Effects of a flavonoid extract from Cynomorium songaricum on the swimming endurance of rats.
The present study investigated the effects of a flavonoid extract from Cynomorium songaricum on the swimming endurance of rats by measuring changes of free radical scavenging enzymes, such as CuZn-SOD (copper, zinc-superoxide dismutase) and GSH-px (glutathione peroxidase), and body weights. Significant and dose-dependent antioxidant and anti-fatigue effects of flavonoids (rutin, catechin and isoquercitrin) on swimming rats were observed during 10 days of swimming exercise. After treatment with the flavonoid extract at doses of 0.5, 1.0, and 2.0 g/kg body weight, the CuZn-SOD and GSH-px activities in swimming rats were increased by 1.4%, 3.3%, 4.1% and 112.2%, 208.7%, 261.7%, respectively, while the levels of MDA (malondialdehyde) were decreased by 64.7%, 79.4%, and 86.4% respectively. Furthermore, the average body weight and the total swimming time were increased by 3.1%, 8.8%, 10.6%, and 7.7%, 34.5%, 61.5%, respectively. Our experimental results suggest that flavonoid supplementation could not only reduce free radical formation and scavenge free radicals, but also enhance endurance exercise performance by reducing muscle fatigue.


Introduction of Graphene Nanofibers into the Perovskite Layer of Perovskite Solar Cells.
Although the application of graphene-derived nanomaterials in the electron transport layer (ETL), hole transport layer (HTL), or top electrode of perovskite solar cells (PSCs) has been thoroughly studied, the effects of inserting such materials into the perovskite layer of PSCs is not well understood. In this study, pristine graphene nanofibers were introduced into the perovskite layer of PSCs for the first time. The quality of the electrospun graphene nanofibers was optimized by controlled centrifugation of graphene sheets in the precursor suspension. Under optimized conditions, the device power conversion efficiency increased from 17.51 % without graphene to 19.83 % with graphene nanofibers, representing a 13 % increase. The introduction of graphene nanofibers into the perovskite layer led to a dramatic increase in the grain size of the perovskite layer to over 2 μm, owing to improved nucleation and crystallization at the nanofiber interface, which led to much higher FF and Jsc values. The significant increases in Jsc and Voc are attributed to the improved charge-transport properties of the graphene nanofibers with superb charge conductivity introduced into the perovskite layer. The latter was independently verified by the measured electron transport time. The stability of the device was also improved. In summary, an effective approach has been developed to improve the performance of PSCs by using pure graphene nanofibers for the first time.


Distinguishing Echinococcus granulosus sensu stricto genotypes G1 and G3 with confidence: A practical guide.
Cystic echinococcosis (CE), a zoonotic disease caused by tapeworms of the species complex Echinococcus granulosus sensu lato, represents a substantial global health and economic burden. Within this complex, E. granulosus sensu stricto (genotypes G1 and G3) is the most frequent causative agent of human CE. Currently, there is no fully reliable method for assigning samples to genotypes G1 and G3, as the commonly used mitochondrial cox1 and nad1 genes are not sufficiently consistent for the identification and differentiation of these genotypes. Thus, a new genetic assay is required for the accurate assignment of G1 and G3. Here we use a large dataset of near-complete mtDNA sequences (n = 303) to reveal the extent of genetic variation of G1 and G3 on a broad geographical scale and to identify reliable informative positions for G1 and G3. Based on extensive sampling and sequencing data, we developed a new method, that is simple and cost-effective, to designate samples to genotypes G1 and G3. We found that the nad5 is the best gene in mtDNA to differentiate between G1 and G3, and developed new primers for the analysis. Our results also highlight problems related to the commonly used cox1 and nad1. To guarantee consistent identification of G1 and G3, we suggest using the sequencing of the nad5 gene region (680 bp). This region contains six informative positions within a relatively short fragment of the mtDNA, allowing the differentiation of G1 and G3 with confidence. Our method offers clear advantages over the previous ones, providing a significantly more consistent means to distinguish G1 and G3 than the commonly used cox1 and nad1.


Clinical Characteristics of Patients With Neuromyelitis Optica Spectrum Disorders With Early Onset.
Neuromyelitis optica spectrum disorder is a severe and disabling disease that manifests with severe relapses of optic neuritis, longitudinally extensive myelitis, and/or brainstem syndromes. The disease is complex and, although onset typically occurs in middle age, children and adolescents may be affected. The present study adds to the literature through detailed clinical data from 36 Brazilian patients with neuromyelitis optica spectrum disorder starting before age 21. This was a retrospective assessment of medical records from 14 specialized units in Brazil. The results showed that the course of neuromyelitis optica spectrum disorder was worse in patients with disease onset before the age of 12 years. Gender and ethnic background did not influence disability accumulation. Over a median period of 8 years, 14% of the patients who presented the initial symptoms of neuromyelitis optica spectrum disorder before the age of 21 years died. In conclusion, the present study adds to the reports from other authors examining the severity of early-onset neuromyelitis optica spectrum disorder.


Clinical Characteristics of Symptomatic Cholecystitis in Post-Gastrectomy Patients: 11 Years of Experience in a Single Center.
Background and Objectives: Gallbladder (GB) stones, a major cause of symptomatic cholecystitis, are more likely to develop in post gastrectomy people. Our purpose is to evaluate characteristics of symptomatic cholecystitis after gastrectomy. Materials and Method: In January 2011−December 2021, total 1587 patients underwent operations for symptomatic cholecystitis at our hospital. We reviewed the patients' general characteristics, operation results, pathologic results, and postoperative complications. We classified the patients into non-gastrectomy and gastrectomy groups, further divided into subtotal gastrectomy and total gastrectomy groups. Result: The patients' ages, male proportion, and the open surgery rate were significantly higher (127/1543 (8.2%) vs. 17/44 (38.6%); p < 0.001), and the operation time was longer (102.51 ± 52.43 vs. 167.39 ± 82.95; p < 0.001) in the gastrectomy group. Extended surgery rates were significantly higher in the gastrectomy group (56/1543 (3.6%) vs. 12/44 (27.3%); p < 0.001). The period from gastrectomy to symptomatic cholecystitis was significantly shorter in the total gastrectomy group (12.72 ± 10.50 vs. 7.25 ± 4.80; p = 0.040). Conclusion: GB stones were more likely to develop in post-gastrectomy patients and extended surgery rates were higher. The period to cholecystitis was shorter in total gastrectomy. Efforts to prevent GB stones are considered in post-gastrectomy patients.


Surfactant TWEEN20 provides stabilisation effect on anthocyanins extracted from red grape pomace.
Red grape pomace, a wine-making by-product is rich in anthocyanins and has many applications in food and pharmaceutical industry. However, anthocyanins are unstable during processing and storage. This study aimed to investigate the stability of anthocyanins obtained by hydroalcoholic extraction (with and without sorbic acid) and colloidal gas aphrons (CGA) separation; a surfactant (TWEEN20) based separation. Anthocyanins in CGA samples showed higher stability (half-life = 55 d) than in the crude extract (half-life = 43 d) and their stability increased with the concentration of TWEEN20 in the CGA fraction (6.07-8.58 mM). The anthocyanins loss in the CGA sample (with the maximum content of surfactant, 8.58 mM) was 34.90%, comparable to that in the crude ethanolic extract with sorbic acid (EE-SA) (31.53%) and lower than in the crude extract (44%). Colour stabilisation was also observed which correlated well with the stability of individual anthocyanins in the EE and CGA samples. Malvidin-3-o-glucoside was the most stable anthocyanin over time.


Earthquake forecasting during the complex Amatrice-Norcia seismic sequence.
Earthquake forecasting is the ultimate challenge for seismologists, because it condenses the scientific knowledge about the earthquake occurrence process, and it is an essential component of any sound risk mitigation planning. It is commonly assumed that, in the short term, trustworthy earthquake forecasts are possible only for typical aftershock sequences, where the largest shock is followed by many smaller earthquakes that decay with time according to the Omori power law. We show that the current Italian operational earthquake forecasting system issued statistically reliable and skillful space-time-magnitude forecasts of the largest earthquakes during the complex 2016-2017 Amatrice-Norcia sequence, which is characterized by several bursts of seismicity and a significant deviation from the Omori law. This capability to deliver statistically reliable forecasts is an essential component of any program to assist public decision-makers and citizens in the challenging risk management of complex seismic sequences.


Mammalian target of rapamycin: a central node of complex signaling cascades.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and metabolism in response to diverse external stimuli. In the presence of mitogenic stimuli, mTOR transduces signals that activate the translational machinery and promote cell growth. mTOR functions as a central node in a complex net of signaling pathways that are involved both in normal physiological, as well as pathogenic events. mTOR signaling occurs in concert with upstream Akt and tuberous sclerosis complex (TSC) and several downstream effectors. During the past few decades, the mTOR-mediated pathway has been shown to promote tumorigenesis through the coordinated phosphorylation of proteins that directly regulate cell-cycle progression and metabolism, as well as transcription factors that regulate the expression of genes involved in the oncogenic processes. The importance of mTOR signaling in oncology is now widely accepted, and agents that selectively target mTOR have been developed as anti-cancer drugs. In this review, we highlight the past research on mTOR, including clinical and pathological analyses, and describe its molecular mechanisms of signaling, and its roles in the physiology and pathology of human diseases, particularly, lung carcinomas. We also discuss strategies that might lead to more effective clinical treatments of several diseases by targeting mTOR.


Atypical botulism sparing palsy of extraocular muscles.
Recent studies of patients with botulism found ophthalmoplegia as a characteristic clinical sign. Here we illustrate a very rare case of atypical foodborne botulism with multiple bilateral cranial nerve palsies sparing palsy of extraocular muscles. Therefore, the classical diagnostic pentad of botulism (dry mouth, nausea, vomiting, dysphagia, diplopia, fixed dilated pupils) may be of limited sensitivity in single cases.


