Psychometric and structural properties of the Karolinska Exhaustion Disorder Scale: a 1,072-patient study.
Exhaustion disorder is a stress-related diagnosis that was introduced in 2005 to the Swedish version of the International Statistical Classification of Diseases and Related Health Problems, 10th edition (ICD-10). The Karolinska Exhaustion Disorder Scale (KEDS) was developed to assess exhaustion disorder symptomatology. While the KEDS is intended to reflect a single construct and be used based on its total score, the instrument's characteristics have received limited attention. This study investigated the KEDS's psychometric and structural properties in a large clinical sample. The study relied on data from 1,072 patients diagnosed with exhaustion disorder that were included in two clinical trials in Sweden. We investigated the dimensionality, homogeneity, and reliability of the KEDS using advanced statistical techniques, including exploratory structural equation modeling (ESEM) bifactor analysis. A one-factor confirmatory analytic model exhibited a poor fit, suggesting at least a degree of multidimensionality. The ESEM bifactor analysis found the general factor to explain about 72% of the common variance extracted, with an omega hierarchical coefficient of 0.680. Thus, the ESEM bifactor analysis did not clearly support the scale's essential unidimensionality. A homogeneity analysis revealed a scale-level H of only 0.296, suggesting that KEDS's total scores do not accurately rank individuals on the latent continuum assumed to underlie the measure. The KEDS's reliability was modest, signaling considerable measurement error. Findings reveal important limitations to the KEDS with possible implications for the status of exhaustion disorder as a nosological category. This study was pre-registered on Open Science Framework (osf.io) on April 24, 2022 ( https://osf.io/p34sq/ ).


Imprint cytology of clear cell sarcoma-like tumor of the gastrointestinal tract in the small intestine: A case report.
Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is an extremely rare malignant neoplasm in the digestive tract. Its cytomorphologic features have never previously been reported. Here, we describe a case of CCSLGT, including its cytologic examination findings. A 47-year-old woman presented with a mass in the small intestine, which was resected and sent for imprint cytology. Imprint smears revealed tumor cells with light eosinophilic or clear cytoplasm in a necrotic background. Many of the tumor cells were arranged in a perivascular growth with a pseudopapillary formation, and there were some non-neoplastic osteoclast-like giant cells. Histological examination revealed solid nests and a pseudopapillary pattern of the tumor cells with clear or pale eosinophilic cytoplasm and large nuclei with small nucleoli. Immunohistochemistry showed positive for vimentin, S-100, and SOX-10, and negative for SMA, c-KIT, cytokeratin, HMB-45, and MelanA. The EWSR1 gene split signal was detected by reverse transcriptase fluorescence in situ hybridization, and EWSR1-CREB1 gene fusion was indicated by reverse transcriptase polymerase chain reaction analysis. From these findings, we diagnosed the tumor as CCSLGT. To best of our knowledge, this is the first description of the imprint cytology features of CCSLGT.


Nutrition of Malaysians: where are we heading ?
Rapid and marked socioeconomic advancements in Malaysia for the past two decades have brought about significant changes in the lifestyles of communities. These include significant changes in the dietary patterns of Malaysians, eg the increase in consumption of fats and oils and refined carbohydrates and a decreased intake of complex carbohydrates. This resulted in a decline in the proportion of energy from carbohydrates, while an increase in the percentage contribution of fat has been observed. Changes in meal patterns are also evident: more families eat out, busy executives skip meals, the younger generation miss breakfasts and rely too much on fast foods. Many Malaysians have the mistaken belief that the taking of vitamin and mineral supplements can make up for the lack of these nutrients in their daily diets. In addition, communities have become generally more sedentary. All these changes have brought about undesirable effects with significant proportions of the affluent segments of the population being afflicted with various non-communicable diseases associated with overnutrition, namely obesity, hypertension, coronary heart disease and cancers. Nutrition activities and programmes are now being directed to tackle this increasing trend, whilst still attempting to eliminate the undernutrition problems. The ultimate strategy towards achieving a healthy nation is the promotion of a healthy lifestyle, including inculcating a culture of healthy eating. Comprehensive long term programmes, including a series of Healthy Lifestyle (HLS) Programmes have been carried out by the government. Launched in 1991 for six consecutive years, the first phase of the Programme comprised one thematic campaign each year, commencing with coronary heart disease and ending with diabetes mellitus. To further strengthen this long-term strategy, another series of activities to be carried out under the second phase of the HLS programme from 1997 to 2002 was launched within the framework of the National Plan of Action on Nutrition (NPAN) for Malaysia. The implementation of these programmes is, however, a challenge to health and nutrition workers. There is a need to examine the strategies for nutrition education to ensure more effective dissemination of information. The challenge is to determine how best to promote healthy eating within the present scenerio of rapid urbanisation, "western" dietary pattern influence, a whole barrage of convenience and "health" foods and nutrition misinformation. Malaysia continues to march ahead with its development plans to elevate the nation and its people to an even higher level of socio-economic status. The crucial question is: are we able to arrest the increase in these diet-related chronic diseases ? Or are we heading towards further deterioration in dietary pattern and increase in these diseases ? It will be a difficult and challenging journey ahead, requiring the concerted effort of all in the country. It is hoped that through this conference of sharing experiences with other Asian countries, a better understanding and improved strategies could be arrived at.


Repair of an Extensive External Cervical Resorption Lesion Using Intentional Replantation with Crown Rotation.
Treatment of large external cervical resorption (ECR) lesions may be compromised, rendering the tooth unrestorable. Intentional replantation is a potential treatment option depending on the site and extent of ECR. We present a case of a large ECR successfully managed with intentional replantation with rotation of the tooth. The female patient consulted the hospital clinic, with an extensive palatal ECR on the maxillary lateral incisor. Routine planar radiographs and cone-beam computed tomography demonstrated a larger palatal than the ECR lesion (Heithersay Class III and Patel's Class 2Bp) not amenable to nonsurgical treatment. Intentional replantation after short-term extrusion was planned. The defect was restored, then a palatal ferrule was achieved by rotating the tooth by 180°. At the 18-month follow-up, the periradicular and periodontal tissues remained healthy, and no other symptoms were reported. In conclusion, this successful video-illustrated clinical case highlights the benefits of intentional replantation in saving teeth with advanced ECR.


Severity of depressive symptoms moderates the sympathoinhibitory effect of local skin warming following exposure to a social stressor.
Depression is the leading cause of disease burden globally. Existing antidepressant treatments that target the central nervous system have limited efficacy and come at the cost of significant side effects. Thus, there is growing interest in novel therapeutic interventions for the prevention and treatment of depression, including interventions that target interoceptive signaling. The thermosensory system may hold particular promise, given evidence that depression is associated with impairments in thermosensory functioning, and that whole-body hyperthermia produces an antidepressant effect in patients with major depressive disorder. In this study, we investigated whether the severity of depressive symptoms in a non-clinical population moderated the effect of local skin warming on subjective and physiological stress responses following exposure to an acute social stressor. Following exposure to the stressor, participants (N = 90) rested their arm on a heat blanket that was either turned on (local skin warming condition) or left off (control condition). We demonstrate that local skin warming increased fingertip temperature, a marker of reduced sympathetic nervous system activity, but only for participants with high levels of depressive symptoms. While local skin warming also inhibited salivary alpha amylase, severity of depressive symptoms did not moderate this effect, and no effect was found for electrodermal activity. These data highlight the importance of incorporating peripheral physiology in our conceptualization of the pathophysiology of depression and show that changes in sympathetic nervous system activity may underpin the antidepressant effect of warm stimuli.


Comparative evaluation of leachate pollution index of MSW landfill site of Kolkata with other metropolitan cities of India.
The uncontrolled tipping of mixed urban solid waste in landfill site causes serious negative impacts on the environment. The major issue in this context is the generation of leachate which possesses potential of polluting freshwater ecosystem including groundwater besides associated health hazards and depletion of soil fertility. In this context, a pseudo computation quantitative tool, known as leachate pollution index (LPI), has been developed by some researchers for scaling pollution potential of landfill site owing to emergence of leachate. This paper. deals with the assessment of leachate quality of existing landfill site of Kolkata situated at Dhapa waste dumping ground through evaluation of the LPI from experimental analysis of leachate. The leachate was collected from this site in different seasons. 18 parameters were tested with real leachate samples in the Environmental Engineering Laboratory of Civil Engineering Department of Jadavpur University Kolkata. The results exhibited a very high value of organic pollutants in the leachate with COD as 21,129 mg/L and also values of TDS, Fe2+, Cr, Zn, chloride and ammonical nitrogen. The LPI value of Kolkata landfill site at Dhapa was estimated and also compared with leachate quality data of other metropolitan cities viz. Mumbai, Delhi, Chennai as available in literatures. It is found that LPI of the Kolkata landfill site is highest compared to all other landfill sites of other metropolitan cities in India.


RNA-dependent chromatin association of transcription elongation factors and Pol II CTD kinases.
For transcription through chromatin, RNA polymerase (Pol) II associates with elongation factors (EFs). Here we show that many EFs crosslink to RNA emerging from transcribing Pol II in the yeast Saccharomyces cerevisiae. Most EFs crosslink preferentially to mRNAs, rather than unstable non-coding RNAs. RNA contributes to chromatin association of many EFs, including the Pol II serine 2 kinases Ctk1 and Bur1 and the histone H3 methyltransferases Set1 and Set2. The Ctk1 kinase complex binds RNA in vitro, consistent with direct EF-RNA interaction. Set1 recruitment to genes in vivo depends on its RNA recognition motifs (RRMs). These results strongly suggest that nascent RNA contributes to EF recruitment to transcribing Pol II. We propose that EF-RNA interactions facilitate assembly of the elongation complex on transcribed genes when RNA emerges from Pol II, and that loss of EF-RNA interactions upon RNA cleavage at the polyadenylation site triggers disassembly of the elongation complex.


