Factor VIII inhibitor development in Egyptian hemophilia patients: does intron 22 inversion mutation play a role?
Hemophilia A (HA) is an X-linked recessive bleeding disorder characterized by qualitative and quantitative deficiency of factor VIII (FVIII). The development of inhibitor antibodies against FVIII is the most challenging complication of treatment. Mutations in the FVIII gene is one of the genetic factors that leads to development of FVIII inhibitors especially intron 22 inversion (Inv22). This study was carried out to assess the frequency of Inv22 of FVIII gene in Egyptian patients with hemophilia A and its role as a risk factor for developing inhibitors. Seventy-two patients with severe HA and 48 patients with moderate HA were enrolled in the current study. All patients were treated on demand with either plasma-derived factor VIII or recombinant factor VIII concentrates. Genotyping of FVIII Inv22 was performed by LD-PCR while the presence and magnitude of inhibitor activity in blood was determined by the Bethesda assay. Around 23% of all hemophilia cases had positive Inv22. Intron 22 inversion mutation was detected in 6 and 33% of patients with moderate and severe HA respectively. Twenty-one cases (18%) of all hemophilic patients developed inhibitors. Thirty-7% of patients with Inv22 had inhibitor in their blood, almost all, but one, had severe HA. The risk of an inhibitor development during replacement therapy was four folds higher among Inv22 positive cases as compared with mutation negative peers (OR 4.3, 95% CI 1.6-11.9, P = 0.003). The prevalence of Inv22 of F VIII in Egyptian hemophiliacs is nearly like that of other population. This mutation was more frequently detected among severe hemophilic patients as compared with moderately affected peers. The presence of Inv22 mutation significantly predispose to FVIII inhibitor development.


Determination of five mTOR inhibitors in human plasma for hepatocellular carcinoma treatment using QuEChERS-UHPLC-MS/MS.
A fast and reliable QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method for pre-processing combined with Ultra - high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS) was established for the analysis of five mammalian rapamycin target protein (mTOR) inhibitors (vistusertib, AZD8055, pictilisib, everolimus, temsirolimus)in human plasma. Extraction was achieved by addition of acetonitrile to the sample followed by anhydrous magnesium sulfate and 30 mg C18 for salting out and purification, respectively. MTOR inhibitors were detected using selective response monitoring (SRM) under positive ion electrospray mode. Vistusertib, AZD8055 and pictilisib showed good linearity with a range of 1-80 ng/ml, Additionally, the concentration of everolimus and temsirolimus was 2.5-200 ng/ml and10-800 ng/ml, respectively. The linear correlation coefficient (R2) of each analysis was ≥ 0.9950. The limit of detection (LOD) and Limit of Quantitation (LOQ) were 0.015-0.75 ng/ml and 1-10 ng/ml, respectively. This method showed a high accuracy with high recovery rate and excellent stability. This method is fast, accurate and reliable, suitable for quantitative detection of mTOR inhibitors in human plasma.


Environmental impact and potential use of coal fly ash and sub-economical quarry fine aggregates in concrete.
The Israeli quarry industry produces 57 Mt of raw material and ∼4-6Mt of associated sub-economical by-products annually. These sub-economical quarry fines are not used because production and transportation costs considerably exceed their retail value. Therefore these by-products, are stored in large piles of fine grain size particles, create environmental risks to their surrondings. This paper evaluates the possibility of mixing the sub-economical quarry by-products of two Israeli quarries with sub-economical Class F coal fly ash (<20wt.% CaO) to form an economical aggregate sand substitute to be used as a concrete filler product. To study the feasibility of the aggregate as partial substitute to sand in concrete several analyses, including leaching experiements (EN12457-2), analytical techinques (SEM-EDX, ICP-MS, ICP-AES, and XRD), as well as an analysis of the mechanical and chemical properties of the concrete aggregate (strength, workability, and penetration) were performed. Scrubbing quarry waste with coal fly ash was found to be very effective for reducing the leaching rate of potentially harmful trace elements. In addition, adding fly ash with quarry fines as partial substitute to sand enhanced the performance of the concrete mixture and the properties of the fresh and harden concrete.


Radial artery perforator flap and external fixation after gunshot injuries in a 10-year-old boy.
Air-powered guns can cause serious trauma to body structures. We describe a 10-year-old boy who suffered injuries to his gluteal and thenar regions as a result of a single gunshot. Surgical management included cleansing of the gluteal region, as well as an external fixation device and a fasciosubcutaneous flap based on a perforator branch of the distal radial artery. To the best of our knowledge, this case illustrates the youngest patient to benefit from this kind of perforator flap. We also underline the long-term risk of lead toxicity for this kind of injury.


Introduction to Bioinformatics Resources for Post-transcriptional Regulation of Gene Expression.
Untranslated regions (UTRs) and, to a lesser extent, coding sequences of mRNAs are involved in defining the fate of the mature transcripts through the modulation of three primary control processes, mRNA localization, degradation and translation; the action of trans-factors such as RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) combined with the presence of defined sequence and structural cis-elements ultimately determines translation levels. Identifying functional regions in UTRs and uncovering post-transcriptional regulators acting upon these regions is thus of paramount importance to understand the spectrum of regulatory possibilities for any given mRNA. This tasks can now be approached computationally, to reduce the space of testable hypotheses and to drive experimental validation.This chapter focuses on presenting databases and tools allowing to study the various aspects of post-transcriptional regulation, including motif search (sequence and secondary structure), prediction of regulatory networks (e.g., RBP and ncRNA binding sites), profiling of the mRNAs translational state, and other aspects of this level of gene expression regulation. Two analysis pipelines are also presented as practical examples of how the described tools could be integrated and effectively employed.


[UPLC Fingerprint of Gentiana officinalis Root].
To establish UPLC fingerprints of Gentiana officinalis root and Gentiana macrophylla root,and to evaluate the similarity of the fingerprints,in order to provide theoretical basis for the quality control of Gentiana officinalis root. The separation was performed on an ACQUITY UPLC~BEH C18column( 50 mm × 2. 1 mm,1. 7 μm) through a gradient elution of methanol-0. 04% aqueous phosphoric at a flow rate of 0. 3 m L/min. The detection wavelength was 242 nm, and the column temperature was set at30 ℃. Similarity evaluation system for chromatographic fingerprint of TCM( Version 2004 A) was used to analyze the fingerprints. 13 common peaks were selected as the fingerprint peaks from 13 batches of Gentiana officinalis root samples, with the similarities between 0. 976 to 0. 997, and Gentiana macrophylla root used for fingerprint applicability test has high similarity( 0. 998) with Gentiana officinalis root. This method with good precision and reliability should be used for the quality control of Gentiana officinalis root.


A novel method for calculating beta band burst durations in Parkinson's disease using a physiological baseline.
Pathologically prolonged bursts of neural activity in the 8-30 Hz frequency range in Parkinson's disease have been measured using high power event detector thresholds. This study introduces a novel method for determining beta bursts using a power baseline based on spectral activity that overlapped a simulated 1/f spectrum. We used resting state local field potentials from people with Parkinson's disease and a simulated 1/f signal to measure beta burst durations, to demonstrate how tuning parameters (i.e., bandwidth and center frequency) affect burst durations, to compare burst duration distributions with high power threshold methods, and to study the effect of increasing neurostimulation intensities on burst duration. The baseline method captured a broad distribution of resting state beta band burst durations. Mean beta band burst durations were significantly shorter on compared to off neurostimulation (p = 0.0046), and their distribution shifted towards that of the 1/f spectrum during increasing intensities of stimulation. High power event detection methods, measure duration of higher power bursts and omit portions of the neural signal. The baseline method captured the broadest distribution of burst durations and was more sensitive than high power detection methods in demonstrating the effect of neurostimulation on beta burst duration. The baseline method captured a broad range of fluctuations in beta band neural activity and demonstrated that subthalamic neurostimulation shortened burst durations in a dose (intensity) dependent manner, suggesting that beta burst duration is a useful control variable for closed loop algorithms.


Sediment deposition rate in the Falefa River basin, Upolu Island, Samoa.
The (137)Cs method was employed to investigate the recent historical rate of sediment deposition on a lowland alluvial floodplain in the Falefa River basin, Upolu Island, Samoa. Caesium stratigraphy in the floodplain sediment profile was clearly defined, with a broad peak at 145-175 cm depth. The measured rate of vertical accretion over the last 40 years is 4.0+/-0.4 cm per year. This rate exceeds observations in humid environments elsewhere, but is similar to that recorded on other tropical Pacific Islands. Available flow data for the Vaisigano River in Samoa give a 'near-catastrophic' index value of 0.6 for flood variability. This is associated with the occurrence of tropical cyclones and storms in the Samoa area. Large floods therefore probably contribute to the high rate of floodplain sedimentation on Upolu Island. A small but growing body of evidence suggests that fluvial sedimentation rates on tropical Pacific islands are some of the highest in the world.


Free fibula flap for humerus segmental reconstruction: report on 13 cases.
In the period between 1994 and 2004, 13 patients (10 male, 3 female) presenting with post-traumatic defects to the humerus were treated with vascularised fibula graft. Age ranged from 21 to 62 (mean 37) years. Length of the bony defect ranged from 6 to 16 cm. Graft fixation was performed with plates in 12 cases, and in one case only screws were used. All patients were clinically reviewed between 120 days and 14 months after surgery. In one patient the flap was lost and a second free fibula flap was performed to achieve the reconstructive goal. Mean time for segmental bony union was 6 months (range from 3 to 13 months). Vascularised fibula graft allows for a successful humerus reconstruction when traditional techniques provide unsatisfactory results.


