Surgical Jeopardy: Play to Learn.
General Surgery residencies use protected education time in various fashions in order to optimize content quality and yield for their learners. This knowledge is tested annually with the American Board for Surgery In-Training Examination (ABSITE) exam and is used to evaluate several aspects of a resident. We hypothesized that using a jeopardy game in educational conference would encourage residents to engage in self-learning and improve ABSITE scores at a single institution. At a single institution, during protected education conference, residents played an hour-long surgical jeopardy game every 7 wk to summarize high yield topics discussed during the previous 6 wk of didactic learning. A 5-point Likert survey was completed by general surgery residents to discern the utility of the game format for learning. The ABSITE category scores were also evaluated from the year before and the year after the game was implemented. Twenty-four general surgery residents took the survey with >80% agreeing that the jeopardy format was either a fun or an effective way to learn general surgery topics. Additionally, over 80% of residents thought the game format helped with retention of knowledge. ABSITE categories that had a jeopardy session improved from 65.9% to 70.4% correct (P = 0.0003). ABSITE categories that did not have dedicated jeopardy had a non-significant increase in scores (67.7%-69.9%, P = 0.1). Implementing surgical jeopardy as a component of educational conferences in general surgery resident training is correlated with improvement of ABSITE scores. Surgical jeopardy may be easily adopted and implemented to stimulate self-directed learning for residents.


Pranlukast, a cysteinyl leukotriene type 1 receptor antagonist, attenuates the progression but not the onset of silica-induced pulmonary fibrosis in mice.
Although cysteinyl leukotrienes (CysLTs) have been implicated in the etiology of acute inflammatory diseases, recent studies have suggested that they also directly stimulate fibroblasts. However, their precise role in the pathogenesis of pulmonary fibrosis is unclear. In this study, we evaluated the effect of both short- and long-term treatment with pranlukast, a CysLT type 1 (CysLT(1)) receptor antagonist, on silica-induced pulmonary fibrosis in mice, which is characterized by persistent progression of fibrosis in the chronic phase. Pranlukast (30 mg/kg/day) was administered orally to mice for 2 or 10 weeks after intratracheal silica instillation. Pranlukast treatment for 10 weeks significantly attenuated the progression of pulmonary fibrosis, and decreased the content of CysLTs and LTB(4), which were markedly increased in the bronchoalveolar lavage fluid (BALF) and lung tissues of silica-instilled mice in the chronic phase. However, pranlukast treatment for 2 weeks neither affected the acute inflammatory response induced by silica instillation nor inhibited the onset of fibrosis. The expression of TGF-β1 and TNF-α was not affected by pranlukast treatment for either 2 or 10 weeks. Pranlukast attenuates the progression of pulmonary fibrosis in the chronic phase but has no effect on the acute inflammatory response or on the onset of pulmonary fibrosis. The antifibrotic effect of pranlukast may be exhibited by antagonizing the direct profibrotic effect of CysLTs, without affecting the expression of other profibrotic cytokines such as TGF-β1 and TNF-α, and also by decreasing the production of CysLTs and LTB(4).


Engineered biosynthesis of biodegradable polymers.
Advances in science and technology have resulted in the rapid development of biobased plastics and the major drivers for this expansion are rising environmental concerns of plastic pollution and the depletion of fossil-fuels. This paper presents a broad view on the recent developments of three promising biobased plastics, polylactic acid (PLA), polyhydroxyalkanoate (PHA) and polybutylene succinate (PBS), well known for their biodegradability. The article discusses the natural and recombinant host organisms used for fermentative production of monomers, alternative carbon feedstocks that have been used to lower production cost, different metabolic engineering strategies used to improve product titers, various fermentation technologies employed to increase productivities and finally, the different downstream processes used for recovery and purification of the monomers and polymers.


E2F3 gene expression is a potential negative prognostic marker for localised and MYCN not-amplified neuroblastoma: Results of in silico analysis of 786 samples.
Neuroblastoma (NB) is an enigmatic childhood malignancy characterised by a wide range of clinical behaviour. Many potential oncogenes for NB have recently been identified. Among them, E2 transcription factor 3 (E2F3) expression was associated with a poor survival in 134 stage 4S patients, but evidence for other stage groups remains poorly investigated. We have analysed the expression of E2F3 gene from a database of 786 NB samples. Overall and event-free survivals (EFS) were assessed by the Kaplan-Meier method, splitting the data on the median and tertile expression values. The Cox model was applied to control for the confounding by stage, age and MYCN amplification. Validation was performed by an in silico analysis of an independent cohort of 283 NB patients. Furthermore, an immunofluorescence analysis on 48 formalin-fixed, paraffin-embedded NB specimens was also performed. E2F3 overexpression was associated with a poor survival (EFS = 84%, 95% CI: 79%-95%, for low expression levels; EFS = 62%, 95% CI: 56%-68% for middle levels; EFS = 30%, 95% CI: 24%-36%, for high levels, p < .001). This association was confirmed in multivariable analysis and was more evident in patients with MYCN not-amplified and localised stages. Immunofluorescence results and the validation on an independent cohort of NB primary samples confirmed these findings. E2F3 is a new potential prognostic marker in NB with favourable characteristics at diagnosis. Further studies are needed to elucidate the potential role of E2F3 in NB oncogenesis and progression, in order to identify new targets for therapeutic interventions.


The utility of endocervical curettage: does routine ECC at the time of colposcopy for low-grade cytologic abnormalities improve diagnosis of high-grade disease?
To determine the use of endocervical curettage at the time of colposcopy for low-grade cytologic abnormalities. We conducted a retrospective chart review of women with low-grade Papanicolaou smears who had undergone satisfactory colposcopic examinations with identifiable lesions. We evaluated results during a 2-year period thereafter to determine whether endocervical curettage increased the diagnosis of high-grade dysplasia. The study group consisted of 374 patients. Of these patients, 16 had endocervical curettages suggestive of high-grade dysplasia. Of these 16 patients, 4 did not have concomitant high-grade dysplasia identified on ectocervical biopsy. Therefore, 93 to 94 endocervical curettages needed to be performed to detect 1 case of high-grade dysplasia that would not have been identified otherwise. Routine endocervical curettage at the time of satisfactory colposcopy for low-grade cytologic abnormalities with a visible lesion does not significantly improve the diagnosis of high-grade dysplasia.


Treatment of broad-based intracranial aneurysms with the LVIS EVO stent: a retrospective observational study at two centers with short- and medium-term follow-up.
The use of stents is well established in the treatment of broad-based intracranial aneurysms. The aim of this study is to report on safety, feasibility and midterm follow-up of the new LVIS EVO braided stent for the treatment of cerebral aneurysms. All consecutive patients with intracranial aneurysms who were treated with the LVIS EVO stent in two high volume neurovascular centers were retrospectively enrolled in this observational study. Clinical and technical complications, angiographic outcome and clinical short-term and midterm results were evaluated. The study included 112 patients with 118 aneurysms. 94 patients presented with incidental aneurysms, 13 patients with acute SAH and 2 patients with acute cranial nerve palsy. For 100 aneurysms a jailing technique was used, re-crossing of the stent was performed in 3 cases. For the residual 15 cases the stent was placed as a bail-out or as a second step. Immediate complete occlusion was observed in 85 aneurysms (72%). Midterm follow-up was available for 84 patients with 86 aneurysms (72.9%). One stent showed asymptomatic complete occlusion on follow-up imaging, in all other cases no in-stent stenosis was observed. The rate of complete occlusion was 79.1% at 6 months and 82.2% at 12-18 months. Midterm follow-up data of this retrospective observational cohort of two neurovascular centers corroborates the safety profile of the LVIS EVO device for treatment of ruptured and unruptured intracranial aneurysms.


Influences of Structural Modification of Naphthalenediimides with Benzothiazole on Organic Field-Effect Transistor and Non-Fullerene Perovskite Solar Cell Characteristics.
Developing air-stable high-performance small organic molecule-based n-type and ambipolar organic field-effect transistors (OFETs) is very important and highly desirable. In this investigation, we designed and synthesized two naphthalenediimide (NDI) derivatives (NDI-BTH1 and NDI-BTH2) and found that introduction of 2-(benzo[d]thiazol-2-yl) acetonitrile groups at the NDI core position gave the lowest unoccupied molecular orbital (LUMO; -4.326 eV) and displayed strong electron affinities, suggesting that NDI-BTH1 might be a promising electron-transporting material (i.e., n-type semiconductor), whereas NDI-BTH2 bearing bis(benzo[d]thiazol-2-yl)methane at the NDI core with a LUMO of -4.243 eV was demonstrated to be an ambipolar material. OFETs based on NDI-BTH1 and NDI-BTH2 have been fabricated, and the electron mobilities of NDI-BTH1 and NDI-BTH2 are 14.00 × 10-5 and 8.64 × 10-4 cm2/V·s, respectively, and the hole mobility of NDI-BTH2 is 1.68 × 10-4 cm2/V·s. Moreover, a difference in NDI-core substituent moieties significantly alters the UV-vis absorption and cyclic voltammetry properties. Thus, we further successfully employed NDI-BTH1 and NDI-BTH2 as electron transport layer (ETL) materials in inverted perovskite solar cells (PSCs). The PSC performance exhibits that NDI-BTH2 as the ETL material gave higher power conversion efficiency as compared to NDI-BTH1, that is, NDI-BTH2 produces 15.4%, while NDI-BTH1 gives 13.7%. The PSC performance is comparable with the results obtained from OFETs. We presume that improvement in solar cell efficiency of NDI-BTH2-based PSCs is due to the well-matched LUMO of NDI-BTH2 toward the conduction band of the perovskite layer, which in turn increase electron extraction and transportation.


