Myasthenia and related disorders of the neuromuscular junction.
Our understanding of transmission at the neuromuscular junction has increased greatly in recent years. We now recognise a wide variety of autoimmune and genetic diseases that affect this specialised synapse, causing muscle weakness and fatigue. These disorders greatly affect quality of life and rarely can be fatal. Myasthenia gravis is the most common disorder and is most commonly caused by autoantibodies targeting postsynaptic acetylcholine receptors. Antibodies to muscle-specific kinase (MuSK) are detected in a variable proportion of the remainder. Treatment is symptomatic and immunomodulatory. Lambert-Eaton myasthenic syndrome is caused by antibodies to presynaptic calcium channels, and approximately 50% of cases are paraneoplastic, most often related to small cell carcinoma of the lung. Botulism is an acquired disorder caused by neurotoxins produced by Clostridium botulinum, impairing acetylcholine release into the synaptic cleft. In addition, several rare congenital myasthenic syndromes have been identified, caused by inherited defects in presynaptic, synaptic basal lamina and postsynaptic proteins necessary for neuromuscular transmission. This review focuses on recent advances in the diagnosis and treatment of these disorders.


[Conflicts of interest: a concept often (voluntary) ignored by physicians].
A conflict of interest is a delicate situation where a person with a confidence role like a physician has professional or personal interests competing with the mission he/she has received, making him difficult to perform his/her duty with impartiality. Commercial or financial conflicts of interest of a physician can be personal and direct (gifts, travels, honoraries, consultant fees, etc.) or indirect (in relationship with those of the family or of the institution). There are also non financial conflicts of interest such as the anonymous peer review of the work performed by a friend or a competitor. An abundant literature mainly deals with the links to the pharmaceutical industry. Those links may lead to restrictions for publication and access to the data obtained by the research. The physicians have difficulties for accepting disclosing their conflict of interest. In this article, the literature published on the topic is reviewed as well as the main biases they can induce and the mistakes made by the physicians who do not declare their conflicts. Measures that can be taken to reduce their impact such as the declaration of conflicts of interest are discussed.


Validation of Montgomery-Åsberg Rating Scale and Cornell Scale for Depression in Dementia in Brazilian elderly patients.
There are few studies on validation of depression scales in the elderly in Latin America. This study aimed to assess the validity of Montgomery-Åsberg. Depression Rating Scale (MADRS) and Cornell Scale for Depression in Dementia (CSDD) in Brazilian elderly outpatients. A convenience sample of 95 outpatients was diagnosed for dementia and depression according to DSM-IV-TR, ICD-10, and PDC-dAD criteria. Receiver Operating Curves (ROC) were used to calculate the area under the curve (AUC) and to assess MADRS and CSDD cut-offs for each diagnostic criterion. Dementia was diagnosed in 71 of 95 patients. Depression was diagnosed in 35, 30, and 51 patients by ICD-10, DSM-IV, and PDC-dAD, respectively. MADRS cut-off score of 10 correctly diagnosed 67.4% and 66.3% patients as depressed according to DSM-IV and ICD-10. A cut-off of 9 correctly identified 74.7% by PDC-dAD criteria; a CSDD cut-off score of 13 best recognized depression according to DSM-IV and ICD-10. A score of 11 diagnosed depression according to PDC-dAD, while MADRS = 9 recognized depression in dementia. CSDD was more efficient in showing depression in mild than in moderate/severe dementia according to DSM-IV/ICD-10. PDC-dAD behaved nicely for any severity stage. MADRS and CSDD cut-offs of 10 and 13 were the optimal ones to diagnose depression in elderly, respectively. CSDD cut-offs are higher than those found in other countries. Other Latin American studies are needed to compare results with our study.


Effects of Aqueous Extract of Berberis integerrima Root on Some Physiological Parameters in Streptozotocin-Induced Diabetic Rats.
Diabetes mellitus is a common endocrine disorder. Anti-diabetic agents from natural and synthetic sources are available for the treatment of this disease. Berberis integerrima is a medicinal shrub used in conventional therapy for a number of diseases. The aim of the present study was to investigate the effects of aqueous extract of Berberis integerrima root (AEBI) on some physiological parameters in normal and streptozotocin-induced (STZ-induced) diabetic male Wistar rats. STZ-induced diabetic rats showed significant increases in the levels of blood glucose, triglycerides (TG), total cholesterol (TC), low density lipoprotein LDL-cholesterol (LDL-C), creatinine (Cr), urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin while body weight, high density lipoprotein HDL-cholesterol (HDL-C) and total protein levels were significantly decreased compared to normal rats. Treatment of diabetic rats with different doses of aqueous extract of Berberis integerrima root (250 and 500 mg/Kg bw) resulted in a significant decrease in blood glucose, triglycerides, cholesterol, LDL-cholesterol, ALT, AST, ALP, total bilirubin, creatinine and urea while HDL-cholesterol and total protein levels were markedly increased after six weeks compared to untreated diabetic rats. The effects of the AEBI at dose of 500 mg/Kg in all parameters except blood glucose (similar) is more than to the standard drug, glibenclamide (0.6 mg/Kg, p.o.). The results of this study indicate that the tested aqueous extract of Berberis integerrima root possesses hypoglycemic, hypolipidemic and antioxidant effects in STZ-induced diabetic rats.


The Cost-Effectiveness of Quadrivalent Human Papillomavirus Vaccination in Indonesia
Objective: National cervical cancer prevention program has been initiated in Indonesia since April 2015 and the ministry of health has started efforts to integrate the HPV Vaccine in the national immunization program since Q4 2015. Thus, it becomes important to analyze the cost-effectiveness of HPV vaccine. The objective of this model is to examine the potential long-term epidemiologic and economic impact of quadrivalent HPV(qHPV;6/11/16/18) vaccination program in Indonesia. Methods: A previously validated transmission dynamic model was used to estimate the long-term epidemiologic and economic consequences of quadrivalent HPV vaccination by comparing cost-effectiveness of 2 dose qHPV vaccination strategy for girls 11-12 years old (with or without catch up; catch up dose for 12–26 years) versus Screening Only (Pap Smear) for reducing cost related to HPV type 6,11,16,18 (cervical cancer, CIN 1, CIN 2/3, and genital warts). Costs of an HPV disease episode-of-care (diagnosis and treatment) were calculated for base case analysis using local Indonesian cost. Result: 2-dose qHPV vaccination strategies without catch up reduce the overall incidence of HPV 16/18–related cervical cancer relative to screening by 54.4% over the 100 year following vaccine introduction. Likewise, vaccination strategies reduce the incidence of HPV type 16/18 CIN 2/3, CIN 1 by 69.1% and 71.8% respectively, also reducing HPV type 6/11 CIN 1, genital warts in female, genital warts in male by 82.9%,84.2%,82.1% respectively, at this time point. From total reduction of health care cost, 67.1% attributable for diseases caused by HPV type 16/18 and 32.9% attributable for diseases caused by HPV type 6/11. Without catch up, cost/QALY would be $450/year. However catch-up strategy is more cost effective versus vaccinates 12-year-old girls only; with cost/QALYs would be $390/year. Conclusion: HPV 6/11/16/18 vaccination of females in Indonesia are 1) substantially reduce genital warts, CIN, and cervical cancer; 2) improve quality of life, and 3) with the Indonesia GDP of USD 3,531.80 in 2014 , Cost/QALYs result with or without catch up is considered very cost-effective when implemented; however with catch up, the cost/QALY can be better.


Thermogel Loaded with Low-Dose Paclitaxel as a Facile Coating to Alleviate Periprosthetic Fibrous Capsule Formation.
Medical-grade silicones as implants have been utilized for decades. However, the postoperative complications, such as capsular formation and contracture, have not yet been fully controlled and resolved. The aim of the present study is to elucidate whether the capsular formation can be alleviated by local and sustained delivery of low-dose paclitaxel (PTX) during the critical phase after the insertion of silicone implants. A biocompatible and thermogelling poly(lactic acid- co-glycolic acid)- b-poly(ethylene glycol)- b-poly(lactic acid- co-glycolic acid) triblock copolymer was synthesized by us. The micelles formed by the amphiphilic polymers in water could act as a reservoir for the solubilization of PTX, a very hydrophobic drug. The concentrated polymer aqueous solution containing PTX exhibited a sol-gel transition upon heating and formed a thermogel depot at body temperature. In vitro release tests demonstrated that the entrapped microgram-level PTX displayed a sustained release manner up to 57 days without a significant initial burst effect. Customized silicone implants coated with the PTX-loaded thermogels at various drug concentrations were inserted into the pockets of the subpanniculus carnosus plane of rats. The histological observations performed 1 month postoperation showed that the sustained release of PTX with an appropriate dose significantly reduced the peri-implant capsule thickness, production and deposition of collagen, and expression of contracture-mediating factors compared with bare silicone implants. More importantly, such an optimum dose had an excellent repeatability for the suppression of the capsular formation. Therefore, this study provides a strategic foothold regarding the sustained release of low-dose PTX to alleviate fibrotic capsule formation after implantation, and the microgram-level PTX-loaded thermogel holds great potential as an "all-purpose antifibrosis coating" for veiling the surfaces of various implantable medical devices.


