Study investigating the impact of pharmacist involvement on the outcomes of diabetes medication therapy adherence program Malaysia.
Involvement of pharmacists in improving medication adherence among diabetic patients is recognized globally. In Malaysian healthcare system, pharmacists are also operating health services i.e. Diabetes Medication Therapy Adherence Clinic (DMTAC). This study aimed to assess the clinical outcomes of patients managed by pharmacists (DMTAC), in a Malaysian hospital setting. This was an open labelled randomised study. Type 2 diabetes patients with HbA1c ≥8% were recruited and arbitrarily divided into the intervention group (usual care plus DMTAC) and the non-intervention group (usual care only). Those enrolled in the intervention group were scheduled for follow-up for eight consecutive visits. Improvements in lab results were compared longitudinally (pre and post analysis) between the groups. Data analysis was done using PASW 18® version. A total of 76 patients were enrolled, with 39 patients in the intervention group and 37 patients in the non-intervention group. Mean HbA1c (-0.90% vs. -0.08%, p=0.011) and fasting blood glucose levels (-3.45 mmol.l vs. +0.79 mmol/l, p=0.002) reduced significantly between the intervention group vs. non-intervention group. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were also significantly reduced in the intervention group (TC -0.34 mmol/l, p=0.018) (LDL -0.45 mmol/l, p=0.001). In conclusion, pharmacists managed DMTAC significantly improved glycaemic control and lipid profile of diabetic patients.


Moral parochialism and causal appraisal of transgressive harm in Seoul and Los Angeles.
The evolutionary fitness payoffs of moral condemnation are greatest within an individual's immediate social milieu. Accordingly, insofar as human moral intuitions have been shaped by adaptive design, we can expect transgressive harms to be perceived as more wrong when transpiring in the here and now than when occurring at a distance, or with the approval of local authority figures. This moral parochialism hypothesis has been supported by research conducted in diverse societies, but has yet to be tested in an East Asian society, despite prior research indicating that East Asians appraise transgressive acts as being caused by situational and contextual factors to a greater extent than do Westerners, who tend to emphasize dispositional factors (i.e., the transgressor's personal nature). Here, in a quasi-experiment using field samples recruited in Seoul and Los Angeles, we tested (i) the moral parochialism hypothesis regarding the perceived wrongness of transgressions, as well as (ii) the extent to which these wrongness judgments might be influenced by cross-cultural differences in causal appraisals. Despite notably large differences across the two societies in situational versus dispositional appraisals of the causes of the transgressions, replicating previous findings elsewhere, in both societies we found that transgressions were deemed less wrong when occurring at spatial or temporal remove or with the consent of authorities. These findings add to the understanding of morality as universally focused on local affairs, notwithstanding cultural variation in perceptions of the situational versus dispositional causes of (im)moral acts.


A new species of Androlaelaps (Acari: Parasitiformes) from the akodontine rodent Deltamys kempi Thomas, 1919, in La Plata River Basin, Argentina.
Androlaelaps maurii , a new species of laelapine mite, is described on the basis of female specimens collected from the pelage of the akodontine rodent, Deltamys kempi, from La Plata River basin in Argentina. Androlaelaps maurii can be differentiated from closely related species by its smaller size, the differing distribution of setae in the dorsal shield, and an unarmed opithogaster. This mite appears to be host specific to D. kempi and occurs on this rodent throughout its distribution in Argentina and Uruguay.


Dandy-Walker Malformation in a Girl with DDX3X-Related Intellectual Disability.
We report on a 4-year-old female patient who presented with severe intellectual disability, autistic features, hyperlaxity of joints, and progressive scoliosis. Whole-exome sequencing identified a de novo missense variant (c.976C>T; p.Arg326Cys) in DDX3X. The girl was born with congenital diaphragmatic hernia a finding which had not previously been associated with variants in DDX3X. Her brain MRI showed hypogenesis of corpus callosum, ventriculomegaly, frontal and perisylvian polymicrogyria, and hypoplastic pons in addition to Dandy-Walker malformation. Our results confirmed the phenotype and genotype correlation of missense variants and the polymicrogyria. Moreover, it further expands the knowledge of the phenotypic and molecular features of DDX3X-related intellectual disability.