Impaired motor learning by a pursuit rotor test reduces functional outcomes during rehabilitation of poststroke ataxia.
Motor learning is essential to gain skills with neurorehabilitation. To investigate whether capacity for motor learning affects rehabilitation outcome and its relevant brain activation in ataxic patients with stroke. Twelve patients presenting with ataxia admitted for inpatient rehabilitation 2 to 3 months after infratentorial stroke and 6 control subjects performed 8 repetitions of 30-second pursuit rotor (PR) task. Cortical oxygenated hemoglobin (oxyHb) signals were measured using functional near-infrared spectroscopy. Both patients and controls learned the PR skill, although the gains in PR performance were significantly lower in patients. In patients, the less learning significantly correlated with smaller rehabilitation gains assessed by the Functional Independence Measure. The Fugl-Meyer score for coordination and balance did not change. Center of task-related increase of cortical oxyHb signals shifted from the presupplementary motor area (preSMA) to the supplementary motor area (SMA) with task repetitions in controls but not in patients. Accordingly, serial changes of ratio of oxyHb increase in the preSMA to SMA (preSMA/SMA ratio) were significantly different between the groups. In patients and controls, gains in PR performance and changes of the preSMA/SMA ratio correlated. Impaired motor sequence learning by the PR task was correlated with reduced rehabilitation gains for ataxic patients with stroke.


Imatinib Inhibits the Renewal and Tumorigenicity of CT-26 Colon Cancer Cells after Cytoreductive Treatment with Doxorubicin.
Conventional anti-cancer drugs preferentially eliminate differentiated cancer cells but those cells that are spared (i.e. cancer stem cells: CSC), initiate recurrence. We tested whether drugs that target receptor tyrosine kinases (RTKs) involved in developmental signaling cascades and activated in CSC, could be used to silence and/or to eliminate colorectal cancer cells refractory to conventional treatment with cytoreductive drugs. A sequential treatment model was thereby developed with doxorubicin (DOX) and imatinib. CT-26 mouse colon carcinoma cells were pre-treated with DOX to select DOX-refractory cells with CSC properties, which were then subsequently treated with RTK inhibitor imatinib, where their regrowth was found to be inhibited. Under both normoxic and hypoxic conditions, imatinib potently inhibited clonogenicity of DOX-refractory CT-26 cells. Treatment with DOX did not eliminate tumorigenic CT-26 cells, since CT-26 cells pre-exposed to DOX in vitro, when inoculated subcutaneously, induced tumors in 90 % of mice, as opposed to a 100 % rate in the case of chemonaive CT-26 cells. In mice inoculated with chemonaive CT-26 cells, tumor formation was not prevented by imatinib. However, imatinib prevented tumor formation in 50 % of mice inoculated with CT-26 cells pre-exposed to DOX in vitro, with the remaining 50 % mice showing delayed tumor formation. These results suggest that the sequential use of the drug imatinib, as a drug targeting cancer cells expressing stem cell features after conventional cytoreductive treatment, is a promising future strategy for preventing tumor recurrence.


The effect of infused fat emulsions on reticuloendothelial function in the rabbit.
The effect of the infusion of different fat emulsions (Intralipid and MCT/LCT mixtures) on the reticuloendothelial function of the rabbit has been investigated. Emulsions containing 20% dispersed triglyceride were administered over 6 h to a total of 3 g/kg body weight. The extent of blockade of the reticuloendothelial system was measured using a labelled probe in the form of technetium-99m labelled albumin microspheres. Scintigraphic and blood and organ level determinations demonstrated that all emulsions caused an impairment of reticuloendoethlial function, but this was small.


Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression.
While most women with ovarian cancer will achieve complete remission after treatment, the majority will relapse within two years, highlighting the need for novel therapies. Cancer stem cells (CSC) have been identified in ovarian cancer and most other carcinomas as a small population of cells that can self-renew. CSC are more chemoresistant and radio-resistant than the bulk tumor cells; it is likely that CSC are responsible for relapse, the major problem in cancer treatment. CD133 has emerged as one of the most promising markers for CSC in ovarian cancer. The hypothesis driving this study is that despite their low numbers in ovarian cancer tumors, CSC can be eradicated using CD133 targeted therapy and tumor growth can be inhibited. Ovarian cancer cell lines were evaluated using flow cytometry for expression of CD133. In vitro viability studies with an anti-CD133 targeted toxin were performed on one of the cell lines, NIH:OVCAR5. The drug was tested in vivo using a stably transfected luciferase-expressing NIH:OVCAR5 subline in nude mice, so that tumor growth could be monitored by digital imaging in real time. Ovarian cancer cell lines showed 5.6% to 16.0% CD133 expression. dCD133KDEL inhibited the in vitro growth of NIH:OVCAR5 cells. Despite low numbers of CD133-expressing cells in the tumor population, intraperitoneal drug therapy caused a selective decrease in tumor progression in intraperitoneal NIH:OVCAR5-luc tumors. Directly targeting CSC that are a major cause of drug resistant tumor relapse with an anti-CD133 targeted toxin shows promise for ovarian cancer therapy.


Laboratory Evolution of Bacillus circulans Xylanase Inserted into Pyrococcus furiosus Maltodextrin-Binding Protein for Increased Xylanase Activity and Thermal Stability Toward Alkaline pH.
High xylanase activity and stability toward alkaline pH is strongly desired for pulping and bleaching processes. We previously enhanced thermal stability of Bacillus circulans xylanase (BCX) by inserting into a thermophilic maltodextrin-binding protein from Pyrococcus furiosus (PfMBP) (the resulting complex named as PfMBP-BCX165). In the present study, we aimed to evolve the inserted BCX domain within PfMBP-BCX165 for greater xylanase activity toward alkaline pH while maintaining enhanced thermal stability. No BCX sequence variation was required for the thermal stabilization, thus allowing us to explore the entire BCX sequence space for the evolution. Specifically, we randomized the BCX sequence within PfMBP-BCX165 and then screened the resulting libraries to identify a PfMBP-BCX165 variant, PfMBP-BCX165T50R. The T50R mutation enhanced xylanase activity of PfMBP-BCX165 toward alkaline pH without compromising thermal stability. When compared to PfMBP-BCX165T50R, the corresponding unfused BCX mutant, BCXT50R, exhibited similar pH dependence of xylanase activity, yet suffered from limited thermal stability. In summary, we showed that one can improve thermal stability and xylanase activity of BCX toward alkaline pH by inserting into PfMBP followed by sequence variation of the BCX domain. Our study also suggested that insertional fusion to PfMBP would be a useful stabilizing platform for evolving many proteins.


PEGylation and preliminary biocompatibility evaluation of magnetite-silica nanocomposites obtained by high energy ball milling.
High energy ball milling (HEBM) has been used for the first time to prepare PEGylated magnetite-silica (Fe(3)O(4)-SiO(2)) nanocomposites intended to be used for biological purposes. Surface amine groups were introduced by a silanization reaction involving 3-aminopropyl triethoxysilane (APTS) followed by PEGylation to yield long-term stable and stealth nanocomposites of 200nm in diameter. The efficient coverage by PEG chains was shown by isothermal titration calorimetry (ITC) where PEGylated nanocomposites did not interact with BSA compared to non-PEGylated counterparts which led to a significant change in enthalpy. By cell viability (MTT) assays and cell morphology investigations, it was evidenced that PEGylated Fe(3)O(4)-SiO(2) nanocomposites did not provide any appreciable cytotoxicity on J774 macrophage and MCF-7 breast cancer cell lines. Furthermore, noticeable internalization was evidenced by J774 cells with PEGylated Fe(3)O(4)-SiO(2) nanocomposites in contrast to MCF-7 cells, in good agreement with the respective tendency of each cell line for endocytosis.


The rabbit as an experimental animal for tracheal surgery.
The circumferential resection of the trachea with end-to-end anastomosis is a well-established clinical procedure. Still, some problems remain to be solved, such as the choice of optimal suture material. Dogs are primarily used for experimental work in this field, but are difficult to obtain. This operation was performed on nine rabbits, eight of whom survived to the preplanned date of sacrifice. Two of the survivors were found to have severe stricture at the anastomosis. This study indicates that the rabbit is a suitable experimental animal for circumferential resection and anastomosis of the trachea.


Evolution of post-pulmonary vein isolation atrial fibrillation inducibility at redo ablation: Electrophysiological evidence of extra-pulmonary vein substrate progression.
The electrophysiological substrate underlying atrial fibrillation (AF) progression remains difficult to identify. The goals of this study were to study the evolution of post-pulmonary vein isolation (PVI) AF inducibility (AFI) after AF ablation and to compare patients with organized atrial tachycardia recurrence (OATr) versus those with paroxysmal or persistent AF recurrence. We studied 99 patients who underwent de novo AF ablation (p1) and redo ablation (p2) for AF recurrence (AFr) or OATr. Stepwise AF ablation was performed at p1 and p2: (1) PVI, (2) coronary sinus defragmentation, and (3) left atrial (LA) defragmentation. Burst pacing followed each step, with AFI defined as sustained AF >5 minutes, triggering the next step. Patients with OATr underwent OAT ablation and inducibility testing post-redo PVI. Inducibility progression (IP) was defined as AFI at further steps of p2 compared to p1. Among patients with AFr, 34 of 72 patients (47%) exhibited post-PVI IP vs 2 of 27 (7.4%) patients with OATr (P = .0002). Stratification for persistent AF/paroxysmal AF/OATr showed a consistent association between recurrence phenotype and IP. Pulmonary vein (PV) reconnection incidence was 90%, without association with recurrence type or IP. LA volume was larger in patients with IP than in those without IP (86.7 ± 25.3 mL vs 72.0 ± 28.9 mL; P = .001). Right atrial dimensions increased between p1 and p2 in patients with IP vs no IP and in patients with AFr vs OATr. Patients with AFr after first ablation exhibit IP more frequently at redo ablation than do patients with OATr. IP correlates with more advanced AFr type, larger LA volumes, and progressive right atrial enlargement. PV reconnection is not associated with AFr. Changes in post-PVI AFI may accurately indicate progression of extra-PV AF-maintaining substrate.