Ligand-Binding Cooperativity Effects in Polymer-Protein Conjugation.
We present an electron paramagnetic resonance (EPR) spectroscopic characterization of structural and dynamic effects that stem from post-translational modifications of bovine serum albumin (BSA), an established model system for polymer-protein conjugation. Beyond the typical drug delivery and biocompatibility aspect of such systems, we illustrate the causes that alter internal dynamics and therefore functionality in terms of ligand-binding to the BSA protein core. Uptake of the paramagnetic fatty acid derivative 16-doxyl stearic acid by several BSA-based squaric acid macroinitiators and polymer-protein conjugates was studied by EPR spectroscopy, aided by dynamic light scattering (DLS) and zeta potential measurements. The conjugates were grafted from oligo(ethylene glycol) methyl ether methacrylate (OEGMA), forming an overall core-shell-like structure. It is found that ligand-binding and associated parameters such as binding affinity, cooperativity, and the number of binding sites of BSA change drastically with the extent of surface modification. In the course of processing BSA, the ligands also change their preference for individual binding sites, as observed from a comparative view of their spatial alignments in double electron electron resonance (DEER) experiments. The protein-attached polymers constitute a diffusion barrier that significantly hamper ligand uptake. Moreover, zeta potentials (ζ) decrease linearly with the degree of surface modification in protein macroinitiators and an effective dielectric constant can be estimated for the polymer layer in the conjugates. All this suggests that ligand uptake characteristics in BSA can be fine-tuned by the extent and nature of such post-translational modifications (PTMs). We show that EPR spectroscopy is suitable for quantifying these subtle PTM-based functional effects from self-assembly of substrate and ligand.


Evaluation of two new methods for routine measurement of alkaline phosphatase isoenzymes.
To evaluate the performance of two new methods for the analysis of alkaline phosphatase (ALP) isoenzymes designed for use in the routine chemical pathology laboratory: pre-incubation with neuraminidase before agarose electrophoresis; and selective precipitation of the bone isoenzyme with wheat germ agglutinin (WGA). Serum samples from 39 patients were analysed. Seventeen were from patients with liver disease, eight from patients with bone disease, and 14 from patients with normal ALP activity and no evidence of liver or bone disease. The two new methods were compared with the established method, wheat germ agglutinin affinity electrophoresis. There was good correlation between the neuraminidase and WGA electrophoretic methods. The WGA precipitation method showed negative interference in the measurement of bone isoenzyme activity in samples containing biliary alkaline phosphatase. Both the new methods had advantages of speed and simplicity over the existing method, but cost per test was considerably higher. The neuraminidase electrophoretic method is a satisfactory alternative to the WGA affinity electrophoretic method, although it is more expensive. The WGA precipitation method cannot be recommended for use with serum samples from patients with suspected liver disease.


Long-term outcomes of deep anterior lamellar versus penetrating keratoplasty for keratoconus.
To compare the long-term outcomes of deep anterior lamellar keratoplasty (DALK) with penetrating keratoplasty (PK) in keratoconus. Retrospective comparative case series (228 DALKs and 274 PKs). A biphasic linear model was used to describe the postoperative outcome of the endothelial cell density (ECD). Visual acuity, specular microscopy, corneal topography and optical coherence tomography findings were recorded. Graft survival of the 502 keratoconus eyes was 96.7 at 10 years and 95.6% at 20 years. Visual acuity improved from 20/378±5.1 lines preoperatively to 20/32±2.1 lines at 30 months. The corneal ECD decreased from 2494±382 cells/mm2 to 1521±659 cells/mm2 at 10 years. The mean simulated keratometry increased from 44.88±2.54 D at 1 year to 46.60±3.0 D at 3 years. The mean follow-up was 103.4 months for DALKs and 106.1 months for PKs. The cumulated incidence of postoperative ocular hypertension requiring treatment was significantly higher in PKs than in DALKs. The early- and late-phase rates of ECD loss were significantly lower in DALKs than in PKs. These figures in DALKs were 50% of those observed in PKs. The simulated mean keratometry was significantly higher in DALKs than in PKs in the mid but not in the long term. No significant differences in visual acuity were observed between both groups. Manual dissection-DALK featured slower visual recovery than PK and big bubble-DALK, whereas big bubble-DALK and PK featured similar visual recovery. DALK featuring higher endothelial survival and lower risk of postoperative ocular hypertension may be superior to PK when indicated for keratoconus.


Simplicity, skills, and pitfalls of ascending aortic cannulation for type A aortic dissection.
Ascending aortic cannulation for an antegrade central perfusion during surgery for type A aortic dissection is simple and can be performed within median sternotomy. This cannulation is performed routinely without problems in our hospital. Using our experience, the skills and pitfalls were clarified to make this challenging procedure successful. 29 cases of ascending aortic cannulation using the Seldinger technique for insertion were studied. All insertions were performed with the guidance of transesophageal echocardiography alone. The cannulas were inserted after decompressing the aorta by initiating cardiopulmonary bypass with femoral artery cannulation. From our experience, the skills required for this procedure are the abilities to carefully assess the needle insertion site preoperatively, sense resistance to needle insertion twice, and ensure the guide wire is in the descending aorta and distal arch. The pitfalls are entrance of the guide wire into the false lumen and dilatation of the false lumen during the insertion procedure. There were no complications associated with ascending aortic cannulation. Regarding morbidity, 2 cases of brain infarction occurred. There were 3 hospital deaths unrelated to the procedure. In surgery for type A aortic dissection, ascending aortic cannulation using the Seldinger technique is simple to perform. We found that some practical skills and precautions were required to make this procedure successful.


The impact of marital status on survival after an acute myocardial infarction: a population-based study.
A nonconcurrent prospective study was conducted in the metropolitan Baltimore, Maryland, area to examine the influence of marital status on the in-hospital and long-term survival rate of 1401 patients who experienced an acute myocardial infarction. Patients were classified as "married" or "unmarried" at the time of their myocardial infarction and any later change in the marital history was not considered. For married males the adjusted in-hospital case fatality rate was 19.7 per cent, whereas for unmarried males the rate was 26.7 per cent (p less than 0.05); similarly, the case fatality rate for married and unmarried females was 23.3 per cent and 37.4 per cent, respectively (p less than 0.05). A 10-year follow-up of 888 subjects who were discharged alive after an acute myocardial infarction also showed a significantly better survival rate for the married compared to the unmarried for both males (p less than 0.0001) and females (p less than 0.025). The results of this study indicate that married men and women who experience an acute myocardial infarction have a significantly better survival prospect, both in-hospital and after discharge, independent of other factors.


Molecular Photoelectrode for Water Oxidation Inspired by Photosystem II.
In artificial photosynthesis, the sun drives water splitting into H2 and O2 or converts CO2 into a useful form of carbon. In most schemes, water oxidation is typically the limiting half-reaction. Here, we introduce a molecular approach to the design of a photoanode that incorporates an electron acceptor, a sensitizer, an electron donor, and a water oxidation catalyst in a single molecular assembly. The strategy mimics the key elements in Photosystem II by initiating light-driven water oxidation with integration of a light absorber, an electron acceptor, an electron donor, and a catalyst in a controlled molecular environment on the surface of a conducting oxide electrode. Visible excitation of the assembly results in the appearance of reductive equivalents at the electrode and oxidative equivalents at a catalyst that persist for seconds in aqueous solutions. Steady-state illumination of the assembly with 440 nm light with an applied bias results in photoelectrochemical water oxidation with a per-photon absorbed efficiency of 2.3%. The results are notable in demonstrating that light-driven water oxidation can be carried out at a conductive electrode in a structure with the functional elements of Photosystem II including charge separation and water oxidation.


Different effects of bone morphogenetic proteins 2, 4, 12, and 13 on the expression of cartilage and bone markers in the MC615 chondrocyte cell line.
In order to study the lineage leading to chondrocyte and osteoblast phenotype in vertebrate development, we examined the effect of recombinant human bone morphogenetic protein (BMP)-2, BMP-4, BMP-12 [or growth and differentiation factor (GDF)-7], and BMP-13 (or GDF-6) on the phenotypic expression of the mouse chondrocyte cell line MC615, grown for 1 or 2 weeks in monolayer. Protein synthesis rates were monitored after incubation with [(14)C]proline. BMP-2 and BMP-4 increased protein synthesis, in agreement with our observation by phase-contrast microscopy of a highly refractile matrix around MC615 cells treated with BMP-2 and -4. Markers of the chondrocytic and osteoblastic differentiation were analyzed at mRNA level. Expression of the type II collagen gene, a marker of the cartilage phenotype, was up-regulated in the presence of low concentration of BMP-2 or -4 (50 ng/ml) and down-regulated at higher concentrations (100-400 ng/ml). In parallel, this expression was stable in the presence of BMP-12 or -13 in the dose range tested (50-400 ng/ml). Expression of the matrix Gla protein (MGP) gene, another marker of cartilage, was also reduced in the presence of 100 ng/ml BMP-2 or -4, while it remained stable in the presence of BMP-12 or -13 at the same concentration. In contrast, expression of the bone Gla protein (BGP) gene, or osteocalcin, a marker of the bone phenotype, was induced when the cells were treated with BMP-2 or -4 but was not detected when the cells were treated with BMP-12 or -13. At the same time, BMP-2 or -4 markedly up-regulated expression of type X collagen mRNA, indicating that MC615 cells possess the ability to express traits associated with endochondral ossification, when exposed to specific BMPs. Furthermore, detailed analysis of type II collagen expression showed that the alternatively spliced transcript collagen IIB, specific for cartilage, is expressed concomitantly with BGP. Therefore, MC615 chondrocytes can simultaneously express chondrocytic and osteoblastic markers, in response to BMP-2 or -4, but show minimal response to BMP-12 (or GDF-7) or to BMP-13 (or GDF-6). These results raise the possibility that chondrocytes in vivo can express osteoblastic properties, provided they are induced by BMP-2 or -4.