Ultraviolet mutagenesis in human lymphocytes: the effect of cellular transformation.
We have assessed the role of cellular transformation in ultraviolet (uv)-induced mutagenic events in human cells. To maintain uniformity of genetic background and to eliminate the effect of DNA repair, primary nontransformed lymphocytes (T-cells) and Epstein-Barr virus-transformed lymphocytes (B-cells) from one patient (XP12Be) with the DNA repair-deficient disorder xeroderma pigmentosum (group A) were transfected with the mutagenesis shuttle vector pZ189. Parallel control experiments were performed with primary, nontransformed lymphocytes from a normal individual and with a repair-proficient Epstein-Barr virus-transformed lymphocyte line (KR6058). pZ189 was treated with uv and introduced into the four cell lines by electroporation. Plasmid survival and mutations inactivating the marker supF suppressor tRNA gene in the recovered pZ189 were scored by transforming an indicator strain of Escherichia coli. Plasmid survival was reduced and mutation frequency elevated equally with both XP-A cell lines compared to both normal cell lines. Base sequence analysis of more than 250 independent plasmids showed that while the G:C----A:T base substitution mutation was found in at least 60% of plasmids with single or tandem mutations with all four cell lines, the frequency with the transformed XP-A (93%) cells was significantly higher (P less than 0.01) than that with the nontransformed XP-A cells (77%). In addition, with the transformed XP-A cells, there were significantly fewer plasmids with transversions and with mutations at a transversion hotspot (base pair 134) than with plasmids recovered from nontransformed XP-A cells. Interleukin-2 and phytohemagglutinin (used to maintain growth of the nontransformed lymphocytes) treatment of transformed XP12Be cells did not change overall plasmid survival or mutation frequency, but increased the transversion frequency and induced a mutational hotspot (at base pair 159), while another mutational hotspot (at base pair 123) disappeared. Thus we have demonstrated that in repair-deficient human cells, cellular transformation, while not affecting overall postuv plasmid survival and mutation frequency, does increase the susceptibility to G:C----A:T transition mutations, a type of mutation associated with uv-induced neoplasia.


Erosion of psoriatic plaques after chronic methotrexate administration.
A 43-year-old white man developed a shallow erosion of a psoriatic plaque after chronic administration of methotrexate. This unusual cutaneous sign may be the first sign of methotrexate toxicity.


The effect of the pandemic period on Bladder Pain Syndrome patients under amitriptyline treatment.
COVID-19 is a disease that may cause anxiety, depression, and stress. Bladder pain syndrome (BPS) is a disease in which stress and psychological factors might negatively affect its course. In this study, we aimed to examine the possible clinical aggregation of the pandemic period on BPS patients. A total of 35 BPS patients diagnosed between 2010 and 2018 were included. All patients were using medical treatment, and the follow-up period was at least 6 months. According to our clinical follow-up protocol, the BPS patients were given the King's Health Questionnaire (KHQ), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Overactive Bladder Form V8 (OAB-V8), and Visual Analog Score (VAS) in every visit. In the sixth month of the pandemic, the clinical course of the patients was questioned by telephone or video interview, and their treatment continuities were questioned. Information was received about the delays in their follow-up and the difficulties in accessing healthcare opportunities. The same questionnaires were filled out and compared with pre-pandemic scores. The mean age of the patients included in the study was 50.2 ± 13.32 (min:20, max:74), 11 were males and 24 were females. The mean follow-up periods were 71.8 ± 35.6 months. All questionnaire scores showed an increase compared to the pre-pandemic period. A statistically significant increase was detected during the pandemic in all sub-units of the KHQ. The VAS and OAB-V8 scores of 16 patients who requested hospital admission were significantly higher than before the pandemic. However, there was no statistically significant difference in the increase in VAS and OAB-V8 scores of the 19 patients who refused to come to the hospital. BPS patients have been negatively affected by the emotional effects of the COVID-19 pandemic. Due to the fear, stress, anxiety, and depression, the symptoms of BPS patients exacerbated, and the patients could not receive the necessary support due to a lack of regular follow-ups.


3D-Quantitated Single Photon Emission Computed Tomography/Computed Tomography: Impact on intended Management Compared to Lung Perfusion Scan in Marginal Candidates for Pulmonary Resection.
Based on previous studies, single-photon emission computed tomography/computed tomography (SPECT/CT) has been proven more accurate and reproducible than planar lung perfusion scintigraphy to assess lobar perfusion. However, the impact of 3D-quantitated SPECT/CT on intended management in functionally marginal candidates for pulmonary resection is unknown. The evaluation of this impact was the main aim of this study. Consecutive candidates for lung resection underwent preoperative evaluation according to ERS/ESTS Algorithm and underwent preoperative lung perfusion imaging. The lobar contribution to the total lung perfusion was estimated using established planar scintigraphic methods and 3-dimensional quantitative SPECT/CT method (CT Pulmo3D and xSPECT-Quant, Siemens). The difference in estimated lobar perfusion with resulting changes in predicted postoperative (ppo) lung function and extent of lung resection were analyzed to reveal possible changes in operability. In-hospital outcome was assessed. One hundred twenty patients (46 females) were enrolled. The mean age (±SD) of patients was 68 ± 9 years, target lesions were in upper lobes in 57.7% and in lower lobes in 33.5%. The median FEV1 (forced expiratory volume in 1 second) was 70.5% (IQR 52-84) and median DLCO (diffusion capacity of lung for carbon monoxide) was 56.6% [47.1-67.4]. The planar posterior oblique method, compared to 3D-quantitated SPECT/CT, underestimated the perfusion of upper lobes by a median difference of 5% (right [2-9], left [2.5-8]; P = <.0001), while it overestimated the perfusion of lower lobes (left by 4% [2-7], right by 6% [2-9]; P = <.0001). In contrast to planar scintigraphy-based evaluation, 4 patients (3.3%), all with upper lobe lesions, were classified as inoperable when 3D-quantitated SPECT/CT was used for calculation of the ppo lung function. In selected patients with upper lobe lesions, 3D-quantitated SPECT/CT would have changed the treatment strategy from operable to inoperable. Importantly, postoperative mortality in this particular subgroup was disproportionally high. 3D-quantitated SPECT/CT shall be further evaluated as it might improve preoperative risk stratification in functionally marginal candidates.


Saccular cysts: a current review of characteristics and management.
To review a large cohort of adult saccular cyst patients and update current management of saccular cysts. Retrospective review of treatment of adult patients with saccular cysts. Medical records were reviewed of all adult patients with saccular cysts identified between July 1, 2005 and August 31, 2009 at a tertiary care voice center. Sixteen patients were identified. All complained of dysphonia. Saccular cysts were predominantly left-sided (62.5%). The majority were anterior (85.7%); 14.3% were combined anterior/lateral. There were no isolated lateral saccular cysts. Surgical intervention was performed in 13 patients (81%); 100% were endoscopic. No patient required an external approach. Two patients recurred (15%), both within 2 months, and were managed conservatively. Saccular cyst is uncommonly encountered but can cause debilitating or even life-threatening symptoms. Over time, management of these lesions has changed dramatically. With current, improved endoscopic techniques, most saccular cysts can be managed endoscopically with great success rates, often without the need for an external approach.


Genetics implicates overactive osteogenesis in the development of diffuse idiopathic skeletal hyperostosis.
Diffuse idiopathic skeletal hyperostosis (DISH) is a condition where adjacent vertebrae become fused through formation of osteophytes. The genetic and epidemiological etiology of this condition is not well understood. Here, we implemented a machine learning algorithm to assess the prevalence and severity of the pathology in ~40,000 lateral DXA scans in the UK Biobank Imaging cohort. We find that DISH is highly prevalent, above the age of 45, ~20% of men and ~8% of women having multiple osteophytes. Surprisingly, we find strong phenotypic and genetic association of DISH with increased bone mineral density and content throughout the entire skeletal system. Genetic association analysis identified ten loci associated with DISH, including multiple genes involved in bone remodeling (RUNX2, IL11, GDF5, CCDC91, NOG, and ROR2). Overall, this study describes genetics of DISH and implicates the role of overactive osteogenesis as a key driver of the pathology.


Changes in soymilk during fermentation with kefir culture: oligosaccharides hydrolysis and isoflavone aglycone production.
The objective of this study was to evaluate the changes in oligosaccharides and isoflavone aglycone content in soymilk during fermentation with commercial kefir culture. Soymilk was fermented with kefir culture at 25 °C for 30 h. The counts of lactic acid bacteria, Lactococcus lactis, Leuconostoc sp and yeasts; measurements of pH, acidity, α-galactosidase and β-glucosidase activity, sugar and isoflavone contents were performed at the intervals of time. In the fermented soymilk, the lactic acid bacteria counts increased from 7.6 log to 9.1 CFU g(-1), pH reached to 4.9 and lactic acid reached 0.34 g 100 g(- 1). The α-galactosidase was produced (0.016 AU g(-1)) with 100% raffinose and 92% stachyose hydrolysis being observed after the depletion of galactose, glucose and sucrose. Kefir culture produced β-glucosidase (0.0164 AU g(-1)), resulting in 100% bioconversion of glycitin and daidzin and 89% bioconversion of genistin into the corresponding aglycones. The fermented soymilk presented 1.67 μmol g(-1) of daidzein, 0.28 μmol g(-1) of glicitein and 1.67 μmol g (-1) of genistein.


The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The ionotropic glutamate receptors are classified into two groups, NMDA (N-methyl-D-aspartate) receptors and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors. The AMPA receptor is a ligand-gated cation channel that mediates the fast component of excitatory postsynaptic currents in the central nervous system. Here we report that AMPA receptors function not only as ion channels but also as cell-surface signal transducers by means of their interaction with the Src-family non-receptor protein tyrosine kinase Lyn. In the cerebellum, Lyn is physically associated with the AMPA receptor and is rapidly activated following stimulation of the receptor. Activation of Lyn is independent of Ca2+ and Na+ influx through AMPA receptors. As a result of activation of Lyn, the mitogen-activated protein kinase (MAPK) signalling pathway is activated, and the expression of brain-derived neurotrophic factor (BDNF) messenger RNA is increased in a Lyn-kinase-dependent manner. Thus, AMPA receptors generate intracellular signals from the cell surface to the nucleus through the Lyn-MAPK pathway, which may contribute to synaptic plasticity by regulating the expression of BDNF.