Selective localization of alpha brain activity with neuromagnetic measurements.
A method of localizing brain activity by a new combination of magnetic and electrical recording, relative covariance, is described. The successful application of this method to alpha EEG is reported. Spontaneous human brain activity was recorded simultaneously with fixed scalp electrodes and a movable magnetometer. The analysis was restricted to the alpha rhythm, which was selected by a narrow bandpass filter centered at the observed alpha frequency. For each magnetometer location, the ratio of the covariance of the magnetic and electric signals to the electric variance was calculated, producing a map reflecting the magnetic field pattern. Clear maxima of opposite polarity over the left and right parietotemporal areas indicate bilateral current source areas near the midline, in the vicinity of the calcarine fissure, at a depth of 4-6 cm from the scalp. This relative covariance method may prove generally useful in localizing bioelectrical sources such as spontaneous brain rhythms.


Recombinant Allergen Production in E. coli.
Recombinant protein allergens have been used in allergy studies, allergy diagnosis, and epitope mapping. Messenger RNAs (mRNAs) are isolated from tissues of interest for complementary DNA (cDNA) library construction. Subsequently, the allergen gene is amplified by polymerase chain reaction (PCR) and sequenced. The amplified gene is then cloned into an expression vector, expressed in Escherichia coli cells, and purified from the cell lysate. This chapter describes the protocols for recombinant allergen production.


Kinetics of procainamide and N-acetylprocainamide in renal failure.
Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.


The use of allodermis prepared from Euro skin bank to prepare autologous tissue engineered skin for clinical use.
Over the past two decades a range of 3D models for human skin have been described. Some include native collagen and intrinsic basement membrane proteins and fibroblasts, others are based on xenogeneic collagen or synthetic supports often without fibroblasts. The aim of this study was to look at the influence of media calcium, basement membrane and fibroblasts on the quality of 3D tissue engineered skin produced using human de-epidermized acellular dermis. In this study we deliberately used Euro skin as the source of the donor dermis to examine to what extent this could provide an effective dermal substrate for producing 3D skin for clinical use. Keratinocytes were cultured in the presence and absence of fibroblasts and both with and without basement membrane on decellularized dermis at calcium concentrations ranging from 250μM to 1.6mM over a period of 14 days. Results showed the formation of a well attached epithelium with many of the features of normal skin in the presence of a basement membrane. This was largely independent of the presence of fibroblasts and not greatly influenced by the concentration of calcium in the media. However there was a clear requirement for physiological levels of calcium in the formation of a stratified epithelium in the absence of a basement membrane.


Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands.
Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant inherited disease, characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems with variable expressivity. The purpose of this study was to identify genetic etiology of an ALSG family. We recruited a Turkish family with ALSG and performed a mutational analysis, based on the candidate gene approach, to clarify the molecular genetic etiology. The candidate gene sequencing of the FGF10 gene identified a novel heterozygous nonsense mutation (c.237G > A, p.Trp79*) in the exon 1. The identified novel mutation would result in a haploinsufficiency of the FGF10, because of nonsense-mediated mRNA decay caused by a premature stop codon. This report further confirms that ALSG is caused by the haploinsufficiency of functional FGF10. Identification of the genetic etiology of the ALSG will help both the family members and dentist understand the nature of the disorder. Therefore, it will positively motivate oral health care to avoid further destruction of the tooth due to the lack of salivary production.


Modulation of protein C inhibitor activity by histidine-rich glycoprotein and platelet factor 4: role of zinc and calcium ions in the heparin-neutralizing ability of histidine-rich glycoprotein.
Effects of zinc and calcium ions on the heparin-neutralizing abilities of histidine-rich glycoprotein (HRG) and platelet factor 4 (PF4) were examined. Both HRG and PF4 effectively neutralized the ability of heparin to accelerate the activated protein C (APC) and the thrombin inhibitions by protein C inhibitor (PCI). the heparin-neutralizing ability of HRG in the APC inhibition by PCI, however, was decreased in a Ca(2+)-dependent manner and apparently lost at 1 mM Ca2+, while it was enhanced by Zn2+ regardless of the presence or absence of Ca2+. The heparin-neutralizing ability of HRG in the thrombin inhibition by PCI was not affected by Ca2+. In contrast to HRG, there was no significant difference in the heparin-neutralizing ability of PF4 in the presence or absence of 1 mM Ca2+. These results strongly suggest additional physiological functions of HRG and PF4 as modulators of PCI.


DEHP induce cholesterol imbalance via disturbing bile acid metabolism by altering the composition of gut microbiota in rats.
Di(2-ethylhexyl) phthalate (DEHP) is one of the most widespread environmental contaminants worldwide because of its massive production, extensive use in common products, and liability to leach from products. This study investigated the mechanisms of DEHP mediated alteration of lipid metabolism. Rats were treated with 0.5 mg kg-1 d-1 of DEHP for 23 weeks. Results showed that the treatment induced cholesterol imbalance. Further fecal transplantation experiments corroborated the involvement of gut microbiota in DEHP-induced cholesterol imbalance. In addition, 16S rRNA gene sequencing analysis of cecal contents showed that DEHP disrupted the gut microbiota diversity in rats and increased the ratio of Firmicutes to Bacteroidetes. Further cecal metabolomic analyses, bile salt hydrolase enzyme activity, and gene expression examination revealed that chronic DEHP exposure generated a bile acid profile in the gut that is a more potent activator of farnesoid X receptor (FXR). The activation of FXR in the gut induced the expression of fibroblast growth factor 15, which subsequently suppressed cytochrome P450 family 7 subfamily A member 1 in the liver and bile acid synthesis. These results suggest that DEHP might induce cholesterol imbalance by regulating bile acid metabolism via the remodeling of the gut microbiota.


Phosphorus recovery through adsorption by layered double hydroxide nano-composites and transfer into a struvite-like fertilizer.
Phosphorus (P) recovery from waste streams is attracting more attention due to the twin problems of aquatic eutrophication and global phosphorus scarcity. Layered double hydroxide mineral materials are promising phosphate adsorbents due to their excellent anion-exchange abilities and large surface area. In this study, the adsorption isotherms estimated the saturation capacity of calcined layered double hydroxide (LDH) nano-composites for phosphate as 100.7 mg-P/g-adsorbent. Ion exchange is proposed as the major mechanism in the sorption process. The commonly utilized desorption method via sodium hydroxide was found to cause recrystallization of LDH particles in increased crystal size based on the dissolution-reprecipitation (D-R) mechanism. Ammonia solution was used to desorb P from LDH adsorbent. However, struvite crystallization occurred during the desorption process because struvite has a higher precipitation tendency than LDH with sufficient NH4+ ions. The comparison of P leaching behavior among P-adsorbed LDH, ammonia-treated LDH, and pure struvite samples demonstrates that ammonia desorption probably weakened the interaction between phosphate species and LDH cationic layers, thus enhancing the bioavailability of P in LDH adsorbents. The ammonia-treated LDH has a high potential to serve like struvite as a P slow-releasing fertilizer.


Optimization of three-dimensional traveling wave drive for a PZT thin-film micro-motor based on stiffness tuning of the supporting structure.
This paper is based on the analysis of the three-dimensional motion of the PZT (lead zirconate titanate) thin-film traveling wave micro-motor and presents an optimization study of the effect of the radial component on the output torque and maximum speed. Based on theoretical analysis, it is proposed that the inconsistency of the equivalent constraint stiffness of the inner and outer rings is the main factor in the radial component of the traveling wave drive. Considering the large computational and time costs of 3D (three-dimensional) transient simulation, the residual stress-relieved deformation state in a steady state is used to equivalently characterize the inner and outer ring constraint stiffness of the micro-motor, and then the outer ring support stiffness is adjusted to achieve the consistency of the inner and outer ring constraint stiffness and the optimization of the radial component reduction, as well as to improve the flatness of the micro-motor interface under residual stress and optimize the contact state between the stator and rotor. Finally, performance testing of the device prepared by the MEMS process showed that the output torque of the PZT traveling wave micro-motor increased by 21% (14.89 μN*m), the maximum speed increased by 18% (>12000 rpm), and the speed instability was optimally reduced by a factor of 3 (<10%).


Size matters -- patient organisations exaggerate prevalence numbers.
Patient organisations serve their members with information and support concerning a specific disease. In many cases they also contribute to research funding and lobby to improve the situation for their members. The larger group of patients an organisation claims to represent, the bigger their potential influence. Our hypothesis is that patient organisations exaggerate the number of persons affected with a specific disease. Prevalence figures from patient organisations in Sweden were collected via their own web sites. About 93 patient organisations were identified, 29 of which presented the estimates of disease occurrence used in this study. We calculated the probability for a person to have at least one disease and the proportion of the population not having any of the diseases listed. About 60% of the Swedish population have at least one disease covered by our sample of patient organisations. Nine tenths (87%) of the population would be ill if one assumes that an individual could only have one disease. Our rough estimates suggest that patient organisations exaggerate the number of ill persons. To render other messages on their agenda more trustworthy, we propose that some patient organisations moderate their prevalence and/or incidence figures.


Denoising Medical Images Using Machine Learning, Deep Learning Approaches: A Survey.
Several denoising methods for medical images have been applied, such as Wavelet Transform, CNN, linear and Non-linear methods. In this paper, A median filter algorithm will be modified and the image denoising method to wavelet transform and Non-local means (NLM), deep convolutional neural network (Dn- CNN), Gaussian noise, and Salt and pepper noise used in the medical image is explained. PSNR values of the CNN method are higher and showed better results than different filters (Adaptive Wiener filter, Median filter, and Adaptive Median filter, Wiener filter). Denoising methods performance with indices SSIM, PSNR, and MSE have been tested, and the results of simulation image denoising are also presented in this article.


Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes.
The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.


A kinetic study of muscular contractions.
In the present work the kinetics of muscular contractions are studied, based on a three-state model which is introduced in Section I. The general properties of this class of models for muscular contractions are derived in Sections II-VI. The kinetic equations are solved for four particular examples in Sections VII-X. These analytical results should be useful for comparison with experimental data to determine the functional dependence of the rate contants alpha and beta on muscle length.


