dichroism analysis of these peptides shows conclusively that acetylation does increase their alpha-helical content. Furthermore, the same spectroscopic analysis shows that this is also true for both the acetylated nucleosome core particle and the whole histone octamer in solution. In contrast to the native tails in which the alpha-helical organization appears to be dependent upon interaction of these histone regions with DNA, the acetylated tails show an increase in alpha-helical content that does not depend on such an interaction.


Magnetic resonance imaging evaluation of Yukatan minipig brains for neurotherapy applications.
Magnetic resonance imaging (MRI) of six Yukatan minipig brains was performed. The animals were placed in stereotaxic conditions currently used in experiments. To allow for correctpositioning of the animal in the MRI instrument, landmarks were previously traced on the snout of the pig. To avoid movements, animal were anesthetized. The animals were placed in a prone position in a Siemens Magnetom Avanto 1.5 System with a head coil. Axial T2-weighted and sagittal T1-weighted MRI images were obtained from each pig. Afterwards, the brains of the pigs were fixed and cut into axial sections. Histologic and MR images were compared. The usefulness of this technique is discussed.


Serial studies of autologous antibody reactivity to melanoma. Relationship to clinical course and circulating immune complexes.
The low titer and incidence of autologous antibody to melanoma has hampered its evaluation. Through acid dissociation and ultrafiltration of serum, we have been able to augment the autologous immune response in 9 of 10 patients studied. This result suggests that autologous antibody is present in most patients with melanoma, but is obscured by circulating antigen and the formation of immune complexes. Because native antibody and antibody derived from circulating immune complexes are produced by the host against physiologically relevant antigens, correlations can be made to clinical course. Serological studies of three patients with melanoma were performed with serum samples obtained over many months; these studies demonstrated correlations with tumor progression and clinical course. Serial serologic studies may yet provide one of the better ways to evaluate these relationships. They have the advantage of detecting transient events that may occur with the inception of metastatic disease or autoimmune phenomena, and of avoiding the difficulties encountered in comparing antibody responses between different individuals.


Premature mortality patterns among American Indians in South Dakota, 2000-2010.
American Indians in South Dakota have the highest mortality rates in the nation compared to other racial and ethnic groups and American Indians in other states. Cause-related and age-specific mortality patterns among American Indians in South Dakota are identified to guide prevention planning and policy efforts designed to reduce mortality within this population, in both South Dakota and other parts of the U.S. Death certificate data from South Dakota (2000-2010), on 5738 American Indians and 70,580 whites, were used to calculate age-specific mortality rates and rate ratios. These values were examined in order to identify patterns among the leading causes of death. Analyses were completed in 2011 and 2012. Within the South Dakota population, 70% of American Indians died before reaching age 70 years, compared to 25% of whites. Fatal injuries and chronic diseases were the leading causes of premature mortality. Nine leading causes of death showed consistent patterns of mortality disparity between American Indians and whites, with American Indians having significantly higher rates of mortality at lower ages. Premature mortality among American Indians in South Dakota is a serious public health problem. Unified efforts at the federal, tribal, state, and local levels are needed to reduce premature death within this population.


Pleomorphic hyalinizing angiectatic tumor revisited: all tumors manifest typical morphologic features of myxoinflammatory fibroblastic sarcoma, further suggesting 2 morphologic variants of a single entity.
We describe 9 cases of pleomorphic hyalinizing angiectatic tumor (PHAT). Recently described TGFBR3 and MGEA5 gene rearrangements in these tumors have confirmed the long-hypothesized link between PHAT and another soft tissue entity, the myxoinflammatory fibroblastic sarcoma (MIFS). Myxoinflammatory fibroblastic sarcoma and PHAT share the same translocation and in addition have a very similar clinical presentation. However, to our best knowledge, no study has ever addressed the striking morphologic similarities between MIFS and PHAT. Our findings based on histological criteria suggest that most, if not all, tumors diagnosed as PHAT might, in fact, represent examples of MIFS that, in addition to a conventional MIFS morphology, manifest aberrant angiectatic hyalinized vessels.


PC12 phaeochromocytoma cells contain an atypical muscarinic receptor binding site.
1. Kinetic, saturation and competition binding studies were conducted on the muscarinic receptor binding site labelled by [3H]-N-methylscopolamine [( 3H]-NMS) in intact PC12 cells and cell membranes. Similar studies were conducted on M1 receptors of rat cortex labelled with [3H]-pirenzepine and M2 and M3 receptors present in rat heart and submaxillary gland respectively, and labelled with [3H]-NMS. 2. The dissociation of [3H]-NMS from muscarinic receptors in PC12 cells was slower than dissociation from both M2 and M3 muscarinic receptors. 3. The Kd of [3H]-NMS in the PC12 cells was significantly lower than that obtained at the M2 and M3 receptor. 4. In competition studies the affinity data for pirenzepine, hexahydroadiphenine and 4-diphenylacetoxy-N-methylpiperidine methiodide were consistent with the presence of an M3 receptor in the PC12 cells. However, for AF-DX 116, cyclohexylphenyl(2-piperidinoethyl)silanol and methoctramine affinity estimates in PC12 cells were 3-6 fold lower than at the M3 receptor. 5. On the basis of these data we conclude that the muscarinic receptor present in the PC12 cells differs from the M1, M2 and M3 subtypes already described.


Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus.
While the 2002-2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4(+) T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.


Solitary phalangeal brown tumour in primary hyperparathyroidism: Report of a rare presentation.
Parathyroid adenoma is the most common cause of primary hyperparathyroidism. Severe cases of primary hyperparathyroidism manifest as osteitis fibrosa cystica generalisata, characterized by generalized bone loss with increased bone resorption, including both subperiosteal and endosteal surfaces. The most common sites for formation of fibrotic cystic lesions (brown tumors) are in the long bones and jaw which present as swelling, pathological fracture, and/or bone pain, usually involving multiple sites. Here, we describe an unusual presentation of a solitary brown tumor in a young male who initially presented to the hand surgeon with a history of right thumb swelling following trivial trauma. Further detailed clinical, biochemical, scintigraphic (Tc 99m methylene diphosphonate scintigraphy and Tc 99m Sestamibi scintigraphy), and radiological investigations aided definitive diagnosis and treatment. The causative parathyroid adenoma was excised curing hyperparathyroidism and the lesion regressed substantially.


T-cell-mediated immunological barriers to xenotransplantation.
Xenotransplantion remains the most viable option for significant expansion of the donor organ pool in clinical transplantation. With the advent of nuclear transfer technologies, the production of transgenic swine has become a possibility. These animals have allowed transplant investigators to overcome humoral mechanisms of hyperacute xenograft rejection in experimental pig-to-non-human primate models. However, other immunologic barriers preclude long-term acceptance of xenografts. This review article focuses on a major feature of xenogeneic rejection: xenogeneic T cell responses. Evidence obtained from both small and large animal models, particularly those using either islet cells or kidneys, have demonstrated that T cell responses play a major role in xenogeneic rejection, and that immunosuppression alone is likely incapable of completely suppressing these responses. Additionally, both the direct and indirect pathway of antigen presentation appear to be involved in these anti donor processes. Enhanced understanding of (i) CD47 and its role in transduced xeno-bone marrow (ii) CD39 and its role in coagulation dysregulation and (iii) thymic transplantation have provided us with encouraging results. Presently, experiments evaluating the possibility of xenogeneic tolerance are underway.


Untangling the waterfall damsels: a review of the Mesoamerican genus Paraphlebia Selys in Hagen, 1861 (Odonata: Thaumatoneuridae) with descriptions of 11 new species.
A review of the Mesoamerican genus Paraphlebia Selys in Hagen, 1861 is presented, including diagnoses, illustrations of diagnostic characters, and distribution maps for all species. A key to the known males and females is provided. Eleven new species are described: P. akan Ortega-Salas Gonzlez-Soriano. sp. nov., P. chaak Ortega-Salas Gonzlez-Soriano sp. nov., P. chiarae Ortega-Salas sp. nov., P. esperanza Ortega-Salas Gonzlez-Soriano sp. nov., P. flinti Ortega-Salas Gonzlez-Soriano sp. nov., P. hunnal Ortega-Salas Gonzlez-Soriano sp. nov., P. itzamna Ortega-Salas, Jocque Gonzlez-Soriano sp. nov., P. ixchel Ortega-Salas Gonzlez-Soriano sp. nov., P. kauil Ortega-Salas Gonzlez-Soriano sp. nov., P. kinich Ortega-Salas Gonzlez-Soriano sp. nov., and P. kukulkan Jocque Ortega-Salas sp. nov.


Therapeutic Plasma Exchange - An Emerging Treatment Modality in Patients with Neurologic and Non-Neurologic Diseases.
Therapeutic Plasma Exchange (TPE) is a procedure in which the patient's blood is passed through an apheresis machine, where the filtered plasma is removed and discarded with reinfusion of red blood cells along with replacement fluid such as plasma or albumin in to the patient. We present our experience with TPE in treatment of various neurologic and non-neurologic diseases. To evaluate TPE as primary therapy or as a first-line adjunct to other initial therapies as mentioned by American Society for Apheresis (ASFA). A retrospective analysis of TPE procedures was done for a period of nine years, from January 2007 to May 2016 in a tertiary care teaching hospital. A total of 584 TPE procedures were performed in 161 patients between 2 to 75 years of age. Clinical and laboratory investigations like ECG, chest X-ray, cardiorespiratory status and serology were carried out before the TPE procedure. A total of 161 patients were enrolled in the present study. Guillain-Barre Syndrome (GBS) (67.7%, n=109) was the main indication for TPE, followed by Myasthenia Gravis (MG) (13.04%, n=21). Overall incidence of adverse reactions was 9.93%, inadequate vascular access was a common complication encountered in paediatric age group. Our results show that TPE is not only safe and effective treatment alternative to Intravenous Immunoglobulin (IVIG), it also strongly holds evidence in the improvement of neurological disorders compared to non-neurological disorders. There is need of further detail evaluation on large number of cases for proper evidence based practice.