Cerebellar climbing fibers modulate simple spikes in Purkinje cells.
Purkinje cells have two action potentials: Climbing fiber responses (CFRs) and simple spikes (SSs). CFRs reflect the discharge of a single climbing fiber at multiple synaptic sites on the proximal dendrite of the Purkinje cell. SSs reflect the summed action of a subset of parallel fiber synapses on Purkinje cell dendritic spines. Because mossy fiber afferents terminate on granule cells, the ascending axons of which bifurcate, giving rise to parallel fibers, the modulation of SSs has been attributed to mossy fiber afferent signals. This inference has never been tested. Conversely, the low discharge frequency of CFRs has led many to conclude that they have a unique and intermittent role in cerebellar signal processing. We examine the relative potency of vestibularly modulated mossy fiber and climbing fiber signals in evoking CFRs and SSs in Purkinje cells of the uvula-nodulus in chloralose-urethane-anesthetized rabbits. Vestibular primary afferents were blocked by unilateral labyrinthectomy (UL). A UL destroys the vestibular primary afferent signal to the ipsilateral uvula-nodulus, while leaving intact the vestibular climbing fiber signal from the contralateral inferior olive. After UL, vestibular stimulation modulated CFRs and SSs in ipsilateral uvula-nodular Purkinje cells, demonstrating that the primary vestibular afferent mossy fiber input to the ipsilateral uvula-nodulus was not necessary for SS modulation. Unilateral microlesions of the caudal half of the beta-nucleus of the inferior olive reduced a modulated climbing fiber signal to the contralateral uvula-nodulus, causing loss of both vestibularly modulated CFRs and SSs in contralateral Purkinje cells. Vestibular climbing fibers not only evoke low-frequency CFRs, but also indirectly modulate higher-frequency SSs. This modulation must be attributed to cerebellar interneurons. Golgi cell inhibition of granule cells may provide the interneuronal mechanism for CFR-induced SS modulation.


Use of ketamine for depression and suicidality in cancer and terminal patients: Review of current data.
Depression and suicidality are significant challenges faced by cancer patients, particularly those in advanced stages of the disease or nearing the end of life. Conventional antidepressant therapies often have limited effectiveness or delayed onset of action, making the exploration of alternative treatments crucial. The use of ketamine as a potential treatment for depression and suicidality in cancer and terminal patients has gained considerable attention in recent years. This review article aims to provide a comprehensive analysis of the current data regarding the efficacy and safety of ketamine in this specific population. This review presents an overview of clinical trials and case studies investigating the use of ketamine in this population. It explores the effectiveness of ketamine as a standalone treatment or in combination with other interventions. Furthermore, the article addresses the limitations and future directions of research in this field. It highlights the need for larger, well-controlled studies with long-term follow-up to establish the efficacy, safety and optimal treatment parameters of ketamine for depression and suicidality in palliative care.


Wound care products: how to choose.
Working in PPS means that agencies and clinicians must determine which wound care regimen will reach the intended patient goal in the most cost-effective way in terms of supply and visit cost. This article outlines the specific rationale clinicians can use when assessing wounds and choosing the dressing(s) that are appropriate to meet patient and agency goals. Using the performance-based model approach, clinicians learn how to choose dressings based on product price versus treatment costs.


Ramadan fasting and diabetes: an observational study among Turkish migrants in Belgium.
To investigate (i) Ramadan participation, (ii) provision of Ramadan-related advice by healthcare providers, (iii) medication use during Ramadan fasting among Turkish migrants with diabetes in Belgium. This pilot observational study was conducted among a convenience sample of 52 Turkish migrants with diabetes in Belgium. Two questionnaires collected information on socio-demographic characteristics, diabetes-related characteristics, current hypoglycaemic medication with dosing regimen, participation in the past Ramadan, reasons for (non-)participation, use of hypoglycaemic medication during the past Ramadan, advice from their healthcare providers about fasting during Ramadan and follow-up of this advice. Sixteen patients (31%) had fasted during the past Ramadan. Main reason for Ramadan participation was reinforcement of faith (12/15), while the main reason for non-participation was having diabetes (34/36). About 56% of the study population had received recommendations from their healthcare provider(s) about fasting and diabetes during Ramadan. The most commonly provided advice was not to participate in Ramadan, followed by modification of drug therapy. Only 3 patients ignored the advice of their health professionals. In addition, only 60% of those who actually fasted received recommendations about intake of diabetes medication during the Ramadan. Most fasters continued their medication dose unchanged (87% of OHA users and 80% of the insulin users). This pilot study found a low prevalence of Ramadan fasting among Turkish migrants with diabetes in Belgium. We also found that provision of advice by healthcare providers could be improved. Larger scale studies are warranted to confirm these findings.


Angioplasty and elective stenting of de novo versus recurrent femoropopliteal lesions: 1-year follow-up.
To investigate patency rates after percutaneous transluminal angioplasty (PTA) and PTA plus elective stenting in de novo versus recurrent femoropopliteal lesions. The data were collected from a prospective registry including 533 consecutive patients (284 men; median age 71 years, interquartile range [IQR] 72-78) with severe claudication (n=387) or critical limb ischemia (n=146) who underwent femoropopliteal percutaneous interventions during a 36-month period. PTA was used to treat 357 de novo and 99 recurrent lesions; PTA plus elective stent implantation was performed in 58 de novo and 19 recurrent lesions. Patients were followed for a median 12 months (IQR 7-14) using color duplex sonography. Rates of restenosis (>/=50%) were compared by multivariate analysis. Overall primary technical success was achieved in 517 (97%) patients; 31 (6%) periprocedural complications were encountered. Restenosis occurred in 213 (40%) patients after a median 6 months (IQR 4-7). Twelve-month patency after PTA was 61% in de novo and 33% in recurrent lesions (p<0.0001). Patients with recurrent lesions had a 2.3-fold increased adjusted risk for restenosis after PTA (95% confidence interval 1.7 to 3.2). Twelve-month patency after stenting was 58% in de novo and 52% in recurrent lesions (p=0.9). In patients with de novo lesions, patency rates after PTA and stent were similar (p=0.8); however, in patients with recurrent lesions, elective stenting performed better (p=0.05). Recurrent stenosis after prior femoropopliteal balloon angioplasty is an independent risk factor for restenosis; these lesions exhibit disappointing patency after repeated PTA. Stent implantation may improve intermediate-term results in these patients.


A method for locating individual leukocytes for comparative study by light and scanning electron microscopy.
A method is presented for locating individual leukocytes and platelets in Wright's stained blood films for comparative study by light and scanning electron microscopy. The individual cells in the blood films were photographed and the field was circled with a diamond marker objective. The slide was scored and broken; pieces of the stained slide containing the numbered circles were fixed (with conductive cement) to a metal stub, air dried, and coated with metallic gold. The metal stub was placed in a scanning electron microscope, and the marked cells were readily located and photographed so that their three-dimensional surface morphology could be compared with the morphologic features of stained cells in the blood film photographed with the light microscope. Characteristics of individual cell types are discussed.


Molteno implants as a treatment for refractory glaucoma in black patients.
Eighty-two black patients with refractory glaucoma were treated with a single-plate Molteno implant inserted in a single-stage procedure. A successful outcome (intraocular pressure less than or equal to 21 mm Hg with or without adjunctive medical therapy) was achieved in 72% of the patients with a mean follow-up of 30 months. Success was achieved in 23 (73%) of the 31 patients with open angle glaucoma, 20 (83%) of the 24 patients with either aphakic or pseudophakic glaucoma, 12 (67%) of the 18 patients with neovascular glaucoma, four (80%) of the five patients with uveitic glaucoma, and two (50%) of the four patients with congenital glaucoma. All but four patients required additional medical therapy. Visual acuities remained the same or improved in 21 (68%) of the 31 patients with open angle glaucoma, 11 (61%) of the 18 with neovascular glaucoma, 19 (79%) of the 24 patients with aphakic/pseudophakic glaucoma, three (75%) of the four patients with congenital glaucoma, and four (80%) of the five patients with uveitic glaucoma. Complications included hyphema (18%), "kissing" choroidal effusion (6%), blocked tube (8%), flat anterior chamber (12%), cataracts (5%), Tenon's cyst (encapsulated bleb) (17%), uveitis (7%), phthisis bulbi (5%), and erosion of the silicone tube (1%).


[Medical radiology--today and tomorrow].
Medical radiology comprises diagnostic radiology, nuclear medicine and radio-oncology. Digital radiography, sonography, computed tomography, magnetic resonance and percutaneous techniques mark the present development of radiodiagnosis. Current advances in nuclear medicine are emission computed tomographic techniques and biochemical radiopharmaceuticals. Computerized planning, combination therapy and particular types of ionizing radiation are the main ongoing developments in radiation oncology. Teaching and research have a decisive bearing on the future of medical radiology.


Association between Fatty Acid Composition in Hair and Energy Availability during Early Lactation in Simmental and German Holstein Cows.
This study examined (1) if fatty acids in bovine hair are influenced by dietary energy levels and (2) if the relationship between energy availability and fatty acids in hair persists across breeds and farms. Sixty-two and 59 Fleckvieh (Simmental), and 55 German Holstein cows from three farms, respectively, were fed two levels of energy concentration of roughage (6.1 and 6.5 MJ net energy for lactation/kg dry matter) and two levels of concentrate supply (150 and 250 g/kg energy-corrected milk). The average body weight was 727 kg (Simmental) and 668 kg (Holstein). The average lactation number was 3.1. Hair samples were taken in lactation weeks 4 and 8. In Simmental cows, a lower energy deficit due to a relatively higher energy intake from high energy concentration of the roughage was associated with higher C18:2n-6 and C18:3n-3 contents in hair at week 8. In cows from all three farms, higher energy intake between lactation weeks 2 and 6 correlated with higher content of C18:2n-6 in hair samples taken in lactation weeks 4 and 8. No correlation was found for C12:0. These results provide the first evidence that increased energy intake increases the contents of C18:2n-6 in hair.