[A new algorithm for affine motion compensation in PROPELLER MRI based on image domain].
Affine motion is common during PROPELLER magnetic resonance imaging (MRI) in abdomen or other soft tissues. The current algorithm, up till now, for affine motion compensation is based on frequency domain, which compensates the motion in k space and then reconstruct the final image based on gridding method. But aliasing and some tiny artifacts may exist. This paper proposed a new algorithm for affine motion compensation based on image domain. Firstly, exact affine motion information was obtained through the image registration, secondly k space coordinate was corrected for compensating the k space strips sampling density, then the images obtained from inverse FFT was compensated using motion information, finally the final results were composited after rotation. The experimental results showed that the proposed method could more effectively suppress the motion artifacts compared to the current algorithm.


Clinical and paraclinical characteristics in pediatric patients with acute recurrent and chronic pancreatitis: a cohort in Mexico.
Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are infrequent clinical entities in pediatric patients, as less than 8% of the literature mentions this population. This study aimed to describe the clinical and paraclinical profile, and the etiology related to patients with ARP and CP attended at a tertiary-level healthcare institute in Mexico. We conducted a retrospective study from medical records of patients with ARP and CP attended between 2010 and 2020, analyzing the clinical characteristics, imaging studies, and the etiology associated with each patient. We analyzed 25 patients: 17 were diagnosed with ARP, and eight with CP. The main etiology identified was an anatomical alteration of the pancreatic duct (32%); pancreas divisum was the most prevalent condition. In 48% of the population, the etiology was not identified. The group with CP was higher in frequency for calcifications and dilation of the pancreatic duct (p < 0.005) compared to the ARP group. The main etiology for ARP and CP was an anatomical alteration of the pancreatic duct; however, in almost half of the cases, no established cause was identified. Although comparing our results with those offered by large cohorts such as the INSPPIRE group can be complex, we found relevant similarities. Currently, the data obtained from this first descriptive study are the foundation for future research in the field of Mexican pediatric pancreatology.


Description of a new species of Apterotoxitiades Adlbauer, 2008 (Cerambycidae, Dorcasominae, Apatophyseini) and the female of A.vivesi Adlbauer, 2008, with notes on the biology of the genus.
Following the description of the Apatophyseini genus Apterotoxitiades Adlbauer, 2008 (Cerambycidae: Dorcasominae) from South Africa, a new species has now been discovered in the eastern Drakensberg range of the country. The holotype female is here described as Apterotoxitiadesaspinosus Björnstad, sp. n. Also, a new small series collected at Hogsback, in the Amathole range, has allowed the description of the previously unknown female of the type species, Apterotoxitiadesvivesi Adlbauer, 2008. Both species are high altitude dwellers, occurring above 1300 m asl and their habitat consists mainly of mountain grassland interspersed with mistbelt forest pockets. All specimens were recorded in the austral winter to early spring, when these mountain ranges are occasionally covered in snow and night temperature plummet below 0 °C. They appear to be nocturnal and their complete lack of wings indicates a remarkable adaptation to cold conditions at high altitude.


Integrated analysis of protein and glucose metabolism during surgery: effects of anesthesia.
The aim of this study was to assess dynamic changes in protein and glucose metabolism during surgery. Twelve patients undergoing colorectal surgery received either intravenous propofol anesthesia (n = 6) or inhalational anesthesia with desflurane (n = 6). Pre- and intraoperative protein and glucose kinetics were analyzed by an isotope dilution technique using L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose. Plasma concentrations of glucose, lactate, free fatty acids, insulin, glucagon, and cortisol were measured before and after 2 h of surgery. The rates of appearance of leucine and glucose, leucine oxidation, protein synthesis, and glucose clearance decreased during surgery, independent of the type of anesthesia (P < 0.05). A correlation between the rate of appearance of leucine and glucose was observed (r = 0.755, P < 0.001). Intraoperative plasma cortisol and glucose concentrations increased (P < 0.05), whereas plasma concentrations of lactate, free fatty acids, insulin, and glucagon did not change. Surgery causes a depression of whole body protein and glucose metabolism, independent of the anesthetic technique. There is a correlation between perioperative glucose production and protein breakdown.


Indium tin oxide nanoparticles with compositionally tunable surface plasmon resonance frequencies in the near-IR region.
Here we report the synthesis of conducting indium tin oxide (ITO) nanoparticles (NPs) and their surface plasmon resonance (SPR) properties. The SPR peaks of the ITO NPs can be easily tuned by changing the concentration of Sn doping from 3 to 30 mol %. The shortest SPR wavelength of 1618 nm in 10% Sn-doped ITO NPs may reflect the highest electron carrier density in the ITO NPs. The controllable SPR frequencies of metal oxides may offer a novel approach for noble-metal-free SPR applications. Unlike noble-metal nanostructures, ITO has no inter- and intraband transitions in the vis-near-IR region and represents a free-electron conduction, allowing us to systematically study the origin of optical effects arising from the SPRs of conduction electrons.


Temporal and spatial coherence of sound at 250 Hz and 1659 km in the Pacific Ocean: demonstrating internal waves and deterministic effects explain observations.
The hypothesis tested is that internal gravity waves explain temporal and spatial coherences of sound at 1659 km in the Pacific Ocean for a signal at 250 Hz and a pulse resolution of 0.02 s. From data collected with a towed array, the measured probability that coherence time is 1.8 min or longer is 0.8. Using a parabolic approximation for the acoustic wave equation with sound speeds fluctuating from internal waves, a Monte-Carlo model yields coherence time of 1.8 min or more with probability of 0.9. For spatial coherence, two subsections of the array are compared that are separated by 142 and 370 m in directions perpendicular and parallel to the geodesic, respectively. Measured coherence is 0.54. This is statistically consistent with the modeled 95% confidence interval of [0.52, 0.76]. The difference of 370 m parallel to the section causes spatial coherence to degrade deterministically by a larger amount than the effect of internal waves acting on the 142 m separation perpendicular to the section. The models are run without any tuning with data.


Genome sequence of Sphingobium yanoikuyae XLDN2-5, an efficient carbazole-degrading strain.
Sphingobium yanoikuyae XLDN2-5 is an efficient carbazole-degrading strain. Carbazole-degrading genes are accompanied on both sides by two copies of IS6100 elements. Here, we describe the draft genome sequence of strain XLDN2-5, which may provide important clues as to how it recruited exogenous genes to establish pathways to degrade the xenobiotics.


Antenatal utilization, family planning and fertility preferences in Tari.
This paper reports on the results of a questionnaire on antenatal utilization, family planning and fertility preferences carried out on 2560 women in Tari in 1998. There is a very high level of utilization of antenatal and delivery services. There is also a broad knowledge of family planning methods, but very low uptake of these services. Part of the reason for this lies in high fertility preferences among women in Tari, part in a lack of confidence regarding the methods, and part in male opposition to their use. Comparison with elsewhere in Papua New Guinea confirms that health service utilization and fertility preferences are high, and family planning uptake is low in Tari. The decline in health services and the collapse of law and order in Tari bodes ill for the future of a family planning program in a district in which the need for such services is rising, due to the effects of population pressure on the environment.


The utility of echocardiography in the diagnostic strategy of postinfarction ventricular septal rupture: a comparison of two-dimensional echocardiography versus Doppler color flow imaging.
The diagnostic accuracy of Doppler color flow imaging in the diagnosis of postinfarction ventricular septal defects has not been established. In this study, 43 patients with unexplained hypotension or a new murmur in the periinfarct period were evaluated with conventional two-dimensional echocardiography and Doppler color flow imaging. The presence of a ventricular septal defect was confirmed by oximetry, ventriculography, operative repair, or autopsy in each case. Both two-dimensional and Doppler color flow imaging were 100% specific in excluding a ventricular septal defect. Doppler color flow imaging correctly identified the 12 confirmed ventricular septal defects in this study (100% sensitivity), whereas any combination of two-dimensional criteria only correctly identified seven (58% sensitive) (p less than 0.05). Doppler color flow imaging is superior to conventional two-dimensional imaging in the diagnosis of a postinfarction ventricular septal defect. In addition, Doppler color flow imaging localized the septal defect, and thus guided therapy and technique for repair. Carefully performed Doppler color flow examination can exclude or result in the rapid diagnosis of a ventricular septal defect, which eliminates the need for further time-consuming confirmatory testing.


Comparing Experiments to the Fault-Tolerance Threshold.
Achieving error rates that meet or exceed the fault-tolerance threshold is a central goal for quantum computing experiments, and measuring these error rates using randomized benchmarking is now routine. However, direct comparison between measured error rates and thresholds is complicated by the fact that benchmarking estimates average error rates while thresholds reflect worst-case behavior when a gate is used as part of a large computation. These two measures of error can differ by orders of magnitude in the regime of interest. Here we facilitate comparison between the experimentally accessible average error rates and the worst-case quantities that arise in current threshold theorems by deriving relations between the two for a variety of physical noise sources. Our results indicate that it is coherent errors that lead to an enormous mismatch between average and worst case, and we quantify how well these errors must be controlled to ensure fair comparison between average error probabilities and fault-tolerance thresholds.


Zonisamide in the treatment of epilepsy.
Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs. The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide. From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.


In-vitro analysis of APA microcapsules for oral delivery of live bacterial cells.
Oral administration of microcapsules containing live bacterial cells has potential as an alternative therapy for several diseases. This article evaluates the suitability of the alginate-poly-L-lysine-alginate (APA) microcapsules for oral delivery of live bacterial cells, in-vitro, using a dynamic simulated human gastro-intestinal (GI) model. Results showed that the APA microcapsules were morphologically stable in the simulated stomach conditions, but did not retain their structural integrity after a 3-day exposure in simulated human GI media. The microbial populations of the tested bacterial cells and the activities of the tested enzymes in the simulated human GI suspension were not substantially altered by the presence of the APA microcapsules, suggesting that there were no significant adverse effects of oral administration of the APA microcapsules on the flora of the human gastrointestinal tract. When the APA microcapsules containing Lactobacillus plantarum 80 (LP80) were challenged in the simulated gastric medium (pH = 2.0), 80.0% of the encapsulated cells remained viable after a 5-min incubation; however, the viability decreased considerably (8.3%) after 15 min and dropped to 2.6% after 30 min and lower than 0.2% after 60 min, indicating the limitations of the currently obtainable APA membrane for oral delivery of live bacteria. Further in-vivo studies are required before conclusions can be made concerning the inadequacy of APA microcapsules for oral delivery of live bacterial cells.