Women's experience of unplanned out-of-hospital birth in Sweden - a phenomenological description.
Between 0.5 and 2 percent of women planning to give birth in a hospital environment in Sweden will have an unplanned out-of-hospital birth. Few studies have described mothers' experiences of out-of-hospital births and none on a Swedish population. In an attempt to fill this gap, we have made this pilot study designed to capture mothers' experiences of unplanned out-of-hospital births in Sweden. Qualitative interviews with eight Swedish women, one to three years after they experienced an unplanned out-of-hospital birth. Data were analysed using the method of phenomenological description. The meaning of giving unplanned birth outside a hospital environment was "The lived experience of a pendular movement between the good fortune and pride in managing the situation and the fear of what could have happened when giving unplanned birth outside a hospital environment." In the analysis two clusters emerged that supported the essence: Balancing Emotions and Handling Unfamiliar Actions. This study contributes to an understanding of the natural processes when giving birth. The findings can be useful when communicating the experience of unplanned out-of-hospital birth to parents in antenatal classes. The women could be encouraged to listen and trust their own body signs as a preparation for giving birth in any type of setting. Guidelines for taking care of women with out-of-hospital birth experiences are suggested.


Investigation of extremely low-frequency (1 Hz-400 kHz) pollution frequently encountered in social life: a case study of a shopping mall.
It is important to periodically measure, analyze, and map electromagnetic radiation levels due to potential risks. This study aims to draw attention to new electromagnetic pollution caused by radio frequencies and extremely low frequencies. For this reason, electric field and magnetic field measurements were carried out in the 1-Hz-400-kHz frequency band in a shopping mall, where electronic devices cause low-frequency electromagnetic radiation intensively. The measurements were performed with the EHP-50F device for 24 h a day for a week. The measurements were made at 10 points in the shopping mall, and the measurement results were evaluated over five different sectors: electronics, clothing and accessories (male-female), personal care and cosmetics, supermarket, and the playland for children. Magnetic maps of each sector were produced. In addition, the specific absorption rates (SAR) of male and female customers in these workplaces were determined. This is the first study carried out to find SAR caused by low-frequency radiation. Although the safe limit value of SAR for the whole body is 0.08 W/kg, the SAR values calculated in the playland and electronics sectors were obtained to be 0.763 and 0.39 W/kg, respectively. Results clearly demonstrate how especially small children are exposed to danger in the long term.


[Force-based local navigation in robot-assisted implantation bed anlage in the lateral skull base. An experimental study].
Excellent precision, miss of retiring, reproducibility are main characteristics of robots in the operating theatre. Because of these facts their use for surgery in the lateral scull base is of great interest. In recent experiments we determined process parameters for robot assisted reaming of a cochlea implant bed and for a mastoidectomy. These results suggested that optimizing parameters for thrilling with the robot is needed. Therefore we implemented a suitable reaming curve from the geometrical data of the implant and a force controlled process control for robot assisted reaming at the lateral scull base. Experiments were performed with an industrial robot on animal and human scull base specimen. Because of online force detection and feedback of sensory data the reaming with the robot was controlled. With increasing force values above a defined limit feed rates were automatically regulated. Furthermore we were able to detect contact of the thrill to dura mater by analyzing the force values. With the new computer program the desired implant bed was exactly prepared. Our examinations showed a successful reaming of an implant bed in the lateral scull base with a robot. Because of a force controlled reaming process locale navigation is possible and enables careful thrilling with a robot.


Comparison of different endoscopic resection techniques for submucosal tumors originating from muscularis propria at the esophagogastric junction.
To compare the outcomes of submucosal tunneling endoscopic resection (STER) and submucosal excavation (ESE) for the treatment of submucosal tumors (SMTs) arising from the muscularis propria (MP) at the esophagogastric junction (EGJ). A retrospective analysis of patients with SMTs at EGJ who underwent STER and ESE from October 2011 to October 2017 was performed. The outcomes evaluated were operation time, complete resection rate, adverse events, and tumor recurrence. Ninety patients were included in this study. Complete resection rates in the STER group were higher than those of the ESE group (100 vs. 92%, p < 0.05). For tumors ≤15 mm, both techniques achieved 100% complete resection rate; but for tumors > 15 mm, complete resection rate was higher in the STER group than the ESE group (100% vs. 77.8%, p < 0.05). Subgroup analyses revealed that the operation time of STER for in cardiac-gastric group was longer than that for ESE (145.14 ± 42.43 min vs. 70.32 ± 39.84 min, p < 0.05). The air leakage symptoms were more frequent in STER group (90.9% vs. 50.0%, p < 0.05). No tumor recurrence occurred in both the STER and ESE groups. For SMTs ≤15 mm, both STER and ESE have similar satisfactory therapeutic outcomes. However, in the cardiac-gastric subgroup, STER had a longer operative time compared to the ESE procedure. For SMTs > 15 mm, STER is the preferred choice due to its higher complete resection rate.


2-(Naphthalen-2-yl-oxy)-N'-[2-(naphthalen-2-yl-oxy)acet-yl]acetohydrazide monohydrate.
The title compound, C24H20N2O4·H2O, crystallizes with half a mol-ecule of 2-(naphthalen-2-yl-oxy)-N'-[2-(naphthalen-2-yl-oxy)acet-yl]acetohydrazide and half a water mol-ecule in the asymmetric unit. In the crystal, mol-ecules form planes parallel to (011). Two mol-ecules are connected by water mol-ecules via O-H⋯O and N-H⋯O hydrogen bonds.


Clinical and epidemiologic characteristics of Mycobacterium haemophilum, an emerging pathogen in immunocompromised patients.
To describe 13 infections caused by Mycobacterium haemophilum. Identification of patients by microbiologic record review, followed by medical record review and a case-control study. Seven metropolitan hospitals in New York. All patients with M. haemophilum infections diagnosed between January 1989 and September 1991 and followed through September 1992. Surviving patients were enrolled in the case-control study. Infection with M. haemophilum causes disseminated cutaneous lesions, bacteremia, and diseases of the bones, joints, lymphatics, and the lungs. Improper culture techniques may delay laboratory diagnosis, and isolates may be identified incorrectly as other mycobacterial species. Persons with profound deficits in cell-mediated immunity have an increased risk for infection. These include persons with human immunodeficiency virus infection or lymphoma and those receiving medication to treat immunosuppression after organ transplant. Various antimycobacterial regimens have been used with apparent success to treat M. haemophilum infection. However, standards for defining antimicrobial susceptibility to the organism do not exist. Clinicians should consider this pathogen when evaluating an immunocompromised patient with cutaneous ulcerating lesions, joint effusions, or osteomyelitis. Microbiologists must be familiar with the fastidious growth requirements of this organism and screen appropriate specimens for mycobacteria using an acid-fast stain. If acid-fast bacilli are seen, M. haemophilum should be considered as the infecting organism as well as other mycobacteria, and appropriate media and incubation conditions should be used.


Lymphoid leukemia in the dog. Acute lymphoblastic leukemia and chronic lymphocytic leukemia.
True lymphoid leukemia of bone-marrow origin may present as two distinct clinical forms in the dog. Acute lymphoblastic leukemia is a rapidly progressive disease associated with proliferation of malignant, undifferentiated lymphoblasts. Chronic lymphocytic leukemia is a more insidious form of malignancy associated with abnormal proliferation of small lymphocytes. Recognition of these clinically distinct forms of leukemia and their differentiation from lymphosarcoma are important in considering prognosis and approach to therapy.


Laser-based three-dimensional multiscale micropatterning of biocompatible hydrogels for customized tissue engineering scaffolds.
Light-induced material phase transitions enable the formation of shapes and patterns from the nano- to the macroscale. From lithographic techniques that enable high-density silicon circuit integration, to laser cutting and welding, light-matter interactions are pervasive in everyday materials fabrication and transformation. These noncontact patterning techniques are ideally suited to reshape soft materials of biological relevance. We present here the use of relatively low-energy (< 2 nJ) ultrafast laser pulses to generate 2D and 3D multiscale patterns in soft silk protein hydrogels without exogenous or chemical cross-linkers. We find that high-resolution features can be generated within bulk hydrogels through nearly 1 cm of material, which is 1.5 orders of magnitude deeper than other biocompatible materials. Examples illustrating the materials, results, and the performance of the machined geometries in vitro and in vivo are presented to demonstrate the versatility of the approach.


Time course differences for statin-induced pleiotropic effects in hypercholesterolemic patients.
It is unclear whether there are temporal differences for the pleiotropic effects for different members of the statin class. The present study investigated differences in the short- and intermediate-term pleiotropic effects of statins in hypercholesterolemic patients. Thirty-five hypercholesterolemic patients were randomly treated with either atorvastatin or cerivastatin for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) at baseline and after 2 weeks and 3 months of therapy. After 2 weeks of therapy, atorvastatin decreased the low density lipoprotein (LDL) cholesterol, small, dense LDL cholesterol (34+/-22 vs. 18+/-20%, P<0.01), remnant-like particles (RLP) cholesterol (8.8+/-6.0 vs. 5.1+/-2.6 mg/ml, P<0.01), and TBARS (3.3+/-1.0 vs. 3.1+/-0.9 nmol/ml, P<0.05), and cerivastatin decreased LDL cholesterol. After 3 months of therapy, atorvastatin decreased small dense LDL cholesterol (8+/-13%, P<0.0001) additionally, and cerivastatin decreased small, dense LDL cholesterol (51+/-11 vs. 12+/-22%, P<0.0001) and plasminogen activator inhibitor type 1 (68+/-32 vs. 51+/-21 ng/ml, P<0.05). FMD increased significantly in both groups after 2 weeks, although the relative change in FMD was greater with cerivastatin therapy after 2 weeks than atorvastatin therapy (60+/-78 vs. 23+/-26%, P<0.05). However, FMD was the same for both groups after 3 months (58+/-65 vs. 66+/-61%, NS), because atorvastatin additionally increased FMD. There was no correlation between these pleiotropic effects and the improvement in the lipid profile for either group. These findings suggest that the degree of pleiotropic effect as well as the time course for the effect are different among members of the statin class of drugs.