An assay for leukoagglutinating lectins using suspension cultured mouse lymphoma cells (BW5147) stained with neutral red.
A sensitive and rapid assay for leukoagglutinating lectins has been developed. This assay utilizes neutral red-stained mouse lymphoma cells from the suspension cultured cell line BW5147. The agglutination of the stained cells can be monitored visually in a manner similar to that for conventional assays for erythroagglutinating lectins using erythrocytes. The activity of lekoagglutinating lectins that are not capable of agglutinating erythrocytes can be quantified by this assay. The utility of the assay was demonstrated using leukoagglutinating and erythroagglutinating lectins from the seeds of Phaseolus vulgaris and Maackia amurensis.


Mapping behaviorally relevant neural circuits with immediate-early gene expression.
Immediate-early genes have gained widespread popularity as activity markers for mapping neuronal circuits involved in specific behaviors in many different species. In situ immediate early gene detection methods provide cellular level resolution, a major benefit for mapping neuronal networks. Recent advances using fluorescence in situ hybridization also afford temporal resolution, enabling within-animal activity maps for two distinct behaviors. Moreover, use of transgenic mice with fluorescent reporter proteins driven by immediate early gene promoters is enabling repeated measurements, over long time scales, of cortical activity within the same animal. These methodological innovations, coupled with recent advances in fluorescence imaging and probe development, will enable large scale mapping of behaviorally relevant circuits with temporal and three-dimensional spatial resolution in experimental animals.


Bile salt micelle can sustain more cholesterol in the intermicellar aqueous phase than the maximal aqueous solubility.
The intermicellar aqueous phase in equilibrium with micelle plays an important role in the uptake of sterol. To test the hypothesis whether cholesterol concentration in the intermicellar aqueous phase of a micellar solution is similar to its maximal aqueous solubility, cholesterol concentration in the intermicellar aqueous phase of a bile salt-cholesterol solution and maximal aqueous cholesterol solubility were quantitatively determined by capillary gas-liquid chromatography after filtration. Cholesterol concentration in the intermicellar aqueous phase increased linearly with cholesterol concentration in the micellar solution and reached 1.3 microM at its micellar solubility limit, while the maximal aqueous solubility of cholesterol was (1.2-1.4) x 10(-8) M. The intermicellar monomer concentration of taurocholate was 5.8 mM in which 26 x 10(-8) M cholesterol was solubilized. The results indicate the presence of a cholesterol concentration in the intermicellar aqueous phase that is significantly higher than its maximal aqueous solubility, which can be ascribed primarily to the presence of an intermicellar concentration of bile salt.


Effects of connectivity on carbon and nitrogen stocks in mangrove and seagrass ecosystems.
Seascape connectivity increases carbon and nitrogen exchange across coastal ecosystems through flow of particulate organic matter (POM). However, there are still critical gaps in knowledge about the drivers that mediate these processes, especially at regional seascape scales. The aim of this study was to associate three seascape-level drivers which could influence carbon and nitrogen stocks in intertidal coastal seascape: connectivity between ecosystems, ecosystem surface area, and standing vegetation biomass of ecosystems. Firstly, we compared whether connected mangrove and seagrass ecosystems contain larger carbon and nitrogen storage than isolated mangrove and seagrass ecosystems. Secondly, we compared autochthonous and allochthonous POM in mangrove patches and seagrass beds, simultaneously estimating the area and biomass relative contribution to POM of the different coastal vegetated ecosystem. Connected vs isolated mangrove and seagrass ecosystems were studied at six locations in a temperate seascape, and their carbon and nitrogen content in the standing vegetation biomass and sediments were measured. POM contributions of these and surrounding ecosystems were determined using stable isotopic tracers. In connected mangrove-seagrass seascapes, mangroves occupied 3 % of total coastal ecosystem surface area, however, their standing biomass carbon content and nitrogen per unit area was 9-12 times higher than seagrasses and twice as high as macroalgal beds (both in connected and isolated seascapes). Additionally in connected mangrove-seagrass seascapes, the largest contributors to POM were mangroves (10-50 %) and macroalgal beds (20-50 %). In isolated seagrasses, seagrass (37-77 %) and macroalgal thalli (9-43 %) contributed the most, whilst in the isolated mangrove, salt marshes were the main contributor (17-47 %). Seagrass connectivity enhances mangrove carbon sequestration per unit area, whilst internal attributes enhance seagrass carbon sequestration. Mangroves and macroalgal beds are potential critical contributors of nitrogen and carbon to other ecosystems. Considering all ecosystems as a continuing system with seascape-level connectivity will support management and improve knowledge of critical ecosystem services.


The completeness of the left atrial appendage amputation during routine cardiac surgery.
Left atrial appendage (LAA) is the origin of most heart thrombi which can lead to stroke or other cerebrovascular event in patients with non-valvular atrial fibrillation (AF). This study aimed to prove safety and low complication rate of surgical LAA amputation using cut and sew technique with control of its effectiveness. 303 patients who have undergone selective LAA amputation were enrolled in the study in a period from 10/17 to 08/20. The LAA amputation was performed concomitant to routine cardiac surgery on cardiopulmonary bypass with cardiac arrest with or without previous history of AF. The operative and clinical data were evaluated. Extent of LAA amputation was examined intraoperatively by transoesophageal echocardiography (TEE). Six months in follow up, the patients were controlled regarding clinical status and episodes of strokes. Average age of study population was 69.9 ± 19.2 and 81.9% of patients were male. In only three patients was residual stump after LAA amputation larger than 1 cm with average stump size 0.28 ± 0.34 cm. 3 patients (1%) developed postoperative bleeding. Postoperatively 77 (25.4%) patients developed postoperative AF (POAF), of which 29 (9.6%) still had AF at discharge. On 6 months follow up only 5 patients had NYHA class III and 1 NYHA class IV. Seven patients reported with leg oedema and no patient experienced any cerebrovascular event in early postoperative follow up. LAA amputation can be performed safely and completely leaving minimal to no LAA residual stump.


Discovery of a DNA Topoisomerase I Inhibitor Huanglongmycin N and Its Congeners from Streptomyces sp. CB09001.
Huanglongmycin (HLM) congeners G-N (7-14) were isolated from Streptomyces sp. CB09001. Among them, 10-12 possesses a tricyclic scaffold with benzene-fused pyran/pyrone, confirmed by X-ray single crystal diffraction analysis of 12. The structure-activity relationship study of 1, 13, and 14 revealed not only the stronger cytotoxicity of 14 against tested cancer cells but also the critical role of the C-7 ethyl group of 14 in its binding to the DNA-topoisomerase I complex.


Survival and phenotypic characteristics of axotomized neurons in spinal ganglia.
Trauma to the peripheral processes of sensory neurons of different subpopulations was followed by indirect immunohistochemical analysis of the expression of Bcl-X(L) and Bax, which are, respectively, antiapoptotic and proapoptotic proteins of the Bcl-2 family, and also of the cytokine interleukin-1beta, with the aim of identifying the roles of these substances in controlling apoptosis. The survival abilities of these neurons after central and peripheral axotomy were compared by studying the expression of the high molecular weight component of the neurofilament triplet NF200 and isolectin B4 (IB4). By day 30 after central axotomy, there were no changes in the total numbers of neurons in ganglia L(IV)-L(V) in rats, though there were significant reductions in the numbers of NF200+ neurons. In spinal ganglion L(V) of mice, the proapoptotic protein was detected in the nuclei of 46% of small neurons, which account for 20% of all neurons in the ganglion. By day 30 after nerve compression, Bax was expressed in the nuclei of 30% of neurons and the cytoplasm of 20% of neurons. In intact animals, the antiapoptotic protein Bcl-X(L) was seen in the cytoplasm of 30% of small neurons, as well as in satellite cells surrounding large and intermediate neurons. By day 30 after nerve trauma, Bcl-X(L) was not expressed in spinal ganglion L(V). Interleukin-1beta was present in the cytoplasm of 17% of neurons belonging to the subpopulations of large and intermediate neurons. By day 30 after nerve compression, interleukin-1 beta+ neurons were not identified.


Possible serotonin-agonist action of veratramine.
Veratramine produces a characteristic excitatory action on the central nervous system, producing both tremor and a characteristic "struggling" behavior. This behavioral excitation is accompanied by changes in serotonin content in hypothalamus. The central serotonin agonist methysergide in doses of 5--15 mg per kg produces a dose-dependent inhibition of veratramine's action, while parachlorophenylalanine has no effect. These results are consistent with a serotonin agonist mechanism to explain veratramine's action.


Advancements in Surgical Performance Evaluation and Feedback.
How today's urology trainees acquire surgical skills has changed dramatically due to multiple forces placing strain on the graduate medical education mission. The development of workplace-based assessments that deliver feedback while capturing performance data has led to a paradigm shift toward individualized learning. Delivering feedback that drives surgical skill development requires the educator to provide a meaningful assessment of the learner after an operative experience. Workplace-based assessment involves direct observation of routine clinical practice and has become a central component of competency-based medical education. Urology has the chance to fully embrace competency-based medical education, employing robust feedback mechanisms and workplace-based assessments. We must first define what it means to be a proficient urologist and design an assessment system that captures this collective sentiment. This can only be done through effective engagement and collaboration with stakeholders across our specialty.


Paced QRS duration predicts left ventricular function in patients with permanent pacemakers - One-year follow-up study using equilibrium radionuclide angiography (ERNA).
Permanent pacing, being non physiological, often results in ventricular dysfunction over time. Narrower paced QRS duration from pacing the right ventricular outflow tract septum, might result in relatively preserved ventricular function over long term follow up.