Surface composition, chemistry, and structure of polystyrene modified by electron-beam-generated plasma.
Polystyrene (PS) surfaces were treated by electron-beam-generated plasmas in argon/oxygen, argon/nitrogen, and argon/sulfur hexafluoride environments. The resulting modifications of the polymer surface energy, morphology, and chemical composition were analyzed by a suite of complementary analytical techniques: contact angle goniometry, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and reflection electron energy loss spectroscopy (REELS). The plasma treatments produced only minimal increases in the surface roughness while introducing the expected chemical modifications: oxygen-based after Ar/O(2) plasma, oxygen- and nitrogen-based after Ar/N(2) plasma, and fluorine-based after Ar/SF(6) plasma. Fluorinated PS surfaces became hydrophobic and did not significantly change their properties over time. In contrast, polymer treated in Ar/O(2) and Ar/N(2) plasmas initially became hydrophilic but underwent hydrophobic recovery after 28 days of aging. The aromatic carbon chemistry in the top 1 nm of these aged surfaces clearly indicated that the hydrophobic recovery was produced by reorientation/diffusion of undamaged aromatic polymer fragments from the bulk rather than by contamination. Nondestructive depth profiles of aged plasma-treated PS films were reconstructed from parallel angle-resolved XPS (ARXPS) measurements using a maximum-entropy algorithm. The salient features of reconstructed profiles were confirmed by sputter profiles obtained with 200 eV Ar ions. Both types of depth profiles showed that the electron-beam-generated plasma modifications are confined to the topmost 3-4 nm of the polymer surface, while valence band measurements and unsaturated carbon signatures in ARXPS and REELS data indicated that much of the PS structure was preserved below 9 nm.


Natural, proteolytic release of a soluble form of human IL-15 receptor alpha-chain that behaves as a specific, high affinity IL-15 antagonist.
IL-15 and IL-2 are two structurally and functionally related cytokines whose high affinity receptors share the IL-2R beta-chain and gamma-chain in association with IL-15R alpha-chain (IL-15R alpha) or IL-2R alpha-chain, respectively. Whereas IL-2 action seems restricted to the adaptative T cells, IL-15 appears to be crucial for the function of the innate immune responses, and the pleiotropic expression of IL-15 and IL-15R alpha hints at a much broader role for the IL-15 system in multiple cell types and tissues. In this report, using a highly sensitive radioimmunoassay, we show the existence of a soluble form of human IL-15R alpha (sIL-15R alpha) that arises from proteolytic shedding of the membrane-anchored receptor. This soluble receptor is spontaneously released from IL-15R alpha-expressing human cell lines as well as from IL-15R alpha transfected COS-7 cells. This release is strongly induced by PMA and ionomycin, and to a lesser extent by IL-1 beta and TNF-alpha. The size of sIL-15R alpha (42 kDa), together with the analysis of deletion mutants in the ectodomain of IL-15R alpha, indicates the existence of cleavage sites that are proximal to the plasma membrane. Whereas shedding induced by PMA was abrogated by the synthetic matrix metalloproteinases inhibitor GM6001, the spontaneous shedding was not, indicating the occurrence of at least two distinct proteolytic mechanisms. The sIL-15R alpha displayed high affinity for IL-15 and behaved as a potent and specific inhibitor of IL-15 binding to the membrane receptor, and of IL-15-induced cell proliferation (IC(50) in the range from 3 to 20 pM). These results suggest that IL-15R alpha shedding may play important immunoregulatory functions.


Pregnancy planning and the impact on work climate, psychological well-being, and work effort in the military.
This study examined the joint effects of demographics and pregnancy planning and timing on work climate, psychological well-being, and work effort among 345 pregnant U.S. military women from the Army, Navy, Air Force, and Marines. Rank predicted both pregnancy planning and career timing. Pregnancy planning was positively associated with support from coworkers and supervisors and with enhanced work effort and psychological well-being. Pregnancy timing was positively associated with support from supervisors, reduced harassment, and increased psychological well-being. Rank interacted with the planning and timing measures. Junior officers and enlisted participants reported reduced command and pregnancy support and increased harassment in conjunction with poorly timed pregnancies.


Comparative chemical analyses of the alloantigenic fragments of HL-A antigens.
Papain-solubilized HL-A antigens have been shown to contain two polypeptide fragments: beta2-micro-globulin with a molecular weight of approximately 12,000 and a larger fragment with a molecular weight of about 34,000. The large fragments isolated from two HL-A preparations carrying different specificities appeared homogeneous both by immunoelectrophoresis and sodium dodecyl sulfate-acrylamide electrophoresis. Both HL-A antigen preparations contained the same NH2-terminal (glycine) and the same COOH-terminal residue (serine). The carbohydrate content of the large fragment was 12.9%, making the carbohydrate-free molecular weight approximately 30,000. Small but significant differences have been found in the amino acid compositions and tryptic peptide maps of the two large fragments containing different specificities.


Retrievable Gunther Tulip inferior vena cava filter: experience in 317 patients.
The aim of our study was to assess our experience with the retrievable Gunther Tulip (GT) inferior vena cava (IVC) filter, with regard to its insertion, efficacy, ease of placement and retrieval, and associated complications. Between November 2001 and October 2005, 322 GT filters were placed in 317 patients. Insertion indications included the following: pulmonary embolus (PE) prophylaxis in trauma patients (n = 232), PE prophylaxis in perioperative patients (n = 27), PE prophylaxis in moribund intensive care unit patients (n = 22), recent PE (n = 48), extensive deep venous thrombosis (n = 66), contraindication to anticoagulation (n = 63), anticoagulation complication (n = 8) and deep venous thrombosis with failed anticoagulation (n = 8). Some patients had more than one indication for caval filter placement. Two hundred and five attempted retrievals have been carried out, with 15 failures. Our successful retrieval rate is 92%. Nineteen filters were originally inserted permanently. There have been three minor complications associated with insertion and five with retrieval. The mean time from filter insertion to attempted retrieval was 76.95 days. The ideal filter implantation time gives the patient the benefit of PE protection, while avoiding the long-term risks associated with caval filters. Although GT retrieval times have lengthened considerably, our data suggest that this is at the expense of successful retrieval rates.


Combination tibial plateau leveling osteotomy and cranial closing wedge osteotomy of the tibia for the treatment of cranial cruciate ligament-deficient stifles with excessive tibial plateau angle.
To describe a surgical technique, and outcome, for treatment of cranial cruciate ligament (CrCL) deficient stifle joints with excessive tibial plateau angle (TPA) by combined tibial plateau leveling osteotomy and cranial closing wedge osteotomy (TPLO/CCWO). Retrospective clinical study. Fifteen client-owned dogs (18 stifle joints). Medical records of dogs that had TPLO/CCWO were reviewed. Pre- and postoperative TPA, CCWO technique, method of fixation and complications were recorded. In-hospital re-evaluation of limb function and length of time to radiographic healing was reviewed. Long-term outcome was assessed by owner telephone interview. Mean pre- and postoperative TPA was 42 degrees and 8 degrees, respectively. The Slocum biradial saw was used to create the CCWO in 4 stifle joints (mean postoperative TPA, 16 degrees) and a sagittal saw was used in 14 stifle joints (mean postoperative TPA, 5 degrees). Postoperative surgical complications were documented in 77.8% of cases; including patellar tendon thickening (61.1%), and implant loosening or breakage (27.8%), seroma formation (11.1%), and local irritation (11.1%). A second surgical procedure was performed in one-third of cases primarily to retrieve implants. Mean time to documented radiographic healing was 18 weeks. Final in-hospital re-evaluation of limb function (mean, 23 weeks postoperatively) was recorded as no lameness in 73.3% and mild lameness in 26.7%. All interviewed owners were satisfied with outcome and 90.9% reported marked improvement or a return to preinjury status. Long-term clinical outcome of TPLO/CCWO was very good in dogs with excessive TPA, with high owner satisfaction. Longer healing times and a higher complication rate were observed compared with TPLO alone. TPLO/CCWO of the tibia in stifle joints with excessive TPA allows for full correction of the TPA to 5 degrees without eliminating buttress support of the tibial tuberosity.


Synthesis and Microtubule-Destabilizing Activity of N-Cyclopropyl-4-((3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzamide and its Analogs.
While clinically useful, microtubule-targeting agents are limited by factors that include their susceptibility to multidrug resistance. A series of aryl sulfonamides, terminally substituted with an amide or carboxylic acid, was synthesized and assayed for biological activity in two human cancer cell lines. The resulting antiproliferative activity data demonstrated that an amide was superior to a carboxylic acid in the para position. The most potent compound (3) had an IC50 for growth inhibition in the low micromolar range, caused cells to accumulate in G2 M of the cell cycle, and led to depolymerization of microtubules. It was also not susceptible to the P-glycoprotein drug efflux pump that underpins the resistance of cells to long-term drug treatment schedules.