Electronic Tuning of 2D MoS2 through Surface Functionalization.
The electronic properties of thiol-functionalized 2D MoS2 nanosheets are investigated. Shifts in the valence and conduction bands and Fermi levels are observed while bandgaps remain unaffected. These findings allow the tuning of energy barriers between 2D MoS2 and other materials, which can lead to improved control over 2D MoS2 -based electronic and optical devices and catalysts.


mRNA expression patterns indicate CD30 mediated activation of different apoptosis pathways in anaplastic large cell lymphoma but not in Hodgkin's lymphoma.
One of the main functions of the tumor necrosis factor receptor (TNFR) family is induction of apoptosis. CD30, a member of the TNFR superfamily is overexpressed in highly proliferating tumors such as anaplastic large cell lymphoma (ALCL) and Hodgkin's lymphoma (HL). CD30 stimulation leads to apoptosis and growth arrest in cultured ALCL, but not in Hodgkin-Reed-Sternberg cells. To identify changes in the transcriptional program responsible for these opposing effects, we performed gene expression analysis in CD30-stimulated ALCL (Karpas 299) and HL (KM-H2) cell lines using cDNA microarrays. Selected genes were validated by real-time PCR. Hierarchical clustering was applied to the whole dataset and separated the cell lines clearly with respect to their origin. In HL, there were only minor CD30-specific alterations, whereas ALCL unequivocally showed a pronounced CD30-specific transcriptional response. Ninety-three genes (6.6% of total) were deregulated by more than a factor of two after CD30 stimulation in ALCL cells. The majority of genes identified are involved in cell cycle regulation and apoptosis. mRNA expression patterns further indicate that in contrast to HL, CD30 stimulation in ALCL induces cell death via the CD95-CD95 ligand (CD95L) pathway and the TNF-R1/TNF-R2 crosstalk. These data provide a detailed view on the transcriptional changes upon CD30 stimulation and may explain the observed functional differences of HL and ALCL.


Study of the Involvement of Phosphatidic Acid Formation in the Expression of Wound-Responsive Genes in Cotton.
Plants use phospholipase D (PLD, EC 220.127.116.11)/phosphatidic acid (PtdOH) for the transduction of environmental signals including those coming from wounding. Based on our previous findings suggesting that wound-induced PLDα-derived PtdOH can act as a local signaling molecule in cotton (Gossypium hirsutum), we show that wounding immediately increases local NADPH oxidase (NADPHox) and cellulose synthase A (CeSA) gene expression. After developing a novel fluorimetric assay for the investigation of n-butanol inhibitory effect on PLD activity, we show that only NADPHox gene upregulation is reduced when n-butanol is applied prior to wounding. This suggests that NADPHox is a possible downstream target of PLD function, while a different CeSA-involving response system may exist in cotton. Overall, this study provides new knowledge on signal-transduction mechanisms following wounding of cotton leaves.


The effect of amblyopia treatment on stereoacuity.
To explore how stereoacuity changes in patients while they are being treated for amblyopia. The Monitored Occlusion Treatment for Amblyopia Study (MOTAS) comprised 3 distinct phases. In the first phase, baseline, assessments of visual function were made to confirm the initial visual and binocular visual deficit. The second phase, refractive adaptation, now commonly termed "optical treatment," was an 18-week period of spectacle wear with measurements of logMAR visual acuity and stereoacuity with the Frisby test at weeks 0, 6, 12, and 18. In the third phase, occlusion, participants were prescribed 6 hours of patching per day. A total of 85 children were enrolled (mean age, 5.1 ± 1.5 years). In 21 children amblyopia was associated with anisometropia; in 29, with strabismus; and in 35, with both. At study entry, poor stereoacuity was associated with poor visual acuity (P < 0.001) in the amblyopic eye and greater angle of strabismus (P < 0.001). Of 66 participants, 25 (38%) who received refractive adaptation and 19 (29%) who received occlusion improved by at least one octave in stereoacuity, exceeding test-retest variability. Overall, 38 (45%) improved one or more octaves across both treatment phases. Unmeasureable stereoacuity was observed in 56 participants (66%) at study entry and in 37 (43%) at study exit. Stereoacuity improved for almost one half of the study participants. Improvement was observed in both treatment phases. Factors associated with poor or nil stereoacuity at study entry and exit were poor visual acuity of the amblyopic eye and large-angle strabismus.


Mediterranean-style diet and intracranial large artery stenosis in the Northern Manhattan Study.
Given Mediterranean-style diet (MeDi) reduces risk of cardiovascular events, we hypothesized MeDi may also be protective against intracranial large artery stenosis (ICAS), a common cause of stroke worldwide. This cross-sectional study included stroke-free participants of the Northern Manhattan Study, a diverse population-based study of stroke risk factors. We represented MeDi continuously (range 0-8) based on enrollment food frequency questionnaires, excluding alcohol consumption. We evaluated ICAS both dichotomously at clinically relevant stenosis severities and continuously as a score (possible range 0-44), summated from stenosis severity scores of major intracranial arteries from time-of-flight magnetic resonance angiography. We used logistic or zero-inflated Poisson regression, adjusting for key confounders. Among 912 included participants (mean age 64±8 years, 59% female, 65% Hispanic, mean MeDi score 4±1.5), 5% and 8% of participants had ≥50% or ≥70% ICAS, respectively (score median [interquartile range]: 0 [0-2]). Increased MeDi score was inversely associated with ICAS, but did not reach statistical significance (≥50% stenosis odds ratio (OR) [95% confidence interval (CI)]: 0.89 [0.79-1.06]; ≥70% stenosis OR [95% CI]: 0.91 [0.74-1.13]; stenosis score β-estimate [95% CI]: -0.02 [-0.06-0.01]). In this stroke-free subsample, we did not find a significant association between MeDi and ICAS. We may have been limited by statistical power.


Interactions of delta9-tetrahydrocannabinol with d-amphetamine, cocaine, and nicotine in rats.
The acute, reciprocal dose-response interactions between delta9-tetrahydrocannabinol (delta9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. delta9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by delta9-THC. dA and COC, but not NIC, stimulated photocell activity. delta9-THC completely blocked this effect of dA, whereas there was mutual antagonism between delta9-THC and COC on this measure and NIC markedly potentiated the depression caused by delta9-THC. dA and COC tended to offset the impairment of rotarod performance caused by delta9-THC, whereas NIC augmented it. The bradycardia and hypothermia caused by delta9-THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with delta9-THC and/or each of the three stimulants. There was evidence for tolerance to the effects of delta9-THC on all measures and this tolerance generally resulted in less interactive effects between delta9-THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants or their interaction with delta9-THC. The time course of radioactivity derived from 14C-delta9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.


Plasma exchange in catastrophic antiphospholipid syndrome.
Plasma exchange is a well-established therapeutic procedure commonly used in many autoimmune disorders. The beneficial effects of plasma exchange are thought to occur through the elimination of pathogenic mediators found in plasma, including autoantibodies, complement components, and cytokines. The catastrophic antiphsopholipid syndrome (CAPS) is a life-threatening variant of the antiphospholipid syndrome (APS) where several thrombosis take place in a short period of time in patients with circulating antiphospholipid antibodies. The triple therapy with anticoagulation, corticosteroids and plasma exchange or intravenous immunoglobulins has been proposed in CAPS. CAPS is a rare disease precluding the conduction of formal clinical trials. However, the observation of a better clinical course of patients who received this treatment supports their use. Plasma exchange has become an established therapeutic procedure in CAPS but there are no studies regarding the better approach and thus its use relies on the experience of the physicians in charge. The current article aims to review potential mechanisms of action of plasma exchange and the technical aspects of this procedure and will focus on its current role in CAPS, the experience published in treating this condition and the treatment protocol that we use in our institution.


Effect of Parkinson's disease on the production of structured and unstructured speaking tasks: respiratory physiologic and linguistic considerations.
To examine the effects of cognitive-linguistic deficits and respiratory physiologic changes on respiratory support for speech in individuals with Parkinson's disease (PD) using two speech tasks: reading and extemporaneous speech. Five women with PD, 9 men with PD, and 14 age- and sex-matched control participants read a passage and spoke extemporaneously on a topic of their choice at comfortable loudness. Sound pressure level, syllables per breath group, speech rate, and lung volume parameters were measured. Number of formulation errors, disfluencies, and filled pauses were counted. Individuals with PD produced shorter utterances compared with control participants. The relationships between utterance length and lung volume initiation and inspiratory duration were weaker for individuals with PD than for control participants, particularly for the extemporaneous speech task. These results suggest less consistent planning for utterance length by individuals with PD in extemporaneous speech. Individuals with PD produced more formulation errors in both tasks and significantly fewer filled pauses in extemporaneous speech. Both respiratory physiologic and cognitive-linguistic issues affected speech production by individuals with PD. Overall, individuals with PD had difficulty planning or coordinating language formulation and respiratory support, particularly during extemporaneous speech.


Screening for T cell-eliciting proteins of Japanese encephalitis virus in a healthy JE-endemic human cohort using recombinant baculovirus-infected insect cell preparations.
The analysis of cell-mediated immune responses in virus-exposed but healthy individuals may contribute to define the features of the T cell response associated with resistance. We report, for the first time, on adaptive T cell responses to 5 largest of the 10 proteins that together constitute 76% of the coding potential of the Japanese encephalitis virus (JEV) genome in a naturally exposed healthy JE-immune human cohort. Fixed and sonified whole cell preparations of insect cells individually expressing recombinant prM, E, NS1, NS3 and NS5 proteins of JEV were used in vitro to stimulate lymphocytes from individuals who had experienced subclinical JEV infections. NS3-specific memory T cells were detected in up to 86% of the JEV-infected cohort whereas prM, E and NS1 each elicited reactions in approximately 45% among individuals tested, suggesting that NS3 is an important target for JEV-specific cell-mediated immune responses. Responses to NS5, the largest viral protein were in contrast the poorest, seen in only 13% of the cohort. Moreover, NS3 stimulated interferon-gamma production in both CD4(+) and CD8(+) T cells indicating that a Th1 immune response to the NS3 protein may be a critical determinant of immune control of JEV infection.