Xenografts on nude mouse diaphragm of human DU145 prostate carcinoma cells: mesothelium removal by outgrowths and angiogenesis.
Human prostate carcinoma DU145 cells, androgen-independent malignant cells, implanted in the athymic nu/nu male mouse, developed numerous tumors on peritoneal and retro-peritoneal organs whose growth aspects and vascular supply have yet to be investigated with fine structure techniques. A series of necropsies from moribund implanted mice diaphragms were examined with light, scanning, and transmission electron microscopy. DU145 xenografts installations, far away from the implanted site, were described as the smallest installation to large diaphragm outgrowths in moribund mice. Carcinomas did not show extracellular matrix and, reaching more than 0.15 mm in thickness, they revealed new structures in these outgrowths. Voids to be gland-like structures with mediocre secretion and, unexpectedly, intercellular spaces connected with fascicles of elongated DU145 cells that merged with a vascular supply originated from either the tumor cells and/or some perimysium vessels. In the largest carcinomas, most important vascular invasions coincidently accompanied the mouse lethality, similarly to human cancers. This androgen-independent model would be useful to study tumor outgrowth's changes related to testing anticancer strategy, including anti-angiogenic therapies involving toxicity, simultaneously with those of other vital organs with combined biomolecular and fine structure techniques.


The effects of resident and nursing home characteristics on activities of daily living.
Existing studies on the relationships between impairments and activities of daily living (ADLs) in nursing home residents have serious limitations. This study examines the relationships among admission impairments, including pain, depression, incontinence, balance, and falls, and follow-up ADLs, as well as the effect of the nursing home on follow-up ADLs of extended-stay nursing home residents. This longitudinal cohort study consisted of 4,942 extended-stay residents who were admitted into 377 Minnesota nursing homes during 2004. General linear mixed models were used for all analyses, with 14 resident-level and 8 facility-level control variables. Incontinence and balance function at admission were significantly associated with increases in ADL dependence at follow-up. Individual nursing homes had independent effects on all three ADL models. Similar findings were found after facility-level control variables were added. Incontinence predicts subsequent ADL functional levels. The relationship between balance dysfunction and subsequent ADL dependence could be causal. Future studies of the causal relationships between impairments and ADL should examine the effectiveness of impairment interventions on ADL as well as these relationships in different subgroups of nursing home residents.


PrediSi: prediction of signal peptides and their cleavage positions.
We have developed PrediSi (Prediction of Signal peptides), a new tool for predicting signal peptide sequences and their cleavage positions in bacterial and eukaryotic amino acid sequences. In contrast to previous prediction tools, our new software is especially useful for the analysis of large datasets in real time with high accuracy. PrediSi allows the evaluation of whole proteome datasets, which are currently accumulating as a result of numerous genome projects and proteomics experiments. The method employed is based on a position weight matrix approach improved by a frequency correction which takes in to consideration the amino acid bias present in proteins. The software was trained using sequences extracted from the most recent version of the SwissProt database. PrediSi is accessible via a web interface. An extra Java package was designed for the integration of PrediSi into other software projects. The tool is freely available on the World Wide Web at http://www.predisi.de.


Exploration of Chemical Diversity and Antitrypanosomal Activity of Some Red Sea-Derived Actinomycetes Using the OSMAC Approach Supported by LC-MS-Based Metabolomics and Molecular Modelling.
In the present study, we investigated the actinomycetes associated with the Red Sea-derived soft coral Sarcophyton glaucum in terms of biological and chemical diversity. Three strains were cultivated and identified to be members of genera Micromonospora, Streptomyces, and Nocardiopsis; out of them, Micromonospora sp. UR17 was putatively characterized as a new species. In order to explore the chemical diversity of these actinobacteria as far as possible, they were subjected to a series of fermentation experiments under altering conditions, that is, solid and liquid fermentation along with co-fermentation with a mycolic acid-containing strain, namely Nocardia sp. UR23. Each treatment was found to affect these actinomycetes differently in terms of biological activity (i.e., antitrypanosomal activity) and chemical profiles evidenced by LC-HRES-MS-based metabolomics and multivariate analysis. Thereafter, orthogonal projections to latent structures discriminant analysis (OPLS-DA) suggested a number of metabolites to be associated with the antitrypanosomal activity of the active extracts. The subsequent in silico screenings (neural networking-based and docking-based) further supported the OPLS-DA results and prioritized desferrioxamine B (3), bafilomycin D (10), and bafilomycin A1 (11) as possible antitrypanosomal agents. Our approach in this study can be applied as a primary step in the exploration of bioactive natural products, particularly those from actinomycetes.


Delayed cord clamping versus cord milking in vigorous neonates ≥35 weeks gestation born via cesarean: A Randomized clinical trial.
Delayed cord clamping (DCC) is the recommended strategy in neonates not requiring resuscitation, but umbilical cord milking (UCM) can also be used in term babies. DCC has been found to offer advantages more than just placental transfusion. To compare the neonatal outcomes of DCC and UCM at birth in vigorous neonates ≥35 weeks born via cesarean section. We included all vigorous neonates born ≥35 weeks of gestation through the cesarean section in this open-label randomized controlled trial. They were randomized into Group-A (DCC-cord was clamped 60 s after birth) or Group B(UCM). For neonates in Group B, the intact cord was milked at 25 cm from the stump 3 times towards the neonate and then clamped. The primary outcome was hematocrit at 72 h of life. Secondary outcomes were serum ferritin between 6 and 10 weeks of life, serum bilirubin at 72 h of life, need and duration of phototherapy, respiratory distress, hypoglycemia, hypotension, and sepsis. Baseline characteristics were similar in both the groups. The mean hematocrit at 72 h was more in the DCC group compared to the UCM group [(55.60±4.50) vs (53.89±4.44), MD (95% CI) = 1.71 (0.26, 3.16); p = 0.021]. There was no significant difference in median serum ferritin between the groups [102.88(84.67-173.24) vs 137.93(85.15-230.40); p = 0.173]. There was no significant difference in clinical outcomes. In neonates born via cesarean section, DCC resulted in improved hematocrit levels by 72 hours compared to UCM. DCC results in better placental transfusion.


Analysis of electric vehicle charging station usage and profitability in Germany based on empirical data.
This paper provides empirical data and a profitability estimation of public charging infrastructure usage in Germany. Given that, in Germany, there are now 2.5 times as many vehicles per charging station compared with 2017, the system needs to allocate charging points efficiently. To this end, this paper presents representative data on energy consumption, arrival times, occupation, and estimated profitability of 22,200 charging stations in Germany. The observed patterns are translated into compact empirical models that allow working with the results without the burden of the large-scale datasets. Charging happens mainly during the day and on weekdays for AC charging stations, whereas DC fast-charging stations are more popular on the weekend. Fast-chargers service approximately three times as many vehicles per charge point at higher profits because of better margins. For AC chargers, up to 20 kWh of energy are charged in an average charge event, whereas fast-chargers supply approximately 40 kWh. Energy transfer typically terminates after 4 h for AC chargers and 45 min for fast-chargers. The power rates are significantly below the rated station power and rarely exceed 11 kW for AC charging. This paper allows fellow researchers to build simulation and test scenarios using presented data or to verify models.


Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension.
Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.


Socio-Demographic and Behavioral Factors Associated with the Desire to Procreate Among Patients Living with HIV in Gabon.
The desire to procreate in patients living with HIV (PLHIV) has been seldom investigated in Africa, particularly in Gabon. The aim of this transversal and descriptive study was to analyze the socio-demographic and behavioral factors associated with a desire to have children in a cohort of PLHIV. The study included 442 patients, predominantly females [79.9% (337/422)], and those with a secondary school education [64.2% 271/422)]. The highest prevalence of HIV was found in patients aged 30-39 years old (44.3%), of which 59% (249/422) were unemployed. The desire to have children was noted in 78% (329/422) of patients, of which 82.4% (271/329) were treated with antiretroviral drugs; this was significantly higher in subjects under 40 years versus those over 40 years old [81% (268/329) versus 19% (61/329), p<0.001]. Sero-discordant couples represented 33.4% (110/329) of patients. The frequency of patients with the desire to have a child was significantly higher when patients wanted to hold the status of parent of a child [77% (255/329) versus 23% (74/329), p<0.001]; this was influenced by the partner's desire [60% 197/329 versus 40% (132/329), p< 0.001], as well as by the absence of weight loss [56% (185/329) versus 44% (144/329), p<0.001]. The average number of children was significantly lower in patients with the desire to procreate compared to those with no desire to have children [1.7 versus 3.2, p<0.001]. These first observations in Gabon highlight the importance of the desire to have children in PLHIV and sero-discordant couples, and they show the level of interest in developing assistance methods for procreation and family planning programs to help this population, as well as to reduce the risk of mother-to-child HIV transmission.


Stabilizing Crystal Framework of an Overlithiated Li1+xMn2O4 Cathode by Heterointerfacial Epitaxial Strain for High-Performance Microbatteries.
To meet the increasing demands of high-energy and high-power-density lithium-ion microbatteries, overlithiated Li1+xMn2O4 (0 ≤ x ≤ 1) is an attractive cathode candidate due to the high theoretical capacity of 296 mAh g-1 and the interconnected lithium-ion diffusion pathways. However, overlithiation triggers the irreversible cubic-tetragonal phase transition due to Jahn-Teller distortion, causing rapid capacity degradation. In contrast to conventional lithium-ion batteries, microbatteries offer the opportunity to develop specific thin-film-based modification strategies. Here, heterointerfacial lattice strain is proposed to stabilize the spinel crystal framework of an overlithiated Li1+xMn2O4 (LMO) cathode by epitaxial thin film growth on an underlying SrRuO3 (SRO) electronic conductor layer. It is demonstrated that the lattice misfit at the LMO/SRO heterointerface results in an in-plane epitaxial constraint in the full LMO film. This suppresses the lattice expansion during overlithiation that typically occurs in the in-plane direction. It is proposed by density functional theory modeling that the epitaxial constraint can accommodate the internal lattice stress originating from the cubic-tetragonal transition during overlithiation. As a result, a doubling of the capacity is achieved by reversibly intercalating a second lithium ion in a LiMn2O4 epitaxial cathode with a complete reversible phase transition. An impressive cycling stability can be obtained with reversible capacity retentions of above 90.3 and 77.4% for the 4 and 3 V range, respectively. This provides an effective strategy toward a stable overlithiated Li1+xMn2O4 epitaxial cathode for high-performance microbatteries.