Seminal plasma alpha-glucosidase activity and male infertility.
Measurement of alpha-glucosidase (alpha-GLUC) activity by means of a simple colorimetric test using a commercial kit (EpiScreen; FertiPro, Lotenhulle, Belgium) yielded results that were strongly correlated with the values obtained for the neutral iso-enzyme measured by a fluorimetric reference method (r=0.85, P=0.003, n=13). The former method was characterized by a low intra- and inter-coefficient of variation (6.6 and 4.3% respectively). Vasectomized men with azoospermia (n=27) had a significantly lower alpha-GLUC activity in semen than vasectomized men with residual spermatozoa present (n=11, P < 0.01) and men with azoospermia of primary testicular origin (n=33, P < 0.01). Receiver operating curve (ROC) analysis showed alpha-GLUC measurement to be reasonably accurate in differentiation between cases with obstructive versus testicular azoospermia at criterion value 13.5 U/l (sensitivity=82%, specificity= 70%). In cases with spermatozoa present, alpha-GLUC activity and output per ejaculate were positively correlated with sperm concentration (r=0.53 and 0.38, n=472), linear velocity (r=0.35 and 0.30, n=224), curvilinear velocity (r=0.32 and r=0.29, n=224), semen adenosine triphosphate (r=0.35 and 0.26, n=64), the concentration of 5alpha-dihydrotestosterone (r=0.31 and 0.29, n=74), and gamma-glutamyltransferase activity (r=0.62 and 0.32, n=275) in seminal plasma. The activity of alpha-GLUC was inversely correlated with ROS generation after 12-myristate, 13-acetate phorbol ester stimulation (r=-0.27, n=104), and both alpha-GLUC activity and total output were inversely correlated with the concentration of peroxidase-positive white blood cells among samples with > or =1x10(6)/ml of these cells (r=-0.30 and -0.19, n=165). It is concluded that simple photometric measurement of alpha-GLUC activity in seminal plasma reflects the functional state of the epididymis and may be helpful for the differential diagnosis of certain cases with azoospermia.


Breast cancer surgical decision-making. Experiences of Non-Caucasian women globally. A qualitative systematic review.
To perform a qualitative systematic review exploring the influencing factors within the surgical decision-making (SDM) processes following a breast cancer diagnosis in non-caucasian women globally. Qualitative systemic review following PRISMA guidelines. A comprehensive search strategy was applied to four databases. 5243 papers were screened using a composed inclusion and exclusion criteria resulting in 10 total papers to be included. These papers underwent JBI quality assessment and ConQual assessment to ensure strength in validation, reliability, and quality. Six main overarching themes relating to SDM were determined: fear, information, patient-doctor relationship, wellbeing, external influences, and culture. All ethnicities experienced fear in one way. Misinformation was widely experienced in concordance with either a lack of education (Iranian and Ghanian women) or language barriers (immigrant populations). Trust was overarching in all patient-doctor relationships, some being overshadowed by an authoritative dynamic in Ghanian and Iranian women. Well-being, both psychological and body image was noted in all but the Ghanian and Iranian women. Every ethnicity experienced external influences involving either others, time or cost. Lastly, cultural expectations and beliefs of the doctor was present in all native or immigrant Asian communities. The study identified several factors which were common between ethnicities, notably multifactorial fear, well-being factors, opinions and trust of others, and timing. Conversely, information availability and the nature of patient-doctor relationships varied widely between ethnicities. The study has identified some realistic and achievable focus areas for practice improvement, but also notes the challenges of changing long-established cultural norms.


Examining differences in developmental work personality across disability category: Implications for individuals with psychiatric disabilities.
The purpose of this exploratory study was to examine the differences in levels of work personality for persons with psychiatric disabilities compared to persons with other types of disabilities. Seventy one adults eligible to receive Vocational Rehabilitation services participated; 30 reported a physical disability, 26 reported a psychiatric disability, and 15 reported a learning disability. Eligible participants were recruited through VR offices and volunteered to participate. Results indicate that persons with psychiatric disabilities scored significantly lower on the Work Task and Social Skills subscales of the Developmental Work Personality Scale (DWPS) when compared to individuals with physical disabilities, but scored higher than individuals with physical and learning disabilities on the Role Model subscale. The results of this study provide some initial clarity regarding developmental work personality differences among three broad categories of disability. Recommendations for future research are provided.


Ultrasonographic patterns of iatrogenic foreign bodies in the in vitro study.
The purpose of the study was application of ultrasonography for description of imaging patterns of iatrogenic foreign bodies in an in vitro model. Examples of radiolucent and poorly radiopaque foreign bodies were embedded in containers filled with gelatine The ultrasound scanning was performed by means of ATL HDI 3500 machine with a high-frequency broadband linear transducer. There was determined the possibility of detection of various types of foreign bodies. All types of used materials were well visible and hyperechoic in ultrasound image. Variations in ultrasonographic image patterns of foreign bodies studied in vitro allowed differentiation of various types of the examined materials. In conclusion, ultrasonography may become a useful, widely available and cost-effective tool in detection and localisation of foreign bodies of iatrogenic origin that otherwise remain undetected.


Effects of Dietary Iron Modulation on Gut Microbial Composition and Function in Monogastrics: A Review.
Dietary iron is a crucial nutrient element for biological processes of both hosts and gut microbiota. Deficiency in dietary iron is a highly common disorder in the developing locations of the world and can be healed by oral iron administration or complementary iron diet. While the redundant iron that enters the gut lumen leads to negative effects, and modulates the gut microbial composition and function. Such modulation led to a significant effect on vital biological pathways of the host, including metabolic disease (obesity and type 2 diabetes), metabolites (SCFA, blood glucose and cholesterol), bile acid metabolism, endocrine, neural, and other well-being patterns. This review covers the multifaceted aspects of different nutritional iron stress on the composition and function of microbial gut in monogastrics and consequential health conditions as well as it reveals unclear points that need further studies.


Leishmania (Viannia) braziliensis: interaction of mannose-binding lectin with surface glycoconjugates and complement activation. An antibody-independent defence mechanism.
The activation of complement on the surface of Leishmania promastigotes appears to be an important factor for parasite infectivity in the mammalian host, allowing their attachment and the invasion of macrophages via complement receptors. Mannose-binding lectin (MBL) is a well-known complement activator and an efficient opsonine. We have investigated here whether serum and purified MBL bind to and promote lysis of live promastigotes of L. braziliensis; and evaluated the deposition of MBL, C1q, C4 and C3 on the parasite surface after interaction with non-immune normal human serum (NHS). We observed that both serum MBL and the purified MBL-MASP complex bind to the surface of L. braziliensis and that this binding occurred via the carbohydrate recognition domains of MBL. The binding of MBL, however, did not affect the lytic effect of complement on the parasites. The deposition of C1q, C4, C3 and parasite lysis was observed after incubation with NHS. EDTA but not EGTA abolished C3 deposition on the parasite surface, indicating the involvement of the alternative pathway in this process. Our results indicate that MBL binds to L. braziliensis and that this is mediated by a specific carbohydrate on the surface of parasites and provides evidence for antibody-independent mechanisms that complement activation on the parasite surface.


Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: relationship with metabolic outcomes.
Body weight, body mass index (BMI) and excess weight loss (EWL) are the most frequently used measures to analyse bariatric surgery outcomes. However, these measurements do not provide accurate information on body composition (BC) with body fat (BF), importantly determining the levels of cardiometabolic risk factors. Our aim was to analyse the evolution of BC after Roux-en-Y Gastric Bypass (RYGB) and its influence on the changes of cardiometabolic risk factors in comparison to BMI and EWL. A group of 81 obese Caucasian patients (19 males/62 females) aged 44.9±1.3 years undergoing RYGB between January 2006 and December 2011 was prospectively followed up for a period of 3 years. BC was determined by air-displacement plethysmography. Visceral adiposity, physical activity and cardiometabolic risk factors were measured. BF was markedly (P<0.001) reduced after the first year, increasing progressively during the second and third years after RYGB, following a different trajectory than body weight, BMI and EWL that decreased up to the second year post surgery. Markers of glucose homeostasis decreased during the first month and continued to decrease during the first year (P<0.05), remaining stabilised or slightly increased between the second and third years following RYGB. However, markers of lipid metabolism decreased (P<0.05) markedly during the first 12 months, increasing thereafter in parallel to the changes observed in BC, with the exception of high-density lipoprotein-cholesterol, which increased progressively throughout the whole period analysed. The adverse switch in the changes in BC between the first and the second years after RYGB may underlie the changes observed in cardiometabolic risk factors. Tracking of adiposity during the follow-up of bariatric/metabolic surgery yields clinically relevant information to better identify patients in need of increased lifestyle advice or treatment intensification.


Macrophage Membrane-Camouflaged Aggregation-Induced Emission Nanoparticles Enhance Photodynamic-Immunotherapy to Delay Postoperative Tumor Recurrence.
Surgery is a traditional tumor treatment, and immunotherapy can reduce the postoperative recurrence of tumors. However, the intrinsic limits of low responsive rate and non-tumor specificity of immunotherapy agents are still insufficient to address therapeutic demands. Herein, the macrophages membrane camouflaged nanoparticles (NPs), named M@PFC, consisting of the aggregation-induced emission photosensitizer (PF3-PPh3 ) and immune adjuvant (CpG), are reported. As the protein on the membrane interacts with the vascular cell adhesion molecule 1 (VCAM-1) of cancer cells, M@PFC efficiently transports CpG to the tumor. Meanwhile, M@PFC can evade clearance by the immune system and prolong the circulation time in vivo; thus, enhancing their accumulation in tumors. PF3-PPh3 promotes high production of reactive oxygen species (ROS) and triggers immune cell death (ICD) in tumor cells under light exposure. Importantly, CpG enrichment in tumors can stimulate tumor cells to produce immune factors to assist in enhancing ICD effects. The synergistic effect combining the PDT properties of the aggregation-induced emission (AIE)-active photosensitizer and immunotherapy properties of CpG significantly delays tumor recurrence after surgery. In conclusion, this strategy achieves the synergistic activation of the immune system for anti-tumor activity, providing a novel paradigm for the development of therapeutic nanodrugs to delay postoperative tumor recurrence.