Agreement between self-reported psychoactive substance use and urine toxicology results for adults with opioid use disorder admitted to hospital.
Hospitals often perform urine drug screens (UDS) upon inpatient admission to confirm self-reported psychoactive substance use for patients with opioid use disorder (OUD). We sought to evaluate the agreement between UDS and patient self-report for psychoactive substances detected with UDS for adults with OUD admitted to hospital. For 11 substance categories, we evaluated agreement between the UDS and the documented history over a 5-year period for consecutive adults admitted to one academic center with a history of OUD. Among the 153 patients, overall agreement across the 1683 different history/UDS pairs (i.e. either history+/UDS + or history-/UDS-) was high (81.3%) but varied (from lowest to highest) by substance [opiates (56.9%), benzodiazepines (66.0%), 6-acetylmorphine (67.3%), cocaine (81.0%), cannabinoids (81.0%), methadone (83.7%), buprenorphine (85.0%), amphetamine (94.8%), barbiturates (95.4%), and phencyclidine (98.7%)]. History+/UDS- pair mismatches were most frequent for 6-acetylmorphine (32.7%), methadone (14.3%) and oxycodone (12.4%); history-/UDS + pair mismatches were most frequent for opiates (43.1%), benzodiazepines (24.8%) and cannabinoids (18.3%). The change in agreement over time of self-reported heroin use may reflect an increasing number of patients unknowingly using illicit fentanyl products. Among hospitalized patients with OUD, agreement between reported psychoactive substance use history and UDS results is strong with the exception of opiates, heroin, and benzodiazepines.


Alcohol use among entrants to a Hong Kong University.
This study of first year entrants to one of the major universities in Hong Kong describes the pattern of their alcohol consumption, their binge drinking, alcohol abuse, and dependence. A retrospective cross-sectional study was conducted. A representative sample of year 1 students 2630/2968 (89%) newly admitted to the Chinese University of Hong Kong in 2003 were recruited to participate in a structured self-administered questionnaire. First year university students in Hong Kong have low rates of ever drinking alcohol (62%), and the rates of binge drinking and alcohol-related problems were 7 and 0.8%, respectively. The pattern of binge drinking is more common than weekly drinking (2.3%). Binge drinkers are more likely to have experienced alcohol-related interpersonal problems or (95% CI) = 6.5 (1.7-24.5). Males were more likely to drink, to binge drink, and to drink frequently. In contrast with students in the west, the majority of first year university students in Hong Kong are not binge or regular drinkers. However, there is a subgroup who smoke, drink more, and use alcohol as a means of coping with stress. This group may be particularly in need of a brief intervention, such as providing counseling and referral services.


Superior mesenteric vein reconstruction during pancreatoduodenectomy using a dilated right ovarian vein in a patient at future risk for pelvic congestion syndrome: a case report.
Pancreatoduodenectomy including resection of the superior mesenteric vein (SMV) is increasingly performed for right-sided pancreatic ductal adenocarcinoma invading the wall of that vessel. Various venous grafts may be chosen for reconstruction. We present a woman with pancreatic cancer who underwent such a pancreatoduodenectomy with venous reconstruction using a dilated right ovarian vein. A 71-year-old woman with cancer involving the pancreatic head, uncinate process, and SMV underwent pancreatoduodenectomy with SMV resection. Reconstruction used a portion of the right ovarian vein that was markedly dilated and had placed her at risk for pelvic congestion syndrome (PCS). Graft patency was confirmed 8 months after surgery. She now finished receiving adjuvant chemotherapy and has no symptoms of PCS. If an ovarian vein has sufficient diameter, it can be used to reconstruct the resected segment of the SMV during pancreatoduodenectomy in suitable patients.


Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?
Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.


Diagnostic performance of magnetic resonance imaging for diagnosing acute appendicitis during pregnancy.
This retrospective study evaluated the diagnostic efficacy of magnetic resonance imaging (MRI) for identifying acute appendicitis during pregnancy. This retrospective study enrolled a total of 46 pregnant patients with clinically suspected acute appendicitis who underwent 1.5 T MRI and received a final pathological diagnosis. We evaluated the imaging characteristics associated with patients diagnosed with acute appendicitis, including the appendix diameter, the appendix wall thickness, intra-appendiceal fluid collection, and peri-appendiceal fat infiltration. A bright appendix on T1-weighted 3-dimensional imaging was identified as a negative sign for appendicitis. Peri-appendiceal fat infiltration had the highest specificity of 97.1% for diagnosing acute appendicitis, whereas increasing appendiceal diameter had the highest sensitivity of 91.7%. The cut-off values for increasing appendiceal diameter and appendiceal wall thickness were 6.55 mm and 2.7 mm, respectively. Using these cut-off values, appendiceal diameter had a sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of 91.7%, 91.2%, 78.4%, and 96.9%, respectively, whereas these values for appendiceal wall thickness were 75.0%, 91.2%, 75.0%, and 91.2%. The combination of increasing appendiceal diameter and appendiceal wall thickness resulted in an area under the receiver operating characteristic curve value of 0.958 with Se, Sp, PPV, and NPV values of 75.0%, 100.0%, 100.0%, and 91.9%, respectively. All five MRI signs examined in this study had significant diagnostic value for detecting acute appendicitis during pregnancy, with p-values <0.01. The combined use of increasing appendiceal diameter and appendiceal wall thickness displayed the excellent ability to diagnose acute appendicitis in pregnant women.


Osteoradionecrosis after postoperative radiotherapy for oral cavity cancer: A retrospective cohort study.
Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT. A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models. Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01). OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks.


The polycation diethylaminoethyl dextran potentiates thermal cell killing.
The polycation diethylaminoethyl dextran (DEAE-dextran) causes marked potentiation of the effects of hyperthermia (45 degrees C) on HA-1 Chinese hamster ovary cells. The effects of the polycation appear to be mediated at the cell surface and are largely reversed by removal of DEAE-dextran with the polyanion dextran sulphate. Maximal potentiation is observed when polycation and heat are given simultaneously. The polycation also inhibits the capping of concanavalin-A acceptors when used singly and is additive with heat in inhibiting capping; reduction in con-A capping may indicate decreased mobility of cell surface glycoproteins. The mechanism of heat potentiation by DEAE-dextran is not fully understood. Effects on surface charge and cytoskeleton-membrane interactions may be involved. However, the polycation appears to have promise, both in probing mechanisms of heat killing and as an adjuvant to heat treatment; potentiation occurs at extremely low DEAE-dextran levels, with considerable potentiation at a concentration of 0.4 microM.


The effects of exenatide bid on metabolic control, medication use and hospitalization in patients with type 2 diabetes mellitus in clinical practice: a systematic review.
The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group. A total of 15 studies meeting the inclusion criteria were identified. The studies revealed significant reductions of -0.4 to -0.9% in A1C, -10 mg/dl in FG, -2 to -11 kg in body weight and -2 to -11 mmHg in SBP. Statistically significant reductions in the use or dosage of either oral glucose-lowering medications or insulin after initiating exenatide treatment were found in every observational study that assessed medication changes, including reductions in dosage of up to 75% in sulphonylureas dosages, 22% in metformin, 66% in thiazolidinediones (TZD) or TZD combination therapy and 75% in prandial insulin. Exenatide-treated patients experienced significantly lower rates of all-cause and CVD-related hospitalization and CVD events than patients treated with other therapies overall. In this review of observational studies, exenatide initiation was associated with significant reductions in clinically relevant outcomes. Improvements in A1C, FG, weight and SBP in the observational studies in this review were consistent with improvements observed in controlled clinical trials.


AMD3100 Attenuates Post-Traumatic Osteoarthritis by Maintaining Transforming Growth Factor-β1-Induced Expression of Tissue Inhibitor of Metalloproteinase-3 via the Phosphatidylinositol 3-Kinase/Akt Pathway.
AMD3100 is a small-molecule inhibitor of the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) axis, while its role in aggrecan metabolism is unclear. We hypothesized that the AMD3100 modulates the transforming growth factor-β1 (TGF-β1)-induced expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) in chondrocytes. We evaluated expression of CXCL12/CXCR4 and TIMP-3 in the knee joints of rats with and without osteoarthritis (OA) by immunohistochemistry, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA). The rats were divided into sham control, destabilization of the medial meniscus/AMD3100-treated (DMM/AMD3100-treated), and DMM/phosphate-buffered saline (PBS)-treated groups. After 6 weeks, the rats were euthanized and subjected to histological and immunohistochemical analyses. Also, interleukin (IL)-1-pretreated primary chondrocytes were cultured in the presence of empty control (-, -), CXCL12a (+,-), CXCL12a + small interfering RNA (siRNA) CXCR4 (+,+), or CXCL12a + siNC (+NC), and the expression levels of target markers were evaluated by Western blotting and real-time reverse transcription PCR (RT-PCR). The CXCL12/CXCR4 levels were higher, and the expression of TIMP-3 was lower, in the OA rats compared to the healthy control rats. The rats in the DMM/AMD3100-treated group revealed a markedly decreased immunological response and mild pathology. Treatment with CXCL12a increased expression of aggrecan and disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) and suppressed that of TIMP-3 in IL-1-pretreated primary chondrocytes. TGF-β1 increased expression of TIMP-3, and this increase was reversed by CXCL12a via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, these effects were inhibited by the CXCR4 antagonist AMD3100 and the PI3K inhibitor LY303511. In conclusion, inhibition of the CXCL12a/CXCR4 signaling axis maintained TIMP-3 expression via the PI3K/Akt pathway. Our findings provide insight into the mechanism by which AMD3100 prevents OA.