Association of tellurite resistance with hypervirulent clonal groups of Klebsiella pneumoniae.
Tellurite-based selective growth media are used for several bacterial pathogens. We found that, in Klebsiella pneumoniae, tellurite resistance is strongly associated with hypervirulent clonal group 23 (CG23), CG65, and CG86, providing a novel approach for screening environmental or carriage samples. The terW gene was also associated with these groups.


A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in the death of motor neurons in the brain and spinal cord. The disorder generally strikes in mid-life, relentlessly leading to paralysis and death, typically 3-5 years after diagnosis. No effective treatments are available. Up to 10% of ALS is familial, usually autosomal dominant. Several causative genes are known and, of these, mutant superoxide dismutase 1 (SOD1) is by far the most frequently found, accounting for up to 20% of familial ALS. A range of human mutant SOD1 transgenic mouse strains has been produced, and these largely successfully model the human disease. Of these, the most widely used is the SOD1 mouse, which expresses a human SOD1 transgene with a causative G93A mutation. This mouse model is excellent for many purposes but carries up to 25 copies of the transgene and produces a great excess of SOD1 protein, which might affect our interpretation of disease processes. A variant of this strain carries a deletion of the transgene array such that the copy number is dropped to eight to ten mutant SOD1 genes. This 'deleted' 'low-copy' mouse undergoes a slower course of disease, over many months. Here we have carried out a comprehensive analysis of phenotype, including nerve and muscle physiology and histology, to add to our knowledge of this 'deleted' strain and give baseline data for future studies. We find differences in phenotype that arise from genetic background and sex, and we quantify the loss of nerve and muscle function over time. The slowly progressive pathology observed in this mouse strain could provide us with a more appropriate model for studying early-stage pathological processes in ALS and aid the development of therapies for early-stage treatments.


Association between DIO2 polymorphism and the risk of Kashin-Beck disease in the Tibetan population.
Kashin-Beck disease (KBD) is a local, multiple and deformable osteoarthropathy, mostly occurring in Tibet. Type 2 iodothyronine deiodinase (DIO2) is implicated in the activation of thyroid hormones to which the bones are very sensitive. Therefore, it is necessary to explore the association between KBD and DIO2 in the Tibetan population. We carried out a case-control study among 316 cases and 320 controls from a Tibetan population. Seven single nucleotide polymorphisms in DIO2 were selected and genotyped using the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. HaploReg (https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php) and GTEx (http://www.gtexportal.org) databases were applied for functional assessment of the polymorphisms. The "A/C" genotype of rs1352815 (OR = 3.18, 95% CI = 1.14-8.85, p = 0.027) and the "A/G" genotype of rs1388382 (OR = 3.80, 95% CI = 1.30-11.11, p = 0.015) were associated with the susceptibility of KBD under the co-dominant model. With gender stratification analysis, rs1388382 showed obvious evidence for correlation with an elevated risk of KBD in females under the co-dominant model (OR = 3.32, 95% CI = 1.06-10.41, p = 0.039). The results obtained in the present study indicate that DIO2 polymorphisms rs1352815 and rs1388382 were correlated with KBD susceptibility among Tibetans, which also sheds new light on the role of DIO2 in the development of KBD.


Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression.
Therapeutic cancer vaccines represent a new class of agents in the treatment of cancer. Sipuleucel-T is an antigen-presenting cell-based vaccine that recently demonstrated a significant 4.8-month improvement in overall survival in advanced prostate cancer patients and was well tolerated. The findings of that study have been met with skepticism, primarily because the agent did not change initial disease progression and yet led to longer survival. Although the commonly accepted treatment paradigm suggests that treatments should initially decrease tumor volume, perhaps vaccines work differently. Vaccines may induce delayed responses not seen in the first few months of therapy or they may initiate a dynamic immune response that ultimately slows the tumor growth rate, resulting in longer survival. Subsequent therapies may also combine with the induced immune response, resulting in a combination that is more effective than conventional treatments alone. Also, other treatments may alter tumor-associated antigen expression, enhancing the immune response. Future trials are currently planned to investigate these hypotheses; however, the results of the sipuleucel-T vaccine in prostate cancer should not be dismissed. Results with another vaccine in prostate cancer are similar, perhaps suggesting a class effect. In a broader context, clinicians may need to reconsider how they measure success. Several agents have been approved that produce superior disease progression results, but do not affect overall survival. Given the toxicity and costs of cancer therapies, perhaps studies should put more weight on long-term survival endpoints than on short-term endpoints that may be less consequential.


Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia.
Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.