What can we learn from international comparisons of costs by DRG?
The objective of this study was to compare costs data by diagnosis related group (DRG) between Belgium and Switzerland. Our hypotheses were that differences between countries can probably be explained by methodological differences in cost calculations, by differences in medical practices and by differences in cost structures within the two countries. Classifications of DRG used in the two countries differ (AP-DRGs version 1.7 in Switzerland and APR-DRGs version 15.0 in Belgium). The first step of this study was to transform Belgian summaries into Swiss AP-DRGs. Belgian and Swiss data were calculated with a clinical costing methodology (full costing). Belgian and Swiss costs were converted into US$ PPP (purchasing power parity) in order to neutralize differences in purchasing power between countries. The results of this study showed higher costs in Switzerland despite standardization of cost data according to PPP. The difference is not explained by the case-mix index because this was similar for inliers between the two countries. The length of stay (LOS) was also quite similar for inliers between the two countries. The case-mix index was, however, higher for high outliers in Belgium, as reflected in a higher LOS for these patients. Higher costs in Switzerland are thus probably explained mainly by the higher number of agency staff by service in this country or because of differences in medical practices. It is possible to make international comparisons but only if there is standardization of the case-mix between countries and only if comparable accountancy methodologies are used. Harmonization of DRGs groups, nomenclature and accountancy is thus required.


Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases.
Gallic acid (GA), also known as 3,4,5-trihydroxybenzoic acid, is a natural secondary metabolite and widely isolated from various fruits, plants and nuts. In recent years, GA has received increasing attention for its powerful anti-inflammatory properties. The purpose of this review is to clearly illuminate the pharmacological activities and related molecular mechanisms of GA in inflammatory diseases. After consulting a large number of literatures, we made a comprehensive exposition on the chemical characteristics, plant origins, pharmacokinetics and toxicity of GA, especially its pharmacological activities and mechanisms of action. Although the plant source of GA is very rich, its lower extraction rate limits the application of GA in development. It is worth mentioning that GA can not only be separated from many plants, but also be produced in large quantities through biological and chemical synthesis. According to pharmacokinetic studies, the absorption and elimination of GA after oral administration are fast, while the structural optimization or dosage form adjustment of GA is beneficial to increase its bioavailability. Promisingly, toxicity studies have shown that GA scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials. The results show that the anti-inflammatory mechanisms of GA mainly involved MAPK and NF-κB signaling pathways. It thus weakens the inflammatory response by reducing the release of inflammatory cytokines, chemokines, adhesion molecule and cell infiltration. Due to its excellent pharmacological activities, GA is expected to be a potential candidate for the treatment of various inflammation-related diseases. This paper will provide theoretical basis for the clinical application of GA and guide the future research and medicinal development of GA.


Genetic control of the in vitro responses of rat blood lymphocytes. I. Comparison of in vitro and in vivo responses.
Nielsen, H. E. & Koch, C. Genetic Control of the In Vitro Responses of Rat Blood Lymphocytes. I. Comparison of In Vitro and In Vivo Responses, Scand. J. Immunol. 4, 31-36, 1975. In vitro DNA synthetic responses of blood lymphocytes from the inbred rat strains BN, Lewis, and AS were compared with each other after stimulation with allogeneic lymphocytes, human lymphocytes, phytohemagglutinin, and anti-Ig antibodies. BN lymphocytes responded less well than AS and Lewis lymphocytes regardless of the stimulus used. The responses of the congenic strains Lewis and Lewis. BN were identical, suggesting that H-1 (Ag-B)-linked loci do not determine in vitro responsiveness in these strains. In vivo, AS and BN rats were equally able to reject third-party skin grafts and to induce graft-versus-host reactions in F1 hybrids. We conclude that the interstrain differences found in vitro reflect genetically determined differences in in vitro kinetics, possibly related to the fraction of short-lived lymphocytes present rather than to demonstrable differences in the frequency of reactive lymphocytes.


Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial.
PROTEA is a randomized controlled trial to assess the efficacy and safety of darunavir/ritonavir (DRV/r) monotherapy as an alternative to triple therapy. Patients fully suppressed on first-line antiretrovirals (viral load < 50 HIV-1 RNA copies/mL) were switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 137) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 136). Treatment failure was HIV-1 RNA level ≥ 50 copies/mL at week 96 or discontinuation of study treatment [Food and Drug Administration (FDA) snapshot algorithm]. Patients were mainly male and white, with mean age 44 years. In the primary efficacy analysis, the percentage of patients with HIV-1 RNA < 50 copies/mL by week 96 [intent to treat (ITT)] was lower in the DRV/r monotherapy arm (103 of 137 patients; 75%) than in the triple therapy arm (116 of 136 patients; 85%) [difference -10.1%; 95% confidence interval (CI) -19.5, -0.7%]. In the switch-included analysis, monotherapy was noninferior to triple therapy. In a post hoc analysis, for patients with nadir CD4 count ≥ 200 cells/μL, rates of HIV-1 RNA suppression were 82 of 96 patients (85%) in the DRV/r monotherapy arm and 88 of 106 patients (83%) in the triple therapy arm. No treatment-emergent primary protease inhibitor mutations were detected in either arm. The frequency of adverse events was similar in the two arms; however, one patient in the monotherapy arm was hospitalized with HIV encephalitis and elevated cerebrospinal fluid HIV-1 RNA. In this study, in patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy vs. triple therapy at week 96 in the primary ITT switch-equals-failure analysis, particularly in patients with CD4 counts < 200 cells/μL.