Hemispheric dominance of cortical activity evoked by focal electrogustatory stimuli.
Functional magnetic resonance imaging was used to observe cortical hemodynamic responses to electric taste stimuli applied separately to the right and left sides of the tongue tip. In 11 right-handed normal adults activation occurred primarily in the insular cortex, superior temporal lobe, inferior frontal lobe, including premotor regions, and in inferior parts of the postcentral gyrus. Unexpectedly, the location and laterality of activation were largely identical regardless of the side of the tongue stimulated. Activation in the superior insula, the presumed location of primary gustatory cortex, was predominantly, but not exclusively, in the right hemisphere, whereas central (more inferior) insular activations were more evenly bilateral. Right hemispheric dominance of activation also occurred in premotor regions (Brodmann areas 6 and 44), whereas left hemispheric dominance occurred only in the superior temporal cortex (Brodmann areas 22/42). The electric taste-evoked hemodynamic response pattern was more consistent with activation of the gustatory system than activation of somatosensory systems. The results suggest that the sites for cortical processing of electric taste information are dependent on hemispheric specialization.


The emerging role of MEIS1 in cell proliferation and differentiation.
Cell proliferation and differentiation are the foundation of reproduction and growth. Mistakes in these processes may affect cell survival, or cause cell cycle dysregulation, such as tumorigenesis, birth defects and degenerative diseases, or cell death. Myeloid ecotropic viral integration site 1 (MEIS1) was initially discovered in leukemic mice. Recent research identified MEIS1 as an important transcription factor that regulates cell proliferation and differentiation during cell fate commitment. MEIS1 has a pro-proliferative effect in leukemia cells; however, its overexpression in cardiomyocytes restrains neonatal and adult cardiomyocyte proliferation. In addition, MEIS1 has carcinogenic or tumor suppressive effects in different neoplasms. Thus, this uncertainty suggests that MEIS1 has a unique function in cell proliferation and differentiation. In this review, we summarize the primary findings of MEIS1 in regulating cell proliferation and differentiation. Correlations between MEIS1 and cell fate specification might suggest MEIS1 as a therapeutic target for diseases.


Multiple modes of interaction between the methylated DNA binding protein MeCP2 and chromatin.
Mutations of the methylated DNA binding protein MeCP2, a multifunctional protein that is thought to transmit epigenetic information encoded as methylated CpG dinucleotides to the transcriptional machinery, give rise to the debilitating neurodevelopmental disease Rett syndrome (RTT). In this in vitro study, the methylation-dependent and -independent interactions of wild-type and mutant human MeCP2 with defined DNA and chromatin substrates were investigated. A combination of electrophoretic mobility shift assays and visualization by electron microscopy made it possible to understand the different conformational changes underlying the gel shifts. MeCP2 is shown to have, in addition to its well-established methylated DNA binding domain, a methylation-independent DNA binding site (or sites) in the first 294 residues, while the C-terminal portion of MeCP2 (residues 295 to 486) contains one or more essential chromatin interaction regions. All of the RTT-inducing mutants tested were quantitatively bound to chromatin under our conditions, but those that tend to be associated with the more severe RTT symptoms failed to induce the extensive compaction observed with wild-type MeCP2. Two modes of MeCP2-driven compaction were observed, one promoting nucleosome clustering and the other forming DNA-MeCP2-DNA complexes. MeCP2 binding to DNA and chromatin involves a number of different molecular interactions, some of which result in compaction and oligomerization. The multifunctional roles of MeCP2 may be reflected in these different interactions.


Value of imprint cytology for ultrasound-guided transthoracic core biopsy.
The aim of this study was to investigate the possible additional diagnostic information provided by imprint cytology when performing ultrasound-guided transthoracic core biopsy and to evaluate whether it could optimise the biopsy procedure. A total of 155 transthoracic core biopsies with touch imprint smears were performed under ultrasound guidance, with 127 malignant and 28 benign lesions. The imprint smears were stained using Riu's method and interpreted by a cytopathologist. These were compared with the histopathology of core biopsy specimens and the final diagnosis of malignant versus benign disease. The overall diagnostic accuracy of imprint cytology was 94% (146 out of 155). Histopathological analysis showed an overall accuracy of 94% (146 out of 155), with a sensitivity of 94% (119 out of 127) and negative predictive value of 79% (27 out of 34). The combination of these two methodologies had an increased overall accuracy and negative predictive value of 98% (152 out of 155) and 90% (28 out of 31), respectively. The results of imprint cytology and histopathology were in agreement in 143 patients (92%). In conclusion, imprint cytology of ultrasound-guided transthoracic core biopsy is a sensitive procedure for diagnosing peripheral thoracic lesions, and it may increase the diagnostic accuracy and cancer negative prediction of biopsy alone. With an on-site approach, imprint cytology may help to assess the adequacy of biopsy specimens and optimise the biopsy procedure.


Integrated microfluidics platforms for investigating injury and regeneration of CNS axons.
We describe the development of experimental platforms to quantify the regeneration of injured central nervous system (CNS) neurons by combining engineering technologies and primary neuronal cultures. Although the regeneration of CNS neurons is an important area of research, there are no currently available methods to screen for drugs. Conventional tissue culture based on Petri dish does not provide controlled microenvironment for the neurons and only provide qualitative information. In this review, we introduced the recent advances to generate in vitro model system that is capable of mimicking the niche of CNS injury and regeneration and also of testing candidate drugs. We reconstructed the microenvironment of the regeneration of CNS neurons after injury to provide as in vivo like model system where the soluble and surface bounded inhibitors for regeneration are presented in physiologically relevant manner using microfluidics and surface patterning methods. The ability to control factors and also to monitor them using live cell imaging allowed us to develop quantitative assays that can be used to compare various drug candidates and also to understand the basic mechanism behind nerve regeneration after injury.


Utilization and Outcomes of Direct Consultation in a Child Psychiatry Access Program.
The high prevalence of child and adolescent psychiatric disorders in the United States, coupled with the severe and pervasive shortage of child and adolescent psychiatrists, has led 46 states and territories to launch programs providing child psychiatry consultation to pediatricians. Although these programs aim to increase access to psychiatric expertise, evidence of favorable program outcomes beyond user satisfaction has been limited. Findings from the authors' child psychiatry consultation program suggest that such programs may enable pediatricians to manage most cases referred for consultation, thereby extending the behavioral health workforce to the primary care setting.


Epidemiology and natural history of HPV.
Human papillomavirus (HPV) is a highly prevalent, sexually transmitted infection responsible for significant morbidity and mortality. High-risk HPV types are now known to be necessary in the etiology of cervical cancer and to lead to both high-grade and low-grade cervical lesions. They are also implicated in a substantial portion of anal, penile, and head and neck precancers and cancers. HPV 16 and 18 are the most common HPV types found in cervical cancer and are responsible for approximately 70% of these cancers. In contrast, low-risk HPV types, the most common of which are HPV 6 and 11, cause genital warts, low-grade cervical lesions, and recurrent respiratory papillomatosis, but they do not cause cervical or other HPV-related cancers. Infection is most common in young, sexually active populations, and an estimated three fourths of adults will be infected with HPV during their lifetime. Cervical screening programs exist in the United States and other developed countries to identify and treat precancerous cervical lesions, but they do not reach all women and are costly. Until recently, no highly effective primary prevention strategy to reduce the risk of HPV acquisition existed. However, a quadrivalent HPV vaccine, which protects against the most common high-risk and low-risk HPV infections (HPV 16, 18, 6, and 11), is now available. In addition, a bivalent HPV vaccine that protects against high-risk HPV types 16 and 18 is in the late stages of clinical development. If implemented widely, vaccination against HPV promises to dramatically reduce HPV-associated morbidity and mortality.


repo: an R package for data-centered management of bioinformatic pipelines.
Reproducibility in Data Analysis research has long been a significant concern, particularly in the areas of Bioinformatics and Computational Biology. Towards the aim of developing reproducible and reusable processes, Data Analysis management tools can help giving structure and coherence to complex data flows. Nonetheless, improved software quality comes at the cost of additional design and planning effort, which may become impractical in rapidly changing development environments. I propose that an adjustment of focus from processes to data in the management of Bioinformatic pipelines may help improving reproducibility with minimal impact on preexisting development practices. In this paper I introduce the repo R package for bioinformatic analysis management. The tool supports a data-centered philosophy that aims at improving analysis reproducibility and reusability with minimal design overhead. The core of repo lies in its support for easy data storage, retrieval, distribution and annotation. In repo the data analysis flow is derived a posteriori from dependency annotations. The repo package constitutes an unobtrusive data and flow management extension of the R statistical language. Its adoption, together with good development practices, can help improving data analysis management, sharing and reproducibility, especially in the fields of Bioinformatics and Computational Biology.


Neurocognitive Correlates of Cerebellar Volumetric Alterations in Youth with Pediatric Bipolar Spectrum Disorders and Bipolar Offspring.
Emerging evidence points towards the involvement of the cerebellum in the processing of emotions and pathophysiology of mood disorders. However, cerebellar and related cognitive alterations in youth with pediatric bipolar disorder (PBD) and those at high risk to develop the disorder, such as bipolar offspring (BD-OFF) are not clearly defined. To investigate cerebellar gray and white matter volumes, cognition, and their relationship in youth with PBD and BD-OFF. Thirty youth (7 to 17 years, inclusive) with PBD, 30 BD-OFF and 40 healthy controls (HC) were recruited. Study participants underwent a computer-based cognitive battery assessing affective processing, executive function, attention, psychomotor speed, and learning. Three-tesla MRI scan was performed to assess cerebellar white and gray matter volumes. Cerebellar segmentation was performed with FreeSurfer. Statistical analyses include between-group differences in cognitive domains, cerebellar gray, and white matter volumes. Relationships between cerebellar volumes and cognitive domains were examined. Youth with PBD showed greater cerebellar gray matter volumes than both BD-OFF and HC, whereas no differences were present between BD-OFF and HC. Both youth with PBD and BD-OFF showed altered processing of negative emotions and a bias towards positive emotions. In youth with PBD and BD-OFF, greater impairment in the processing of emotions correlated with greater cerebellar gray matter volumes. The present findings corroborate hypotheses on cerebellar involvement in the processing of emotions and the pathophysiology of PBD. The presence of cerebellar dysfunction in BD-OFF is unclear.