Ergonomic analysis of construction worker's body postures using wearable mobile sensors.
Construction jobs are more labor-intensive compared to other industries. As such, construction workers are often required to exceed their natural physical capability to cope with the increasing complexity and challenges in this industry. Over long periods of time, this sustained physical labor causes bodily injuries to the workers which in turn, conveys huge losses to the industry in terms of money, time, and productivity. Various safety and health organizations have established rules and regulations that limit the amount and intensity of workers' physical movements to mitigate work-related bodily injuries. A precursor to enforcing and implementing such regulations and improving the ergonomics conditions on the jobsite is to identify physical risks associated with a particular task. Manually assessing a field activity to identify the ergonomic risks is not trivial and often requires extra effort which may render it to be challenging if not impossible. In this paper, a low-cost ubiquitous approach is presented and validated which deploys built-in smartphone sensors to unobtrusively monitor workers' bodily postures and autonomously identify potential work-related ergonomic risks. Results indicates that measurements of trunk and shoulder flexions of a worker by smartphone sensory data are very close to corresponding measurements by observation. The proposed method is applicable for workers in various occupations who are exposed to WMSDs due to awkward postures. Examples include, but are not limited to industry laborers, carpenters, welders, farmers, health assistants, teachers, and office workers.


Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs: 18F-Fluorodeoxyglucose Positron Emission Tomography Imaging Study.
Although coronary perivascular adipose tissue (PVAT) may play important roles as a source of inflammation, the association of coronary PVAT inflammation and coronary hyperconstricting responses remains to be examined. We addressed this important issue in a porcine model of coronary hyperconstricting responses after drug-eluting stent implantation with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomographic imaging. An everolimus-eluting stent (EES) was randomly implanted in pigs into the left anterior descending or the left circumflex coronary artery while nonstented coronary artery was used as a control. After 1 month, coronary vasoconstricting responses to intracoronary serotonin (10 and 100 μg/kg) were examined by coronary angiography in vivo, followed by in vivo and ex vivo 18F-FDG positron emission tomographic/computed tomographic imaging. Coronary vasoconstricting responses to serotonin were significantly enhanced at the EES edges compared with the control site (P<0.01; n=40). Notably, in vivo and ex vivo 18F-FDG positron emission tomographic/computed tomographic imaging and autoradiography showed enhanced 18F-FDG uptake and its accumulation in PVAT at the EES edges compared with the control site, respectively (both P<0.05). Furthermore, histological and reverse transcription polymerase chain reaction analysis showed that inflammatory changes of coronary PVAT were significantly enhanced at the EES edges compared with the control site (all P<0.01). Importantly, Rho-kinase expressions (ROCK1/ROCK2) and Rho-kinase activity (phosphorylated myosin phosphatase target subunit-1) at the EES edges were significantly enhanced compared with the control site. These results indicate for the first time that inflammatory changes of coronary PVAT are associated with drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo and that 18F-FDG positron emission tomographic imaging is useful for assessment of coronary PVAT inflammation.


[A 47-year-old dog breeder with chronic polyarthritis, weight loss and high fever].
A 47-year-old dog breeder had suffered from unclassified polyarthritis for four years. During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and Adalimumab he developed severe systemic inflammatory disease with high fever, weight loss, and severe arthralgia. Fever and arthralgias temporarily improved under antibiotic therapy, although a causative organism had not been found. The clinical picture led to the differential diagnosis of Whipple's disease, but PAS-positive macrophages were not detected in duodenal biopsies. The diagnosis was finally based on a positive PCR result for Tropheryma whipplii, typical clinical symptoms and a complete response on adequate antibiotic long-term treatment with cotrimoxazol. The diagnosis of Whipple's disease was possibly masked by the initial antibiotic therapies. Therapies with immunomodulators, TNF-inhibitors, and corticosteroids may transform an infection with Tropheryma whipplii, normally in a subacute stage, into a septic, life-threatening disease.


Comparative study of the folding/unfolding dynamics of poly(glutamic acid) in light and heavy water.
The folding/unfolding equilibrium is investigated in poly(glutamic acid) (PGA) by two complementary sets of experiments: temperature-dependent steady-state circular dichroism spectra on the one hand and time-resolved circular dichroism measurements coupled with a T-jump experiment on the other hand. The experiments are performed for PGA dissolved in water for various pH values, as well as in heavy water. The kinetic and thermodynamic parameters extracted from these measurements are shown to be markedly different between light and heavy water, which is assigned to the difference in hydrogen bond energies in both solvents.