A middle range theory of self- and family management of chronic illness.
The Self- and Family Management Framework was created in 2006 to help structure self- and family management science. Based on a series of reviews and syntheses of emerging research and critical evaluation, we developed the Framework into a robust nursing theory. In this article, we reintroduce the Self- and Family Management Framework as the Middle Range Theory of Self- and Family Management of Chronic Illness. We review steps in the development and updating of the Framework, share rationale for advancement to a middle range theory, explicate components of the newly designed model, and propose future directions. It is our hope that this middle range theory will guide researchers and clinicians more comprehensively in supporting patients and families managing chronic illness, which will in turn inform continued theory development.


Lung function and exercise capacity in prematurely born young people.
To determine if lung function abnormalities in young people born very prematurely routinely exposed to antenatal corticosteroids and postnatal surfactant were associated with reduced exercise capacity. In the current era, lung function abnormalities would not be associated with exercise intolerance STUDY DESIGN: Follow-up of young people from the United Kingdom Oscillation study (UKOS). One hundred twenty-six young people of 797 recruited to UKOS, born at a mean gestational age of 27 weeks were assessed at a mean age of 17 years. Forced expiratory flow at 75% of the expired vital capacity (FEF75 ), forced expiratory volume in 1 second (FEV1 ) and lung volumes (forced vital capacity [FVC]) and residual volume (RV) and functional residual capacity (FRCpleth ) were assessed. Abnormal lung function was below the fifth centile and very abnormal lung function below the 2.5th centile. Exercise capacity was assessed using a modified shuttle sprint test and self-reported hours of exercise. Thirty-nine young people had an abnormal FEF75 with an adjusted reduction in sprint distance of 114 m (P = .018) and an adjusted difference in self-reported exercise of 0.73 hours (P = .036). Twenty-seven young people had a very abnormal FEF75 with an adjusted reduction in sprint distance of 159 m (P = .002) and adjusted reduction in self-reported exercise of 1.15 hours (P = .002). Very prematurely born young people with abnormal airway function had a significant reduction in exercise capacity.


Defective interleukin-2 induction of lymphokine-activated killer (LAK) activity in peripheral blood T lymphocytes of patients with monoclonal gammopathies.
The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cells was investigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activity was significantly decreased in MM, but not in MGUS patients, and was partially recovered in MM in the remission phase. This finding was unexpected, because CD8+ CD11b+ cells, which contain LAK precursors, are significantly increased in MM. LAK activity was investigated in purified CD8+ CD11b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation by other T cell subsets. These cells were intrinsically unable to generate LAK activity fully following rIL-2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showed intermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA-DR+ cells in MM patients. These data reveal another dysregulation of T cell effector functions in patients with monoclonal gammopathies and offer further evidence of the impairment of their cell-mediated immunity.


Regulation of the activation of C1 in serum.
C1 has been partially purified from serum and its ability to activate has been studied. The activation status of C1 was measured using a sensitive hemolytic assay which allowed the activation status of C1 in serum to be monitored. C1 did not activate in serum but would spontaneously activate when separated from certain other serum proteins, in particular, the C1-inhibitor protein. The activation of C1 was time and concn dependent, but addition of fully activated C1 did not affect either the rate or extent of activation. The activation of C1 could be inhibited reversibly by C1-inhibitor. This action of the C1-inhibitor was over and above its ability to regulate fully activated C1 by covalent bond formation with either the serine esterase of C1s or C1r. The results presented suggest that the C1-inhibitor plays a dual role in the regulation of C1 activation. The regulatory actions of C1-inhibitor would account for the presence of C1 in a zymogen form and for the episodic nature of complement consumption observed in individuals with genetic deficiencies of the C1-inhibitor protein.


Examining intra-rater and inter-rater response agreement: a medical chart abstraction study of a community-based asthma care program.
To assess the intra- and inter-rater agreement of chart abstractors from multiple sites involved in the evaluation of an Asthma Care Program (ACP). For intra-rater agreement, 110 charts randomly selected from 1,433 patients enrolled in the ACP across eight Ontario communities were re-abstracted by 10 abstractors. For inter-rater agreement, data abstractors reviewed a set of eight fictitious charts. Data abstraction involved information pertaining to six categories: physical assessment, asthma control, spirometry, asthma education, referral visits, and medication side effects. Percentage agreement and the kappa statistic (kappa) were used to measure agreement. Sensitivity and specificity estimates were calculated comparing results from all raters against the gold standard. Intra-rater re-abstraction yielded an overall kappa of 0.81. Kappa values for the chart abstraction categories were: physical assessment (kappa 0.84), asthma control (kappa 0.83), spirometry (kappa 0.84), asthma education (kappa 0.72), referral visits (kappa 0.59) and medication side effects (kappa 0.51). Inter-rater abstraction of the fictitious charts produced an overall kappa of 0.75, sensitivity of 0.91 and specificity of 0.89. Abstractors demonstrated agreement for physical assessment (kappa 0.88, sensitivity and specificity 0.95), asthma control (kappa 0.68, sensitivity 0.89, specificity 0.85), referral visits (kappa 0.77, sensitivity 0.88, specificity 0.95), and asthma education (kappa 0.49, sensitivity 0.87, specificity 0.77). Though collected by multiple abstractors, the results show high sensitivity and specificity and substantial to excellent inter- and intra-rater agreement, assuring confidence in the use of chart abstraction for evaluating the ACP.


Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis.
Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93-1.08]), seizures (1.18 [0.91-1.53]), venous thromboembolism (1.04 [0.92-1.17]), acute coronary syndrome (0.88 [0.78-1.00]) or stroke (1.12 [0.98-1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01-9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011). Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.


Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis. Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis.
Here we report that photoactivated hypericin can induce either apoptosis or necrosis in HeLa cells. Under apoptotic conditions the cleavage of poly(ADP-ribose) polymerase (PARP) into the 85-kDa product is blocked by the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk). Both inhibitors protect cells from apoptosis but cannot prevent hypericin-induced necrosis. Conversely, HeLa cells overexpressing the viral cytokine response modifier A (CrmA), which inhibits caspase-1 and -8, still undergo hypericin-induced apoptosis and necrosis. Evidence is provided for the release of mitochondrial cytochrome c in the cytosol and for procaspase-3 activation in the hypericin-induced cell killing.


Nuclear Magnetic resonance quadrupole relaxation studies of chloride binding to the isolated hemoglobins from trout (Salmo irideus).
NMR studies of chloride binding to the main components of trout blood, Hb Trout I and Hb Trout IV, indicate that although the affinity of chloride is high for both hemoglobins, the characteristics of the binding process are markedly differnet. In Hb Trout IV chemical exchange at the chloride binding site(s) is fast and quadrupole effects determine the linewidth; chloride binding has a definite pH dependence, but there is no significant oxygen linkage. In contrast Hb Trout I represents a unique case of slow chemical exchange, which may depend on unusual stereoche mical characteristics of the chloride binding site; chloride binding is pH independent, but shows a significant oxygen linkage, which may be attributed to changes of the lifetime of chloride at the binding site. The chloride binding properties displayed by Hb Trout I and IV have been compared with those of normal and modified human hemoglobins and discussed in terms of the structural differences in the C- and N-terminal regions of the alpha- and beta-chains.


Valorization of household food wastes to lactic acid production: A response surface methodology approach to optimize fermentation process.
Lactic acid is a valuable compound used in several industrial processes such as polymers, emulsifiers manufacturing, pharmaceutical, and cosmetic formulations. The present study aims to evaluate the potential use of food waste to produce lactic acid through fermentation, both by indigenous microbiota and by the bio-augmentation with two lactic acid bacteria, namely Lactobacillus plantarum BS17 and Lactobacillus casei BP2. Fermentation was studied both in batch and continuously fed anaerobic reactors at mesophilic conditions and a Response Surface Methodology approach was used to optimize the bioprocess performance and determine the environmental parameters (namely pH and time) that lead to the enhancement of lactic acid production during the batch fermentation by indigenous microorganisms. Results revealed an optimum set of conditions for lactic acid production at a pH value of 6.5 and a fermentation period of 3.5 days at 37 °C. Under these conditions lactic acid production reached a value of 23.07 g/L, which was very similar to the mathematically predicted ones, thus verifying the accuracy of the experimental design. This optimum set of conditions was further employed to examine the production of lactic acid under continuous fermentation operation. Furthermore, concentrations of volatile fatty acids and ethanol were monitored and found to be relatively low, with ethanol being the dominant by-product of fermentation, indicating the presence of heterofermentative bacteria in the food wastes. A final step of downstream process was performed resulting in the successful recovery of lactic acid with purity over 90%.


Glycopyrronium and hypotension following combined spinal-epidural anaesthesia for elective Caesarean section in women with relative bradycardia.
The ability of glycopyrronium to reduce the severity of hypotension following subarachnoid block in parturients with a relative bradycardia was evaluated in a double-blind randomised controlled study. Women with a resting heart rate of < or = 80 beat x min(-1) presenting for elective Caesarean section were randomly allocated to receive either glycopyrronium 2 microg x kg(-1) or normal saline intravenously once positioned for combined spinal-epidural anaesthesia. Following spinal injection of 2.6 ml hyperbaric bupivacaine 0.5% and fentanyl 15 microg, women randomly allocated to the saline group were given 6 mg ephedrine so that all parturients received some prophylaxis against hypotension other than the fluid preload. Further ephedrine and fluid boluses were administered if mean arterial pressure fell 20% or more from resting values. Using a sequential analysis technique, analysis after the first 20 subjects indicated the study should be stopped, with no difference in ephedrine requirements or hypotension between the groups. We conclude that pretreatment with glycopyrronium 2 microg x kg(-1) is no more effective than 6 mg ephedrine in preventing hypotension following subarachnoid block in parturients with relatively low resting heart rates.