(Z)-3-(4-Chloro-phen-yl)-2-{[N-(2-formyl-phen-yl)-4-methyl-benzene-sulfonamido]-meth-yl}prop-2-ene-nitrile.
In the title compound, C(24)H(19)ClN(2)O(3)S, the sulfonyl-bound benzene ring forms dihedral angles of 38.1 (2) and 81.2 (1)°, respectively, with the formyl benzene and benzene rings. The mol-ecular conformation is stabilized by a weak intra-molecular C-H⋯O hydrogen bond, which generates an S(5) ring motif. The crystal packing is stabilized by C-H⋯O hydrogen bonds, which generate C(7) zigzag chains along [010] and R(3) (3)(19) ring motifs along [010]. The crystal packing is further stabilized by C-Cl⋯π inter-actions [Cl⋯centroid = 3.456 (2) Å and C-Cl⋯centroid = 173.4 (2)°].


Changes in mandibular incisor position and arch form resulting from Invisalign correction of the crowded dentition treated nonextraction.
To investigate changes in mandibular incisor position resulting from Invisalign correction of the crowded dentition without extraction. A retrospective chart review was completed on 61 adult White patients. Patients were categorized into three groups based on the value of pretreatment crowding of the lower dentition: 20 mild (2.0-3.9 mm), 22 moderate (4.0-5.9 mm), and 19 severe (>6.0 mm). Cephalometric radiographs were measured to determine lower incisor changes. Interproximal reduction and changes in arch width were also measured. Statistical evaluation of T0 and T1 values using paired t-tests and analysis of covariance were applied to evaluate mean value changes. Lower incisor position and angulation changes were statistically significant in the severe crowding group. There were no statistically significant differences in lower incisor position between the mild and moderate crowding groups. There was a statistically significant increase in buccal expansion in each of the three groups. Invisalign(®) treatment can successfully resolve mandibular arch crowding using a combination of buccal arch expansion, interproximal reduction, and lower incisor proclination. When there is <6 mm of crowding, lower incisor position remained relatively stable. The lower incisors proclined and protruded in the more severely crowded dentitions (>6 mm).


Network pharmacology of apigeniflavan: a novel bioactive compound of Trema orientalis Linn. in the treatment of pancreatic cancer through bioinformatics approaches.
Pancreatic cancer is the seventh most prevalent cause of mortality globally. Since time immemorial, plant-derived products have been in use as therapeutic agents due to the existence of biologically active molecules called secondary metabolites. Flavonoids obtained from plants participate in cell cycle arrest, induce autophagy and apoptosis, and decrease oxidative stress in pancreatic cancer. The present study involves network pharmacology-based study of the methanolic leaf extract of Trema orientalis (MLETO) Linn. From the high-resolution mass spectrometry (HRMS) analysis, 21 nucleated flavonoids were screened out, of which only apigeniflavan was selected for further studies because it followed Lipinski's rule and showed no toxicity. The pharmacokinetics and physiochemical characteristics of apigeniflavan were performed using the online web servers pkCSM, Swiss ADME, and ProTox-II. This is the first in silico study to report the efficiency of apigeniflavan in pancreatic cancer treatment. The targets of apigeniflavan were fetched from SwissTargetPrediction database. The targets of pancreatic cancer were retrieved from DisGeNET and GeneCards. The protein-protein interaction of the common genes using Cytoscape yielded the top five hub genes: KDR, VEGFA, AKT1, SRC, and ESR1. Upon molecular docking, the lowest binding energies corresponded to best docking score which indicated the highest protein-ligand affinity. Kyoto Encyclopaedia of Genes and Genomes (KEGG) database was employed to see the involvement of hub genes in pathways related to pancreatic cancer. The following, pancreatic cancer pathway, MAPK, VEGF, PI3K-Akt, and ErbB signaling pathways, were found to be significant. Our results indicate the involvement of the hub genes in tumor growth, invasion and proliferation in the above-mentioned pathways, and therefore necessitating their downregulation. Moreover, apigeniflavan can flourish as a promising drug for the treatment of pancreatic cancer in future.


Nordihydroguaiaretic acid inhibits urokinase synthesis by phorbol myristate acetate-stimulated LLC-PK1 cells.
Protein kinase C (PKC) activation is regulated by Ca2+, phospholipids, diacylglycerol (DAG) and fatty acids. Phorbol myristate acetate (PMA) which mimics the effect of DAG on PKC induces transcriptional activation of the urokinase-type plasminogen activator (u-PA) gene in LLC-PK1 cells. We examined in the present work the relationships between PKC activity, fatty acids, and u-PA synthesis in this cell line. We showed that H7, an inhibitor of PKC, inhibited the PMA-induced u-PA synthesis by LLC-PK1 cells. PMA-induced u-PA synthesis was enhanced by eicosatetraynoic acid (ETYA), a competitive inhibitor of both the lipoxygenase and cyclooxygenase pathways and inhibited by nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway. Three other unrelated lipoxygenase inhibitors (phenidone 100 microM, BW755 50 microM and diethylcarbamazine 50 microM) had no effect on u-PA biosynthesis. Two polyunsaturated fatty acids other than ETYA, arachidonic acid and linoleic acid, also potentiated the PMA effect and a lipoxygenase derivative, 12 hydroxyeicosatetraenoic acid (12 HETE), did not modify the basal and PMA-stimulated u-PA syntheses. PKC activity purified from cytosol of LLC-PK1 cells was stimulated by addition of 16 nM PMA in vitro and this effect was blunted by simultaneous addition of 5 microM NDGA. By Northern blot analysis using a pig u-PA cDNA probe we found that PMA increased the steady state level of u-PA mRNA after 2 h of incubation and that NDGA inhibited this effect. These data suggest that NDGA inhibits PMA-stimulated PKC activity in intact cells leading to a decrease of u-PA mRNA level and u-PA biosynthesis in PMA-stimulated LLC-PK1 cells. Polyunsaturated fatty acids have opposite effects.


Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation.
An increasing number of recently described tau mutations show considerable clinical heterogeneity. The assessment of this phenotypic variation is of vital importance in the differential diagnosis of neurodegenerative diseases. To assess the neuropathologic heterogeneity in a comprehensive study of 12 brains with a tau mutation at exon 10(+16) (C-to-T) splice site from 9 families. A comprehensive neuropathologic examination has been carried out, using a wide range of tau antibodies. All brains showed frontotemporal atrophy of varying severity and pallor of the pigmented nuclei of the brainstem. The histologic changes were more extensive to include other cortical areas, the deep gray matter, and the white matter. The hallmark histologic lesions were the tau-positive neuronal and glial inclusions. In neurons, these ranged from typical neurofibrillary tangles through well-circumscribed inclusions to diffuse cytoplasmic staining. This tau pathology was complemented by the presence of large, abnormal achromatic neurons, neuronal loss, astrocytosis, and superficial status spongiosus. The distribution, type, and severity of these histologic abnormalities varied not only from case to case but also within the same brain. These brains with a common tau mutation raise important differential diagnostic problems: cases in the past might have been misdiagnosed as corticobasal degeneration or even atypical Pick disease, disorders with similar, if not identical, phenotypic manifestations.


Tetrahydro anthranilic acid as a surrogate for anthranilic acid: application to the discovery of potent niacin receptor agonists.
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.


[Safety of ciprofibrate. Open study in a Portuguese population].
To determine the safety of ciprofibrate in portuguese patients with dyslipidaemia. Open-label study with 6-month therapy. Sequential sample of 40 patients, 20 from each hospital, 37 patients (92.5%) completed the study. After at least one month of diet or washout period, all participants were given 100 mg/day of ciprofibrate, taken after the evening meal. Analysis and clinical examinations were performed at weeks (-4), (0), (+8), (+16) and (+24). Glycemia, uric acid, creatine kinase, creatinine and transaminases were determined. Thirty-seven patients ended the study (92.5%), three abandoned because of gastrointestinal adverse effects, six other patients also complaint of gastrointestinal side effects. The creatinine and creatine kinase levels increased 9.7% and 19.2%, although kept in the normal range. There were no statistically significant changes in glycemia, uric acid and transaminases levels. These results confirm the high safety of ciprofibrate in patients with dislipidaemia. The short term of this study does not allows taking conclusions about long term use of this drug.


LC-MS/MS quantitation of α-amylase/trypsin inhibitor CM3 and glutathione during wheat sourdough breadmaking.
This study aimed to quantify α-amylase/trypsin inhibitor (ATI) CM3 and glutathione (GSH) during wheat sourdough breadmaking. Breads were made with two wheat cultivars and fermented with Fructilactobacillus sanfranciscensis, F. sanfranciscensis ΔgshR or Latilactobacillus sakei; chemically acidified and straight doughs served as controls. Samples were analysed after mixing, after proofing and after baking. GSH and CM3 were quantified by multi-reaction-monitoring-based methods on an LC-QTRAP mass spectrometer. Undigested ATI extracts were further examined by SDS-PAGE. GSH abundance was similar after mixing and after proofing but increased after baking (p < 0.001), regardless of fermentation. In breads baked with cv. Brennan, the samples fermented with lactobacilli had higher GSH abundance (p < 0.001) than in the controls. CM3 relative abundance remained similar after mixing and after proofing but decreased after baking (p < 0.001) across all treatments. This trend was supported by the SDS-PAGE analysis in which ATI band intensities decreased after baking (p < 0.001) in all experimental conditions. The overall effect of baking exerted a greater effect on the abundances of GSH and CM3 than fermentation conditions. This is the first report to quantify ATI over the course of breadmaking by LC-MS/MS in sourdough and straight dough processes.


Efficacy and safety of empagliflozin in patients with type 2 diabetes from Asian countries: pooled data from four phase III trials.
We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes (T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add-on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin (HbA1c) were -0.66% [95% confidence interval (CI) -0.76, -0.56] and -0.73% (95% CI -0.83, -0.64) and in weight were -1.6 kg (95% CI -1.9, -1.3) and -1.8 kg (95% CI -2.1, -1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated.