Influence of operation duration on perioperative morbidity in revision total hip arthroplasty.
This retrospective study investigated the impact of patient and procedure-related parameters on the complication rate following revision total hip arthroplasty. Complications included vessel and nerve damage, periprosthetic femoral fracture, wound infection, wound bleeding, prosthesis dislocations, thromboembolism, cardiac and pulmonary complications, and death. The influence of operation duration, gender, revision status, ASA classification, and type of fixation of the primary implant on the perioperative morbidity was investigated in a sample of 60 revision procedures (cemented stems, cemented or cementless cups). Odds ratio [OR] and 95% confidence interval [CI] were estimated with multiple regression models. Perioperative morbidity was significantly correlated to operation duration (OR = 1.03; CI: 1.00-1.05), but not to age (OR = 1.01; CI: 0.93-1.09), gender (OR = 2.66; CI: 0.50-14.05), revision status (OR = 2.34; CI: 0.54-10.05), ASA classification (OR = 1.24; CI: 0.30-5.18), or type of fixation of the primary implant (OR = 2.49; CI: 0.47-13.17) Duration of the revision operation appeared as a predictive parameter for perioperative morbidity in revision total hip arthroplasty in our study group.


Furosemide causes acute and long-term hyperglycaemia and reduces glucose tolerance in mice.
The effect of furosemide on carbohydrate metabolism was studied in mice. Single-dose administration (200 mg kg-1 body weight) resulted in transient hyperglycaemia and a rise in the glucose/insulin ratio within 60 min. The glucose tolerance was impaired with elevated serum glucose and reduced insulin response 2 h after the furosemide injection, but had recovered within 24 h. In mice made hypoglycaemic by prior injection of insulin, the basal serum glucose and the glucose tolerance were impaired 22 h after the injection of furosemide. It is suggested that furosemide has both acute and long-term effects on carbohydrate metabolism in mice and that, at least in part, this is due to reduced insulin secretion. Glucose may protect against the diabetogenic action of furosemide.


Asymptomatic Bacteriuria in Noncatheterized Adults.
Asymptomatic bacteriuria (ASB) is a common finding and frequently detected in premenopausal nonpregnant women, institutionalized patients, patients with diabetes mellitus, and the ambulatory elderly population. Despite clear recommendations regarding diagnosis and management of ASB in these populations from the Infectious Diseases Society of America (IDSA), there remains an alarming rate of antimicrobial overuse. This article reviews definitions of ASB, epidemiology of ASB, literature surrounding ASB in diabetic patients, risk factors of ASB, microbiologic data regarding bacterial virulence, use of ASB strains for treatment of symptomatic urinary tract infection, and approaches to addressing translational barriers to implementing IDSA recommendations regarding diagnosis and management of ASB.


The up-regulation of miR-21 by gastrodin to promote the angiogenesis ability of human umbilical vein endothelial cells by activating the signaling pathway of PI3K/Akt.
Studies have shown that gastrodin has a protective effect on blood vessels. The purpose of this study was to investigate the influence of gastrodin on the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) and its mechanism. We found that treatment of HUVECs with 10 µM and 25 µM gastrodin, and Vascular endothelial growth factor (VEGF) significantly upregulated the miR-21 expression in the cells. Meanwhile, gastrodin significantly increased the cell proliferation, migration and tube formation ability of HUVECs and increased the expression of MMP-2 and MMP-9 mRNA. In addition, gastrodin promoted the phosphorylation level of PI3K/Akt protein. However, down-regulating the miR-21 expression reduced the promoting effect of gastrodin on the HUVECs angiogenesis. In conclusion, gastrodin activates the PI3K/Akt pathway by up-regulating the miR-21 expression and promotes the HUVECs angiogenesis.


Condylar nonunions of the elbow.
Between 1968 and 1978, 32 patients were seen with nonunion of distal humerus fractures in close proximity to the elbow: 25 were treated with open reduction and fixation of the nonunion, and seven patients were treated with excision of the distal fragments and total elbow arthroplasty. Of the 25 patients treated with open reduction and fixation, 22 had union at an average of 7.74 months. However, six of these patients needed secondary procedures for repeat bone grafting or revision of the fixation device. Two of the seven patients with total elbow arthroplasty needed reoperation for loose humeral components.


Emergence of Bruton's tyrosine kinase-negative Hodgkin lymphoma during ibrutinib treatment of chronic lymphocytic leukaemia.
Chronic lymphocytic leukaemia (CLL) is a chronic B-cell lympho-proliferative disorder in which lymphomatous transformations occur in 5%-15% of patients. Histologically these cases resemble diffuse large B-cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67-year-old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno-histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.


Heterologous expression, immunochemical and computational analysis of recombinant human interferon alpha 2b.
Interferon alpha 2b (IFNα-2b) is an important cytokine and used for antiviral and anticancer treatment. The low cost production of IFNα-2b with high biological activity is necessary to provide the interferon therapy to the hepatitis patients in Pakistan. In the present study, human interferon alpha 2b (hIFNα-2b) gene from a healthy person was cloned and overexpressed in E. coli BL21(DE3). The molecular weight of the expressed hIFNα-2b is 19 kDa. The over expressed recombinant hIFNα-2b was checked by ELISA using antibodies raised against commercially available hIFNα-2b. The biocomputational analysis of recombinant hIFNα-2b gene showed the 99.9% nucleotide sequence and 100% deduced amino acid sequence homology with reported sequences of IFNα-2b. The predicted 3D-structure showed mainly five α-helices, one 310 helix and two disulfide bonds at Cys1-Cys98 and Cys129-Cys138. The amino acid sequence alignment indicated that the disulfide linkage position is conserved in all IFNα family members. On the basis of sequence homology among interferon alpha family, new potent variants of hIFNα-2b with enhance efficacy can be produced. Indigenous production of IFNα-2b from gene of local population will reduce the cost and increase tolerability of interferon therapy.


Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome.
Annexin A5 (A5) forms 2-dimensional crystals over phospholipid bilayers, blocking their availability for coagulation reactions. Recently, human antiphospholipid (aPL) monoclonal antibodies (mAbs) have been demonstrated by atomic force microscopy (AFM) to disrupt this crystallization and accelerate coagulation. We therefore performed a study with small, well-defined groups of patients to investigate whether these effects on A5 binding and activity are also detectable in plasmas from patients with the aPL syndrome. A5 binding to phospholipid was significantly reduced by plasmas of patients with the aPL syndrome and thromboembolism compared with healthy controls (mean +/- SD, 26.7 +/- 4.3 ng/well [n = 25] vs 30.5 +/- 3.1 ng/well [n = 20], P < .01) and the non-aPL thromboembolism group (29.9 +/- 3.2 ng/well [n = 15], P < .05). A5 anticoagulant activity was reduced by plasmas of patients with aPL syndrome and thromboembolism compared with aPL antibodies without thrombosis (182 +/- 31% [n = 25] vs 210 +/- 35% [n = 26], P < .01), non-aPL thromboembolism (229 +/- 16% [n = 15], P < .001), and healthy controls (231 +/- 14% [n = 30], P < .001). In conclusion, in accordance with recent AFM data with monoclonal human aPL antibodies, plasmas from patients with aPL antibodies with thromboembolism reduce both A5 binding to phospholipid and A5 anticoagulant activity. This "annexin A5 resistance" identifies a novel mechanism for thrombosis in the aPL syndrome.


Molecular cloning, sequence, expression, and processing of the interleukin 16 precursor.
Interleukin 16 (IL-16) has been shown to function as chemoattractant factor, as a modulator of T-cell activation, and as an inhibitor of immunodeficiency virus replication. The recent identification of inconsistencies in published IL-16 cDNA nucleotide sequences led to the proposal that IL-16 is synthesized in the form of a large precursor protein (pro-IL-16). To identify the true transcriptional start of the IL-16 mRNA rapid amplification of cDNA ends methods were applied. The complete pro-IL-16 cDNA was subsequently molecularly cloned, sequenced, and expressed in COS-7 cells. We report here that pro-IL-16 is most likely synthesized as a 67-kDa protein and is encoded from a major 2.6-kb transcript. Recombinant pro-IL-16 polypeptides are specifically cleaved in lysates of CD8(+) cells, suggesting that the naturally secreted bioactive form of IL-16 is smaller than the originally published 130 amino acids fragment. Moreover, in contrast to other interleukins such as IL-15, IL-16 mRNA expression is almost exclusively limited to lymphatic tissues underlining the potential of IL-16 as an immune regulatory molecule.