Relationships between glycosaminoglycan and receptor binding sites in chemokines-the CXCL12 example.
Chemokines are small proteins, promoting directional migration and activation of different cells through binding to specific receptors. Most chemokines also bind to heparan sulfate (HS), a family of complex and highly sulfated glycosaminoglycan (GAG) found at the cell surface and in the extracellular matrix. This class of molecules has recently emerged as critical regulators of many events involving cell response to the external environment. Binding to HS is thought to be functionally important. Current models suggested that HS ensures the correct positioning of chemokines within tissues and maintains haptotactic gradients of the proteins along cell surfaces, thus providing directional cues for migrating cells. On the chemokine surface, the GAG binding epitopes can be displayed on different areas, some of which overlap the receptor binding domain, while others are clearly separated. We review here some structural aspects of the interaction between GAGs or receptors and chemokines. In particular, we will address the case of CXCL12, a chemokine whose receptor binding site is distinct from the GAG binding site and whose different isoforms display different GAG binding abilities. This chemokine system thus offers an unprecedented opportunity to ascertain the importance of chemokine/GAG interaction in the regulation of cell migration.


The role of Zinc L-Carnosine in the prevention and treatment of gastrointestinal mucosal disease in humans: a review.
Zinc L-carnosine is a pharmaceutical compound with direct mucosal cytoprotective and anti-inflammatory action through its antioxidative effects, cytokine modulation and membrane-stabilizing properties. Chemically, it is not an anti-secretory, antacid or raft-forming agent; its properties are mainly mediated by its higher affinity for damaged mucosa that permits the release of zinc locally by ligand exchange. Beneficial effects on various types of mucosal damage have been described in vitro and in vivo, in both animals and humans. It has been shown to promote repair of mucosal injury in human studies and has been widely used for the treatment of peptic ulcers, chemoradiotherapy-induced oral mucositis and esophagitis. More recently, the therapeutic applications of Zinc L-carnosine have been extended to the prevention and cure of various types of intestinal damage, including ulcerative colitis, iatrogenic ulcers after operative endoscopy, hemorrhoidal disease and impaired intestinal permeability. This review concentrates mainly on the current and future applications of zinc L-carnosine in gastrointestinal disease, and may be of use to gastroenterologists and endoscopists. It describes the therapeutic principles and benefits of this interesting molecule and discusses the potential future fields of interest for clinical use in humans.


The Australian funding debate on quadrivalent HPV vaccine: a case study for the national pharmaceutical policy.
To analyse the media and political reactions to the initial decision of the Pharmaceutical Benefits Advisory Committee (PBAC) to reject funding of the quadrivalent human papilloma virus (HPV) vaccine in Australia. A case study, informed by media reports and government documents, was utilised to examine the reactions of key stakeholders; PBAC, consumers, consumer organisations, pharmaceutical industry, politicians, health professionals and the media to the initial decision to reject funding of HPV vaccine. The initial decision to reject funding of the HPV vaccine led to unprecedented public response with over 300 newspaper articles and calls by consumers, health professionals and politicians to intervene in the decision making process. Misunderstanding of the decision making process, particularly cost-effectiveness assessments, the need for an independent process, the legislated inability of a timely and transparent response from policy makers and the lack of a risk mitigation strategy all played a role in the public outcry. Despite 15 years of implementation of cost-effectiveness assessments there is still a need for improving stakeholder understanding of the decision making process and for timely transfer of complete information. Risk mitigation strategies should be considered as part of the communication plan for all decisions.


Volume-regulated anion channel--a frenemy within the brain.
The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is the contribution of VRAC to the release of the excitatory amino acid neurotransmitters glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field, the molecular nature of VRAC remained unknown until less than 2 years ago. Two pioneer publications identified VRAC as the heterohexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research.


Evaluation of peripheral nerve regeneration by nerve growth factor locally administered with a novel system.
An experimental model is presented for the local administration of neurotrophic substances at the site of peripheral nerve lesion. The model consists of a subcutaneously implanted silicone reservoir and a connecting tube with its distal end facing the severed and repaired nerve. Wistar rats (n = 180) were divided into two groups: a control group (saline-treated) (n = 90) and an NGF-treated group (n = 90). After sciatic nerve axotomy, an epineural repair was performed. NGF or saline were injected daily into the subcutaneous reservoir for the first 4 weeks after axotomy and weekly single dose between the 8th and 12th weeks. Both groups were divided into three subgroups of 30 animals each. The animals were sacrificed at 4, 8 and 12 weeks. Myelinated and non-myelinated axonal and thickness of myelin sheaths were quantified at the tibialis branch 25 mm distal to the nerve repair site. Axonal counts showed statistically significant differences between the treated and control groups at 4, 8 and 12 weeks. Finally, at 4 weeks the myelinated axons in the NGF group had significantly thicker myelin sheaths than in the control group. In comparison with other models of administration of different neurotrophic agents, NGF delivered through this system demonstrates a significant capacity for improving nerve regeneration without the problems inherent in multiple anesthesia, device exchange, or short half-life of the NGF single-dose administration.


Corticotropin-releasing factor: a physiologic regulator of adrenal epinephrine secretion.
Pituitary adrenocorticotropic hormone (ACTH) secretion following stress is mediated primarily by the release of corticotropin-releasing factor (CRF) from the brain. We have hypothesized that stress-induced alterations of autonomic nervous system activity also may be dependent on CRF release within the brain because administration of CRF into the brain produces changes in autonomic nervous system function that are similar to those observed following exposure to various types of stress. We now report confirmation of this hypothesis with studies using a CRF receptor antagonist. The CRF receptor antagonist, alpha-helical CRF9-41, placed into the brains of rats suppressed stress-induced elevations of plasma epinephrine levels. Thus, CRF appears to be physiologically involved in coordinating the pituitary and autonomic nervous system responses to stress.


Immunocytochemical demonstration of reduced glutathione in neurons of rat forebrain.
Histochemical studies show reduced glutathione (GSH) in neuroglia, whereas immunocytochemistry of glutaraldehyde-fixed tissue reveals GSH also in neurons. Using an antibody suitable for formaldehyde-fixed tissue, we find GSH staining in the cytoplasm of neurons throughout the brain. Staining was prominent in large pyramidal neurons of cerebral cortex, in basal ganglia, and in reticular and ventrobasal thalamic nuclei.


Sperm preparation after freezing improves motile sperm count, motility, and viability in frozen-thawed sperm compared with sperm preparation before freezing-thawing process.
The aim of this study is to evaluate which cryopreservation protocol, freezing before or after swim-up, optimizes cryopreservation outcomes in terms of motile sperm count, motility, morphology, and viability, and also to establish whether sperm viability could be assessed based on sperm motility. Fifty-three fresh and 53 swim-up prepared samples were considered for the first experiment. In parallel, total motility evaluation by CASA system (computer-assisted sperm analyzer) and hypoosmotic swelling test (HOS-test) was performed in each sample to compare the viability results of both methods. In the second experiment, 21 normozoospermic semen samples and 20 semen samples from male factor patients were included. After fresh ejaculate evaluation, the semen sample of each patient was divided into two aliquots, one of them was frozen before swim-up and the other was frozen after swim-up. Motility, sperm count, morphology, and viability were evaluated after thawing. A linear regression model allows prediction of HOS-test viability results based on total motility: HOS = 1.38 + 0.97 · TM (R 2 = 99.10, residual mean squares = 9.51). Freezing before sperm selection leads to higher total and progressive motility, total motile sperm count, and viability rates than when sperm selection is performed before freezing (P < 0.005 in all cases). In fact, sperm selection prior to freezing reaches critical values when subfertile patients are considered. To conclude, total motility evaluation can predict HOS-test viability results, resulting in a more objective and less time-consuming method to assess viability. In addition, sperm freezing prior to swim-up selection must be considered in order to achieve better outcomes after thawing, especially in patients presenting poor sperm baseline.


The epitranscriptome: RNA modifications in vascular remodelling.
RNA transcripts are not finished products. Like proteins undergo posttranslational modifications, RNAs undergo posttranscriptional modifications. Some of these modifications affect processing, stability or turnover of RNAs, others can 'edit' nucleotides, change the RNA's function and rewrite the genetic code. The body of RNA modifications is collectively called the 'epitranscriptome'. The epitranscriptome is dynamically regulated. This is the most clear for N6-methyladenosine (m6A), where both m6A-'writers' and -'erasers' have been identified and are also already being employed in studies on the effects of broad-scale m6A modifications on human disease, including cardiovascular disease. Even though not all modifications are readily reversible like m6A, most, if not all, other modifications are actively regulated in response to stressors, such as ischemia, starvation, or incubation with for example cytokines or oxidized LDL, all important factors in vascular remodelling and cardiovascular disease. Epitranscriptome research in human disease in general and in cardiovascular research is still in its infancy and methods to reliably detect and/or manipulate most RNA modifications are still lacking. Nonetheless, the number of studies on RNA modification and on writer-, eraser-, and reader-protein in various forms of vascular remodelling has increased dramatically over the last three years. This review aimed to discuss the available literature on the most common RNA modifications in different forms of vascular remodelling. Both adaptive vascular remodelling, including postischemic angiogenesis, as well as maladaptive remodelling, like atherosclerosis and aneurysm formation, and their direct consequences, such as myocardial infarction, acute stroke, peripheral artery disease and abdominal aorta aneurysm, have been discussed.


Extensions of paranasal sinus tumors and inflammatory disease as evaluated by CT and pluridirectional tomography.
CT and pluridirectinal tomography are compared in their ability to show the extent of paranasal sinus tumors or benign aggressive processes. Thirty-one cases are reviewed; CT was superior to pluridirectional tomography in showing spreads of tumor to all clinically important areas, including the infratemporal fossa, nasopharynx, orbit, and intracranial compartment. CT not only consistently allowed less equivocal interpretation, but also enabled us to qualify orbital involvement as intra- or extraconal, and to quantitate better both brain and infratemporal fossa involvement. We feel that CT scanning is the better way to determine the extent of such pathology.