Premature Atrial Contractions and Their Association with Stroke Features and Outcome.
Frequent premature atrial contractions (PACs) are associated with atrial fibrillation, stroke, and mortality. However, the cut-off value for PAC counts that could identify patients with different stroke features is unclear, and the association of PACs to outcome is not determined. The study retrospectively included patients with acute ischemic stroke who had underwent both a 24 h Holter recording and a brain MRI in Taipei Veterans General Hospital from January 2015 to May 2016. Patients were categorized into four groups according to their PAC frequencies on 24 h Holter recording. We compared the clinical severity, neuroimage features, stroke subtypes, and functional outcome among the four groups of patients. Among the 278 patients, the lower, middle, and upper quartiles of the PAC counts were 23, 74, and 459.5, respectively. In contrast to the 1st quartile of patients, the 3rd (PAC 75-459/24 h) and the 4th (PAC ≥460/24 h) quartiles of patients had higher NIH Stroke Scale (NIHSS) at admission (p = 0.014 and p = 0.002, respectively). The frequencies of cryptogenic stroke were not different among the 4 quartiles of the patients, but cryptogenic stroke patients with ≥ 75PACs/24hours had higher stroke severity compared to those with PACs < 75counts/24 h (NIHSS 9.1 vs. 5.2, p = 0.043). There was an increased trend in infarcts of multiple vascular territories and in mortality at 1 year among the four groups of patients with increased PAC frequency (p = 0.045 and p = 0.002, respectively). The 4th PAC quartile was associated with poor functional outcome (modified Rankin Scale ≥ 4) at 3 months in univariate analysis (OR: 5.66, CI: 2.69-11.91, p < 0.001), but was not an independent predictor after controlling for initial stroke severity. PACs ≥ 75 counts/24 h was associated with higher clinical severity in patients with acute ischemic stroke.


The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1.
Integrins, matrix metalloproteases (MMPs), and the cytokine TGF-beta have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-beta exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-beta. Because the latent domain of TGF-beta1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-beta (SLC) to the cell surface where TGF-beta activation could be locally controlled. Here, we show that SLC binds to alpha(v)beta8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP-dependent release of active TGF-beta, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell-matrix interactions.


Ferritin and body mass index predict cardiac dysfunction in female adolescents with anorexia of the restrictive type.
Decreased left ventricular mass index in anorexia nervosa is amply reported. The aim of this study is to identify non-burdensome predictors of reduced left yentricular mass/height (cLVM) in a cohort of adolescent restrictive anorexic girls. This is a retrospective study of all anorexic girls of the restrictive type referred to our tertiary eating disorder unit between September 2002 and December 2012, for somatic assessment of weig ht loss. All subjects fulfilled DMS-IV criteria, without a family history of cardiac or cardiovascular diseases. In all, 283 restrictive anorexic girls (age: 14.63 +/- 1.65 y; body mass index: 15.72 +/- 1.81 kg/m2) were included. Ferritin and body mass index were independent, statistically significant predictors of the corrected left ventricular mass (P <0.05). Decreased cLVM is very common in anorexia nervosa of the restrictive type. Two factors predicted decreased cLVM in our population: ferritin and BMI.


Treatment of chronic postsurgical osteomyelitis with ciprofloxacin.
Sixteen patients (11F, 5M, age 18-83, mean 59.8 years) with chronic postsurgical osteomyelitis were treated with ciprofloxacin. The dosage was 500 or 750 mg twice daily orally during one to six months; four patients started with 300 mg twice daily intravenously and changed after 3-7 days to oral therapy. Twelve patients had implanted prostheses. The organisms involved were Enterobacteriaceae (11), Pseudomonas aeruginosa (7), Staphylococcus aureus (5), Streptococcus faecalis (4) and Bacteroides fragilis (1). Nine patients had pure cultures, seven mixed cultures. Cure (disappearance of infection symptoms, return of normal function with negative cultures, without resurgery) was obtained in 11 patients, improvement (resurgery required to obtain complete cure) in two. Three patients with infections by Staphylococcus aureus (2) and Pseudomonas aeruginosa (1) failed to respond after one and four months treatment respectively. No side effects were observed.


Cleavage agents for soluble oligomers of human islet amyloid polypeptide.
Soluble oligomers of human islet amyloid polypeptide (h-IAPP) are implicated in the initiation of beta-cell apoptosis leading to type 2 diabetes mellitus (T2DM). Cleavage of the h-IAPP included in an oligomer may provide a novel method for reducing the level of h-IAPP oligomers, offering a new therapeutic option for T2DM. From the combinatorial library of triazine derivatives prepared by exploiting the Co(III) complex of cyclen as the cleavage center for peptide bonds, eight compounds were selected as cleavage agents for oligomers of h-IAPP. After reaction with cleavage agents for 36 h at 37 degrees C and pH 7.50, up to 20 mol% of h-IAPP (initial concentration: 4.0 microM) was cleaved, although the target oligomers existed as transient species. Considerable activity was manifested at agent concentrations as low as 100 nM.