The Early Variation of Left Ventricular Strain after Aortic Valve Replacement by Three-Dimensional Echocardiography.
Aortic stenosis (AS) and aortic incompetence (AI) are common aortic valve diseases. Both may deteriorate into irreversible myocardial dysfunction and will increase the risk of sudden death. In this study, we aimed to investigate the early variation trend of left ventricular function by three-dimensional speckle tracking echocardiography (3D-STE) in the patients who underwent cardiac surgeries for aortic valve disease. Twenty patients with severe aortic AS and 16 patients with severe AI were enrolled. All of them underwent the aortic valve replacement (AVR) procedures. The patients' global longitudinal strain (GLS) and global circumferential strain (GCS) were evaluated by 3D-STE before surgery and at 1 week after surgery. In addition, GLS and GCS were followed at 1 month as well as 3 months after AVR. In AS patients, the GCS after AVR altered little both at 1 week (p = 0.562) and at 1 month (p = 0.953) compared with the data before the surgery. And it increased significantly at 3 months of follow-up observation compared to that before AVR (p<0.05). Meanwhile, GLS increased progressively after AVR and improved significantly at 3 months after surgery (p<0.05). For the AI patients, GLS as well as GCS decreased at 1 week after AVR compared to those data at baseline (p<0.05). However, these two parameters recovered at 1 month after AVR. Furthermore, GLS and GCS improved significantly at 3 months after the surgery (p<0.05). Therefore, both GLS and GCS were influenced by AVR and would be improved at 3 months after surgery both in AS patients or AI patients. GLS and GCS can be finely evaluated by 3D-STE, and they are helpful to determine the variation tendency of left ventricular function in patients with AVR.


Stratospheric harbingers of anomalous weather regimes.
Observations show that large variations in the strength of the stratospheric circulation, appearing first above approximately 50 kilometers, descend to the lowermost stratosphere and are followed by anomalous tropospheric weather regimes. During the 60 days after the onset of these events, average surface pressure maps resemble closely the Arctic Oscillation pattern. These stratospheric events also precede shifts in the probability distributions of extreme values of the Arctic and North Atlantic Oscillations, the location of storm tracks, and the local likelihood of mid-latitude storms. Our observations suggest that these stratospheric harbingers may be used as a predictor of tropospheric weather regimes.


[Effects of early enriched environment on long-term behavior development and serum corticosterone level in rats].
To study the effects of early enriched environment on behavioral development and serum corticosterone level in rats. Forty-five neonatal rats were randomly assigned into three groups:blank control, enriched environment and isolated environment. The open-field environment test and the Lat maze test were performed to assess anxiety/irritability-related behaviors of the rats on postnatal day 31. The level of serum corticosterone was measured by radioimmunology assay. The level of serum corticosterone in the enriched environment group (8±3 ng/mL) was significantly lower than the blank control (11±4 ng/mL) and the isolated groups (22±4 ng/mL) (P<0.01). The open-field environment test showed that the numbers of passing panels, keeping an erect posture and grooming were less than those in the blank control and the isolated groups (P<0.05). According to the results of the Lat maze test, the frequencies of running across the corner, keeping an erect posture and leaning against the wall in the enriched environment group were less than those in the blank control and the isolated groups (P<0.05). Early enriched environment can decrease serum corticosterone level and thus alleviates anxiety and irritability in rats. It may play an important role in the improvement of brain development.


Assessing changes over time in healthcare provider performance: addressing regression to the mean over multiple time points.
In recent years, the evaluation of healthcare provider performance has become standard for governments, insurance companies, and other stakeholders. Often, performance is compared across providers using indicators in one time period, for example a year. However it is often important to assess changes in the performance of individual providers over time. Such analyses can be used to determine if any providers have significant improvements, deteriorations, unusual patterns or systematic changes in performance. Studies which monitor healthcare provider performance in this way have to date typically been limited to comparing performance in the most recent period with performance in a previous period. It is also important to consider a longer-term view of performance and assess changes over more than two periods. In this paper, we develop test statistics that account for variable numbers of prior performance indicators, and show that these are particularly useful for assessing consecutive improvements or deteriorations in performance. We apply the tests to coronary artery bypass graft mortality rates in New York State hospitals, and mortality data from Australian and New Zealand intensive care units. Although our applications are to medical data, the new tests have broad application in other areas.


Ultra-Efficient Americium/Lanthanide Separation through Oxidation State Control.
Lanthanide/actinide separation is a worldwide challenge for atomic energy and nuclear waste treatment. Separation of americium (Am), a critical actinide element in the nuclear fuel cycle, from lanthanides (Ln) is highly desirable for minimizing the long-term radiotoxicity of nuclear waste, yet it is extremely challenging given the chemical similarity between trivalent Am(III) and Ln(III). Selective oxidation of Am(III) to a higher oxidation state (OS) could facilitate this separation, but so far, it is far from satisfactory for practical application as a result of the unstable nature of Am in a high OS. Herein, we find a novel strategy to generate stable pentavalent Am (Am(V)) through coordination of Am(III) with a diglycolamide ligand and oxidation with Bi(V) species in the presence of an organic solvent. This strategy leads to efficient stabilization of Am(V) and an extraordinarily high separation factor (>104) of Am from Ln through one single contact in solvent extraction, thereby opening a new avenue to study the high-OS chemistry of Am and fulfill the crucial task of Ln/Am separation in the nuclear fuel cycle. The synergistic coordination and oxidation process is found to occur in the organic solvent, and the mechanism has been well elucidated by quantum-theoretical modeling.


MMPs and ADAMTSs: functional studies.
Members of the MMP (matrix metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motifs) families of enzymes are capable of cleaving a diverse array of cellular, extracellular and extracellular matrix substrates, including collagens and procollagens, proteoglycans, cytokines and cytokine ligands, chemokines, elastin and von Willebrand factor, thereby modulating tissue structure and function during both health and disease. Physiologically relevant roles attributable to various members of these metalloproteinase families have been discerned from functional studies correlating in vitro substrate processing events with catabolic cleavages occurring in vivo/in situ, and the consequences thereof. Mechanisms regulating the post-translational activities of MMPs and ADAMTSs can clearly also have an influential impact on cell metabolism and tissue structure/function, and a number of functional studies have addressed the contributions of ancillary (non-catalytic) domains and endogenous inhibitors in this regard. Further revelations and affirmations of proteinase function, in an in vivo context, have emanated with the characterization of genetically manipulated animals misexpressing specific MMPs or ADAMTSs (or their substrates). An increased understanding thereby attained for the physiological functions of MMPs and ADAMTSs, and the means by which their activities are controlled, may lead to the realization of rational therapeutic strategies to counteract pathologies associated with aberrant proteolysis of homeostatic tissue macromolecules.


The role of movement in the development of a digital flexor tendon.
D-tubocurarine was injected into the air sac of 8-day chick embryos to prevent movement of the digits of the hind limb. The embryos were paralyzed from the tenth to the eighteenth day, when the experiment was terminated. The immobilization of the flexor digitorum profundus tendons in the tarsus resulted in a loss of specialized structures around and on this tendon, as determined by light and electron microscopy. Specialized areas observed in the normal chick (synovial cavity, fibrocartilaginous area, and elastic vinculum) failed to form, as a result of the paralysis of the digit. Several authors have shown previously that movement is a requirement for the molding and maintenance of joint cavities in vivo, in ovo and in vitro (see text for references). We have shown that movement of the tendon is required to produce a functional tendon apparatus in the embryo and predict that movement is also required for regeneration after injury.


Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain.
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function. We developed an H3K9me3 peptide displacement assay, which was used to screen a library of 44,000 compounds for small molecules that disrupt the UHRF1-H3K9me3 interaction. This screen resulted in the identification of NV01, which bound to UHRF1-TTD with a Kd value of 5 μM. The structure of UHRF1-TTD in complex with NV01 confirmed binding to the H3K9me3-binding pocket. Limited structure-based optimization of NV01 led to the discovery of NV03 (Kd of 2.4 μM). These well-characterized small-molecule antagonists of the UHRF1-H3K9me2/3 interaction could be valuable starting chemical matter for developing more potent and cell-active probes toward further characterizing UHRF1 function, with possible applications as anticancer therapeutics.


[Comprehension of community healthcare agents on the National Humanization Policy].
To identify the comprehension of Community Healthcare Agents on the National Humanization Policy (NHP), as well as to analyze whether they recognize healthcare actions developed in their daily lives, as those established by the NHP. Exploratory and descriptive qualitative research, conducted between June and September 2013, with 15 Community Healthcare Agents of the Family Health Strategy Program in a city located in the West of Sao Paulo state. The data collection was conducted through individual interviews, using a semi-structured script and submitted to content analysis. Two categories emerged: "Superficial knowledge: an obstacle to the construction of humanized care" and "Actions of humanized health: trying to get closer". The basic concepts of NHP are part of the knowledge of these professionals, but the understanding they possess is superficial, which directly affects the actions provided to the community.


Myenteric plexus of the hind-gut: developmental abnormalities in humans and experimental studies.
Intraluminal pressure studies on patients with congenital aganglionosis showed that the aganglionic rectum contracted in an uncoordinated manner and failed to relax. Histochemical assessment of the innervation helped to explain the variable severity of the symptoms in this condition. It is concluded that (1) absence of ganglia prevents normal coordinated peristalsis and creates an obstructive element; (2) absence of reflex relaxation adds to the obstruction; (3) the degree of uncoordinated motor activity in distal aganglionic bowel probably relates to the number of cholinesterase-positive nerves in the circular muscle and adds another variable obstructive element; and (4) deficient innervation of distal ganglionic bowel probably creates a poor propulsive force and so accentuates more distal obstructive factors. Neurohistochemical and functional studies in the anorectum of cats reveal a somewhat different innervation pattern from that in humans but show that sphincteric tone is mainly due to alpha-adrenergic neural activity. Reflex relaxation of the internal anal sphincter is a complex function in which inhibitory responses override motor responses, and it involves an important non-adrenergic non-cholinergic component. The role of cholinergic nerves in the sphincter remains uncertain. Neurohistochemical assessment of full thickness biopsy specimens of rectal muscle from patients with disabling constipation shows that developmental neuronal dysplasias of the hind-gut may be divided into three main categories: (1) aganglionosis (Hirschsprung's disease), (2) hypoganglionosis and (3) hyperganglionosis, and that the different neuronal elements may be affected to differing degrees in individuals within each group. Resection of the aganglionic bowel is required in congenital aganglionosis but the combined diagnostic-therapeutic procedure of anorectal myotomy has been found beneficial in patients with hypoganglionosis.