The intrarenal renin-angiotensin system and diabetic nephropathy.
The renin-angiotensin system (RAS) is a coordinated cascade of proteins and peptide hormones, the principal effector of which is angiotensin II (ANG II). Evidence now indicates that the kidney regulates its function via a self-contained RAS in a paracrine fashion. In diabetic nephropathy, the intrarenal generation of ANG II is increased, in spite of suppression of the systemic RAS. This increase can contribute to the progression of diabetic nephropathy via several hemodynamic, tubular and growth-promoting actions. ANG II induces insulin resistance. ANG II type-1 (AT(1)) and type-2 (AT(2)) receptors are downregulated in chronic diabetes, but decreased AT(2) receptor expression might contribute to early diabetic nephropathy by reducing AT(2) receptor-mediated beneficial actions that are counter-regulatory to those of the AT(1) receptor. AT(2) receptor stimulation might account for part of the renal protection seen with AT(1) receptor blockade. A rat model of accelerated diabetic nephropathy is the (mREN-2) 27 renin transgenic rat treated with streptozotocin in which both the intrarenal and extrarenal RAS is activated.


Trichoblastoma: management of a rare skin lesion.
A 15-year-old girl presented with a 2-year history of an enlarging parietal scalp lesion. Excisional biopsy revealed trichoblastoma, a benign secondary tumor arising from a nevus sebaceous. There is no consensus in the literature about the surgical management of nevus sebaceous in children owing to the low incidence of secondary malignancy. There is a 20% lifetime risk of transformation to a soft tissue neoplasm, most of which are benign; but malignant neoplasms have also been reported. At minimum, these lesions need to be followed clinically over the patient's lifetime if left in situ. Recurrence after excision is rare.


Drosophila Krüppel protein is a transcriptional repressor.
Krüppel (Kr), one of the zygotically active Drosophila segmentation genes, is expressed in a restricted domain during the blastoderm stage of embryogenesis and is involved in the control of development of the thoracic and abdominal segments of the fly. Kr encodes a polypeptide containing DNA-binding zinc-finger motifs, disruptions of which yield Kr mutants. We have assayed the transcriptional activities of wild-type Kr protein as well as Lac repressor/Kr fusion proteins in HeLa and CV-1 cells. Wild-type Kr and a Lac-Kr chimaeric protein repressed transcription from reporter promoters in which a consensus Kr binding site derived from sequences within the even-skipped promoter had been inserted in an upstream position. We mapped the repression function of Kr to an alanine-rich amino-terminal region of the protein, as a Lac/Kr fusion protein containing only amino acids 26-110 of Kr repressed transcription from a reporter promoter containing upstream lac operators. This demonstrates that the DNA-binding and repression activities of the Kr protein are distinct. These data are consistent with genetic evidence that Kr represses even-skipped and hunchback expression, and suggest that Kr is a negative regulator of transcription in Drosophila.


Na+-driven flagellar motors of an alkalophilic Bacillus strain YN-1.
Flagellar motors of some alkalophilic Bacillus strains have been suggested to be powered by the electrochemical potential gradient of Na+, namely the (formula: see text) (Hirota, N., Kitada, M., and Imae, Y. (1981) FEBS Lett. 132, 278-280). In the present study, we quantitatively measured the (formula: see text) and motility of one of the strains, YN-1. Swimming speed of YN-1 cells increased linearly with a logarithmic increase of Na+ concentration in the medium up to 100 mM. The intracellular Na+ concentration and the membrane potential of the cell were about 30 mM and -170 mV, respectively, and stayed constant irrespective of Na+ concentration in the medium. Thus, the swimming speed changed as a function of the chemical potential difference of Na+ across the cell membrane. When the membrane potential of YN-1 cells was decreased by a combination of valinomycin and various concentrations of K+ in the medium, the swimming speed of the cells decreased linearly and reached zero at around -90 mV. Under the condition, the intracellular Na+ concentration stayed constant. Thus, the membrane potential was also a determinant of the swimming speed. Furthermore, the chemical potential of Na+ and the membrane potential were found to be equivalent as the energy source for motility. Therefore, it is concluded that the (formula: see text) is the energy source for the flagellar motors of YN-1 cells. Threshold value of the (formula: see text) for motility was about -100 mV.


Effects of ethanol, acetaldehyde, and lactate on proteoglycan synthesis and proliferation of cultured rat liver fat-storing cells.
The hypothesis that ethanol and some of its metabolites are directly involved in the process of fat-storing cell activation and stimulated proteoglycan synthesis in alcoholic liver injury was investigated. The effects of short-term (24 h) and long-term (4 days) exposure of rat liver fat-storing cells at various times of culture to ethanol, acetaldehyde, and lactate on the synthesis of proteoglycans and total protein and on the proliferation activity of the cells were studied. Ethanol and lactate did not stimulate the incorporation of [35S]sulfate into glycosaminoglycans. Acetaldehyde inhibited strongly glycosaminoglycan synthesis, reaching 50% inhibition at 330 mumol/L. The compound preferentially inhibited the synthesis of dermatan sulfate. No significant changes of glycosaminoglycan chain length or of the degree of polysaccharide sulfation were noted in acetaldehyde-treated cultures. The inhibition was reversed by the addition of beta-D-xylopyranoside (0.5 mmol/L), an artificial initiator of chain elongation, to the medium. Total protein synthesis, cell number, deoxyribonucleic acid content of the cultures, and [3H]thymidine incorporation were not affected by the compounds. The results do not support the view that ethanol, its oxidation product acetaldehyde, or lactate are directly involved in the activation of fat-storing cells and in enhanced matrix proteoglycan synthesis and secretion.


The human platelet-activating factor receptor gene (PTAFR) contains no introns and maps to chromosome 1.
Platelet-activating factor (PAF), a phospholipid, exhibits a variety of potent inflammatory bioactivities that are mediated by a specific cell surface receptor. The gene for the human PAF receptor (PTAFR) has been isolated by hybridization with a guinea pig probe. The coding sequence contains no intervening sequences. The encoded protein is highly homologous to the guinea pig PAF receptor (82% identity) and contains seven putative transmembrane domains. The PAF receptor therefore appears to be a member of the G protein coupled family of receptors and exhibits significant similarity to many members of the family. Analysis of somatic cell hybrids suggests that the PAF receptor is encoded by a single gene on human chromosome 1.


Cases of toxic anterior segment syndrome after primary pterygium surgery.
Toxic anterior segment syndrome (TASS) is an acute, sterile, inflammatory reaction of the anterior segment after intraocular surgeries. We aimed to report an outbreak of TASS which occurred following pterygium surgeries. A case series. Four eyes of four patients developed TASS associated with formaldehyde after uneventful primary pterygium surgery with conjunctival autograft. No patients reported pain; all patients demonstrated diffuse corneal edema, epithelial defects, and anterior chamber inflammation without hypopyon, fibrin formation, and vitreous involvement on the first postoperative day. TASS diagnosis was made based on clinical findings. All patients were treated with hourly topical 1% prednisolone acetate (Pred Forte, Allergan, CA), moxifloxacin 0.5% (Vigamox, Alcon, TX), and 0.24% of hyaluronic acid (Artelac complete, Bausch & Lomb). Oral steroid (prednisolone 1 mg/kg) was added on the first week and gradually tapered over weeks. None of the affected corneas improved spontaneously. Best-corrected visual acuity ranged from 20/25000 to 20/200 in the second month after surgery. Keratoplasty was scheduled for all patients. This is the first study to present TASS cases after pterygium surgery. Clinicians should be aware of TASS that can emerge after an extraocular surgery. In our analysis, since 2% formaldehyde was used by the operating room personnel for cleaning and sterilizing reusable ocular instruments, it was thought that formaldehyde was the most likely cause.


Wildfires-A Growing Public Health Crisis.
Toxic smoke from wildfires can travel thousands of miles, endangering people far from the flames.


Effects of AV3V lesion on pilocarpine-induced pressor response and salivary gland vasodilation.
The cholinergic agonist pilocarpine injected intraperitoneally (ip) increases mean arterial pressure (MAP) and superior mesenteric (SM) vascular resistance and reduces submandibular/sublingual gland (SSG) vascular resistance. In the present study, we investigated the effects of electrolytic lesions of the anteroventral third ventricle (AV3V) region on the changes in MAP, SM, and SSG vascular resistances induced by ip pilocarpine. Male Holtzman rats anesthetized with urethane (1.0 g/kg) and chloralose (60 mg/kg) were submitted to sham or electrolytic AV3V lesions and had pulsed Doppler flow probes implanted around the arteries. Contrary to sham rats, in 1-h and 2-day AV3V-lesioned rats, pilocarpine (4 micromol/kg) ip decreased MAP (-41 +/- 4 and -26 +/- 4 mm Hg, respectively, vs. sham: 19 +/- 4 mm Hg) and SM (-48 +/- 11 and -45 +/- 10%, respectively, vs. sham: 41 +/- 10%) and hindlimb vascular resistances (-65 +/- 32 and -113 +/- 29%, respectively, vs. sham: 19 +/- 29%). In 7-day AV3V-lesioned rats, pilocarpine produced no changes on MAP and SM and hindlimb vascular resistances. Similar to sham rats, pilocarpine reduced SSG vascular resistance 1 h after AV3V lesions (-46 +/- 6%, vs. sham: -40 +/- 6%), but it produced no effect 2 days after AV3V lesions and increased SSG vascular resistance (37 +/- 6%) in 7-day AV3V-lesioned rats. The responses to ip pilocarpine were similar in 15-day sham and AV3V-lesioned rats. The cholinergic antagonist atropine methyl bromide (10 nmol) iv slightly increased the pressor response to ip pilocarpine in sham rats and abolished for 40 min the fall in MAP induced by ip pilocarpine in 1-h AV3V-lesioned rats. The results suggest that central mechanisms dependent on the AV3V region are involved in the pressor responses to ip pilocarpine. Although it was impaired 2 and 7 days after AV3V lesions, pilocarpine-induced salivary gland vasodilation was not altered 1 h after AV3V lesions which suggests that this vasodilation is not directly dependent on the AV3V region.