Risk factors associated with bovine tuberculosis in traditional cattle of the livestock/wildlife interface areas in the Kafue basin of Zambia.
We conducted a cross-sectional study from August 2003 to February 2004 to identify risk factors for bovine tuberculosis (BTB) in the Kafue basin of Zambia. We investigated a total of 106 herds of cattle for presence of BTB using the comparative intradermal tuberculin test (CITT) while an interviewer-administered questionnaire was used to gather epidemiological data on herd structure, management and grazing strategies. BTB prevalence at herd level was estimated and possible risk factors were investigated using the multiple logistic regression model. The true herd level prevalence of BTB was estimated at 49.8% (95% CI: 37.9, 61.7%). The logistic regression model showed that cattle herd BTB status was highly associated with area and husbandry practices. When compared to Kazungula, cattle herds in Blue Lagoon were more likely to test positive for BTB when other factors such as management practices were controlled (OR=10.5). In terms of grazing strategies, transhumant herds (TH) had higher odds (OR=3.0) of being positive compared to sedentary herds (OR=1.0). The results in this study provide preliminary information about potential risk factors that were found to be associated with BTB status in cattle.


Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus.
Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.


Staining of Bartonella henselae with carboxyfluorescein diacetate succinimidyl ester for tracking infection in erythrocytes and epithelial cells.
Bartonella infection (Bartonella henselae in particular) is responsible for a widening spectrum of human diseases. The persistent colonization of erythrocytes is a feature of Bartonella infection. Endothelial and epithelial cells are also widely used to study the pathogenesis of bartonellosis in vitro. Exploring a convenient method for visualizing the bacillus without affecting infectivity would be very interesting. Carboxyfluorescein diacetate succinimidyl ester (CFSE) has been previously used for staining several bacterial species to study their adhesion to host cells. The present study demonstrated the efficiency and safety of using CFSE in staining B. henselae. The staining of bacillus-invaded erythrocytes and epithelial cells in vitro successfully allowed for flow cytometry and confocol microscopy analyses. Parallel tests using untreated bacteria confirmed that CFSE staining did not result in side effects on the infectivity of B. henselae. Labeling Bartonella with CFSE is a valuable method for studying the bacteria-host interaction.


Quality of life in patients treated by adjuvant radiotherapy for endometrial and cervical cancers: correlation with dose-volume parameters.
Modern multidisciplinary cancer treatments aim at obtaining minimal influence on patients' quality of life (QoL). The purpose of this study was to assess QoL and correlate it with dose-volume parameters of organ at risks (OARs) in patients who received adjuvant radiotherapy for endometrial and cervical cancers. We administered the EORTC QLQ-C30 and EN24 or CX24 questionnaires to 124 patients, 100 with endometrial cancer and 24 with cervical cancer treated with postoperative radiotherapy ± chemotherapy in regular follow-up. Bladder function, fecal incontinence or urgency and sexual functioning were investigated and correlated with dose-volume parameters of OAR by multiple linear regression analysis. This correlation was assessed by R (2) value. QoL was very high in the majority of patients (82.3 % of patients). Few patients referred urinary incontinence (3.2 %) or abdominal discomfort of high grade (4.0 %). We found a significant correlation between bladder V40, i.e., absolute percentage of bladder volume that received a dose of 40 Gy, and global health status (p < 0.05, R (2) = 0.17), urinary urgency (p < 0.05, R (2) = 0.24), urinary incontinence (p < 0.05, R (2) = 0.23) and dyspareunia (p < 0.05, R (2) = 0.04). We found also a correlation between global health status and mean dose to vagina (p < 0.05, R (2) = 0.17) and between maximum dose to lumbo-sacral plexus and abdominal pain (p < 0.05, R (2) = 0.07). Women treated with surgery and adjuvant radiotherapy for endometrial and cervical cancers have good QoL with minimal limitations of daily activities. QoL was correlated with dose-volume parameters such as bladder V40, mean dose to vagina, maximum dose to trigone and LSP.


The cAMP-dependent signalling cascade in the two luteal cell types of the pregnant rat corpus luteum.
Corpora lutea of rats, like those of many other species, contain two sub-populations of luteal cells. In this report we sought to determine whether the luteinizing hormone (LH)- and beta-adrenergic cAMP signal transduction pathways known to be present in rat corpora lutea were segregated into separate luteal cell types. Results showed that large rat luteal cells, obtained on day 3 of pregnancy, exhibited elevated LH- and most notably epinephrine-stimulated adenylyl cyclase activities but equivalent cAMP-dependent catalytic protein kinase and total regulatory subunit cAMP binding activities compared to small luteal cells. Progesterone production by the large cell was greater than that by the small cell but both cells were equally sensitive to stimulation of progesterone by LH. However, neither the large nor the small rat luteal cell produced significant progesterone in response to epinephrine despite a marked epinephrine-stimulated adenylyl cyclase in both cell populations. The LH-stimulated progesterone synthetic response of the two sub-populations of rat luteal cells is more similar to that of the developing monkey corpus luteum and contrasts sharply with that of ruminants.


The predictive value of electrocardiographic polarization parameters on appropriate ICD shock in primary prevention heart failure patients.
The effect of frontal QRS-T angle, Tp-e and Tp-e/QT ratio on cardiac events have been shown in many studies. In this study, we aimed to determine the prognostic value of frontal QRS-T angle, TPe and Tp-e/QT ratio on ICD shock in patients who had ICD (Implantable Cardioverter Defibrillator) implanted due to heart failure with reduced ejection fraction (HFrEF). 158 patients with HFrEF who had previous ICD implantation were retrospectively analyzed. 27 patients were found to have an appropriate shock. Frontal QRS-T angle, Tp-e interval, Tp-e/QT ratio were calculated by evaluating the basal ECG records of the patients. Comparisons of these arrhythmogenic predictors were made in patients with and without ICD shock at follow-up. When 158 patients with previous ICD implantation were analyzed in two groups with and without ICD shock, the number of patients with frontal QRS-T angle >120°, Tp-e interval > 105 ms, Tp-e/QT > 0.2 in the shock group (n: 27) was found to be high with a different significance (p:<0.01, p:<0.01, p:<0.01). There was no significant difference between the two groups regarding other ECG parameters such as QRS duration, QT interval, PR interval, fragmented QRS and positive T wave. In addition, more amiodarone use was observed in the shock group, and more hyperlipidemia cases were observed in the non-shocked group (p:0.01; p:<0.01). Increased frontal QRS-T angle, Tp-e interval, and Tp-e/QT ratio are arrhythmogenic parameters and predict appropriate ICD shock.


Engineering selectivity and discrimination into ligand-receptor interfaces.
The reengineering of protein-ligand (or enzyme-substrate) interfaces using a combination of chemical and genetic methods has become an increasingly common technique to create new tools to manipulate and study biological systems. Many applications of ligand receptor engineering require that the engineered ligand and receptor function independently of endogenous ligands and receptors. Engineered ligands must selectively interact with modified receptors, and modified receptors must effectively discriminate against endogenous ligands. A variety of chemical design strategies have been used to reengineer ligand-receptor interfaces. The advantages and limitations of various strategies, which involve the manipulation of hydrophobic, polar, and charged residues, are compared. New design strategies and potential applications of ligand-receptor engineering are also discussed.


Multi-analyte surface plasmon resonance biosensing.
Surface plasmon resonance (SPR) biosensors are affinity sensing devices exploiting a special mode of electromagnetic field-surface plasmon-polariton-to detect the binding of analyte molecules from a liquid sample to biomolecular recognition elements immobilized on the surface of the sensor. In this paper, we review advances of SPR biosensor technology towards detection systems for the simultaneous detection of multiple analytes (multi-analyte detection). In addition, we report application of a recently developed multichannel SPR sensor based on spectroscopy of surface plasmons and wavelength division multiplexing of sensing channels to multi-analyte detection.


Synthesis and structure-activity relationship of substituted 1,2,3,4-tetrahydroisoquinolines as N-type calcium channel blockers.
Voltage Activated Calcium Channel (VACC) blockers have been demonstrated to have utility in the treatment of pain and stroke. A series of aminomethyl substituted isoquinolinol derivatives with potent functional activity for N-type VACC's have been identified. Their synthesis and preliminary pharmacology are discussed herein.


Association between immediate oxygenation response and survival in preterm infants receiving rescue inhaled nitric oxide therapy for hypoxemia from pulmonary hypertension: A systematic review and meta-analysis.
To investigate whether immediate response to inhaled nitric oxide (iNO) therapy is associated with reduced mortality in preterm infants with hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH). A systematic review and meta-analysis of observational studies was conducted to examine the association between immediate response (improved oxygenation ≤6 h) compared to non-response, and all-cause mortality among preterm infants <34 weeks gestational age without congenital anomalies or genetic disorders who received iNO treatment. Adjusted and unadjusted odds ratio, were pooled using a random effects meta-analysis Hartung-Knapp-Sidik-Jonkman approach. Subgroup analyses were planned for infants with preterm premature rupture of membranes (PPROM) and those treated within 72 h after birth. The primary analysis included 5 eligible studies, a total of 400 infants (196 responders; 204 non-responders). The studies were rated as low to moderate risk of bias based on the Quality in Prognostic Studies tool. Immediate iNO responsiveness was associated with reduced odds of mortality [odds ratio (OR) 0.22, 95 % confidence interval (95 % CI) (0.10-0.49)]. Although there was insufficient data for a subgroup analysis of infants with PPROM, infants treated with iNO within 72 h demonstrated consistent findings of reduced mortality [OR 0.21 95 % CI (0.13-0.36)]. Based on the GRADE approach, considering the risk of bias of included studies, the overall strength of evidence was rated as moderate. There is evidence to suggest that immediate improvement in oxygenation following iNO therapy is associated with reduced odds of mortality before discharge in preterm infants with HRF and clinically suspected or confirmed PH.