CBP mediates NF-κB-dependent histone acetylation and estrogen receptor recruitment to an estrogen response element in the BIRC3 promoter.
Estrogen receptor (ER) and NF-κB are transcription factors with profound effects on breast cancer cell proliferation and survival. While many studies demonstrate that ER and NF-κB can repress each other, we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors. Herein, we examine a novel mechanism of cross talk between ER and NF-κB that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-κB, acting through two response elements, is required for ER recruitment to an adjacent estrogen response element (ERE) in the BIRC3 promoter. This effect is accompanied by a major increase in NF-κB-dependent histone acetylation around the ERE. Interestingly, CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-κB, plays a permissive role by promoting histone acetylation and ER recruitment, as well as enhanced expression of BIRC3. These findings suggest a new gene regulatory mechanism by which inflammation and NF-κB activation can influence ER recruitment to inherently inactive ER binding sites. This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression.


Small Cell Carcinoma in the Head and Neck.
Small cell carcinomas in extrapulmonary sites (ESmCCs) are very rare. ESmCCs originating in the head and neck account for approximately 10% of all ESmCCs, and there are few reports about this disease. ESmCCs have an aggressive natural history characterized by widespread metastasis. The aim of this study was to investigate the characteristics and outcomes of patients with ESmCCs of the head and neck. The outcomes of 21 patients with ESmCCs of the head and neck treated between January 2001 and December 2015 at the authors' hospital and associated facilities were reviewed. There were 18 men and 3 women, and the median age was 74 years (range, 53-91 years). The tumor site was the larynx in 6 patients; the paranasal sinus in 5; the hypopharynx in 3; the oropharynx in 2; the nasopharynx in 2; and the oral cavity, salivary gland, and primary unknown in 1 patient each. The extent of the disease was staged as follows: stage I or II, 3 cases; stage III, 4 cases; stage IVA, 9 cases; stage IVB, 1 case; and stage IVC, 4 cases. The median observation time was 17 months (range, 1-103 months). Four patients (19%) had distant metastasis at initial treatment, and 13 patients (62%) developed distant metastasis within 3 years. Treatments were administered, including radical surgery (9 patients), radiation therapy (5 patients), chemoradiotherapy (7 patients), and chemotherapy (6 patients). The 1- and 3-year overall survival rates of patients were 56% and 37%, respectively. More than half of the patients died of distant metastasis. ESmCCs of the head and neck have a poor prognosis, similar to those of carcinomas in many other sites. Control of distant metastasis would contribute to improving the prognosis of ESmCCs of the head and neck. Further studies are required for better understanding these disease entities and their response to treatment modalities.


Proteomics analysis of the brain from a Gaucher disease mouse identifies pathological pathways including a possible role for transglutaminase 1.
Gaucher disease (GD) is a lysosomal storage disorder (LSD) caused by the defective activity of acid β-glucosidase (GCase) which results from mutations in GBA1. Neurological forms of GD (nGD) can be generated in mice by intra-peritoneal injection of conduritol B-epoxide (CBE) which irreversibly inhibits GCase. Using this approach, a number of pathological pathways have been identified in mouse brain by RNAseq. However, unlike transcriptomics, proteomics gives direct information about protein expression which is more likely to provide insight into which cellular pathways are impacted in disease. We now perform non-targeted, mass spectrometry-based quantitative proteomics on brains from mice injected with 50 mg/kg body weight CBE for 13 days. Of the 5038 detected proteins, 472 were differentially expressed between control and CBE-injected mice of which 104 were selected for further analysis based on higher stringency criteria. We also compared these proteins with differentially expressed genes (DEGs) identified by RNAseq. Some lysosomal proteins were up-regulated as was interferon signaling, whereas levels of ion channel related proteins and some proteins associated with neurotransmitter signaling were reduced, as was cholesterol metabolism. One protein, transglutaminase 1 (TGM1), which is elevated in a number of neurodegenerative diseases, was absent from the control group but was found at high levels in CBE-injected mice, and located in the extracellular matrix (ECM) in layer V of the cortex and intracellularly in Purkinje cells in the cerebellum. Together, the proteomics data confirm previous RNAseq data and add additional mechanistic understanding about cellular pathways that may play a role in nGD pathology.