Posterior Circulation Stroke Patients Receive Less Reperfusion Therapy Because of Late Arrival and Relative Contraindications: A Retrospective Study.
Reperfusion treatment (RT) is administered to individuals with posterior circulation strokes (PCS) later and less frequently. We aimed to study the impact of demographic and clinical factors on the decision for RT in PCS. We conducted a retrospective analysis of the data from 500 subjects admitted to the tertiary stroke centre's emergency department between 2018 and 2020 due to PCS. Demographic and clinical factors were analysed among three groups: the RT group, the group with no RT because of absolute contraindications (ACI), and the group with no RT because of relative contraindications (RCI). Of the patients, 202 (40.3%) were female. The median NIHSS was four (4), and the subjects' median age was 69 (18). RT was performed on 120 (24%) subjects. FAST symptoms (OR-5.62, 95% CI [2.90-12.28]) and higher NIHSS (OR-1.13, 95% CI [1.09-1.18]) at presentation, atrial fibrillation (OR-1.56, 95% CI [1.02-2.38]), hypertension (OR-2.19, 95% CI [1.17-4.53]) and diabetes (OR-1.70, 95% CI [1.06-2.71]) increased the chance of RT. Late arrival was the most prevalent ACI for 291 (58.2%) patients. FAST-negative subjects (OR-2.92, 95% CI [1.84-4.77]) and males (OR-1.58, 95% CI [1.11-2.28]) had a higher risk of arriving late. Because of RCI, 50 (10%) subjects did not receive RT; the majority were above 80 and had NIHSS ≤ 5. Subjects with RCI who received the RT had a higher NIHSS (4 vs. 3, p < 0.001), higher hypertension (59 (92.2%) vs. 35 (77.8%), p = 0.032) and heart failure (23 (35.9%) vs. 7 (15.6%), p = 0.018) prevalence. There was a trend for less RT in females with RCI. Late arrival was the most common barrier to RT, and the male gender increased this risk. because of relative contraindications, 10% of subjects were not considered for RT. The presence of FAST symptoms, vascular risk factors, and a higher NIHSS increased the chance of RT.


Controlling the amount of coupling agents on the synthesis of coating antigens to enhance the sensitivity of fluoroquinolone immunodetection.
There is now increasing demand to improve the sensitivity of various immunoassays for fluoroquinolones (FQs) and other food hazards. In this study, different coating antigens were prepared by adjusting the content of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) to explore its influence on the immunoassay sensitivity of FQs. The results indicated that, unlike traditional assumptions, a reasonable EDC dosage should be addressed to reach the best analytical efficiency, and excessive EDC could enhance the hapten-carrier conjugation but significantly reduce the detection sensitivity. For the FQs investigated, the hapten:EDC:BSA proportion of 20:2.5:50 (Mole ratio:74:34:1) seemed the best for preparation of coating antigens, and the sensitivity could be improved more than 1000 times both for indirect competitive enzyme linked immunosorbent assay ELISA (ic-ELISA) and gold immunochromatography assay (GICA) due to two key factors including coupling-ratios and amide bond groups. Such an improved efficiency was also validated well with different food samples, which indicated the reasonable optimization of EDC in coating antigen synthesis may be widely used as a new, simple and more effective strategy to improve the immunoassay for low molecular targets in medical, environment and food detection filed.


Anatomical observation and transcriptome analysis of branch-twisted mutations in Chinese jujube.
Plant organs grow in a certain direction and organ twisted growth, a rare and distinctive trait, is associated with internal structure changes and special genes. The twisted branch mutant of Chinese jujube jujube, an important fruit tree native to China and introduced to nearly 50 countries, provides new typical materials for exploration of plant twisted growth. In this study, the cytological characteristics and related genes of twisted branches in Chinese jujube were revealed by microscopy observation and transcriptome analysis. The unique coexistence of primary and secondary structures appeared in the twisted parts of branches, and special structures such as collateral bundle, cortical bundles, and internal phloem were formed. Ninety differentially expressed genes of 'Dongzao' and its twisted mutant were observed, in which ZjTBL43, ZjFLA11, ZjFLA12 and ZjIQD1 were selected as candidate genes. ZjTBL43 was homologous to AtTBL43 in Arabidopsis, which was involved in the synthesis and deposition of cellular secondary wall cellulose. The attbl43 mutant showed significant inflorescence stem bending growth. The transgenic lines of attbl43 with overexpression of ZjTBL43 were phenotypically normal.The branch twisted growth may be caused by mutations in ZjTBL43 in Chinese jujube. AtIQD10, AtFLA11 and AtFLA12 were homologous to ZjIQD1, ZjFLA11 and ZjFLA12, respectively. However, the phenotype of their function defect mutants was normal. In summary, these findings will provide new insights into the plant organ twisted growth and a reference for investigation of controlling mechanisms of plant growth direction.