[Recent developments in capillary electrophoresis-mass spectrometry].
Capillary electrophoresis-mass spectrometry (CE-MS) has become a well-accepted analytical approach by combining high separation power, wide applicability of CE with high sensitivity, molecular information availability of MS. In this review, the new advances in CE-MS interface over the past few years are presented, and the recent applications are summarized in the fields of life sciences, food science and pharmaceutical analysis and so on.


Generation of dynamic Bessel beams and dynamic bottle beams using acousto-optic effect.
We present a novel optical configuration that allows for generation of ultra-high speed dynamic Bessel beams and dynamic bottle beams. The method is based on combination of the axisymmetric acousto-optic device and the spatial filtering enabled by a mask or a digital micromirror device. Selected features of dynamic non-diffracting beams and bottle beams are investigated using time-resolved approach with stroboscopic pulsed illumination, including spatial intensity distribution, spatial modulation factors, MHz-range temporal modulation, and scalability. The numerical simulations based on Fourier optics as well as experimental realizations are demonstrated.


Monotherapy with Lopinavir/Ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMo study).
Long-term adverse events and expenses associated with HAART have led to an interest in simplified therapy. Lopinavir/ritonavir monotherapy is attractive due to its potency and high genetic barrier. This is a 96-week, open-label, randomized study to assess the feasibility of using LPV/r monotherapy in patients with undetectable viral load after being on successful HAART for at least 6 months. Subjects were randomized (1:1) to either switch from HAART to LPV/r monotherapy or to maintain their previous regimen. 60 patients were enrolled. Baseline characteristics were similar in both groups. At Week 96, by intention-to-treat analysis, 24/30 (80.0%) subjects in monotherapy group and 26/30(86.6%) in the control group had a plasma viral load of <80 copies/mL. There was one virologic failure (defined as VL not greater-than 500 copies/mL) in each arm. Genotyping testing identified no resistance-associated mutations. The patient on the monotherapy arm was successfully resuppressed to <80 copies/mL after intensification with tenofovir and lamivudine. No statistically significant differences were found with regard to changes in CD4 counts. One subject in the monotherapy group discontinued due to diarrhea. Five subjects in the control group underwent regimen changes due to drug-related toxicities. Viral load from semen samples collected at the end of follow-up was undetectable on 14/15 patients randomized to monotherapy. Switching from various HAART regimens to LPV/r monotherapy in patients who were virologically suppressed and without a history of previous virologic failure was effective, safe, and well tolerated through 96 weeks.


Robust Operating Room Scheduling Model with Violation Probability Consideration under Uncertain Surgery Duration.
This paper proposes an operating room (OR) scheduling model to assign a group of next-day patients to ORs while adhering to OR availability, priorities, and OR overtime constraints. Existing studies usually consider OR scheduling problems by ignoring the influence of uncertainties in surgery durations on the OR assignment. In this paper, we address this issue by formulating accurate patient waiting times as the cumulative sum of uncertain surgery durations from the robust discrete approach point of view. Specifically, by considering the patients' uncertain surgery duration, we formulate the robust OR scheduling model to minimize the sum of the fixed OR opening cost, the patient waiting penalty cost, and the OR overtime cost. Then, we adopt the box uncertainty set to specify the uncertain surgery duration, and a robustness coefficient is introduced to control the robustness of the model. This resulting robust model is essentially intractable in its original form because there are uncertain variables in both the objective function and constraint. To make this model solvable, we then transform it into a Mixed Integer Linear Programming (MILP) model by employing the robust discrete optimization theory and the strong dual theory. Moreover, to evaluate the reliability of the robust OR scheduling model under different robustness coefficients, we theoretically analyze the constraint violation probability associated with overtime constraints. Finally, an in-depth numerical analysis is conducted to verify the proposed model's effectiveness and to evaluate the robustness coefficient's impact on the model performance. Our analytical results indicate the following: (1) With the robustness coefficient, we obtain the tradeoff relationship between the total management cost and the constraint violation probability, i.e., a smaller robustness coefficient yields remarkably lower total management cost at the expense of a noticeably higher constraint violation probability and vice versa. (2) The obtained total management cost is sensitive to small robustness coefficient values, but it hardly changes as the robustness coefficient increases to a specific value. (3) The obtained total management cost becomes increasingly sensitive to the perturbation factor with the decrease in constraint violation probability.


[A case report of a double cancer of the ureter and stomach].
A 63-year-old man complained of hunger epigastralgia. X-ray and endoscopic examination demonstrated Borrmann II type gastric carcinoma. Radical gastrectomy was performed on October 20, 1982. The histological findings revealed moderately differentiated tubular adenocarcinoma. In May 1983, right hydronephrosis was recognized by ultrasonography. A papillary tumor was visualized in the right ureter in retrograde pyelography, and percutaneous transrenal urinary tract drainage was performed. Cytological findings revealed class V. Total nephro-uretectomy was performed on June 16, 1983. The histological findings revealed transitional cell carcinoma.


End-stage renal disease replacement therapy in Israel: demographic and regional differences.
Incidence (by sex and ethnic group), prevalence and mortality rates (by age) of end-stage renal disease (ESRD) replacement therapy in Israel were calculated for the periods 1975-78 and 1979-82. Rates were higher for males (relative risk male/female 1.70 for the first period and 1.83 for the second). Incidence and prevalence rates increased with age among men; among women the maximal rates were attained by the 45-64 age-group. Incidence and prevalence rates were higher during the second period. Among the Jewish population, rates of treatment were higher in the Asian and African-born groups, and European-American and Israeli-born Jews showed the lowest rates. Mortality rates during treatment were lower among Arabs. Rates of therapy rose with age, were higher for males and had a well-defined ethnic pattern. In order to assess differences in ESRD replacement therapy between districts, rates of incidence, prevalence and mortality during treatment (for the Jewish population) were computed by district and adjusted by age and continent of birth for both periods. Significant differences in ESRD therapy coverage were detected only during the second period. Prevalence rates were considerably higher in the central, Tel Aviv and southern districts, and incidence rates were considerably elevated in the central and Tel Aviv districts and low in Jerusalem. Mortality during treatment was lowest in Haifa. It seems improbable that these findings are due to differences in accessibility to ESRD replacement therapy; however, early diagnosis and prevention of disabling kidney conditions at the primary care level may play an important role.


Reduced intestinal butyrate availability is associated with the vascular remodeling in resistance arteries of hypertensive rats.
During hypertension an unbalance of short-chain fatty acids (SCFAs) production by intestinal bacteria is described. However, no data evaluate the association of SCFAs and vascular remodeling in hypertension, which is an important hallmark of this disease. Thus, the present study aims to evaluate the correlations between SCFAs availability and the resistance arteries remodeling in hypertension, as well as to identify the possible pathway by which the SCFAs could exert a structural and mechanical influence. Hence, male spontaneously hypertensive rats (SHR) and normotensive Wistar rats had blood pressure measured by tail-cuff plethysmography; fecal SCFAs content assessed by gas chromatography; gene expression of SCFAs-transporters in gut epithelium and SCFAs-sensing receptors on mesenteric resistance arteries (MRA) quantified by PCR; and MRA structural and mechanical parameters analyzed by pressure myograph. Reduced butyrate fecal content was found in SHR, with no changes in propionate and acetate, as well as decreased mRNA levels of SCFAs-transporters (MCT1, MCT4, and SMCT1) in the intestinal epithelium. In addition, lower gene expression of SCFAs-sensing receptors (GPR41, GPR43, and GPR109a, but not Olfr78) was identified in MRAs of SHR, which also shows inward eutrophic remodeling with stiffness. Butyrate content presented a negative correlation with systolic blood pressure and with the structural alterations found on MRAs, while a positive correlation between butyrate content and mechanical parameters was detected. Altogether the present study suggests that lower butyrate content due to ineffective SCFA bioavailability, associated with lower SCFAs-sensing receptors expression, could favor MRA remodeling, increasing peripheral vascular resistance and worsening hypertension prognosis.


Combined topical paromomycin and oral miltefosine treatment of mice experimentally infected with Leishmania (Leishmania) major leads to reduction in both lesion size and systemic parasite burdens.
This study aimed to investigate the activity of the combination of topical paromomycin gel and oral miltefosine for the treatment of experimental cutaneous leishmaniasis caused by Leishmania (Leishmania) major. The efficacy of the combination, evaluated by measuring lesion size and parasite burden in the skin and spleen, was assessed in BALB/c mice infected by L. (L.) major. Miltefosine was administered orally at 25 mg/kg/day for 10 days, while 10% paromomycin gel was applied topically twice a day for 10 days. Treatment of the experimentally infected animals with topical paromomycin + oral miltefosine combination induced a statistically significant reduction in lesion size and parasite burden in the skin, with complete healing of ulcers, as compared with those treated with oral miltefosine or placebo. Furthermore, topical paromomycin + oral miltefosine combination was as effective as topical paromomycin alone to reduce the lesion size and parasite load in lesions. However, the efficacy of the combination was significantly higher than that observed for the other treatments, including topical paromomycin alone, in reducing the parasite burden in spleen. The combination of topical paromomycin gel and oral miltefosine provides an enhanced efficacy in the treatment of L. (L.) major-infected mice, thus presenting a significantly higher activity than that observed for the monotherapeutic regimens.