Purinergic signaling in microglia in the pathogenesis of neuropathic pain.
Nerve injury often causes debilitating chronic pain, referred to as neuropathic pain, which is refractory to currently available analgesics including morphine. Many reports indicate that activated spinal microglia evoke neuropathic pain. The P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, is upregulated in spinal microglia after nerve injury by several factors, including CC chemokine receptor CCR2, the extracellular matrix protein fibronectin in the spinal cord, interferon regulatory factor 8 (IRF8) and IRF5. Inhibition of P2X4R function suppresses neuropathic pain, indicating that microglial P2X4R play a key role in evoking neuropathic pain.


[Problematic breastfeeding due to a short frenulum].
Ankyloglossia (tongue tie) in the neonate can be a cause of breastfeeding problems. Frenotomy (cutting of the frenulum linguae) had fallen into disrepute, but has regained its place as a standard medical procedure in Anglo-Saxon countries, though not in the Netherlands. We present two neonates, both boys, presenting with breastfeeding problems caused by ankyloglossia. The first baby described did not drink enough and hence did not gain any weight. The mother of the second patient experienced a great deal of pain and had cracked nipples, caused by an abnormal suckling action. Both boys underwent frenotomy with good result. Recent ultrasound studies reveal that frenotomy immediately normalizes the suckling action in babies with ankyloglossia. Randomized controlled trials show that 95% of breastfeeding problems disappear. There is sufficient evidence to state that frenotomy is a very safe and useful procedure in neonates.


Surgical Removal of Submacular Perfluorocarbon Liquid Using a 41-Gauge Extendible Subretinal Injection Needle.
Submacular perfluorocarbon liquid (PFCL) retention is a well-known complication of vitreoretinal surgeries; however, the optimal surgical technique for the removal of subfoveal PFCL is yet to be determined. We describe a novel surgical technique for the removal of retained submacular PFCL by performing a retinotomy adjacent to the inferotemporal arcade using a 41-gauge extendible subretinal injection needle and inducing a therapeutic retinal detachment. Through the same retinotomy, the bent 41-gauge needle was advanced into the subretinal space to reach the PFCL bubble. Subsequently, active aspiration of PFCL was performed. The surgical procedure was successfully performed in two patients. This technique appears to be an effective surgical approach for removing retained submacular PFCL bubble.


Sexually Transmitted Infections in Pregnancy and Reproductive Health: Proceedings of the STAR Sexually Transmitted Infection Clinical Trial Group Programmatic Meeting.
The goal of the STAR Sexually Transmitted Infection Clinical Trial Group (STI CTG) Programmatic meeting on Sexually Transmitted Infections (STIs) in Pregnancy and Reproductive Health in April 2018 was to review the latest research and develop recommendations to improve prevention and management of STIs during pregnancy. Experts from academia, government, nonprofit, and industry discussed the burden of STIs during pregnancy; the impact of STIs on adverse pregnancy and birth outcomes; interventions that work to reduce STIs in pregnancy, and the evidence, policy, and technology needed to improve STI care during pregnancy. Key points of the meeting are as follows: (i) alternative treatments and therapies for use during pregnancy are needed; (ii) further research into the relationship between the vaginal microbiome and STIs during pregnancy should be supported; (iii) more research to determine whether STI tests function equally well in pregnant as nonpregnant women is needed; (iv) development of new lower cost, rapid point-of-care testing assays could allow for expanded STI screening globally; (v) policies should be implemented that create standard screening and treatment practices globally; (vi) federal funding should be increased for STI testing and treatment initiatives supported by the Centers for Disease Control and Prevention (CDC), the Centers of Excellence in STI Treatment, public STD clinics, and the President's Emergency Plan for AIDS Relief (PEPFAR).


A comparable efficacy and safety between intracardiac echocardiography and transesophageal echocardiography for percutaneous left atrial appendage occlusion.
Accumulated clinical studies utilized intracardiac echocardiography (ICE) to guide percutaneous left atrial appendage occlusion (LAAO). However, its procedural success and safety compared to traditional transesophageal echocardiography (TEE) remained elusive. Therefore, we performed a meta-analysis to compare efficacy and safety of ICE and TEE for LAAO. We screened studies from four online databases (including the Cochrane Library, Embase, PubMed, and Web of Science) from their inception to 1 December 2022. We used a random or fixed-effect model to synthesize the clinical outcomes and conducted a subgroup analysis to identify the potential confounding factors. A total of twenty eligible studies with 3,610 atrial fibrillation (AF) patients (1,564 patients for ICE and 2,046 patients for TEE) were enrolled. Compared with TEE group, there was no significant difference in procedural success rate [risk ratio (RR) = 1.01; P = 0.171], total procedural time [weighted mean difference (WMD) = -5.58; P = 0.292], contrast volume (WMD = -2.61; P = 0.595), fluoroscopic time (WMD = -0.34; P = 0.705; I2 = 82.80%), procedural complications (RR = 0.82; P = 0.261), and long-term adverse events (RR = 0.86; P = 0.329) in the ICE group. Subgroup analysis revealed that ICE group might be associated with the reduction of contrast use and fluoroscopic time in the hypertension proportion <90 subgroup, with lower total procedure time, contrast volume, and the fluoroscopic time in device type subgroup with multi-seal mechanism, and with the lower contrast use in paroxysmal AF (PAF) proportion ≤50 subgroup. Whereas, ICE group might increase the total procedure time in PAF proportion >50 subgroup and contrast use in multi-center subgroup, respectively. Our study suggests that ICE may have comparable efficacy and safety compared to TEE for LAAO.


Bilateral and recurrent optic neuritis in multiple sclerosis.
To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG.


Cycloartane glycosides from Astragalus aureus.
Eight cycloartane-type triterpene glycosides (1-8) were isolated from Astragalus aureus Willd along with ten known cycloartane-type glycosides (9-18). Their structures were established by the extensive use of 1D and 2D-NMR experiments along with ESIMS and HRMS analyses. Compounds 1-5 are cyclocanthogenin glycosides, whereas compounds 6-8 are based on cyclocephalogenin as aglycon, more unusual in the plant kingdom, so far reported only from Astragalus spp. Moreover, for the first time monoglycosides of cyclocanthogenin (5) and cyclocephalogenin (7, 8) are reported. All of the compounds tested for their cytotoxic activities against a number of cancer cell lines. Among the compounds, only 8 exhibited activity versus human breast cancer (MCF7) at 45 μM concentration.


Application of Potassium Myristate as an Antifungal and a Dough Improving in Bread-Making.
Surface-acting agents are used as bread improvers in bread making to increase the specific loaf volume. We focused on the use of fatty acid salts as surface acting agents and new food additives. Fatty acid salts are the main components of soaps and display antibacterial activity. In this study, we investigated the mold-proofing activity and baking property with fatty acid salts. We examined the influence of fatty acid salts with different lengths of carbon chains on the dough expansion ability and found that the dough expansion ability increased significantly in the presence of more than 5% potassium myristate (C14K) . No significant difference was observed in the dough fermentation abilities between the control dough and C14K-treated dough, indicating of the absence of any effect of C14K on the fermentation ability. The antifungal test showed that C14K effectively inhibited fungal growth. Thus, C14K may serve as a promising bread improver.


Identification of a sequence-specific protein binding the 5'-transcribed spacer of rat ribosomal genes.
A novel 85-kD protein factor which interacts specifically with the 5'-transcribed spacer of rat ribosomal genes was identified using the gel mobility shift, DNase I protection and UV-crosslinking techniques. The binding site of the factor is located inside the 36 bp Alul-HindIII fragment of transcribed spacer, most probably in the region +94 to +115 with respect to the transcription initiation site. Factors giving very similar gel mobility shift patterns were also found in mouse and human cell extracts. Sequences resembling the binding site of this factor were revealed in corresponding regions of mouse and human ribosomal genes. The biological function of FTS remains to be elucidated.


The hepatitis B virus MHBst167 protein is a pleiotropic transactivator mediating its effect via ubiquitous cellular transcription factors.
C-terminally truncated surface proteins of hepatitis B virus (HBV) are frequently translated from genomically integrated viral sequences. They may be relevant for hepatocarcinogenesis by stimulating gene expression. First, we examined the transactivating potential of middle hepatitis B surface protein truncated at amino acid (aa) position 167 (MHBst167) on the HBV regulatory element. In transient cotransfection assays using Chang liver or HepG2 cell lines and chloramphenicol acetyltransferase (CAT) reporter constructs only the HBV enhancer I, but no other HBV regulatory elements like the X promoter, the S1 or S2 promoter or the enhancer II/core promoter could be stimulated by MHBst167. Since there is no evidence for a direct interaction of MHBst167 with DNA, we subsequently analysed whether cellular transcription factors were involved in mediating transactivation. This was tested both with isolated transcription-factor-binding sites and in the natural context of viral and cellular promoter elements. Deletion analysis and electrophoretic mobility shift assays revealed that Sp1, AP1 and NF-kappa B can mediate transactivation by MHBst167. No involvement of CREB, NF1 or the liver-specific factor C/EBP was found. These data indicate that MHBst167 is a pleiotropic, non-liver-specific transactivator which exerts its effect via ubiquitous cellular transcription factors that are also involved in the regulation of expression of cellular genes relevant for proliferation and inflammation.


BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts.
Programmed death ligand 1 (PD-L1) is an immune checkpoint protein; however, emerging data suggest that tumor cell PD-L1 may regulate immune-independent and intrinsic cellular functions. We demonstrate regulation of PD-L1 by oncogenic BRAFV600E and investigated its ability to influence apoptotic susceptibility in colorectal cancer (CRC) cells. Endogenous or exogenous mutant vs. wild-type BRAF were shown to increase PD-L1 messenger RNA (mRNA) and protein expression that was attenuated by MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase) inhibition or c-JUN and YAP knockdown. Deletion of PD-L1 reduced tumor cell growth in vitro and in vivo. Loss of PD-L1 was also shown to attenuate DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1, but not mutants with deletion of its extra- or intracellular domain. The effect of PD-L1 on chemosensitivity was confirmed in MC38 murine tumor xenografts generated from PD-L1-knockout vs. parental cells. Deletion of PD-L1 suppressed BH3-only BIM and BIK proteins that could be restored by re-expression of PD-L1; re-introduction of BIM enhanced apoptosis. PD-L1 expression was significantly increased in BRAFV600E human colon cancers, and patients whose tumors had high vs. low PD-L1 had significantly better survival. In summary, BRAFV600E can transcriptionally upregulate PD-L1 expression that was shown to induce BIM and BIK to enhance chemotherapy-induced apoptosis. These data indicate an intrinsic, non-immune function of PD-L1, and suggest the potential for tumor cell PD-L1 as a predictive biomarker.


[The selective suppression of GABA on cone-driven horizontal cells in carp retina].
Intracellular recordings were made from horizontal cells in the superfused, isolated carp retina and effects of GABA on rod- and cone-driven horizontal cells were studied. Bath-applied GABA (0.5-5 mmol/L) resulted in a hyperpolarization of dark membrane potential and a suppression of light responses of L-type cone horizontal cells. In 7 out of 10 cells tested the effects of GABA were completely blocked by bicuculline, an antagonist of GABAA receptors. In the presence of 0.5 mmol/L Co2+, 2 mmol/L GABA could not induce any change in dark membrane potential in 8 out of 12 cells, but cause slight depolarization in other 4 cells. These results suggest that the GABA effects may be mediated by GABAA receptors on cone terminals in the majority of the L-type cone horizontal cells. GABA had no effect on rod horizontal cells.


Overactivity or blockade of transforming growth factor-β each generate a specific ureter malformation.
Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGFβ ligands, as well as Tgfbr1 and Tgfbr2 coding for TGFβ receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGFβ1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGFβ1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGFβ. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon-like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Ten-year results from the Natrelle 410 anatomical form-stable silicone breast implant core study.
Silicone breast implants have long been used for breast augmentation and reconstruction. During this time, these medical devices have gone through a number of modifications to improve their safety, quality, and clinical outcome performance. The authors conducted a 10-year study to determine the safety and effectiveness of Natrelle 410 silicone breast implants. This prospective, multicenter study enrolled 941 subjects who were undergoing either augmentation, augmentation revision, reconstruction, or reconstruction revision. Data on complications, reoperations, explantations, and subject satisfaction were collected at annual clinic visits, and one-third of subjects underwent biennial magnetic resonance imaging (MRI) to screen for implant rupture. The authors used the Kaplan-Meier estimator to calculate risk rates for local complications, reoperations, and explantations. Capsular contracture rates increased approximately 1% per year from the previously reported 6-year rates. The rates were significantly lower than those from the Natrelle round gel core study. The overall rate of confirmed ruptured implants in subjects who underwent MRI was 5.7%. Eleven late seromas were reported. The most common reason for explantation was a subject requesting a size or style change. Satisfaction rates remained high through 10 years, with most subjects saying they were somewhat or definitely satisfied with their implants. This 10-year prospective trial demonstrated the long-term safety and effectiveness of Natrelle 410 anatomical form-stable implants. The complication rates were low and the satisfaction rates were high. LEVEL OF EVIDENCE 1: Therapeutic.


Ecology-driven stereotypes override race stereotypes.
Why do race stereotypes take the forms they do? Life history theory posits that features of the ecology shape individuals' behavior. Harsh and unpredictable ("desperate") ecologies induce fast strategy behaviors such as impulsivity, whereas resource-sufficient and predictable ("hopeful") ecologies induce slow strategy behaviors such as future focus. We suggest that individuals possess a lay understanding of ecology's influence on behavior, resulting in ecology-driven stereotypes. Importantly, because race is confounded with ecology in the United States, we propose that Americans' stereotypes about racial groups actually reflect stereotypes about these groups' presumed home ecologies. Study 1 demonstrates that individuals hold ecology stereotypes, stereotyping people from desperate ecologies as possessing faster life history strategies than people from hopeful ecologies. Studies 2-4 rule out alternative explanations for those findings. Study 5, which independently manipulates race and ecology information, demonstrates that when provided with information about a person's race (but not ecology), individuals' inferences about blacks track stereotypes of people from desperate ecologies, and individuals' inferences about whites track stereotypes of people from hopeful ecologies. However, when provided with information about both the race and ecology of others, individuals' inferences reflect the targets' ecology rather than their race: black and white targets from desperate ecologies are stereotyped as equally fast life history strategists, whereas black and white targets from hopeful ecologies are stereotyped as equally slow life history strategists. These findings suggest that the content of several predominant race stereotypes may not reflect race, per se, but rather inferences about how one's ecology influences behavior.


A minimal DNA cassette as a vector for genetic transformation of soybean (Glycine max).
Currently, the market demands products committed to protecting human health and the environment, known as clean products. We developed a protocol using DNA fragments containing only the gene sequence of interest, to replace the circular vectors containing genes for antibiotic resistance and other undesirable sequences, for obtaining transgenic soybeans for microparticle bombardment. Vector pAC321 was digested with the restriction enzyme PvuII to produce the 6159 bp ahas fragment, which contains the mutated ahas gene from Arabidopsis thaliana (Brassicaceae), under the control of its own promoter and terminator. This gene confers resistance against imazapyr, a herbicidal molecule of the imidazolinone class, capable of systemically translocating and concentrating in the apical meristematic region of the plant, the same region used for the introduction of the transgenes. This fragment was used to generate 10 putative transgenic soybean lines.


Using hypnosis in clinical practice for the management of chronic pain: A qualitative study.
Interventions used in chronic pain management do not routinely use clinical hypnosis (CH), despite evidence to suggest its effectiveness in improving pain outcomes. This study aimed to explore the beliefs and attitudes of clinicians' towards the implementation of CH in chronic pain management. We conducted a cross-sectional qualitative analysis following online CH training. Clinicians working in three tertiary pain clinics, were recruited to participate in the online training program and invited to focus groups following completion of the training to explore beliefs and attitudes towards CH and the training program. We identified three themes regarding barriers and two themes regarding facilitators to implementation of CH. Barriers: (i) misconceptions about CH, (ii) reduced confidence in implementing CH, and (iii) concerns about integrating CH with current treatment frameworks. Facilitators: (i) change in knowledge and attitude following training and (ii) an openness to exploring the technique and skills. The online training program was evaluated as positive with two themes: (i) training structure and (ii) training credibility. Successful implementation of CH requires the development of training programs that address existing misconceptions of CH, allow for knowledge and skills acquisition, and adapt to the contextual setting within which the intervention is implemented. Training of clinicians in the process and skills required to deliver clinical hypnosis for chronic pain should be supported to facilitate its successful implementation into clinical settings.


Fitness change effects on midlife metabolic outcomes.
Fitness decline, high body mass index (BMI), and insulin resistance (IR) are associated with worsening cardiometabolic risk factors prospectively; modification of the fitness change effect by BMI and IR remains unknown. Participants from the Coronary Artery Risk Development in Young Adults study without diabetes at year 0 (Y0) (n = 2048, 43.4% men; mean age, 25 yr) had fitness quantified by treadmill at Y0 and Y20. Y0 BMI was normal (nBMI <25 kg·m) or high (hBMI ≥25 kg·m). Y0 IR status was insulin sensitive (IS) (homeostatic model assessment IR <1.84 (75th percentile)) or insulin resistant (IR) (homeostatic model assessment IR ≥1.84). Four groups were established: nBMI/IS, hBMI/IS, nBMI/IR, and hBMI/IR. Y0 fitness was low (<33rd percentile for sex) or average high (≥33rd percentile for sex). Fitness change (treadmill time: Y20-Y0) was maintained (increase or decline ≤20th percentile for sex) or decreased (decline >20th percentile for sex). The outcomes were incident diabetes and percentage change over 25 yr in weight, waist girth, blood pressure, and lipid profile. Analysis was by multiple linear regression and proportional hazards regression with adjustment for individual characteristics. Maintained fitness after 20 yr was associated with greater increase in HDL cholesterol and less increase in weight, waist girth, blood pressure, and triglycerides than decreased fitness, similarly for the groups defined by BMI and IR. Maintained fitness reduced the rate of incident diabetes in IS but not IR participants. Maintained fitness after 20 yr was associated with more favorable middle-age cardiometabolic risk factors than decreased fitness; this benefit might be blunted by baseline IR.


AI-assisted biparametric MRI surveillance of prostate cancer: feasibility study.
To evaluate the feasibility of automatic longitudinal analysis of consecutive biparametric MRI (bpMRI) scans to detect clinically significant (cs) prostate cancer (PCa). This retrospective study included a multi-center dataset of 1513 patients who underwent bpMRI (T2 + DWI) between 2014 and 2020, of whom 73 patients underwent at least two consecutive bpMRI scans and repeat biopsies. A deep learning PCa detection model was developed to produce a heatmap of all PIRADS ≥ 2 lesions across prior and current studies. The heatmaps for each patient's prior and current examination were used to extract differential volumetric and likelihood features reflecting explainable changes between examinations. A machine learning classifier was trained to predict from these features csPCa (ISUP > 1) at the current examination according to biopsy. A classifier trained on the current study only was developed for comparison. An extended classifier was developed to incorporate clinical parameters (PSA, PSA density, and age). The cross-validated diagnostic accuracies were compared using ROC analysis. The diagnostic performance of the best model was compared to the radiologist scores. The model including prior and current study (AUC 0.81, CI: 0.69, 0.91) resulted in a higher (p = 0.04) diagnostic accuracy than the current only model (AUC 0.73, CI: 0.61, 0.84). Adding clinical variables further improved diagnostic performance (AUC 0.86, CI: 0.77, 0.93). The diagnostic performance of the surveillance AI model was significantly better (p = 0.02) than of radiologists (AUC 0.69, CI: 0.54, 0.81). Our proposed AI-assisted surveillance of prostate MRI can pick up explainable, diagnostically relevant changes with promising diagnostic accuracy. • Sequential prostate MRI scans can be automatically evaluated using a hybrid deep learning and machine learning approach. • The diagnostic accuracy of our csPCa detection AI model improved by including clinical parameters.