Comparing the Ipswich Touch Test (IpTT) and 10gm-SMWF (10-gm Semmes-Weinstein mono-filament) in Indian population subset with type 2 diabetes mellitus to detect diabetes neuropathy.
Diabetic neuropathy diagnosis involves invasive procedures like nerve biopsy and nerve conduction studies which are seldom available at rural health centers. The Ipswich Touch Test (IpTT) is one test that can be performed by the caregiver and it's simple to perform. This study was aimed to compare the validity of the IpTT and 10gm-SMWF (10-gm Semmes-Weinstein mono-filament) test with the vibration perception threshold (VPT) using biothesiometer. Two hundred patients with type 2 diabetes, between the age of 30 and 50 years, were included in the study. The neuropathy assessment was performed by biothesiometer, 10gm-SMWF test, and IpTT. Taking VPT(> 25 V) as the gold standard; the sensitivity and specificity of IpTT and 10gm-SMWF are calculated and compared to each other. On comparing with the VPT, the 10gm-SMWF test had a sensitivity of 94.7% and specificity of 85.7%, and the IpTT had a sensitivity of 91.9% and specificity of 85.7%. 10gm-SMWF test (Kappa value 0.733) had better agreement with VPT than IpTT (Kappa value 0.675). On Spearman's correlation, the 10gm-SMWF test and the IpTT had r values of 0.738 and 0.686 respectively (P = 0.000). 10gm-SMWFis a better test to diagnose neuropathy than the IpTT; but in the absence of 10gm-SMWFs, the IpTT is an ideal alternative. IpTT can be performed in a bedside or chairside setting in the absence of a professional health care provider who can screen patients for neuropathy and alert the physician of an impending complication where amputation can be avoided.


[Bile salt nephropathy/cholemic nephrosis].
Bile cast nephropathy is a tubulo-interstitial nephropathy. Its diagnosis may be under-estimated. It develops in patients who have cholestatic jaundice, with high bilirubinemia. Bile salts are freely filtered through glomerulus. Under certain circumstances, it forms casts into the tubule and cause an acute tubular necrosis. The diagnosis evidence is histologic, but fulfilment of renal biopsy is often made difficult, because of the hemostatic abnormalities that patients with hepatocellular injury develop. The treatment is supportive and etiological. We report here the case of a patient who presented a drug-induced hepatic jaundice, complicated with acute kidney failure secondary to bile cast nephropathy. We present the histological diagnosis evidence.


Domiciliary cockroaches found in restaurants in five zones of Kuala Lumpur Federal Territory, peninsular Malaysia.
The following domiciliary cockroaches were collected from restaurants in five zones of Kuala Lumpur Federal Territory, Malaysia using 1L glass beaker traps baited with ground mouse-pellets: Periplaneta americana (Linnaeus) (n = 820), Periplaneta brunnea Burmeister (n = 46), Blattella germanica (Linnaeus) (n = 12504), Supella longipalpa (Fabricius) (n = 321), Symploce pallens Stephens (n = 29) and Neostylopyga rhombifolia (Stoll) (n = 5). The following bacteria were isolated from 10 cockroach specimens: Enterobacter cloacae, Klebsiella pneumoniae ssp. pneumoniae, Klebsiella pneumoniae ssp. rhinoscleromatis and Serratia liquefaciens from 5 B. germanica; Acinetobacter calcoaceticus var. anitratus, Citrobacter diversus/amalonaticus, Escherichia vulneris and K.p. pneumoniae from 3 P. brunnea; and Citrobacter freundii, Enterobacter agglomerans 4, Escherichia adecarboxylate, E. vulneris, K. p. pneumonia, K. p. rhinoscleromatis and Proteus vulgeris from 2 P. americana.


Distribution of HIV Self-tests by Men Who have Sex with Men (MSM) to Social Network Associates.
Internet-recruited gay, bisexual, and other men who have sex with men (MSM) were offered HIV self-tests (HIVSTs) after completing baseline, 3-, 6-, and 9-month follow-up surveys. The surveys asked about the use and distribution of these HIVSTs. Among 995 who reported on their distribution of HIVSTs, 667 (67.0%) distributed HIVSTs to their social network associates (SNAs), which resulted in 34 newly identified HIV infections among 2301 SNAs (1.5%). The main reasons participants reported not distributing HIVSTs included: wanting to use the HIVSTs themselves (74.9%); thinking that their SNAs would get angry or upset if offered HIVSTs (12.5%); or not knowing that they could give the HIVSTs away (11.3%). Self-testing programs can provide multiple HIVSTs and encourage the distribution of HIVST by MSM to their SNAs to increase awareness of HIV status among persons disproportionately affected by HIV.


Lidocaine stabilizes the open state of CNS voltage-dependent sodium channels.
We have previously reported that the lidocaine action is different between CNS and muscle batrachotoxin-modified Na+ channels [Salazar et al., J. Gen. Physiol. 107 (1996) 743-754; Brain Res. 699 (1995) 305-314]. In this study we examined lidocaine action on CNS Na+ currents, to investigate the mechanism of lidocaine action on this channel isoform and to compare it with that proposed for muscle Na+ currents. Na+ currents were measured with the whole cell voltage clamp configuration in stably transfected cells expressing the brain alpha-subunit (type IIA) by itself (alpha-brain) or together with the brain beta(1)-subunit (alphabeta(1)-brain), or the cardiac alpha-subunit (hH1) (alpha-cardiac). Lidocaine (100 microM) produced comparable levels of Na+ current block at positive potentials and of hyperpolarizing shift of the steady-state inactivation curve in alpha-brain and alphabeta(1)-brain Na+ currents. Lidocaine accelerated the rates of activation and inactivation, produced an hyperpolarizing shift in the steady-state activation curve and increased the current magnitude at negative potentials in alpha-brain but not in alphabeta(1)-brain Na+ currents. The lidocaine action in alphabeta(1)-brain resembled that observed in alpha-cardiac Na+ currents. The lidocaine-induced increase in current magnitude at negative potentials and the hyperpolarizing shift in the steady-state activation curve of alpha-brain, are novel effects and suggest that lidocaine treatment does not always lead to current reduction/block when it interacts with Na+ channels. The data are explained by using a modified version of the model proposed by Vedantham and Cannon [J. Gen. Physiol., 113 (1999) 7-16] in which we postulate that the difference in lidocaine action between alpha-brain and alphabeta(1)-brain Na+ currents could be explained by differences in the lidocaine action on the open channel state.