Meningeal Hemangiopericytoma with Intracranial Metastases in an HIV-Positive Male: Case Report and Review of the Literature.
Meningeal hemangiopericytoma is a rare, aggressive CNS tumor that tends to invade locally, metastasize, and has a high rate of recurrence. HIV classically increases the risk of 3 AIDS-defining malignancies: Kaposi's sarcoma, non-Hodgkin's lymphoma and invasive cervical cancer. More recently, considerable interest has been paid to the link between HIV and a wider range of non-AIDS-defining cancers. An HIV-positive patient with meningeal hemangiopericytoma is described. A 36-year-old HIV-positive male presented with worsening headache and ataxia. The patient had experienced similar neurologic symptoms 4 months prior and MRI at that time had showed an extra-axial left cerebellar mass most consistent with benign meningioma. Repeat MRI showed the tumor had increased in size by a factor of greater than 20 in this 4-month period, with 4 small additional foci of similar enhancement. Subtotal resection was performed on the mass and final pathological diagnosis was meningeal hemangiopericytoma. This represents the first reported case of meningeal hemangiopericytoma in an HIV-positive patient. This is also the shortest time to intracranial metastasis ever reported for a meningeal hemangiopericytoma. Although the increased risk in the HIV-positive population of non-AIDS-defining cancers that has been observed in recent years can largely be attributed to cancers with a known viral pathogenesis, it is speculated that HIV infection in this patient may have contributed to the occurrence or unique behavior of this rare tumor.


A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia.
Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.


Self-motion with Hearing Impairment and (Directional) Hearing Aids.
When listening to a sound source in everyday situations, typical movement behavior is highly individual and may not result in the listener directly facing the sound source. Behavioral differences can affect the performance of directional algorithms in hearing aids, as was shown in previous work by using head movement trajectories of normal-hearing (NH) listeners in acoustic simulations for noise-suppression performance predictions. However, the movement behavior of hearing-impaired (HI) listeners with or without hearing aids may differ, and hearing-aid users might adapt their self-motion to improve the performance of directional algorithms. This work investigates the influence of hearing impairment on self-motion, and the interaction of hearing aids with self-motion. In order to do this, the self-motion of three HI participant groups----aided with an adaptive differential microphone (ADM), aided without ADM, and unaided-was measured and compared to previously measured self-motion data from younger and older NH participants. Self-motion was measured in virtual audiovisual environments (VEs) in the laboratory, and the signal-to-noise ratios (SNRs) and SNR improvement of the ADM resulting from the head movements of the participants were estimated using acoustic simulations. HI participants did almost all of the movement with their head and less with their eyes compared to NH participants, which led to a 0.3 dB increase in estimated SNR and to differences in estimated SNR improvement of the ADM. However, the self-motion of the HI participants aided with ADM was similar to that of other HI participants, indicating that the ADM did not cause listeners to adapt their self-motion.


Evaluation of the Amniostat-FLM assay for assessment of fetal lung maturity.
Results of the "Amniostat-FLM" assay, a rapid semiquantitative test for phosphatidylglycerol, were compared with determinations of the lecithin/sphingomyelin (L/S) ratio, with phosphatidylglycerol measured by two-dimensional thin-layer chromatography, and with results of the "shake test" for 94 specimens of amniotic fluid. Correlation between results with the Amniostat and the other tests was excellent. All four tests are very accurate when predicting lung maturity. The predictive value of a negative test, i.e., that hyaline membrane disease would not occur, was between 92 and 100%. However, the accuracy of predicted lung immaturity is poor. For all four tests, predictions of lung immaturity were incorrect in more than 50% of the cases. Of the 49 infants born within 72 h of testing, none developed hyaline membrane disease when phosphatidylglycerol was detectable by either method or when the shake test indicated fetal lung maturity, but three infants with L/S ratio greater than 2/1 did develop the disease. The Amniostat provides a rapid screening method for detecting phosphatidylglycerol in amniotic fluid, which could well replace the thin-layer chromatographic method for measuring phosphatidylglycerol in the panel of diagnostic tests for fetal lung maturity.


Ultrashort pulse generation from continuous wave by pulse trapping in birefringent fibers.
We investigated the phenomenon of orthogonally polarized pulse trapping between a continuous-wave beam and an ultrashort soliton pulse in birefringent fibers both experimentally and numerically. Using pulse trapping and amplification, we demonstrated ultrashort pulse generation from a continuous-wave beam. The generated pulse had a nearly transform-limited sech(2)-shape and a temporal width of 350 fs. The obtained maximum pulse energy was 300 pJ using a 400 m-long low-birefringence fiber, and the corresponding gain was as large as 41 dB.


Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.
Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.


A scoping review of network meta-analyses assessing the efficacy and safety of complementary and alternative medicine interventions.
Network meta-analysis (NMA) has rapidly grown in use during the past decade for the comparison of healthcare interventions. While its general use in the comparison of conventional medicines has been studied previously, to our awareness, its use to assess complementary and alternative medicines (CAM) has not been studied. A scoping review of the literature was performed to identify systematic reviews incorporating NMAs involving one or more CAM interventions. An information specialist executed a multi-database search (e.g., MEDLINE, Embase, Cochrane), and two reviewers performed study selection and data collection. Information on publication characteristics, diseases studied, interventions compared, reporting transparency, outcomes assessed, and other parameters were extracted from each review. A total of 89 SR/NMAs were included. The largest number of NMAs was conducted in China (39.3%), followed by the United Kingdom (12.4%) and the United States (9.0%). Reviews were published between 2010 and 2018, with the majority published between 2015 and 2018. More than 90 different CAM therapies appeared at least once, and the median number per NMA was 2 (IQR 1-4); 20.2% of reviews consisted of only CAM therapies. Dietary supplements (51.1%) and vitamins and minerals (42.2%) were the most commonly studied therapies, followed by electrical stimulation (31.1%), herbal medicines (24.4%), and acupuncture and related treatments (22.2%). A diverse set of conditions was identified, the most common being various forms of cancer (11.1%), osteoarthritis of the hip/knee (7.8%), and depression (5.9%). Most reviews adequately addressed a majority of the PRISMA NMA extension items; however, there were limitations in indication of an existing review protocol, exploration of network geometry, and exploration of risk of bias across studies, such as publication bias. The use of NMA to assess the effectiveness of CAM interventions is growing rapidly. Efforts to identify priority topics for future CAM-related NMAs and to enhance methods for CAM comparisons with conventional medicine are needed. SYSTEMATIC REVIEW REGISTRATION: https://ruor.uottawa.ca/handle/10393/35658.


Analysis of limb anomalies induced in vitro by vitamin A (retinol) in mice.
Forelimb buds of day 11 ICR-JCL mouse embryos were cultured on liquid medium consisting of 90% Eagle's MEM and 10% fetal calf serum. Experimental medium contained 10 iu/ml vitamin A alcohol (retinol). In controls four of five metacarpals chondrified and the epidermis began to keratinize after 3-4 days of culturing. In experimental explants many pycnotic cells were observed in the peripheral mesenchyme in the hand plate, especially in pre- and postaxial regions. Only 2-3 metacarpals chondrified, and keratinization was inhibited in the experimental explants. Uptake of labeled sulfate was suppresssed by vitamin A. Excess vitamin A is thus thought (1) to act directly on limb buds, and thereby to induce limb anomalies, (2) to induce cell death in the mesenchyme, (3) to suppres the formation of chondroitin sulfate, and (4) to inhibit keratinization.


Drug safety assessment of oral formulations of ketoconazole.
Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others. This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy 'ketoconazole OR Nizoral AND hepat*', references from relevant publications, and data from the FDA Adverse Event Reporting System. Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.


Behaviour-modifying compounds for management of the red palm weevil (Rhynchophorus ferrugineus Oliver).
Populations of red palm weevil (RPW), a severe pest of palms in Mediterranean countries, might be limited by semiochemical-based behaviour-disrupting methods. We evaluated the effects of electroantennogram (EAG)-active plant volatiles on the behaviour of RPWs from Italy and Israel. In field experiments, α-pinene, citronellol, geraniol, citral and 1-octen-3-ol were tested for their ability to disrupt attraction to pheromone-kairomone and molasses baited traps. Those that were found to be disruptive in the field were evaluated in a laboratory choice bioassay in individual cages for their effect on RPW female feeding and oviposition. Field experiments showed reduced captures in traps loaded with geraniol (-57%), 1-octen-3-ol (-50%) or α-pinene (-45% to -60%); captures in citronellol- or citral-loaded traps did not differ from control. In laboratory experiments, 1-octen-3-ol was the most potent behaviour-modifying compound, eliciting a significant/marginally significant reduction in both feeding and oviposition at the lowest dose tested in both populations. Geraniol generally caused a strong reduction in feeding and oviposition at each dose tested (Israel), or at the highest dose (Italy). α-Pinene caused some reduction in feeding activity at the highest dose tested (Italy), but no consistent repellency (Israel). Field and laboratory data suggest the potential for the use of 1-octen-3-ol, geraniol and α-pinene for RPW population management.