RNA interference of the P450 CYP6CM1 gene has different efficacy in B and Q biotypes of Bemisia tabaci.
Cytochrome P450 monooxygenases have been proven to be associated with high resistance in Bemisia tabaci B biotype (Middle East-Asia Minor 1 genetic group) and Q biotype (Mediterranean genetic group) to the neonicotinoid class of insecticides. In this study, the RNA interference (RNAi) effects on P450 CYP6CM1 gene expression, mortality and pesticide-detoxifying ability between B. tabaci B and Q biotypes were compared in an attempt to provide a basis for potential RNAi application in management of this pest. Double-stranded RNAs (dsRNAs) of P450 CYP6CM1 genes corresponding to the B and Q biotypes were synthesised using specific primers and introduced into the insect body of B. tabaci adults through membrane feeding. The results showed that dsRNAs significantly silenced the target genes in B. tabaci with dsRNA concentration or treatment time, and silencing was more effective in B biotype than in Q biotype. Feeding dsRNAs led to high mortality in both biotypes, with higher mortality in B biotype (up to 85.88%) than in Q biotype (up to 56.40%). In addition, ability to detoxify imidacloprid and nicotine was inhibited in dsRNA-treated adults of both biotypes, more efficiently in B biotype than in Q biotype. RNA interference of the P450 CYP6CM1 gene reduced gene expression, increased mortality, and inhibited the ability to detoxify a pesticide or a plant secondary metabolite in both biotypes of B. tabaci, with better efficacy in B biotype than in Q biotype.


A Low-G Silicon Inertial Micro-Switch with Enhanced Contact Effect Using Squeeze-Film Damping.
Contact time is one of the most important properties for inertial micro-switches. However, it is usually less than 20 μs for the switch with rigid electrode, which is difficult for the external circuit to recognize. This issue is traditionally addressed by designing the switch with a keep-close function or flexible electrode. However, the switch with keep-close function requires an additional operation to re-open itself, causing inconvenience for some applications wherein repeated monitoring is needed. The switch with a flexible electrode is usually fabricated by electroplating technology, and it is difficult to realize low-g switches (<50 g) due to inherent fabrication errors. This paper reports a contact enhancement using squeeze-film damping effect for low-g switches. A vertically driven switch with large proof mass and flexible springs was designed based on silicon micromachining, in order to achieve a damping ratio of 2 and a threshold value of 10 g. The proposed contact enhancement was investigated by theoretical and experimental studies. The results show that the damping effect can not only prolong the contact time for the dynamic acceleration load, but also reduce the contact bounce for the quasi-static acceleration load. The contact time under dynamic and quasi-static loads was 40 μs and 570 μs, respectively.


Endoscopic management of bile duct stones in patients with surgically altered anatomy.
Bile duct stones in patients with surgically altered anatomy still pose a challenge to endoscopists. For successful endoscopic management of bile duct stones, there are multiple hurdles: Intubation to the afferent limb, biliary cannulation, ampullary intervention and stone extraction. The major advancement in this area is the development of dedicated device-assisted endoscopes for endoscopic retrograde cholangiopancreatography (ERCP). In patients with Billroth II reconstruction, a high technical success rate is reported using a duodenoscope but can be complicated by a potentially high perforation rate. In patients with Roux-en-Y reconstruction, device-assisted ERCP shows high technical success and low adverse event rates. Meanwhile, endoscopic papillary large balloon dilation enables safe and effective stone extraction with less use of endoscopic mechanical lithotripsy in patients with a dilated distal bile duct, but intraductal lithotripsy is sometimes necessary for management of very large bile duct stones. In cases with difficult stones, alternative approaches such as laparoscopy-assisted ERCP and endoscopic ultrasound (EUS)-guided intervention are increasingly reported with preliminary but promising results. However, comparative studies are still lacking in this area and prospective randomized controlled trials are warranted in terms of safety, efficacy and cost-effectiveness.


Steroidogenic factor 1 gene transcription is inhibited by transforming growth factor beta.
The orphan nuclear receptor, steroidogenic factor 1 (SF-1), plays a major role in adrenal and gonadal development, as well as in sexual differentiation. It has been demonstrated that the expression of a number of genes regulated by SF-1 is inhibited by the transforming growth factor, (TGF-beta). To date, however, the influence of TGF-beta on the expression of SF-1 gene has not been reported. A Northern blot analysis with the use of a radiolabeled cDNA probe, and immunodetection with antibodies directed against SF-1, demonstrated that the Sf-1 transcript and the SF-1 protein levels were lowered by TGF-beta in Y-1 adrenocortical cells, both in untreated and adenylyl cyclase activator, forskolin-treated cells. An examination of the Sf-1 transcript stability in the presence of actinomycin D revealed no influence of TGF-beta on the rate of Sf-1 mRNA decay. Inhibition of Sf-1 expression by TGF-beta was abolished by cycloheximide, suggesting that the growth factor inhibitory effect requires ongoing protein synthesis. We conclude that in Y-1 cells TGF-beta inhibits the expression of SF-1 gene at a transcriptional level, and we postulate that the inhibitory effect of TGF-beta on steroid hormone synthesis in the adrenal cortex could be due to an attenuated transcription of Sf-1.


Implications of pregnancy for residents and their training programs.
This study investigated the implications of pregnancy on residents and their training programs and how programs have planned for pregnancy disruptions compared to other employers. We received questionnaires from 236 male and female residents and their families who had experienced at least one pregnancy during their training. Results for female residents were compared with working spouses of male residents. Approximately half of the female residents reported that their programs had formal leave policies compared to 70% of the working spouses. The average amount of leave taken by residents was considerably less than that taken by the spouse group. For both groups, 35% of all pregnancies were unplanned; 19% of these without benefit of birth control. Approximately 30% of both groups said they should have timed their pregnancies differently. Female residents were more likely to perceive their pregnancies as a stressful time. Despite this greater stress, female residents were equally as unlikely as spouses of male residents to miss work for pregnancy-related causes. This study supports the need for better planning for pregnancy during residency training.


Diversity of beta-lactamases produced by ceftazidime-resistant Pseudomonas aeruginosa isolates causing bloodstream infections in Brazil.
A retrospective survey was conducted to characterize beta-lactamases in a collection of 43 ceftazidime-resistant Pseudomonas aeruginosa isolates recovered from patients with bloodstream infections hospitalized at a Brazilian teaching hospital between January and December 2005. Resistance rates for carbapenems, aminoglycosides, and quinolones were over 80%, with only colistin remaining active against all isolates. Pulsed-field gel electrophoresis analysis identified seven different genotypes. AmpC overproduction was found to be the sole beta-lactamase-mediated mechanism responsible for ceftazidime resistance in four isolates (9.3%). Nine isolates (20.9%) produced an extended-spectrum beta-lactamase (ESBL), either GES-1 (n = 7, 16.3%) or CTX-M-2 (n = 2, 4.6%). Carbapenemase activity was detected in 30 (70%) additional isolates. Among those isolates, two isolates (4.6%) produced the ESBL GES-5, possessing the ability to hydrolyze imipenem; a single isolate (2.3%) produced the metallo-beta-lactamase (MBL) IMP-1; and 27 isolates produced the MBL SPM-1 (62.8%). None of the isolates coproduced both ESBL and MBL. Insertion sequence elements ISCR4 and ISCR1 were associated with bla(SPM-1) and bla(CTX-M-2) genes, respectively, whereas the bla(GES-1) and bla(GES-5) genes were part of class 1 integron structures. This study underlines the spread of MBL- and ESBL-producing P. aeruginosa isolates as an important source of ceftazidime resistance in Brazil.


Quantitative considerations for suspension array assays.
A novel format of a multiplex microbead assay that is capable of accurately and reproducibly measuring small changes in 10(8) copies of a nucleic acid is reported herein. The dynamic range of the assay was 32-fold greater than conventional multiplex microbead assays. The assay was modeled mathematically which enabled the accuracy of DNA quantification to be formally analysed using a logical theoretical framework. The assay was also evaluated on RNA extracts taken from stimulated macrophages, to demonstrate that changes in gene expression can be accurately monitored in a biological system. We believe the reproducibility and accuracy of the assay presented herein will be useful for high-throughput, multiplex sensitive detection of nucleic acids over a large dynamic range in a research or diagnostic setting.


Computational modelling of multiscale morphologies in polymer-liquid crystal blends.
Simulations of material architectures in polymer-liquid crystal blends driven by phase separation-phase ordering-texturing processes are presented. The study shows that mixtures of polymers and liquid crystals result in blend morphologies that organize at several scales. For thermally driven instabilities, morphologies of polymer droplets embedded in a liquid crystal matrix show colloidal crystallinity. Large polymer drops strongly affect the orientation of the matrix, producing textures consisting of defect lattices. This work shows that thermally driven phase separation-phase ordering-texturing processes can result in multiscale materials, with length scales cascading down from droplets to interfaces, and finally to nanoscale defects.


Chlorine dioxide remediation of a virus-contaminated manufacturing facility.
CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) Chlorine dioxide fumigation was successfully used to decontaminate a virally contaminated biotech manufacturing facility. Addressing safety, product quality, and corrosion risks were important factors in planning the building fumigation. Studies were performed to define the conditions in which minute mouse virus (MMV) is inactivated by chlorine dioxide and to understand equipment and facility risks. Written plans and procedures documented activities necessary to safely fumigate the building and requalify it to manufacture commercial product.


Biological artificial vessel graft in distal arterial bypass for treating diabetic lower limb ischemia: a case report.
A 68-year-old female patient was treated for unhealed ulcer in the fourth toe of the left foot. Clinical examinations identified severe stenosis of the proximal segment and occlusion of the distal segment of the left anterior tibial artery, and occlusion of the left posterior tibial artery and the peroneal artery. The proximal stenotic segment of the left anterior tibial artery was dilated, but the distal occlusive part failed to be re-canalized. Left anterior tibial artery to dorsal pedal artery bypass was performed on the patient with an epoxide-crosslinked, special radicals antigen-sealed, porcine-derived biological graft; debridement of the left 4th digiti pedis was also performed. Postoperation course was uneventful. The pulse of the left dorsal pedal artery was strong. The ankle brachial index (ABI) increased from 0.60 to 1.09. Warfarin and two antiplatelet drugs were given after the operation. Six months after operation, computed tomographic angiogram (CTA) identified the patent graft.