Ankle Torque Estimation With Motor Unit Discharges in Residual Muscles Following Lower-Limb Amputation.
There has been increased interest in using residual muscle activity for neural control of powered lower-limb prostheses. However, only surface electromyography (EMG)-based decoders have been investigated. This study aims to investigate the potential of using motor unit (MU)-based decoding methods as an alternative to EMG-based intent recognition for ankle torque estimation. Eight people without amputation (NON) and seven people with amputation (AMP) participated in the experiments. Subjects conducted isometric dorsi- and plantarflexion with their intact limb by tracing desired muscle activity of the tibialis anterior (TA) and gastrocnemius (GA) while ankle torque was recorded. To match phantom limb and intact limb activity, AMP mirrored muscle activation with their residual TA and GA. We compared neuromuscular decoders (linear regression) for ankle joint torque estimation based on 1) EMG amplitude (aEMG), 2) MU firing frequencies representing neural drive (ND), and 3) MU firings convolved with modeled twitch forces (MUDrive). In addition, sensitivity analysis and dimensionality reduction of optimization were performed on the MUDrive method to further improve its practical value. Our results suggest MUDrive significantly outperforms (lower root-mean-square error) EMG and ND methods in muscles of NON, as well as both intact and residual muscles of AMP. Reducing the number of optimized MUDrive parameters degraded performance. Even so, optimization computational time was reduced and MUDrive still outperformed aEMG. Our outcomes indicate integrating MU discharges with modeled biomechanical outputs may provide a more accurate torque control signal than direct EMG control of assistive, lower-limb devices, such as exoskeletons and powered prostheses.


Induction of acute thrombocytopenia and infection of megakaryocytes by Rauscher murine leukemia virus reflect the genetic susceptibility to leukemogenesis.
Acute thrombocytopenia and megakaryocyte infection have been investigated during the preleukemic phase of the disease induced by the Rauscher murine leukemia virus (RMuLV) in mice. Injection of RMuLV, either intravenously or intraperitoneally, rapidly induced thrombocytopenia, possibly as a result of direct interaction between platelets and viral particles. The susceptibility to this acute thrombocytopenia was genetically controlled and was inherited as a dominant trait. Murine strains with H-2d or H-2k haplotype, which are susceptible to the induction of leukemia by RMuLV, developed thrombocytopenia, whereas leukemia-resistant H-2b and H-2q strains of mice failed to develop thrombocytopenia. Using B10 H-2-congenic and intra-H-2-recombinant mice, it was shown that the susceptibility to RMuLV-induced thrombocytopenia was controlled by gene(s) in or closely linked to the D region of the H-2 complex. Megakaryocytes may be one of the first sites for the replication of RMuLV. Indeed, among bone marrow cells, only megakaryocytes expressed viral antigens gp70 and p30 during the initial phase of RMuLV infection. In addition, megakaryocytes from infected mice were able to transfer preleukemic thrombocytopenia as well as leukemia in syngeneic mice. The infection of megakaryocytes by RMuLV appears to be genetically controlled in a manner similar to the induction of thrombocytopenia, since only the megakaryocytes from mice developing thrombocytopenia were infected by RMuLV. These results indicate that the gene(s) governing the induction of thrombocytopenia by RMuLV may be the same gene(s) (or closely linked to the gene) that controls the susceptibility to leukemogenesis, and would be consistent with the expression of the gene product, presumably a receptor-like molecule for RMuLV, on platelet and megakaryocyte membranes.


Generation of isogenic models of Angelman syndrome and Prader-Willi syndrome in CRISPR/Cas9-engineered human embryonic stem cells.
Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS.


An outcome and cost analysis of anal fistula plug insertion vs endorectal advancement flap for complex anal fistulae.
The study aimed to compare the rate of success and cost of anal fistula plug (AFP) insertion and endorectal advancement flap (ERAF) for anal fistula. Patients receiving an AFP or ERAF for a complex single fistula tract, defined as involving more than a third of the longitudinal length of of the anal sphincter, were registered in a prospective database. A regression analysis was performed of factors predicting recurrence and contributing to cost. Seventy-one patients (AFP 31, ERAF 40) were analysed. Twelve (39%) recurrences occurred in the AFP and 17 (43%) in the ERAF group (P = 1.00). The median length of stay was 1.23 and 2.0 days (P < 0.001), respectively, and the mean cost of treatment was €5439 ± €2629 and €7957 ± €5905 (P = 0.021), respectively. On multivariable analysis, postoperative complications, underlying inflammatory bowel disease and fistula recurring after previous treatment were independent predictors of de novo recurrence. It also showed that length of hospital stay ≤ 1 day to be the most significant independent contributor to lower cost (P = 0.023). Anal fistula plug and ERAF were equally effective in treating fistula-in-ano, but AFP has a mean cost saving of €2518 per procedure compared with ERAF. The higher cost for ERAF is due to a longer median length of stay.


Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta.
Plasmodium falciparum infection during pregnancy results in the accumulation of infected red blood cells (IRBCs) in the placenta, leading to poor pregnancy outcome. In the preceding paper (Achur, R. N., Valiyaveettil, M., Alkhalil, A., Ockenhouse, C. F., and Gowda, D. C. (2000) J. Biol. Chem. 275, 40344-40356), we reported that unusually low sulfated chondroitin sulfate proteoglycans (CSPGs) in the intervillous spaces of the placenta mediate the IRBC adherence. In this study, we report the structural requirements for the adherence and the minimum chondroitin 4-sulfate (C4S) structural motif that supports IRBC adherence. Partially sulfated C4Ss with varying sulfate contents were prepared by solvolytic desulfation of a fully sulfated C4S. These and other nonmodified C4Ss, with different proportions of 4-, 6-, and nonsulfated disaccharide repeats, were analyzed for inhibition of IRBC adherence to the placental CSPG. C4Ss containing 30-50% 4-sulfated and 50-70% nonsulfated disaccharide repeats efficiently inhibited IRBC adherence; C6S had no inhibitory activity. Oligosaccharides of varying sizes were prepared by the partial depolymerization of C4Ss containing varying levels of 4-sulfation, and their ability to inhibit the IRBC adherence was studied. Oligosaccharides with six or more disaccharide repeats inhibited IRBC adherence to the same level as that of the intact C4Ss, indicating that a dodecasaccharide is the minimum structural motif required for optimal IRBC adherence. Of the C4S dodecasaccharides, only those with two or three sulfate groups per molecule showed maximum IRBC inhibition. These data define the structural requirements for the IRBC adherence to placental CSPGs with implications for the development of therapeutics for maternal malaria.


Reduction in impulse noise-induced permanent threshold shift with intracochlear application of an NADPH oxidase inhibitor.
Toxic levels of reactive oxygen species are key contributors to the lesion of dead outer hair cells (OHCs) seen in the cochlea after noise exposure. The current study follows previous work in which paraquat was used to demonstrate that NADPH oxidase is active in the cochlea and can contribute to cochlear reactive oxygen species formation and hair cell loss. The current study was undertaken to test whether pharmacological blockade of NADPH oxidase in the cochlea would lead to reduced noise-induced hearing loss and OHC death. A total of 18 chinchillas (36 ears) were assessed in the study. AEBSF (4-[2-aminoethyl]benzenesulfonyl fluoride), an inhibitor of NADPH oxidase activation, was dissolved in distilled water and delivered into the cochlea via diffusion across the round window membrane. The contralateral ears received distilled water as a vehicle control. Following treatment, chinchillas were exposed to one of two noises: a 4 kHz octave band noise at 106 dB SPL for 6 hr or an impulse noise that consisted of 75 pairs of 155 dB pSPL impulses. Pre- and post-noise exposure, thresholds of the auditory brainstem response at 2-8 kHz were measured. Postmortem OHC counts were conducted at the conclusion of the study. Two- and three-factor ANOVAs were used for statistical analysis of the OHC losses and ABR threshold shifts induced by the noise exposures. Permanent threshold shift from the impulse noise was reduced in the ears treated with the NADPH oxidase inhibitor, but no differences were found in the groups exposed to the continuous noise. OHC losses were not statistically different between the treated and untreated ears for either noise exposure. The results suggest that NADPH oxidase-mediated superoxide has a role in cochlear damage from impulse noise, and pharmacologic inhibition of NADPH oxidase can reduce cochlear susceptibility to noise damage. The lack of protection from the longer-duration continuous noise can be attributed to a number of possibilities related to dose level and delivery schedule.