CT versus MR Imaging in Estimating Cochlear Radiation Dose during Gamma Knife Surgery for Vestibular Schwannomas.
Leksell stereotactic radiosurgery is an effective option for patients with vestibular schwannomas. Some centers use a combination of stereotactic CT fused with stereotactic MR imaging to achieve an optimal target definition as well as minimize the radiation dose delivered to adjacent structures that correlate with hearing outcomes. The present prospective study was designed to determine whether there is cochlear dose variability between MR imaging and CT. Fifty consecutive patients underwent stereotactic radiosurgery for vestibular schwannomas. Dose-planning was performed using high-definition fused stereotactic MR imaging and stereotactic CT images. The 3D cochlear volume was determined by delineating the cochlea on both CT and T2-weighted MR imaging. The mean radiation dose, maximum dose, and 3- and 4.20-Gy cochlear volumes were identified using standard Leksell Gamma Knife software. The median mean radiation dose delivered to the cochlea was 3.50 Gy (range, 1.20-6.80 Gy) on CT and 3.40 Gy (range, 1-6.70 Gy) on MR imaging (concordance correlation coefficient = 0.86, r 2 = 0.9, P ≤ .001). The median maximum dose delivered to the cochlea was 6.7 Gy on CT and 6.6 Gy on MR imaging (concordance correlation coefficient = 0.89, r 2 = 0.90, P ≤ .001). Dose-volume histograms generated from CT and MR imaging demonstrated a strong level of correlation in estimating the 3- and 4.20-Gy volumes (concordance correlation coefficient = 0.81, r 2 = 0.82, P ≤ .001 and concordance correlation coefficient = 0.87, r 2 = 0.89, P ≤ .001). Both MR imaging and CT provide similar cochlear dose parameters. Despite the reported superiority of CT in identifying bony structures, high-definition MR imaging alone is sufficient to identify the radiation doses delivered to the cochlea.


Intra-carotid angiotensin II activates tyrosine hydroxylase-expressing rostral ventrolateral medulla neurons following blood-brain barrier disruption in rats.
Angiotensin II (Ang II) in the periphery and within the brain plays important roles in blood pressure control. Circulating angiotensin is normally excluded from the brain by the blood-brain barrier (BBB), but there is evidence that in some diseases there is disruption of the BBB that could allow circulating Ang II to access nuclei from which it is normally excluded, such as the rostral ventrolateral medulla (RVLM). We therefore investigated whether disruption of the BBB leads to increased activation by circulating Ang II of tyrosine hydroxylase (TH)-containing neurons in the RVLM. In anaesthetised rats, in which the BBB was disrupted with intracarotid hypertonic mannitol (1.6M, 2mL/kg), subsequent intracarotid infusion of a subpressor dose of Ang II (5ng/kg) activated ∼24% of TH-containing RVLM neurons whereas saline only activated ∼8% of TH neurons. Intracarotid pretreatment with the Ang II receptor type 1 (AT1R) blocker, losartan (20μg/kg), significantly reduced the number of TH cells activated to ∼11% (P<0.05, one-way analysis of variance, n=5). In summary, disruption of the BBB resulted in increased activation by circulating Ang II of TH-containing cells in the RVLM. The activation was reduced by losartan indicating a specific action on AT1Rs. These results suggest that disruption of the BBB allows entry of circulating Ang II into the RVLM, which could increase sympathetic outflow. This potential source of Ang II within the RVLM might be an important consideration when assessing sympathetic nerve activity in disease states associated with a compromised BBB.


[Effect of brain edema on the recurrence pattern of malignant gliomas].
To assess the influence of initial preoperative brain edema in malignant gliomas on regrowth patterns. 79 patients with histologically verified supratentorial malignant glioma were prospectively studied by magnetic resonance imaging (MRI) before and every 2-3 months after surgery. The median follow-up time was 11 months. We correlated the configuration of the initial vasogenic edema on T2-weighted images with tumor regrowth patterns on contrast-enhanced T1-weighted images. 35/47 tumor regrowths (75%) imitated the initial edema configuration, while 11/47 occurred within the initial tumor bed; in one case tumor recurrence was multilocal. In glioblastoma, tumor regrowth patterns correlate positively with the configuration of the initial vasogenic brain edema. The initial, "presurgical" peritumoral edema should thus be considered when planning further treatment.


Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity.
A novel heterodimeric three-finger neurotoxin, irditoxin, was isolated from venom of the brown treesnake Boiga irregularis (Colubridae). Irditoxin subunit amino acid sequences were determined by Edman degradation and cDNA sequencing. The crystal structure revealed two subunits with a three-finger protein fold, typical for "nonconventional" toxins such as denmotoxin, bucandin, and candoxin. This is the first colubrid three-finger toxin dimer, covalently connected via an interchain disulfide bond. Irditoxin showed taxon-specific lethality toward birds and lizards and was nontoxic toward mice. It produced a potent neuromuscular blockade at the avian neuromuscular junction (IC(50)=10 nM), comparable to alpha-bungarotoxin, but was three orders of magnitude less effective at the mammalian neuromuscular junction. Covalently linked heterodimeric three-finger toxins found in colubrid venoms constitute a new class of venom peptides, which may be a useful source of new neurobiology probes and therapeutic leads.