Porcine Organotypic Epicardial Slice Protocol: A Tool for the Study of Epicardium in Cardiovascular Research.
The epicardium has recently gained interest in the cardiovascular field due to its capacity to support heart regeneration after ischemic injury. Models to study the epicardium of large animals in vitro are limited and mainly based on epicardial cell isolation/differentiation from stem cells, followed by 2D cells culture. In this method paper, we describe the procedure to obtain and culture 3D organotypic heart slices presenting an intact epicardium, as a novel model to study the epicardial physiology and activation. Epicardial slices are obtained from porcine hearts using a high-precision vibratome and retain a healthy epicardial layer embedded in its native extracellular environment and connected with other cardiac cells (cardiomyocytes, fibroblasts, vascular cells etc.). Epicardial slices can be cultured for 72 h, providing an ideal model for studying the epicardium physiology or perform pharmacological interventions/gene therapy approaches. We also report on methods to assesses the viability and composition of the epicardial slices, and evaluate their architecture in 3D through tissue decoloration. Finally, we present a potential application for a nanomaterial-based gene transfer method for tracking of epicardial cells within the slice. Crucially, given the similarity in morphology and physiology of porcine heart with its human counterpart, our system provides a platform for translational research while providing a clinically relevant and ethical alternative to the use of small animals in this type of research.


Single-site multiport vs. conventional multiport robot-assisted radical prostatectomy: A propensity score matching comparative study.
Robot-assisted radical prostatectomy (RARP) is a dynamically evolving technique with its new evolution of single-site RARP. Here we sought to describe our extraperitoneal technique, named the single-site multiport RARP (ssmpRARP) using the da Vinci Si® platform and compare it with the transperitoneal conventional multiport RARP (cmpRARP). Data were retrospectively collected for patients who underwent RARP for localized prostate cancer from June 2020 to January 2022 in a single center. Propensity score matching was performed based on age, prostate size, body mass index, neoadjuvant hormonal therapy usage, prostate-specific antigen levels, and clinical T stage. The differences between the matched two groups were investigated. Of the patients, 20 underwent ssmpRARP and 42 underwent cmpRARP during the period. After matching, 18 patients from each group were selected. Median follow-up was 7.8 months (2-12 months) for the ssmpRARP group, and 15.0 months (3-26 months) for cmpRARP. The demographic features between the two groups were comparable. The median total operative time, estimated blood loss, pathologic data, early follow-up outcomes, and hospitalization stays and costs were similar between the two groups. The ssmpRARP group tended to return to their bowel activities earlier (44.78 ± 10.83 h vs. 54.89 ± 12.97 h, p = 0.016). There were no significant differences in complication rates. We demonstrated the feasibility and safety of performing extraperitoneal ssmpRARP using the da Vinci Si® robotic platform. Our technique showed comparable short-term outcomes with the transperitoneal cmpRARP. Prospective trials and long-term follow-up are necessary to confirm these results.


[Integrin Beta 3 PlA1/PlA2 polimorphism does not contribute to complications in both type 1 and type 2 diabetes].
The glycoprotein IIIa (beta3 integrin) is an integral part of two glicoprotein receptors of platelets and, respectively, endothelium and vascular smooth muscle cells. The gene encoding the GPIIIa, a receptor for fibrinogen, vWF and fibronectin, shows polymorphism (PlA1/PlA2); the PlA2 allele has been associated with myocardial infarction, stroke and cardiovascular disease. Seven hundred and thirty-two subjects with type 1 diabetes and 605 subjects with type 2 were recruited. The prevalence of complications in type 1 diabetes was: microalbuminuria (uA) 17%, overt nephropathy (MA) 10%; background retinopathy (bR) 27%, proliferative retinopathy (pR) 22%; hypertension (HYP) 13%; coronary heart disease (CHD) 9%. The respective figures for type 2 diabetes were: uA 34%, MA 21%; bR 38%, pR 18%; HYP 80%; CHD 26%. A 247 bp fragment (exon 2) was amplified by PCR. For the detection of the point mutation CDGE (Constant Denaturing Gel Electrophoresis) after optimum denaturing conditions setting by DGGE (Denaturing Gradient GE) and/or RFLP by NciI digestion were employed. In type 1 diabetes, PlA1PlA1/PlA1PlA2 distribution was 77/23%. No differences were found among normoalbuminuric (nA: 76/24%), microalbuminuric (uA: 79/21%) and macroalbuminuric subjects (MA: 75/25%, p=0.79) as well as among subjects with no retinopathy (Ret-) (74/26%), bR (76/24%) and pR (78/22%, p=0.81), and between HYP- (78/22%) and HYP+ (72/28%, p=0.27) as well as CHD- (76/24%) and CHD+ (75/25%, p=0.72). Systolic blood pressure, HbA1c and retinopathy were independent predictors of nephropathy. No contribution of diastolic BP, sex, BMI, duration of diabetes and PlA2 allele was found for the risk of nephropathy. In type 2 diabetes, PlA1PlA1/PlA1PlA2/PlA2PlA2 distribution was 74.4/23.3/2.3%, with no differences foud among nA (73/25/2%), uA (75/23/2%) and MA (81/17/2%, p=0.66). No significant difference was detected among subjects with Ret- (74/22/4%), bR (77/22/1%) and pR (77/22/1%, p=0.62). Also, no differences were found between HYP- (81/17/2%) and HYP+ (74/24/2%, p=0.28) as well CHD- (76/22/2%) and CHD+ (74/24/2%, p=0.93). Systolic BP, HbA1c, presence of retinopathy, gender and BMI were independent predictors of nephropathy. Diastolic BP, duration of diabetes and PlA2 allele did not contribute to the risk of nephropathy. The PlA1/PlA2 polymorphism of the GPIIIa gene does not contribute to the development of nephropathy or retinopathy in type 1 and type 2 diabetes. Furthermore, no association was found between the PlA1/PlA2 polymorphism, hypertension, and coronary heart disease.


An experimental analysis of milieu language intervention: teaching the action-object form.
The syntactic and pragmatic effects of a milieu language teaching intervention implemented to teach the action-object form were investigated. Subjects were 3 young children with borderline to moderate levels of mental retardation, all in the early stages of productive language development. After a prolonged baseline period, each subject received three to four training sessions per week in a small group interactive play situation. Experimental control was demonstrated by a multiple baseline design across subjects. Generalization was measured along a variety of dimensions. Results indicated that subjects learned to generatively produce action-object combinations. These combinations were used in nonobligatory conversational situations as requests for objects/actions and as declaratives. Subjects also began to respond correctly to probe questions. The results support the conclusion that milieu training procedures can be used to enhance the acquisition and generative use of basic syntactic-semantic forms. The results also suggest that systemic adult commenting, child conversational "scaffolding," and spontaneous imitation may play significant roles for some children in the acquisition and generalization of language taught via a milieu approach.


GFAP immunoreactivity within the rat nucleus ambiguus after laryngeal nerve injury.
Changes that occur in astroglial populations of the nucleus ambiguus after recurrent (RLN) or superior (SLN) laryngeal nerve injury have hitherto not been fully characterised. In the present study, rat RLN and SLN were lesioned. After 3, 7, 14, 28 or 56 days of survival, the nucleus ambiguus was investigated by means of glial fibrillary acidic protein (GFAP) immunofluorescence or a combination of GFAP immunofluorescence and the application of retrograde tracers. GFAP immunoreactivity was significantly increased 3 days after RLN resection and it remained significantly elevated until after 28 days post injury (dpi). By 56 dpi it had returned to basal levels. In contrast, following RLN transection with repair, GFAP immunoreactivity was significantly elevated at 7 dpi and remained significantly elevated until 14 dpi. It had returned to basal levels by 28 dpi. Topographical analysis of the distribution of GFAP immunoreactivity revealed that after RLN injury, GFAP immunoreactivity was increased beyond the area of the nucleus ambiguus within which RLN motor neuron somata were located. GFAP immunoreactivity was also observed in the vicinity of neuronal somata that project into the uninjured SLN. Similarly, lesion of the SLN resulted in increased GFAP immunoreactivity around the neuronal somata projecting into it and also in the vicinity of the motor neuron somata projecting into the RLN. The increase in GFAP immunoreactivity outside of the region containing the motor neurons projecting into the injured nerve, may reflect the onset of a regenerative process attempting to compensate for impairment of one of the laryngeal nerves and may occur because of the dual innervation of the posterior cricoarytenoid muscle. This dual innervation of a very specialised muscle could provide a useful model system for studying the molecular mechanisms underlying axonal regeneration process and the results of the current study could provide the basis for studies into functional regeneration following laryngeal nerve injury, with subsequent application to humans.


Use of physical performance tests in a group of Brazilian Portuguese-speaking individuals with low back pain.
Low back pain (LBP) is a prevalent condition across cultures, and the tools used for assessment of distinct groups need to be evaluated. Our goal was to investigate the psychometric properties of physical performance tests (PPTs) in a group of Brazilian Portuguese-speaking (BPS) individuals with LBP in a nonexperimental, descriptive study. BPS individuals with and without LBP were studied, and PPTs, self-report questionnaires, and VAS pain score were evaluated. Thirty individuals with LBP (Patient Group (PG)) and 30 healthy subjects (Control Group (CG)) were assessed by 7 PPTs: timed up and go (TUG), loaded forward reach (LFR), 50-foot walk (50 FW), 5-minute walking (5 MW), sit-stand (SS), repeated trunk flexion (RTF), and lumbar flexion (LF). The PG completed the Roland Morris Disability Questionnaire (RMDQ) and the Self-efficacy Scale (SES) and rated their current level of pain by a Visual Analog Scale (VAS). PPTs were highly reliable in the PG with ICC scores ranging from 0.92 to 0.99 (p < 0.0001). The CG performed better in all PPTs but the LFR. In the PG the correlations among the PPT varied from 0.38 to 0.78 (p < 0.05). RMDQ correlated significantly with RTF, SS, 5 MW (0.38 to 0.47, p < 0.05). PPTs were reliable with the BPS patients and able to differentiate groups. RMDQ complements the assessment of these patients.