Vitamin D in Fibromyalgia: A Causative or Confounding Biological Interplay?
Fibromyalgia (FM) is a chronic syndrome with an increasing prevalence, characterized by widespread musculoskeletal pain in combination with a variety of cognitive symptoms and fatigue. A plethora of scientific evidence that has accumulated during the last decades, resulted in a significant improvement of the understanding of the pathophysiology of the disease. However, current therapeutic approaches in patients with FM remains a multidimensional approach including patient education, behavioral therapy, exercise, pain management, and relief of chronic symptoms, rather than the use drug therapies, based on the mechanisms of disease development. Vitamin D, a fat-soluble vitamin derived mainly from skin synthesis through ultraviolet radiation, has been recognized to manifest a plethora of extraskeletal actions, apart from its fundamental role in skeletal and calcium homeostasis, including modulation of cell growth, neuromuscular actions, and potential anti-inflammatory properties. Recent findings indicate that hypovitaminosis D to be highly prevalent in patients with FM. Supplementation studies are limited so far, indicating potential beneficial effects on pain and severity of the disease, however specific recommendations are lacking. This review aims to summarize and critically appraise data regarding the pathophysiological interplay between vitamin D and FM, available results from observational and supplementation studies so far, with a clinical discourse on current knowledge gaps and future research agenda.


Lipid-polymorphism of plant thylakoid membranes. Enhanced non-bilayer lipid phases associated with increased membrane permeability.
Earlier experiments, using 31 P-NMR and time-resolved merocyanine fluorescence spectroscopy, have shown that isolated intact, fully functional plant thylakoid membranes, in addition to the bilayer phase, contain three non-bilayer (or non-lamellar) lipid phases. It has also been shown that the lipid polymorphism of thylakoid membranes can be characterized by remarkable plasticity, i.e. by significant variations in 31 P-NMR signatures. However, changes in the lipid-phase behaviour of thylakoids could not be assigned to changes in the overall membrane organization and the photosynthetic activity, as tested by circular dichroism and 77 K fluorescence emission spectroscopy and the magnitude of the variable fluorescence of photosystem II, which all showed only marginal variations. In this work, we investigated in more detail the temporal stability of the different lipid phases by recording 31 P-NMR spectra on isolated thylakoid membranes that were suspended in sorbitol- or NaCl-based media. We observed, at 5°C during 8 h in the dark, substantial gradual enhancement of the isotropic lipid phases and diminishment of the bilayer phase in the sorbitol-based medium. These changes compared well with the gradually increasing membrane permeability, as testified by the gradual acceleration of the decay of flash-induced electrochromic absorption changes and characteristic changes in the kinetics of fast chlorophyll a-fluorescence transients; all variations were much less pronounced in the NaCl-based medium. These observations suggest that non-bilayer lipids and non-lamellar lipid phases play significant roles in the structural dynamics and functional plasticity of thylakoid membranes.


Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer.
De novo or acquired resistance to endocrine therapy limits its utility in a significant number of estrogen receptor-positive (ER-positive) breast cancers. It is crucial to identify novel targets for therapeutic intervention and improve the success of endocrine therapies. Splicing factor 3b, subunit 1 (SF3B1) mutations are described in luminal breast cancer albeit in low frequency. In this study, we evaluated the role of SF3B1 and SF3B3, critical parts of the SF3b splicing complex, in ER-positive endocrine resistance. To ascertain the role of SF3B1/SF3B3 in endocrine resistance, their expression levels were evaluated in ER-positive/endocrine-resistant cell lines (MCF-7/LCC2 and MCF-7/LCC9) using a real-time quantitative reverse transcription PCR (qRT-PCR). To further determine their clinical relevance, expression analysis was performed in a cohort of 60 paraffin-embedded ER-positive, node-negative breast carcinomas with low, intermediate, and high Oncotype DX recurrence scores. Expression levels of SF3B1 and SF3B3 and their prognostic value were validated in large cohorts using publicly available gene expression data sets including The Cancer Genome Atlas. SF3B1 and SF3B3 levels were significantly increased in ERα-positive cells with acquired tamoxifen (MCF-7/LCC2; both P<0.0002) and fulvestrant/tamoxifen resistance (MCF-7/LCC9; P=0.008 for SF3B1 and P=0.0006 for SF3B3). Expression levels of both MCF-7/LCC2 and MCF-7/LCC9 were not affected by additional treatments with E2 and/or tamoxifen. Furthermore, qRT-PCR analysis confirmed that SF3B3 expression is significantly upregulated in Oncotype DX high-risk groups when compared with low risk (P=0.019). Similarly, in publicly available breast cancer gene expression data sets, overexpression of SF3B3, but not SF3B1, was significantly correlated with overall survival. Furthermore, the correlation was significant in ER-positive, but not in ER-negative tumors.This is the first study to document the role of SF3B3 in endocrine resistance and prognosis in ER-positive breast cancer. Potential strategies for therapeutic targeting of the splicing mechanism(s) need to be evaluated.


Group Problem Solving in Class Improves Undergraduate Learning.
Developing methods for improving student learning is a long-standing goal in undergraduate science education. However, the extent to which students working on problems in small groups versus individually results in improved learning among undergraduate science students has not been evaluated in a randomized controlled trial. We have performed such a trial with 80 students in an undergraduate biochemistry class, in which students were randomized to either learning in groups or learning individually. All students participated in the same class, which consisted of a lecture with periodic breaks for students to solve problems using an audience response system. Students in the individual learning condition answered these questions on their own, but students in the group-based learning condition answered these questions in an assigned group of four students. At the end of the class, all students then took the same exam as individuals. The exam had two types of questions-recall questions, in which students had to simply recall information provided to them, and predict questions, in which students had to apply their new knowledge to a new context. Students in the individual and group-based learning conditions performed similarly well on recall questions. However, students who had been in the group-based learning condition performed significantly better as individuals on the predict questions. This suggests that learning in groups may be more effective than individual learning for undergraduate science students, particularly for applying their knowledge to new contexts; this highlights the potential need for pedagogical approaches in undergraduate science courses that incorporate learning in groups.


The role of responsible gambling strategy and gambling passion in the online gamblers' decision-making process: revising the theory of planned behavior.
This study revised the theory of planned behavior (TPB) by incorporating the new concepts of gambling passion and responsible gambling strategy (RGS) to predict gamblers' intention to gamble in online sports betting. The data were collected at the end of March in 2012 through an online gambling website. The findings indicated that the inclusion of two types of gambling passion and two types of RGS explains online gambling intention well. Specifically, out of the original antecedent predictors of TPB, attitude toward online gambling was positively related to harmonious passion. Subjective norm had a positive relationship with both harmonious and obsessive passion. The results also showed that perceived behavioral control does not have a significant effect on the two gambling passions but has a direct and significant influence on behavioral intention. Additionally, the compulsory RGS had a negative effect on obsessive passion, whereas supplementary RGS had concurrent positive impacts on harmonious and obsessive passion. Lastly, the two gambling passions were notable predictors of behavioral intention toward online sports betting.


Respiratory symptoms and chronic obstructive pulmonary disease among cement factory workers.
This study assessed chronic respiratory symptoms and chronic obstructive pulmonary disease (COPD) among workers exposed to cement dust at a Tanzanian cement factory. A total of 120 exposed workers and 107 controls participated in this cross-sectional investigation. Information on demographics, occupational history, chronic respiratory symptoms, smoking habits, and use of respiratory protection equipment was collected by questionnaire. Ventilatory function testing and measurement of personal total dust exposure were also carried out. COPD was diagnosed for workers with chronic bronchitis who also had spirometric airflow obstruction. Chronic respiratory symptoms and COPD were correlated with cumulative total dust exposure and adjusted for age, pack-years, and education. The exposed workers had more chronic cough [odds ratio (OR) 4.5, 95% confidence interval (95% CI) 1.9-10.4], chronic sputum production (OR 10.8, 95% CI 4.4-26.4.), dyspnea (OR 5.3, 95% CI 1.9-15.2), work-related shortness of breath (OR 4.8, 95% CI 1.6-14.2), and chronic bronchitis (OR 5.5, 95% CI 2.0-15.3) than the controls. Chronic cough, chronic sputum production, dyspnea, work-related shortness of breath, and chronic bronchitis were significantly related to cumulative dust exposure of 20.0-99.9 and > or = 100.0 versus <20.0 mg/m3-years. The prevalence of COPD was higher for the exposed group (18.8%) than for the controls (4.8%). The odds ratio for COPD was significantly increased for cumulative dust exposure, > or = 100.0 versus <20.0 mg/m3-years (OR 11.2, 95% CI 2.2-56.0). Cement workers seem to be at high risk of developing chronic respiratory symptoms and COPD, probably caused by cumulative total dust exposure independent of smoking habits.


Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.
Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.


CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.
Extracellular matrix remodelling regulated by matrix-metalloproteinase (MMP) inducer (CD147) is a crucial process during tumor cell invasion and regulation of blood supply. In this study, we evaluated the correlation of CD147 and MMP-2 expression with major prognostic factors for uveal melanoma and the development of metastasis. The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression). CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident. These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.