The kinetics of the reactions of Br atoms with the xylenes: an experimental and theoretical study.
This work reports the temperature dependence of the rate coefficients for the reactions of atomic bromine with the xylenes that are determined experimentally and theoretically. The experiments were carried out in a Pyrex chamber equipped with fluorescent lamps to measure the rate coefficients at temperatures from 295 K to 346 K. Experiments were made at several concentrations of oxygen to assess its potential kinetic role under atmospheric conditions and to validate comparison of our rate coefficients with those obtained by others using air as the diluent. Br2 was used to generate Br atoms photolytically. The relative rate method was used to obtain the rate coefficients for the reactions of Br atoms with the xylenes. The reactions of Br with both toluene and diethyl ether (DEE) were used as reference reactions where the loss of the organic reactants was measured by gas chromatography. The rate coefficient for the reaction of Br with diethyl ether was also measured in the same way over the same temperature range with toluene as the reference reactant. The rate coefficients were independent of the concentration of O2. The experimentally determined temperature dependence of the rate coefficients of these reactions can be given in the units cm3 molecule-1 s-1 by: o-xylene + Br, log10(k) = (-10.03 ± 0.35) - (921 ± 110)/T; m-xylene + Br, log10(k) = (-10.78 ± 0.09) - (787 ± 92/T); p-xylene + Br, log10(k) = (-9.98 ± 0.39) - (956 ± 121)/T; diethyl ether + Br, log10(k) = (-7.69 ± 0.55) - (1700 ± 180)/T). This leads to the following rate coefficients, in the units of cm3 molecule-1 s-1, based on our experimental measurements: o-xylene + Br, k(298 K) = 7.53 × 10-14; m-xylene + Br, k(298 K) = 3.77 × 10-14; p-xylene + Br, k(298 K) = 6.43 × 10-14; diethyl ether + Br, k(298 K) = 4.02 × 10-14. Various ab initio methods including G3, G4, CCSD(T)/cc-pV(D,T)Z//MP2/aug-cc-pVDZ and CCSD(T)/cc-pV(D,T)Z//B3LYP/cc-pVTZ levels of theory were employed to gain detailed information about the kinetics as well as the thermochemical quantities. Among the ab initio methods, the G4 method performed remarkably well in describing the kinetics and thermochemistry of the xylenes + Br reaction system. Our theoretical calculations revealed that the reaction of Br atoms with the xylenes proceeds via a complex forming mechanism in an overall endothermic reaction. The rate determining step is the intramolecular rearrangement of the pre-reactive complex leading to the post-reactive complex. After lowering the relative energy of the corresponding transition state by less than 1.5 kJ mol-1 for this step in the reaction of each of the xylenes with Br, the calculated rate coefficients are in very good agreement with the experimental data.


Viral Diversity in Samples of Freshwater Gastropods Benedictia baicalensis (Caenogastropoda: Benedictiidae) Revealed by Total RNA-Sequencing.
Previously, the main studies were focused on viruses that cause disease in commercial and farmed shellfish and cause damage to food enterprises (for example, Ostreavirusostreidmalaco1, Aurivirus haliotidmalaco1 and Aquabirnavirus tellinae). Advances in high-throughput sequencing technologies have extended the studies to natural populations of mollusks (and other invertebrates) as unexplored niches of viral diversity and possible sources of emerging diseases. These studies have revealed a huge diversity of mostly previously unknown viruses and filled gaps in the evolutionary history of viruses. In the present study, we estimated the viral diversity in samples of the Baikal endemic gastropod Benedictia baicalensis using metatranscriptomic analysis (total RNA-sequencing); we were able to identify a wide variety of RNA-containing viruses in four samples (pools) of mollusks collected at three stations of Lake Baikal. Most of the identified viral genomes (scaffolds) had only distant similarities to known viruses or (in most cases) to metagenome-assembled viral genomes from various natural samples (mollusks, crustaceans, insects and others) mainly from freshwater ecosystems. We were able to identify viruses similar to those previously identified in mollusks (in particular to the picornaviruses Biomphalaria virus 1 and Biomphalaria virus 3 from the freshwater gastropods); it is possible that picorna-like viruses (as well as a number of other identified viruses) are pathogenic for Baikal gastropods. Our results also suggested that Baikal mollusks, like other species, may bioaccumulate or serve as a reservoir for numerous viruses that infect a variety of organisms (including vertebrates).


The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex.
Human polo-like kinase Plk1 localizes to the centrosomes, kinetochores and central spindle structures during mitosis. It plays an essential role in promoting mitosis and cytokinesis through phosphorylation of a number of different substrates. Kinase activity is regulated by a conserved C-terminal domain, termed the polo box domain (PBD), which acts both as an autoinhibitory domain and as a subcellular localization domain. We have determined the crystal structure of Plk1 PBD (residues 367-603) to 2.2 A resolution and the structure of a phospho-peptide-PBD (residues 345-603) complex to 2.3 A resolution. The two polo boxes of the PBD exhibit identical folds based on a six-stranded beta-sheet and an alpha-helix, despite only 12% sequence identity. The phospho-peptide binds at a site between the two polo boxes. It makes a short antiparallel beta-sheet connection and critical contacts to residues Trp414, Leu490, His538 and Lys540. Most of these residues had been shown to be important for biological activity through mutational studies. The results provide an explanation for phospho-peptide recognition and create the basis for new functional studies.


Cloning, Stability, and Modification of Mycoplasma hominis Genome in Yeast.
Mycoplasma hominis is a minimal human pathogen that is responsible for genital and neonatal infections. Despite many attempts, there is no efficient genetic tool to manipulate this bacterium, limiting most investigations of its pathogenicity and its uncommon energy metabolism that relies on arginine. The recent cloning and subsequent engineering of other mycoplasma genomes in yeast opens new possibilities for studies of the genomes of genetically intractable organisms. Here, we report the successful one-step cloning of the M. hominis PG21 genome in yeast using the transformation-associated recombination (TAR) cloning method. At low passages, the M. hominis genome cloned into yeast displayed a conserved size. However, after ∼60 generations in selective media, this stability was affected, and large degradation events were detected, raising questions regarding the stability of large heterologous DNA molecules cloned in yeast and the need to minimize host propagation. Taking these results into account, we selected early passage yeast clones and successfully modified the M. hominis PG21 genome using the CRISPR/Cas9 editing tool, available in Saccharomyces cerevisiae. Complete M. hominis PG21 genomes lacking the adhesion-related vaa gene were efficiently obtained.


Characteristics and outcomes of patients requiring rapid response system activation within hours of emergency admission.
To establish the prevalence of emergency responses for clinical deterioration (cardiac arrest team or medical emergency team [MET] activation) within 24 hours of emergency admission, and determine if there were differences in characteristics and outcomes of ward patients whose emergency response was within, or beyond, 24 hours of emergency admission. A retrospective, descriptive, exploratory study using MET, cardiac arrest, emergency department and inpatient databases, set in a 365-bed urban district hospital in Melbourne, Australia. Participants were adult hospital inpatients admitted to a medical or surgical ward via the emergency department (ED) who needed an emergency response for clinical deterioration during 2012. Inhospital mortality, unplanned intensive care unit admission and hospital length of stay (LOS). A total of 819 patients needed an emergency response for clinical deterioration: 587 patients were admitted via the ED and 28.4% of emergency responses occurred within 24 hours of emergency admission. Patients whose first emergency response was within 24 hours of emergency admission (compared with beyond 24 hours) were more likely to be triaged to Australasian triage scale category 1 (5.4% v 1.2%, P=0.005), less likely to require ICU admission after the emergency response (7.6% v 13.9%, P=0.039), less likely to have recurrent emergency responses during their hospital stay (9.7% v 34%, P < 0.001) and had a shorter median hospital LOS (7 days v 11 days, P < 0.001). One-quarter of emergency responses after admission via the ED occurred within 24 hours. Further research is needed to understand the predictors of deterioration in patients needing emergency admission.


Characteristics of obstructive sleep apnea in myasthenia gravis patients: a single center study.
Recent studies have shown a high prevalence of obstructive sleep apnea in myasthenia gravis compared to the normal population. The aim of this study was to elucidate clinical and polysomnographic differences between clinically stable Korean MG patients with and without OSA. A total of 18 consecutively stable MG patients were included in this prospective study. We compared MG patients with OSA (n = 7) and without OSA (n = 11) with respect to the baseline characteristics and overnight polysomnography (PSG) parameters. Demographic parameters, prescribed medication status, thymectomy status, myasthenia gravis foundation of America score, and antibody status were obtained from their medical records. We performed the Korean version of Pittsburg sleep quality index to assess the subjective quality of sleep. Statistical analyses were performed using SPSS version 18.0 with Wilcoxon rank sum test, chi-square test, Fisher's exact test, and Spearman correlation test. Among the clinical parameters, MG patients with OSA showed a higher proportion of male sex (p = 0.016) and increased body mass index (p = 0.033). The PSG showed an 11-fold higher supine apnea-hyponea index (AHI) in MG patients with OSA. AHI was further analyzed with supine and non-supine position. MG patients with OSA had a higher supine AHI (19.5 ± 15.8) compared to those without OSA (1.9 ± 1.2, P = 0.008). Most of MG patients with OSA (85.7%) showed more than two times higher supine AHI than non-supine AHI. This study showed that the occurrence of OSA in patients with MG is associated with male sex and obesity, which is in accordance with the normal population. Moreover, PSG data showed a high prevalence of supine dominant OSA in MG patients with OSA.