DNA binding hairpin polyamides with antifungal activity.
Eight-ring hairpin polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids have been shown to bind with subnanomolar affinity to discrete DNA sites and to modulate a variety of DNA-dependent biological processes. We show here that addition of a second positive charge at the C terminus of an 8-ring hairpin polyamide confers activity against a number of clinically relevant fungal strains in vitro, and activity against Candida albicans in a mouse model. Control experiments indicate that the observed antifungal activity results from a DNA binding mechanism-of-action that does not involve DNA damage or disruption of chromosomal integrity. Hairpin activity is shown to be proportional to yeast DNA content (ploidy). Transcriptional interference is proposed as the likely explanation for fungal cytotoxicity. Experiments with sensitized yeast strains indicate the potential for discrete sites of action rather than global effects.


Predicting loss of height in surgically treated displaced intra-articular fractures of the calcaneus.
The goal of calcaneal fracture surgery is to restore its anatomy and good foot function. However, loss of height of the subtalar joint can occur post-operatively, as expressed by a decrease in Böhler's angle (BA). The aim of this study was to identify potential factors associated with a post-operative decrease in BA. All consecutive adult patients treated with open reduction and internal fixation (ORIF) by an extended lateral approach (ELA) between 2000 and 2013 were retrospectively included. Primary outcome was the occurrence of a calcaneal collapse, defined as a postoperative decrease of ≥10° in BA. The BA was measured pre-operatively, directly following surgery and at one year follow-up. Patient characteristics (body mass index, diabetes mellitus, smoking/alcohol/substance abuse, American Society of Anaesthesiologist classification), fracture classification and treatment characteristics: per-operative increase in BA and occurrence of post-operative wound infection (POWI) were collected. A total of 262 patients with 276 calcaneal fractures were included. A calcaneal collapse occurred in 46 cases (17%). The median preoperative BA, per-operative increase in BA and post-operative decrease in BA were, respectively, 2°, 27° and 4°. A calcaneal collapse was seen more often following a per-operative increase of >25° in BA, but no significant association was found (p = 0.056). Uni- and multivariate analysis showed that patients with substance abuse and those with POWI had significantly more calcaneal collapse (p < 0.05). No association was found between substance abuse and the occurrence of POWI (p = 0.293). In nearly one in six patients with an intra-articular calcaneal fracture treated with ORIF by an ELA, a post-operative collapse of ≥10° was found during follow-up. Calcaneal collapse was correlated with the occurrence of a POWI and substance abuse.


Distributions of serum thyroid-stimulating hormone in 2020 thyroid disease-free adults from areas with different iodine levels: a cross-sectional survey in China.
The aim of the present study was to describe the distributions of serum thyroid- stimulating hormone (TSH) levels in thyroid disease-free adults from areas with different iodine levels in China. Meanwhile, we aimed to evaluate the influence of age and gender on the distribution of TSH, assess the relationship between concentrations of TSH and free thyroxine (FT4), and analyze the factors that may affect TSH levels. 2020 adults were included from April 2016 to June 2019. Urinary iodine concentration, serum iodine concentration, serum TSH, FT4, free triiodothyronine, thyroid peroxidase antibodies and thyroglobulin antibodies were measured, and thyroid ultrasonography was performed. The median of TSH in iodine-fortification areas (IFA), iodine-adequate areas (IAA), iodine-excessive areas (IEA) were 2.32, 2.11 and 2.34 mIU/L, respectively. Serum TSH concentrations were significantly higher in IFA and IEA than that in IAA (p = 0.005 and < 0.0001). The TSH values of most adults were distributed within the range of 1.01-3.00 mIU/L with the same trend in three groups. In our study, TSH levels did not change with age, and the TSH level of females was higher than that of males (p < 0.0001). There was a negative correlation between FT4 and TSH in IAA (r = - 0.160, p < 0.0001) and IEA (r = - 0.177, p < 0.0001), but there was no correlation between FT4 and TSH in IFA (r = - 0.046, p = 0.370). BMI, smoking status, education levels, and marital status were associated with TSH. Our study provides a basis for establishing the reference intervals of TSH in different iodine level areas.


4-(4-Fluoro-phen-yl)-6-methyl-amino-5-nitro-2-phenyl-4H-pyran-3-carbo-nitrile.
In the title compound, C19H14FN3O3, the central pyran ring adopts a boat conformation with the O atom and the quaternary C atom diagonally opposite displaced by 0.068 (1) and 0.075 (1) Å, respectively, above the mean plane defined by the other four ring atoms. The co-planar atoms of the pyran ring and the fluoro-phenyl ring are nearly perpendicular, as evidenced by the dihedral angle of 87.11 (1)°. The amine group forms an intra-molecular N-H⋯O(nitro) hydrogen bond. In the crystal, mol-ecules are linked into parallel chains along [100] by weak N-H⋯N and C-H⋯N(nitro) hydrogen bonds, generating C(8) and C(9) graph-set motifs, respectively.