CNTNAP4 Impacts Epilepsy Through GABAA Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models.
Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin-associated protein-like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus-mediated knock-down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus-mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg2+-free epilepsy cell model. Down-regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma-aminobutyric acid A receptor β2/3 (GABAARβ2/3) membrane protein, without affecting total GABAARβ2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABAARβ2/3 and gamma-aminobutyric acid receptor-associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABAAR function, and may be a promising target for the development of epilepsy treatment.


Outcomes and factors contributing to poor prognosis of Pneumocystis jirovecii pneumonia in HIV-negative patients: a cross-sectional retrospective study in a Chinese single center.
Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection mainly occurring in immunocompromised patients. Almost half of the 30 HIV-negative patients enrolled in this study from 2016-2020 in a Chinese single-center contracted 17 hematological malignancies, and 25 received long-term systemic corticosteroids. Only 4 patients received prophylaxis. The overall mortality was 30%. Patients with older age (> 43 years), dyspnea, and LDH > 404U/L had significantly higher risk of developing into a severe form. LDH > 424 U/L, PaO2 < 60 mmHg, monocyte < 0.2 × 10^9/L, and lymphocyte < 0.3 × 10^9/L were factors contributing to a poor survival outcome.


[Hemolytic uremic syndrome and febrile urinary Escherichia coli infection].
The authors report on 2 cases of hemolytic uremic syndrome in 2 infants during a febrile Escherichia coli urinary tract infection. They discuss the role of urinary tract infection in the occurrence of hemolytic uremic syndrome and the possible role of specific Escherichia coli strains.


Dissecting the non-neuronal cell contribution to Parkinson's disease pathogenesis using induced pluripotent stem cells.
Parkinson's disease (PD) is an incurable age-linked neurodegenerative disease with characteristic movement impairments that are caused by the progressive loss of dopamine-containing neurons (DAn) within the substantia nigra pars compacta. It has been suggested that misfolded protein aggregates together with neuroinflammation and glial reactivity, may impact nerve cell function, leading to neurodegeneration and diseases, such as PD. However, not many studies have been able to examine the role of human glial cells in the pathogenesis of PD. With the advent of induced pluripotent stem cell (iPSC) technology, it is now possible to reprogram human somatic cells to pluripotency and to generate viable human patient-specific DA neurons and glial cells, providing a tremendous opportunity for dissecting cellular and molecular pathological mechanisms occurring at early stages of PD. This reviews will report on recent work using human iPSC and 3D brain organoid models showing that iPSC technology can be used to recapitulate PD-relevant disease-associated phenotypes, including protein aggregation, cell death or loss of neurite complexity and deficient autophagic vacuoles clearance and focus on the recent co-culture systems that are revealing new insights into the complex interactions that occur between different brain cell types during neurodegeneration. Consequently, such advances are the key to improve our understanding of PD pathology and generate potential targets for new therapies aimed at curing PD patients.


Evaluation of Ex-PRESS mini glaucoma shunt implantation with preoperative intracameral bevacizumab injection in refractory neovascular glaucoma.
To evaluate the efficacy and safety of Ex-PRESS mini glaucoma shunt implantation with preoperative intracameral bevacizumab injection in eyes with refractory neovascular glaucoma. A retrospective chart review of patients with medically uncontrolled neovascular glaucoma who had received 50-µL intracameral bevacizumab (1.25 mg) before undergoing Ex-PRESS mini glaucoma shunt implantation was performed. Success was defined as a postoperative intraocular pressure (IOP) between 5 and 21 mm Hg without (complete success) or with or without (qualified success) glaucoma medications and no additional glaucoma surgery, or loss of light perception. In total, 33 eyes of 33 patients (15 female, 18 male) were enrolled in the study. The mean age of the study population was 61.2 years (range 36-78). The mean IOP decreased from 41.0 mm Hg (range 24-72) to 17.6 mm Hg (range 8-28) over a mean follow-up of 20.9 months (range 6-60) (p<0.001; Wilcoxon signed-rank test). Complete and qualified success rates were 36.4% and 66.7%, respectively. The average number of antiglaucoma medications decreased from 3.5 (range 2-4) preoperatively to 1.8 (range 1-4) postoperatively (p<0.001; Wilcoxon signed rank test). In 81.8% of cases, the decrease in IOP was 30% or more postoperatively. Ex-PRESS mini glaucoma shunt implantation with preoperative bevacizumab injection may be an effective alternative procedure for refractory neovascular glaucoma.


Correction to: Program Abstracts from The GSA 2021 Annual Scientific Meeting, "Disruption to Transformation: Aging in the 'New Normal'".
[This corrects the article DOI: 10.1093/geroni/igab046.].


Characteristics of protein-aqueous medium interactions measured by partition in aqueous Ficoll-Dextran biphasic system.
Partitioning of a number of proteins in the aqueous Ficoll-400-Dextran-70 biphasic system was studied at pH 7.4 under varied ionic compositions. The relative hydrophobicities of the proteins have been estimated, and the contributions of the interactions of the ionogenic and non-ionic groups of a protein with an aqueous environment to the total hydrophobicity of the protein have been evaluated. Some arguments in support of the biological significance of the effect of ionic composition on the relative hydrophobicity of biological macromolecules are given. Possible applications of the partition technique to protein research are discussed.


Myocardial contractile dysfunction contributes to the development of heart failure in rats with aortic stenosis.
To analyze the potential contribution of contractility state and ventricular geometry to the development of heart failure in rats with aortic stenosis. Rats were divided into three groups: compensated aortic stenosis (AS, n=11), heart failure AS (n=12) and control rats (C, n=13). After 21 weeks, failing AS rats presented higher systolic (C=36.6+/-3.1, AS=78.6+/-4.8*, failing AS=104.6+/-7.8*(dagger)) and diastolic meridian stress (C=6.9+/-0.4, AS=20.1+/-1.1*, failing AS=43.2+/-3.2*(dagger)), hydroxyproline (C=3.6+/-0.7 mg/g, AS=6.6+/-0.6* mg/g, failing AS=9.2+/-1.4*(dagger) mg/g) and cross-sectional area (C=338+/-25 microm2, AS=451+/-32* microm2, failing AS=508+/-36*(dagger) microm2), in comparison with control and compensated AS animals (*p<0.05 vs. control, (dagger)p<0.05 vs. AS). In the isometric contraction study, considering the time from peak tension to 50% relaxation (RT50), the relative variation responses, following post-rest contraction and increase in Ca2+ concentration, were higher in failing AS than compensated AS animals. In contrast, following post-rest contraction, compensated AS group presented higher values of the peak developed tension (DT) than failing AS group. Following beta-adrenergic stimulation, control animals presented higher values of +dT/dt and -dT/dt than AS animals. In addition, failing AS animals presented higher TPT values than compensated AS animals. Myocardial contractile dysfunction contributes to the development of heart failure in rats with aortic stenosis.


Comparison of Metformin and N Acetylcysteine on Clinical, Metabolic Parameter and Hormonal Profile in Women with Polycystic Ovarian Syndrome.
Comparison of metformin and N acetylcysteine on clinical, metabolic parameter and hormonal profile in women with polycystic ovarian syndrome. Prospective comparative study. Obstetrics and Gynecology department in Kamala Nehru Memorial Hospital Allahabad. On the basis of inclusion and exclusion criteria, 100 patients of PCOS were selected for study and assigned randomly in two groups to receive either metformin (1500 mg/day) (group M) or N acetylcysteine (1800 mg/day) (group N) for 24 weeks. Metabolic parameter and hormonal profile were determined before and after the treatment. Metabolic parameters, fasting glucose, fasting insulin and testosterone changes. Forty-five patients of both groups were ultimately evaluated. There was a significant improvement of body mass index, waist circumference and waist-hip ratio in group N, but there was no significant difference found in weight reduction among two groups. The biochemical marker of insulin resistance like fasting insulin, fasting glucose/insulin ratio improved significantly in group N. Greater reduction of total testosterone was observed in group N. Better improvement of metabolic and hormonal profile was observed in N acetylcysteine group. Because of its less side effect comparing to metformin, NAC can be used as a substitute for insulin-sensitizing agent in treatment of PCOS.


[Myasthenia gravis].
The present review updates myasthenia gravis. Immunopathogenesis of this condition, the clinical picture and degrees of involvement according to Osserman's classification, diagnostic procedures currently available, medical treatment and repercussion on the patient who is going yo be thymectomized are discussed. We review the works of several authors as far as concern to the use of muscle relaxants in myasthenic patients, peroperative monitoring of neuromuscular blockade, anesthetic techniques to be used, analgesia and intensive care required during postoperative period.


Principles of quality management in medicine: the British concept.
The National Health Service in Great Britain is undergoing radical change particularly with regard to clinical governance, self-regulation, revalidation, career structures and training and patterns of healthcare delivery. All these changes are relevant to risk-control and quality management. This review surveys these generic changes and illustrates the implications for neurosurgery. Neurosurgery in the UK has the opportunity to enhance their patients care by expanding the number of consultants, developing further sub-specialisation and enhancing its training and review and dissemination programmes but only if extra resources are provided.


Angiography and En Face Optical Coherence Tomography Findings in Acute Syphilitic Posterior Placoid Chorioretinopathy.
Acute syphilitic posterior placoid chorioretinopathy (ASPPC) is one of the rarest ocular manifestations of syphilis. The pathophysiology of this entity is still unknown. We report the outer retinal findings on en face optical coherence tomography (OCT) and the alteration of choriocapillaris flow findings on OCT angiography in a patient with ASPPC at the time of presentation, after penicillin treatment completion and during follow-up.