Apparent declines in the global HIV transmission rate.
Estimates of global and regional HIV incidence and prevalence are helpful for gauging the state of the epidemic. However, they do not contain as much information as the HIV transmission rate for judging the potential speed of HIV spread. The HIV transmission rate can be defined as follows: for every 100 persons living with HIV, the number of HIV infections transmitted to seronegative partners in one year. Here, we estimate the transmission rate for the global epidemic for the years 2001 and 2007, and for 10 major international regions for the year 2007. The transmission rate is calculated as incidence divided by prevalence, and the quotient then multiplied by 100. Previously published and publicly available, the Joint United Nations Programme on HIV/AIDS estimates of HIV incidence and prevalence at the global and regional levels were utilized. Between 2001 and 2007, the global HIV transmission rate dropped from 10.2 to 8.2, a decrease of 19.6% in six years time. The regional estimates for 2007 ranged from 3.7 in Western and Central Europe, to 10.5 in the Middle East and Northern Africa, to 17.6 in Oceania. The global transmission rate for 2007 of 8.2 indicates that 91.8% or more of persons living with HIV are not transmitting to other persons in a given year. The 19.6% decrease in HIV transmission rate between 2001 and 2007 appears to indicate some success in global HIV prevention efforts. The range of regional estimates helps to identify areas with the potential for rapidly growing epidemics, even if the raw numbers of new infections and prevalence are low. I believe the transmission rate to be a useful statistic and recommend its further adoption.


Annotation: The similarities and differences between autistic disorder and Asperger's disorder: a review of the empirical evidence.
The ongoing controversy over the distinction between autistic disorder and Asperger's disorder is important to resolve because of the implications regarding an understanding of the aetiology and prognosis, and the diagnostic and clinical practices relating to these conditions. This paper provides a critical evaluation of current published research evidence. Databases, such as PsychINFO and Medline, as well as book chapters, reference lists from relevant articles, and recent editions of key journals were searched for all relevant studies (until 2002) which incorporated participants diagnosed with high-functioning autism and Asperger's disorder using either cluster analysis or comparative approaches to examine similarities and differences between these groups. Keywords used in the searches included autistic disorder, Asperger's disorder, autism, high-functioning autism, and pervasive developmental disorder. On the basis of the available evidence, there seem to be few qualitative differences between autistic disorder and Asperger's disorder. There is currently insufficient evidence to establish the validity of Asperger's disorder as a syndrome distinct from high-functioning autism. The findings are consistent with the view that these disorders belong on an autism spectrum.


Turnover of the cystic fibrosis transmembrane conductance regulator (CFTR): slow degradation of wild-type and delta F508 CFTR in surface membrane preparations of immortalized airway epithelial cells.
The protein product of the cystic fibrosis (CF) gene, termed the cystic fibrosis transmembrane conductance regulator (CFTR), is known to function as an apical chloride channel at the surface of airway epithelial cells. It has been proposed that CFTR has additional intracellular functions and that there is altered processing of mutant forms. In examining these functions we found a stable form of CFTR with slow turnover in surface membrane preparations from CF and non-CF immortalized airway epithelial cell lines. The methods used to study the turnover of CFTR were pulse/chase experiments utilizing saturation labeling of [35S] Met with chase periods of 5-24 h in the presence of 8 mM Met and cell fractionation techniques. Preparations of morphologically identifiable surface membranes were compared to total cell membrane preparations containing intracellular membranes. Surface membrane CFTR had lower turnover defined by pulse/chase ratios than that of the total cell membrane preparations. Moreover, mutant CFTR was stable in the surface membrane fraction with little degradation even after a 24 h chase, whereas wild-type CFTR had a higher pulse/chase ratio at 24 h. In the presence of 50 microM castanospermine, which is an inhibitor of processing alpha-glucosidases, a more rapid turnover of mutant CFTR was found in the total cell membrane preparation, whereas wild-type CFTR had a lower response. The results are compatible with a pool of CFTR in or near the surface membranes which has an altered turnover in CF and a glycosylation-dependent alteration in the processing of mutant CFTR.


Fluorescence quenching-based immunological probe for ticagrelor monitoring.
Introduction: Ticagrelor is extensively utilized for the treatment of acute coronary syndromes (ACS), but its platelet aggregation inhibitory effects can potentially result in tissue bleeding, posing a serious risk to patients' lives. Methods: In this study, we developed highly sensitive full length anti-ticagrelor Quenchbodies (Q-bodies) for fast monitoring of ticagrelor both in solution and serum for the first time. Ticagrelor coupled with N- hydroxysuccinimide (Ticagrelor-NHS) ester was also designed and synthesized for interaction and biological activity detection. Results: Both ATTO-labeled MEDI2452 (2452A) Q-body and TAMRA-labeled IgG 152 (152T) Q-body demonstrated efficient detection of ticagrelor and its active metabolite (TAM). The 2452A Q-body exhibited a broader detection range, while the 152T Q-body displayed a lower limit of detection (LOD). Under physiological conditions (Ticagrelor:TAM, 3:1), the concentration of ticagrelor was further measured, yielding LOD values of 4.65 pg/mL and 2.75 pg/mL for the two Q-bodies, with half-maximal effect concentrations of 8.15 ng/mL and 3.0 ng/mL, respectively. Discussion: Compared with traditional liquid chromatography-mass spectrometry (LC-MS) methods, anti-ticagrelor Q-bodies have higher sensitivity and detection speed. It enabled the completion of analysis within 3 min, facilitating rapid preoperative detection of blood drug concentration in ACS to determine the feasibility of surgery and mitigate the risk of intraoperative and postoperative hemorrhage. The swift detection of ticagrelor holds promise for enhancing individualized drug administration, preventing adverse reactions, and providing preoperative guidance.


Update on prevention and screening of cervical cancer.
Cervical cancer is the third most common cause of cancer in women in the world. During the past few decades tremendous strides have been made toward decreasing the incidence and mortality of cervical cancer with the implementation of various prevention and screening strategies. The causative agent linked to cervical cancer development and its precursors is the human papillomavirus (HPV). Prevention and screening measures for cervical cancer are paramount because the ability to identify and treat the illness at its premature stage often disrupts the process of neoplasia. Cervical carcinogenesis can be the result of infections from multiple high-risk HPV types that act synergistically. This imposes a level of complexity to identifying and vaccinating against the actual causative agent. Additionally, most HPV infections spontaneously clear. Therefore, screening strategies should optimally weigh the benefits and risks of screening to avoid the discovery and needless treatment of transient HPV infections. This article provides an update of the preventative and screening methods for cervical cancer, mainly HPV vaccination, screening with Pap smear cytology, and HPV testing. It also provides a discussion of the newest United States 2012 guidelines for cervical cancer screening, which changed the age to begin and end screening and lengthened the screening intervals.


[Usefulness and controversial issues of middle-chain fatty acids consumption on lipid-protein metabolism and obesity].
Middle-chain fatty acids (MCFA) contain 6-12 carbon atoms and are digested, absorbed and metabolized differently than long-chain fatty acids (LCFA). This work reviews some of the potential and real utilities of MCFA and their role on health. For this reason, they are used in enteral and parenteral nutrition because of their good absorption, and in premature-feeding milk-based formulas in order to improve calcium absorption. MCFA have become particularly important because of their possible role in treating and preventing obesity. Since they are more water soluble, they are taken-up by chylomicrons, and it is believed that they do not directly participate in lipogenesis. They are able to increase the thermogenic effect of foods, and its metabolism increases the production of ketonic agents with the subsequent anorexigenic effect. However, high doses of MCFA are required to obtain significant effects on weight reduction. The effects on lipid-protein metabolism are controversial. So, although they seem to reduce the post-prandial triglyceridemic response, the results their effects are not uniform regarding triglyceridemia and cholesterolemia. In spite of this, more and more products are being designed incorporating MCFA to treat obesity and overweight, having been considered as "GRAS" (Generally Recommended as Safe") components by the ADA. Further long-term studies are needed to warrant the usefulness of consumption of these compounds, particularly in the treatment and prevention of obesity.


Na+ imaging reveals little difference in action potential-evoked Na+ influx between axon and soma.
In cortical pyramidal neurons, the axon initial segment (AIS) is pivotal in synaptic integration. It has been asserted that this is because there is a high density of Na(+) channels in the AIS. However, we found that action potential-associated Na(+) flux, as measured by high-speed fluorescence Na(+) imaging, was about threefold larger in the rat AIS than in the soma. Spike-evoked Na(+) flux in the AIS and the first node of Ranvier was similar and was eightfold lower in basal dendrites. At near-threshold voltages, persistent Na(+) conductance was almost entirely axonal. On a time scale of seconds, passive diffusion, and not pumping, was responsible for maintaining transmembrane Na(+) gradients in thin axons during high-frequency action potential firing. In computer simulations, these data were consistent with the known features of action potential generation in these neurons.


Global exponential stability for uncertain delayed neural networks of neutral type with mixed time delays.
The global exponential stability for a class of uncertain delayed neural networks (DNNs) of neutral type with mixed delays is investigated in this paper. Delay-dependent and delay-independent stability criteria are proposed to guarantee the robust stability and uniqueness of equilibrium point of DNNs via linear matrix inequality and Razumikhin-like approaches. Two classes of perturbations on weighting matrices are considered in this paper. Some numerical examples are illustrated to show the effectiveness of our results.