Association Rule Analysis for Validating Interrelationships of Combined Medication of Compound Kushen Injection in Treating Colon Carcinoma: A Hospital Information System-Based Real-World Study.
Real world evidence is important for informing healthcare practice and developing medical products and has gained broad interest in healthcare. Compound Kushen Injection (CKI) has been widely applied into treatment of colon carcinoma (CC) in China. Postapproval drug assessment related retrospective studies using electrical medical record (EMR) collected from hospital information system (HIS) is one of the most important categories of real-world study (RWS). Based on HIS EMR, interrelationships of combined medication of CKI in treating CC can be validated in real world settings. This study was conducted based on a large-scale integrated database of EMR derived from HIS. EMR of 3328 patients initially diagnosed with CC among 49,597 patients treated with CKI were included in the study. Descriptive statistical analyses and apriori algorithm based association rule analyses were performed, respectively, to validate frequency distribution and interrelationships of combined medication of CKI in treating CC. The pharmacological mechanisms of TCMs that have been commonly used in conjunction with CKI include heat-clearing and detoxifying, qi-reinforcing, blood circulation-promoting and stasis-removing, blood-stanching, and qi-regulating. For modern medicines, antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5-HT receptor antagonist drugs, and corticosteroids are most often combined with CKI. The association rules of medication combinations of CKI in treating CC in real world manifest certain laws for both TCMs and modern medicines. They are generally in line with CC treatment guidelines. It is a common practice for CKI to be integrated with both modern medicines and TCMs when treating CC in China. The associations of medication combinations of CKI in treating CC manifest certain laws for both TCMs and modern medicines. The RWS for validating interrelationships of combined medication may provide evidence for rational use of CKI. Further explorations are needed to verify and expand the conclusions.


Merkel cell carcinoma in the community setting: a case report.
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin initially believed to arise from the Merkel cells. In the community setting a general radiation oncologist may only encounter this pathology in a handful of cases over the course of their career. Due to the low incidence of this malignancy, few prospective randomized controlled trials have ever been conducted and therefore guidelines are based on relatively lower levels of evidence upon which the clinical recommendations are made. We discuss the case of a female in her 90s presenting with a classic MCC primary lesion, as well as satellite lesions proximal to both the primary and the draining regional lymph nodes with no evidence of nodal involvement. Here we discuss the presentation, management, treatment planning, underlying pathology, results and sequelae of treatment. We also review new treatment modalities, and the most current staging systems and guidelines.


What Factors Are Associated With Delayed Wound Closure in Open Reduction and Internal Fixation of Adult Both-bone Forearm Fractures?
Delayed wound closure is often used after open reduction and internal fixation (ORIF) of both-bone forearm fractures to reduce the risk of skin necrosis and subsequent infection caused by excessive swelling. However, no studies we are aware of have evaluated factors associated with the use of delayed wound closure after ORIF. (1) What proportion of patients undergo delayed wound closure after ORIF of adult both-bone forearm fractures? (2) What factors are associated with delayed wound closure? The medical records of all patients who underwent ORIF with plate fixation for both-bone fractures by the adult orthopaedic trauma service at our institution were considered potentially eligible for analysis. Between January 2010 and April 2022, we treated 74 patients with ORIF for both-bone forearm fractures. Patients were excluded if they had fractures that were fixed more than 2 weeks from injury (six patients), if their fracture was treated with an intramedullary nail (one patient), or if the patient experienced compartment syndrome preoperatively (one patient). No patients with Gustilo-Anderson Type IIIB and C open fractures were included. Based on these criteria, 89% (66 of 74) of the patients were eligible. No further patients were excluded for loss of follow-up because the primary endpoint was the use of delayed wound closure, which was performed at the time of ORIF. However, one further patient was excluded for having bilateral forearm fractures to ensure that each patient had a single fracture for statistical analysis. Thus, 88% (65 of 74) of patients were included in the analysis. These patients were captured by an electronic medical record search of CPT code 25575. The mean ± SD age was 34 ± 15 years and mean BMI was 28 ± 7 kg/m 2 . The mean follow-up duration was 4 ± 5 months. The primary endpoint was the use of delayed wound closure, which was determined at the time of definitive fixation if tension-free closure could not be achieved. All surgeons used a volar Henry or modified Henry approach and a dorsal subcutaneous approach to the ulna for ORIF. Univariate logistic regression was used to identify which factors might be associated with delayed wound closure. A multivariable logistic regression analysis was then performed for male gender, open fractures, age, and BMI. Twenty percent (13 of 65) of patients underwent delayed wound closure, 18% (12 of 65) of which occurred in patients who had high-energy injuries and 14% (nine of 65) in patients who had open fractures. Being a man (adjusted odds ratio 9.9 [95% confidence interval 1 to 87]; p = 0.04) was independently associated with delayed wound closure, after adjusting for open fractures, age, and BMI. One of five patients had delayed wound closure after ORIF of both-bone forearm fractures. Being a man was independently associated with greater odds of delayed wound closure. Surgeons should counsel all patients with these fractures about the possibility of delayed wound closure, with particular attention to men with high-energy and open fractures. Future larger-scale studies are necessary to confirm which factors are associated with the use of delayed wound closure in ORIF of both-bone fractures and its effects on fracture healing. Level III, therapeutic study.


Quenching of Protein Fluorescence by Fullerenol C60(OH)36 Nanoparticles.
The effect of the interaction between fullerenol C60(OH)36 (FUL) and alcohol dehydrogenase (ADH) from Saccharomyces cerevisiae and human serum albumin (HSA) was studied by absorption spectroscopy, fluorescence spectroscopy, and time-resolved fluorescence spectroscopy. As shown in the study, the fluorescence intensities of ADH and HSA at excitation wavelengths λex = 280 nm (Trp, Tyr) and λex = 295 nm (Trp) are decreased with the increase in the FUL concentration. The results of time-resolved measurements indicate that both quenching mechanisms, dynamic and static, are present. The binding constant Kb and the number of binding sites were obtained for HSA and ADH. Thus, the results indicated the formation of FUL complexes and proteins. However, the binding of FUL to HSA is much stronger than that of ADH. The transfer of energy from the protein to FUL was also proved.


The Quorum Sensing Auto-Inducer 2 (AI-2) Stimulates Nitrogen Fixation and Favors Ethanol Production over Biomass Accumulation in Zymomonas mobilis.
Autoinducer 2 (or AI-2) is one of the molecules used by bacteria to trigger the Quorum Sensing (QS) response, which activates expression of genes involved in a series of alternative mechanisms, when cells reach high population densities (including bioluminescence, motility, biofilm formation, stress resistance, and production of public goods, or pathogenicity factors, among others). Contrary to most autoinducers, AI-2 can induce QS responses in both Gram-negative and Gram-positive bacteria, and has been suggested to constitute a trans-specific system of bacterial communication, capable of affecting even bacteria that cannot produce this autoinducer. In this work, we demonstrate that the ethanologenic Gram-negative bacterium Zymomonas mobilis (a non-AI-2 producer) responds to exogenous AI-2 by modulating expression of genes involved in mechanisms typically associated with QS in other bacteria, such as motility, DNA repair, and nitrogen fixation. Interestingly, the metabolism of AI-2-induced Z. mobilis cells seems to favor ethanol production over biomass accumulation, probably as an adaptation to the high-energy demand of N2 fixation. This opens the possibility of employing AI-2 during the industrial production of second-generation ethanol, as a way to boost N2 fixation by these bacteria, which could reduce costs associated with the use of nitrogen-based fertilizers, without compromising ethanol production in industrial plants.


SNPs3D: candidate gene and SNP selection for association studies.
The relationship between disease susceptibility and genetic variation is complex, and many different types of data are relevant. We describe a web resource and database that provides and integrates as much information as possible on disease/gene relationships at the molecular level. The resource http://www.SNPs3D.org has three primary modules. One module identifies which genes are candidates for involvement in a specified disease. A second module provides information about the relationships between sets of candidate genes. The third module analyzes the likely impact of non-synonymous SNPs on protein function. Disease/candidate gene relationships and gene-gene relationships are derived from the literature using simple but effective text profiling. SNP/protein function relationships are derived by two methods, one using principles of protein structure and stability, the other based on sequence conservation. Entries for each gene include a number of links to other data, such as expression profiles, pathway context, mouse knockout information and papers. Gene-gene interactions are presented in an interactive graphical interface, providing rapid access to the underlying information, as well as convenient navigation through the network. Use of the resource is illustrated with aspects of the inflammatory response and hypertension. The combination of SNP impact analysis, a knowledge based network of gene relationships and candidate genes, and access to a wide range of data and literature allow a user to quickly assimilate available information, and so develop models of gene-pathway-disease interaction.


Enantioselective organocatalytic fluorination using organofluoro nucleophiles.
Synthetic fluorinated compounds are enormously useful in areas such as materials, agrochemicals, pharmaceuticals and fine chemicals. While methods of electrophilic fluorination have been extensively developed to stereoselectively install fluorine atoms onto molecules, nucleophilic fluorination is a much less explored approach. Recently, several organofluoro reagents have been designed and used as nucleophiles in the asymmetric synthesis of fluorinated compounds, significantly expanding the scope of enantio-enriched fluorine-containing compounds that can be synthesised. Such organofluoro nucleophiles are particularly useful in organocatalytic transformations. In this review, recent advances in the application of organofluoro nucleophiles in organocatalysis are summarised.