Effectiveness of pelvic floor muscle training alone or combined with either a novel biofeedback device or conventional biofeedback for improving stress urinary incontinence: A randomized controlled pilot trial.
To (i) compare the acceptance of a newly developed, novel biofeedback device (PelviSense) with that of conventional biofeedback (CB) using an intravaginal probe for the treatment of stress urinary incontinence (SUI) in women, (ii) examine the feasibility and safety of using the PelviSense device as a pelvic floor muscle (PFM) training (PFMT) adjunct, and (iii) compare the PFMT adherence and effectiveness of CB, the PelviSense device, with PFMT alone for women with SUI. An assessor-blinded, three-arm, randomized controlled pilot trial was conducted among 51 women with SUI. Women were randomly allocated to one of three study groups (PelviSense-assisted PFMT, CB-assisted PFMT, or PFMT alone [control]). Outcome measures included the International Consultation on Incontinence Questionnaire-Short Form, the 1-h pad test, and the Modified Oxford Scale. Participants in the PelviSense-assisted PFMT group expressed good device acceptance. PFMT adherence was greater in the PelviSense-assisted PFMT group than in the unassisted or CB-assisted PFMT groups. Between-groups analysis revealed significant effects on improved SUI symptoms, urine loss severity, and PFM strength for the PelviSense-assisted PFMT group compared with the CB-assisted and PFMT alone groups. The pilot trial results demonstrated moderate to high PFMT adherence in the PelviSense-assisted PFMT group and supported the safety of using the PelviSense device. The preliminary results of the pilot trial showed that PelviSense-assisted PFMT was more effective for reducing SUI symptoms among women than unassisted or CB-assisted PFMT. This trial was registered in http://ClinicalTrials.gov (reference number: NCT04638348) before the recruitment of the first participant.


Laparoscopic myotomy vs endoscopic dilation in the treatment of achalasia.
The aim of this study was to compare the results obtained in 14 patients with achalasia who underwent laparoscopic Heller's myotomy and Dor's fundoplication with those of 16 patients who had endoscopic dilation. The diagnosis of achalasia was confirmed by manometry, endoscopy, and barium swallow. Esophageal symptoms were quantified before and after treatment using a clinical scale. Six patients had had endoscopic dilation prior to surgery. Before treatment, the patients in the surgical group complained of more severe dysphagia (median, 5; range, 0-5 vs median 4; range, 3-5) and chest pain (median, 3; range, 0-5 vs median, 1.5; range, 0-5), but both groups were comparable with respect to regurgitation, heartburn, and manometric results. Both groups achieved significant clinical improvement. The severity score decreased from 5 (range, 0-5) to 1 (range, 0-3) (p < 0.05) for dysphagia to solids in the laparoscopic group and from 4 (range, 3-5) to 1 (range, 0-5) (p < 0.05) in the endoscopic group. Lower esophageal sphincter (LES) basal pressure decreased significantly in both groups (from 29.3 to 11.8 mmHg in the laparoscopic group and from 28.9 to 16.5 mmHg in the endoscopic group). After treatment, there were no significant clinical differences between the two groups. Two patients in the surgical group were converted to open surgery. Laparoscopic myotomy is as save and effective as endoscopic dilation in the treatment of achalasia.


PresbyLASIK: A review of PresbyMAX, Supracor, and laser blended vision: Principles, planning, and outcomes.
PresbyLASIK is one of the most commonly used modalities of surgical correction in presbyopes with no cataract. Unlike monovision procedures, both the eyes are adjusted for near and distance, providing a good stereopsis. This works by creating a corneal multifocality and increasing the depth of focus. Most techniques of presbyLASIK currently employ hybrid methods, i.e., a component of monovision added on to a multifocal corneal ablation. Choosing an appropriate proportion of these two components according to the patients' requirements and meticulous patient selection are key to obtaining desirable outcomes. Being corneal-based procedures, presbyLASIK has shown to be reversible. Thorough updated knowledge of the different presbyLASIK procedures, their principles and outcomes based on previous studies is required before a refractive surgeon plans to start providing presbyLASIK services. We performed a comprehensive search on PubMed with the keywords "Presbyopia surgery," "PresbyLASIK" "PresbyMAX," "Supracor," and "Custom-Q." In this review article, we have explained the principles of the various presbyLASIK procedures, appropriate patient selection and planning on the devices with examples, and summarized the previously published outcomes of these techniques.


Analysis of the femoral neck from rats in the periestropause treated with oxytocin and submitted to strength training.
Among the interventions used to prevent osteoporosis in female organisms, strength training (ST) and oxytocin (OT) stand out, as a promising hormone with anabolic action on bone. This study aimed to verify whether the combined action of OT and ST, compared to isolated interventions, potentiates the bone remodeling process of the femoral neck of Wistar rats during periestropause. Forty Wistar rats (18 months) with irregular estrous cycle were randomly distributed into groups: 1-Vehicle (Veh; NaCl 0.15 mol/L ip); 2-Oxytocin (Ot; 134 μg/kg/ip); 3-Strength training (St); 4-Ot + St. The animals of the 1, 2 and 4 groups received two intraperitoneal injections with an interval of 12 h every 30 days, totaling 8 injections at the end of the experimental period (18 to 21 months). The animals in the St and Ot + St groups performed ST on a ladder 3 times a week, maximal voluntary carrying capacity (MVCC) test monthly. After 120 days, the animals were euthanized; the femur was collected for analysis of biomechanical testing, densitometry, bone microtomography, Raman spectroscopy, tissue PCR, and blood for analysis of bone biomarkers, liver damage, and oxidative stress. The main effects in the Ot group were observed in the maximum load and energy in the compression testing (femoral head), and stiffness and energy in the three-points bending testing (femur diaphysis). In addition, the main effects occurred on the bone mineral density (BMD), cortical thickness (Ct.Th), number of pores (Po.N), polar moment of inertia (J), trabecular thickness (Tb.Th), and connectivity density (Conn.Dn), Bone alkaline phosphatase (Alp), Tumor necrosis factor receptor superfamily member 11b (Opg), Tumor necrosis factor ligand superfamily member 11 (Rankl) and Cathepsin K (Ctsk) expression. There was an effect in the tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP). In the St group, the main effect was observed on the energy (compression and the three-points bending), stiffness, aBMD, BMD, cortical bone area (Ct.Ar), Po.N, trabecular bone volume (BV/TV), Tb.Th and in the mineralization ratio (ѵ1PO4/proline), Runt-related transcription factor 2 (Runx2), Bone morphogenetic protein 2 (Bmp2), Alp, Osteopontin/secreted phosphoprotein 1 (Opn/Spp1), Opg, Tumor necrosis factor receptor superfamily member 11ª (Rank), Rankl, Ctsk expression. There was an effect in the TRAP and ALP. The interaction in the combination of therapies in the Ot + St group was verified in energy to maximum load (compression and three-points bending testing), stiffness, BMD, Ct.Th, J, Tb.Th and ѵ1PO4/proline. In the gene analysis there was interaction in the Runx2, Osterix/Sp7 transcription factor (Osx/Sp7), Bmp2, Alp, Osteocalcin/Bone gamma-carboxyglutamate protein (Ocn/Bglap), Opg, Rankl and Acid phosphatase 5, tartrate resistant (Trap/Acp5) expression. In addition, the combination of OT and ST resulted in a higher maximum load compared to the Veh group, with higher BV/TV than the Ot group, higher Rankl and Ctsk expression than Veh and Ot groups, and lower Po.N and lower activity of TRAP than the other groups. In oxidative stress, total antioxidant capacity (TAC) was lower. These results showed that the combination of interventions is a promising anabolic strategy for the prevention of osteoporosis in the period of periestropause, standing out from the effects of isolated interventions.


Efficient removal of antibiotic in single and binary mixture of nickel by electrocoagulation process: Hydrogen generation and cost analysis.
In discharged water, antibiotics and heavy metals frequently coexist, forming stable and recalcitrant complexes. Environmental concerns about how to efficiently treat this type of pollution are growing. Using Fe and Al electrodes, electrocoagulation (EC) was applied to remove tetracycline (TC) as a single pollutant as well as TC-nickel ions in a binary mixture from water. The effects of critical variables and the TC-Ni molar ratio (1:1, 1:2, and 2:1) were studied. The Fe electrode achieved 99.3% TC removal after 60 min in a single pollutant system containing 15 mgL-1 of TC, while the Al electrode achieved 99.8% removal in 20 min at optimal conditions. The EC process demonstrated excellent electrodegradation efficiency towards TC-Ni complexes. When the TC to Ni2+ ratio was 1:1 and 1:2, respectively, TC elimination was 100% in 10 min and 99.6% in 20 min. We noted that a sufficient amount of Ni2+ could increase TC decomposition by electrocatalysis. The amount of hydrogen gas produced after treatment of a 0.2 L TC solution alone is 22.2-13.99 mol m-3, whereas it was 27.2-40.8 mol m-3 in the TC-Ni binary mixture, which can generate more than 35% of the electrical energy needed to power the EC system. To evaluate the generated sludge, FTIR analysis was performed.


Use of a monoclonal, anti Plasmodium berghei antibody, cross reacting with P. falciparum, for the detection of P. falciparum in in vitro infected blood.
This report describes an immunoradiometric assay for Plasmodium falciparum in infected blood, based on a cross-reacting monoclonal antibody (mAb) raised against P. berghei. In this assay, binding of the mAb to intact P. berghei parasites coated on microtiter plates is inhibited by solubilized P. falciparum infected red blood cells. The use of P. berghei parasites in conjunction with monoclonal antibodies should facilitate the development of an inexpensive and reproducible test for the immunodiagnosis of malaria.


Surgical interventions of Freiberg's disease: A systematic review.
Freiberg's disease is an osteonecrosis of the metatarsal head bone. Numerous surgical interventions can be provided; however, the literature is limited in systematic reviews discussing the various options. The study aimed to systematically review the quantity and quality of literatures exploring the surgical interventions. Fifty articles were found to be relevant for assessing the efficacy of common surgical interventions. The articles were assigned a level of evidence (I-V) to assess their quality. Next, the studies were reviewed to provide a grade of recommendation (A-C, I). Two studies were found at level III that explored osteotomy and autologous transplantation; the other studies were level IV-V. There is poor evidence (grade C) in supporting of joint sparing and joint sacrificing for Freiberg's disease. Poor evidence exists to support the surgical interventions for Freiberg's disease, higher quality trials are needed to support the increasing application of these surgical techniques. Level IV, Systematic review.