Ex Vivo Pharmacokinetics and Pharmacodynamics Modeling and Optimal Regimens Evaluation of Cefquinome Against Bovine Mastitis Caused by Staphylococcus aureus.
Cefquinome, the fourth-generation cephalosporin applied solely for veterinary medicine, is commonly used for bovine mastitis caused by Staphylococcus aureus. The present study aims to establish an optimal dose and provide a PK/PD Cutoff value (COPD) for cefquinome against S. aureus based on ex vivo pharmacokinetics and pharmacodynamics (PK/PD) integration. This study investigated the pharmacokinetics (PK) of cefquinome when administered as three consecutive intramammary (IMM) doses of cefquinome in three healthy dairy cows at 75 mg/gland. Drug concentration was determined by HPLC-MS/MS assay. The ex vivo pharmacodynamics (PD) of cefquinome were evaluated by using a milk sample from a PK experiment. The relationship between the AUC/ MIC of cefquinome and bacterial loading reduction was simulated using a Sigmoid Emax model. The cefquinome concentration in milk attained a maximum level of 1.55 ± 0.21 mg/mL at 1.8 h after the third administration. The mean value of the area under the concentration-time curve (AUC0-24) was 26.12 ± 2.42 mg·h/mL after the third administration. The elimination half-life was 10.6 h. For PD profile, the MICs of cefquinome in milk were 2-4 times higher than those in the broth. In vitro time-killing curve shows that initial bacterial concentration has a huge impact on antibacterial effect on three strains. The antibacterial effect was weakened with the initial bacterial concentration increasing from 106 to 108 CFU/mL. The AUC0-24h/MIC index correlated well with ex vivo efficacy both for the initial inoculum of 106 CFU/mL and 108 CFU/mL (R 2 > 0.84). According to the inhibitory sigmoid Emax model analysis, the PK/PD surrogate (AUC0-24/MIC) values were 8,638, 1,397, and 3,851 for bactericidal effect (E = -3) with an initial inoculum of 106 CFU/mL, while the corresponding values were 12,266, 2,295, and 5,337, respectively, with the initial inoculum of 108 CFU/mL. The ex vivo PK/PD based population dose prediction indicated a target attainment rate (TAR) of 90% of 55 mg/gland/12 h. The COPD for cefquinome against S. aureus was 2 μg/mL under the recommended dose of 55 mg/gland/12 h. However, it should be validated in clinical practice in future investigations. These results contribute to the rational use of cefquinome for mastitis treatment in clinical veterinary medicine.


Bilateral endoscopic adrenalectomy for Cushing's syndrome in a patient with polycystic liver and kidney disease.
Microadenomectomy via a transsphenoidal approach is today's treatment of choice to achieve normal cortisol blood levels in patients with ACTH-secreting pituitary tumors. Should neurosurgery fail, bilateral adrenalectomy is recommended. Today the endoscopic, transabdominal or retroperitoneal adrenalectomy is regarded as the gold standard for the operation of endocrine-active adrenal tumors. Therefore, in principle, the question of the indication for the endoscopic operation no longer arises but only the question of the technical feasibility in individual cases. We report on a patient with a pituitary-dependent Cushing's syndrome after a twice-repeated unsuccessful transsphenoidal adenomectomy and with additional polycystic kidney and liver disease, who underwent bilateral retroperitoneoscopic adrenalectomy. Despite the massive enlargement of both kidneys, it was possible to safely perform a bilateral retroperitoneoscopic adrenalectomy. In the case of marked bilateral cystic kidneys, a bilateral retroperitoneoscopic adrenalectomy in Cushing's syndrome is technical possible and a safe and effective method of treatment.


Predicting OncoDx recurrence scores with immunohistochemical markers.
Recent reports suggest that immunohistochemistry (IHC) markers can be used to give prognostic information in breast cancer that is similar to that contained in the Genomic Health Inc. OncoDx recurrence score (Onco-RS). The goal of this study is to examine the potential prognostic value of a score derived from results of a simple set of IHC tests in the prediction of the Onco-RS. A score (IHC-RS) was derived to predict the Onco-RS using IHC-based quantitative and semiquantitative results from a subset of markers selected from those used in the generation of an Onco-RS score. The patient population consists of a retrospectively identified cohort of 158 women with ER-positive, HER2neu-negative breast cancer who completed OncoDx testing. A predictive model was developed to generate the IHC-RS using stepwise multiple regression incorporating Ki67 percentage and semiquantitative ER and PR scores. Using only these 3 IHC markers, the IHC-RS predicted 62% of the Onco-RS variability (adjusted R=0.624, P=0.004). In addition, analysis of outliers in the correlation between the IHC-RS and the Onco-RS reveals the possibility of sampling error as a drawback of the Onco-RS. This is contrasted against potential interlab and intralab variability and preanalytic issues that may negatively impact the implementation of an IHC-RS.


Glucagon-like peptide-1 induces a cAMP-dependent increase of [Na+]i associated with insulin secretion in pancreatic beta-cells.
Glucagon-like peptide-1 (GLP-1) elevates the intracellular free calcium concentration ([Ca2+]i) and insulin secretion in a Na+-dependent manner. To investigate a possible role of Na ion in the action of GLP-1 on pancreatic islet cells, we measured the glucose-and GLP-1-induced intracellular Na+ concentration ([Na+]i), [Ca2+]i, and insulin secretion in hamster islet cells in various concentrations of Na+. The [Na+]i and [Ca2+]i were monitored in islet cells loaded with sodium-binding benzofuran isophthalate and fura 2, respectively. In the presence of 135 mM Na+ and 8 mM glucose, GLP-1 (10 nM) strongly increased the [Na+]i, [Ca2+]i, and insulin secretion. In the presence of 13.5 mM Na+, both glucose and GLP-1 increased neither the [Na+]i nor the [Ca2+]i. In a Na+-free medium, GLP-1 and glucose did not increase the [Na+]i. SQ-22536, an inhibitor of adenylate cyclase, and H-89, an inhibitor of PKA, incompletely inhibited the response. In the presence of both 8 mM glucose and H-89, 8-pCPT-2'-O-Me-cAMP, a PKA-independent cAMP analog, increased the insulin secretion and the [Na+]i. Therefore, we conclude that GLP-1 increases the cAMP level via activation of adenylate cyclase, which augments the membrane Na+ permeability through PKA-dependent and PKA-independent mechanisms, thereby increasing the [Ca2+]i and promoting insulin secretion from hamster islet cells.


Pathways followed by membrane recovered from the surface of plasma cells and myeloma cells.
Evidence for recovery of surface membrane and its fusion with Golgi cisternae has been obtained previously in several glandular cells. This study was conducted to determine whether or not membrane is similarly retrieved from the surfaces of plasma cells from lymph nodes (of rats immunized with horseradish peroxidase [HRP]) and mouse myeloma cells (RPC 5.4 and X63 Ag 8 cell lines). Electron-dense tracers (cationic and anionic ferritin, HRP) were used to trace the pathways followed by surface membrane recovered by endocytosis, and immunocytochemistry was used to identify the secretory compartments. When plasma cells or myeloma cells were incubated with cationized ferritin (CF), it bound to the cell surfaces and was taken up in endocytic vesicles, for the most part bound to the vesicle membrane. After 30-60 min, it was found increasingly within lysosomes and in several secretory compartments- notably in multiple stacked Golgi cisternae and secretory vacuoles. By immunocytochemistry the secretory product (immunoglobulins) and CF could be demonstrated in the same Golgi components. When myeloma cells were incubated with native (anionic) ferritin or in HRP, these tracers were taken up in much smaller amounts, primarily within the contents of endocytic vesicles. With continued incubation, they appeared only in lysosomes. When cells were doubly incubated, first in CF and then in HRP, both tracers were taken up (often within the same endocytic vesicle), but they maintained their same destinations as when incubated in a single tracer alone: the content marker, HRP, was localized exclusively within the lysosomal system, whereas the membrane marker, CF, was found within elements along the secretory pathway as well as within lysosomes. The findings demonstrate the existence of considerable membrane traffic between the cell membrane and the Golgi cisternae and lysosomes in both normal plasma cells and myeloma cells. Because myeloma cells behave like the glandular cells studied previously with regard to pathways of retrieved surface membrane, they represent a suitable and promising system for further studies of mechanisms and pathways of membrane retrieval and recycling in secretory cells.


Salmeterol versus sodium cromoglycate for the protection of exercise induced asthma in children--a randomised cross-over study.
Physical activity is an important and frequent trigger of airways obstruction in asthmatic children. We aimed to compare the efficacies of 50 microg salmeterol twice daily and 2 mg SCG four times daily with respect to protection from exercise induced bronchoconstriction (EIB). Twenty seven children and adolescents aged 4 to 16 years with mild or moderate exercise induced asthma (FEV1 70% to 90% predicted) were admitted to the study. Exercise challenge was performed on a treadmill using a predefined protocol in order to produce 10 minutes of exercise at near-maximum targets. The trial had a randomised, cross-over design comprising a 3-day run-in period and two 7-day treatment periods, separated by a one-week washout period. The mean protective efficacy of salmeterol was larger than that of SCG. A difference between treatments of 39.7% (95% CI, - 0,8 to 68.9%) in favour of salmeterol was calculated using a Hodges-Lehmann-estimate. The maximum post-challenge fall in FEV subset 1 was significantly lower (p<0.001) after salmeterol than after SCG (- 5.6 +/- 6.4% vs. -12.1 +/- 9.3%, respectively). In addition, salmeterol improved base-line lung function to a greater degree than SCG. FEV1 increased by 0.4 l/sec after salmeterol, whereas no improvement was observed after SCG. A one-week treatment with salmeterol 50 microg b.i.d in asthmatic children and adolescents provided better protection against EIB and improved baseline lung function as compared to SCG four times daily.