Major obstetric hemorrhage.
Major obstetric hemorrhage remains the leading cause of maternal mortality and morbidity worldwide, and is associated with a high rate of substandard care. A well-defined and multidisciplinary approach that aims to act quickly and avoid omissions or conflicting strategies is key. The most common etiologies of hemorrhage are abruptio placenta, placenta previa/accreta, uterine rupture in the antepartum period and retained placenta, uterine atony, and genital-tract trauma in the postpartum period. Basic treatment of postpartum hemorrhage relies on manual removal of the placenta or manual exploration of the uterus plus bladder emptying and oxytocin administration. If this does not arrest bleeding, or if there is any suspicion of genital-tract trauma, examination of the vagina and cervix with appropriate valves and analgesia/anesthesia must follow quickly. Postpartum uterine atony resistant to oxytocin must be treated with prostaglandin within 15 to 30 minutes; uterine balloon tamponade can be also useful at this stage. Aggressive transfusion therapy and resuscitation are mandatory in major obstetric hemorrhage. Specific invasive treatment must be considered within no more than 30 to 60 minutes, if previous measures have failed -- and even earlier in some particular etiologies. The two main options are radiologic embolization and surgical artery ligations. Recombinant factor VIIa may also be considered, but should not delay the performance of a life-saving procedure such as embolization or surgery. Hysterectomy must be implemented when all other interventions have failed.


Lingual versus buccal mucosa graft urethroplasty for anterior urethral stricture: a prospective comparative analysis.
To compare lingual and buccal mucosa graft urethroplasty for anterior urethral stricture with respect to intraoperative, postoperative parameters and urethroplasty outcome. From January 2011 to December 2011, a total of 30 patients with anterior urethral stricture whereas group 2 underwent dorsal onlay buccal mucosa graft urethroplasty. Patients were evaluated for postoperative, tongue protrusion, oral opening, and difficulty in speech and swallowing pain score. Surgical outcome was evaluated with pre- and postoperative work-up involving retrograde urethrogram, uroflow and urethroscopy. Mean age, stricture length and overall pain score were comparable in two groups. All the patients were mostly pain free by postoperative day 7. Group 1 patients had significant difficulty in speech and delayed return to normal diet as compared with group 2. The group 2 patients had a significant reduction in oral opening for the first week after surgery. In group 1, approximately 20% patients (with bilateral lingual grafts and stricture length >7 cm) complained of a change in speech character with restricted tongue movement in the long term, whereas there was no significant long-term morbidity in group 2. At mean follow up of 14.5 months, urethroplasty outcome was comparable in the two groups with one failure in group 1, and two failures in group 2. Lingual mucosa graft urethroplasty provides outcomes equivalent to those of buccal mucosa graft urethroplasty. Postoperative morbidity and long-term change in speech make it a second choice for strictures >7 cm, only for cases where buccal mucosa graft is unavailable.


Effects of lidoflazine and mioflazine against potassium and veratrine induced shape changes in isolated rat cardiac myocytes.
The protective effects of lidoflazine and mioflazine against shape changes in isolated rat cardiac myocytes induced by depolarizing concentrations of potassium and veratrine have been examined. Myocardial cells, isolated from adult rat hearts and plated in Petri-dishes, yielded a population of nearly 100% rod-shaped calcium-tolerant myocytes. Addition of veratrine or potassium resulted in a calcium-dependent cell shortening and finally rounding up of nearly all cells. Ultrastructurally, the shape changes were accompanied by a complete loss of calcium associated with the sarcolemmal and T-tubular bilayer. Calcium deposits accumulated in the mitochondria, indicating intracellular calcium overload. Pretreatment of the myocytes with lidoflazine or mioflazine (10(-7)-10(-5) M) dose-dependently increased the number of remaining rod-shaped cells after potassium or veratrine addition. Such rod-shaped cells retained a normal pattern of calcium distribution along the sarcolemma and T-tubuli with no evidence of mitochondrial calcium overload. The protective effects of lidoflazine and mioflazine are explained in terms of preserving sarcolemmal integrity, whereby excessive calcium influx and subsequent cytosolic calcium overload could be prevented.


Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.


Giant, calcified colloid cyst of the lateral ventricle.
We report a patient with a giant, calcified colloid cyst in the left lateral ventricle. Colloid cysts are slow growing, benign lesions, commonly originating in the roof of the anterior third ventricle near the foramen of Monro. Many colloid cysts are small lesions which are either discovered incidentally or cause headache, visual changes, memory deficits, and/or syncope. Giant colloid cysts are rare. A 40-year-old man presented with a month long history of worsening headaches and was found to have a multiloculated 5 cm intraventricular mass with an anterior hyperdensity, suggestive of calcification, arising within the lateral ventricles. He underwent an interhemispheric transcallosal approach for resection of the mass. The pathology was consistent with a giant colloid cyst with calcification in the anterior cyst wall. Giant, calcified mass is a rare presentation of colloid cyst. Although rare, this diagnosis remains an important consideration in the differential diagnosis of any calcified, cystic intraventricular mass.


Spatio-temporal variability of vegetation and its relation to different hydroclimatic factors in Bangladesh.
Bangladesh, known for its remarkable ecological diversity, is faced with the pressing challenges of contemporary climate change. It is crucial to understand how vegetation dynamics respond to different climatic factors. Hence, this study aimed to investigate the spatio-temporal variations of vegetation and their interconnectedness with a range of hydroclimatic factors. The majority of the dataset used in this study relies on MODIS satellite imagery. The Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), precipitation (PPT), evapotranspiration (ET), and land surface temperature (LST) data from the years 2001 to 2020 have been obtained from Google Earth Engine (GEE). In this study, the temporal variations of the NDVI, EVI, PPT, ET, and LST have been investigated. The findings of the Mann-Kendall trend test indicate noticeable trends in both the NDVI and the EVI. Sen's slope value for NDVI and EVI is 0.00424/year and 0.00256/year, respectively. Compared to NDVI, EVI has shown a stronger connection with hydroclimatic factors. In particular, EVI exhibits a better relationship with ET, as indicated by a r2 value of 0.37 and a P-value of 6.81 × 10-26, whereas NDVI exhibits a r2 value of 0.17 and a P-value of 2.96 × 10-11. Furthermore, ET can explain 17% of the fluctuation in NDVI, and no correlation between NDVI and PPT has been found. The results clarify the significant relationship between the EVI and hydroclimatic factors and highlight the efficiency of the EVI for detecting vegetation changes.


RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned.
The surgical difficulty of partial nephrectomy (PN) varies depending on the operative approach. Existing nephrometry classifications for assessment of surgical difficulty are not specific to the robotic approach. To develop an international robotic-specific classification of renal masses for preoperative assessment of surgical difficulty of robotic PN. The RPN classification (Radius, Position of tumour, iNvasion of renal sinus) considers three parameters: tumour size, tumour position, and invasion of the renal sinus. In an international survey, 45 experienced robotic surgeons independently reviewed de-identified computed tomography images of 144 patients with renal tumours to assess surgical difficulty of robot-assisted PN using a 10-point Likert scale. A separate data set of 248 patients was used for external validation. Multiple linear regression was conducted and a risk score was developed after rounding the regression coefficients. The RPN classification was correlated with the surgical difficulty score derived from the international survey. External validation was performed using a retrospective cohort of 248 patients. RPN classification was also compared with the RENAL (Radius; Exophytic/endophytic; Nearness; Anterior/posterior; Location), PADUA (Preoperative Aspects and Dimensions Used for Anatomic), and SPARE (Simplified PADUA REnal) scoring systems. The median tumour size was 38 mm (interquartile range 27-49). The majority (81%) of renal tumours were peripheral, followed by hilar (12%) and central (7.6%) locations. Noninvasive and semi-invasive tumours accounted for 37% each, and 26% of the tumours were invasive. The mean surgical difficulty score was 5.2 (standard deviation 1.9). Linear regression analysis indicated that the RPN classification correlated very well with the surgical difficulty score (R2 = 0.80). The R2 values for the other scoring systems were: 0.66 for RENAL, 0.75 for PADUA, and 0.70 for SPARE. In an external validation cohort, the performance of all four classification systems in predicting perioperative outcomes was similar, with low R2 values. The proposed RPN classification is the first nephrometry system to assess the surgical difficulty of renal masses for which robot-assisted PN is planned, and is a useful tool to assist in surgical planning, training and data reporting. We describe a simple classification system to help urologists in preoperative assessment of the difficulty of robotic surgery for partial kidney removal for kidney tumours.


Cloning and sequencing of a cDNA encoding a taste-modifying protein, miraculin.
A cDNA clone encoding a taste-modifying protein, miraculin (MIR), was isolated and sequenced. The encoded precursor to MIR was composed of 220 amino acid (aa) residues, including a possible signal sequence of 29 aa. Northern blot analysis showed that the mRNA encoding MIR was already expressed in fruits of Richadella dulcifica at 3 weeks after pollination and was present specifically in the pulp.


Challenges in Preparing and Managing the Critical Care Services for a Large Urban Area During COVID-19 Outbreak: Perspective From Delhi.
The coronavirus disease-2019 (COVID-19) pandemic has put healthcare services all over the world into a challenging situation. The contagious nature of the disease and the respiratory failure necessitating ventilatory care of these patients have put extra burden on intensive care unit (ICU) services. India has been no exception; by March 2020, the number of COVID-19 patients started increasing in India. This article describes the measures taken and challenges faced in creating ample ICU bed capacity to cater to the anticipated load of patients in the state of Delhi, India, as a result of the COVID-19 pandemic. The main challenges faced, among others, were estimating the number of ICU beds to be created; deciding on dedicated hospitals to treat COVID-19 patients; procuring ventilators, personal protective equipment, and other related material; mobilizing human resources and providing their training; and providing isolated in-house accommodations to the staff on duty. The authors acknowledge and agree that the methodology proposed in this article is but one way of approaching this difficult scenario and that there could be other, perhaps better, methods of dealing with such a problem.