Metabolic syndrome and the risk of abdominal aortic aneurysm: A nationwide cohort study.
The association between metabolic syndrome (MetS) and abdominal aortic aneurysm (AAA) remains unclear. We investigated the potential association between AAA and MetS and its components in a large population-based cohort. We used the Korean National Health Insurance Service database including 4,162,640 participants aged ≥50 years who received a routine health examination in 2009. Cox proportional hazards models were used to analyze the association between MetS and its components (elevated waist circumference, blood pressure, glucose, triglycerides, and reduced high-density lipoprotein cholesterol [HDL-C]) with AAA incidence, with adjustment for confounders. During a median 9.4 years of follow-up, 18,160 participants developed incident AAA. MetS was associated with an increased risk of AAA compared to the non-MetS group (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.34-1.43). Among the individual components, elevated waist circumference, blood pressure, triglycerides, and reduced HDL-C were associated with increased AAA risk, while elevated glucose alone was associated with reduced AAA risk (aHR, 0.85; 95% CI, 0.82-0.87). AAA risk also increased linearly with the increasing number of MetS components, with the highest risk found in the presence of all 5 components (aHR, 1.98, 95% CI, 1.83-2.15). MetS and its individual components, with the exclusion of elevated glucose, were associated with higher risk of AAA. Further studies are warranted to elucidate the association between MetS and AAA.


Liver development and regeneration: from laboratory study to clinical therapy.
The liver has an unusual capacity to regenerate after a loss of mass and function caused by surgical resection or toxic liver injury. Over the last 10 years there have been major advances in our understanding of the molecular and cellular mechanisms underlying liver development and regeneration. The numerous factors crucial to these phenomena have been identified mainly by using knockout mice. Forward-genetics studies using zebrafish and medaka have also generated many mutants with liver disorders or defects in liver formation. Our goal is to translate knowledge gained from laboratory work and animal models into novel therapies for human liver diseases. Exciting progress has been achieved using human partial liver transplantation and autologous cell therapy.


Triglyceride glucose index and common carotid wall shear stress.
Alterations in wall shear stress contribute to both clinical and subclinical atherosclerosis. Several conditions such as hypertension, diabetes, and obesity can impair shear stress, but the role of insulin resistance has never been investigated. The present study was designed to investigate whether insulin resistance assessed by TyG Index associates with wall shear stress in the common carotid artery. One hundred six individuals were enrolled. Blood pressure, lipids, glucose, and cigarette smoking were evaluated. TyG Index was calculated as log[fasting triglycerides × fasting glucose / 2]. Subjects underwent blood viscosity measurement and echo-Doppler evaluation of carotid arteries to calculate wall shear stress. The association between TyG Index and carotid wall shear stress was assessed by simple and multiple regression analyses. TyG Index was significantly and inversely associated with carotid wall shear stress both in simple (r = -0.44, P < 0.001) and multiple regression analyses accounting for age, sex, and major cardiovascular risk factors. The association was further confirmed after exclusion of subjects with diabetes, dyslipidemia, fasting blood glucose greater than 100 mg/dL, and triglycerides greater than 150 mg/dL. The present findings suggest that increasing insulin resistance, as assessed by TyG Index, associates with atherosclerosis-prone shear stress reduction in the common carotid artery.


[Comparison of the data of computed tomography and bacteriological studies in the complicated forms of primary tuberculosis in children and adolescents].
To establish the causes of bacterial excretion in complicated primary tuberculosis in children and adolescents, by comparing the data of computed tomography and the results of bacteriological studies. The material of the study was data on 36 children and adolescents with complicated primary tuberculosis, including 14 and 22 children and adolescents with and without bacterial excretion, respectively. All the children and adolescents underwent computed tomography and bacteriological studies encompassing luminescence microscopy and sputum and bronchial and gastric wash cultures for Mycobacterium tuberculosis. The bacterial excretion group showed a preponderance of a tuberculous process concurrent with the involvement of lung tissue and intrathoracic lymph nodes. Bacterial excretion was detected in the primary tuberculosis complex (50%), generalized tuberculosis process with the involvement of a few organs and systems (14.3%), and caseous pneumonia (7.1%). Bacterial excretion was accompanied by the tuberculous involvement of intrathoracic lymph nodes in 28.6%. In Group 1, sputum cultures and luminescence microscopy were carried out in all the children. At the same time, the most effective result was yielded by sputum culture that showed Mycobacterium tuberculosis in 78.6%; luminescence microscopy revealed mycobacteria in only 35.7% of cases. In 72.7% of the children and adolescents without bacterial excretion, the tuberculous process was located in the intrathoracic lymph nodes, without involving lung tissue in the pathological process. In the other 27.3%, the computed tomographic pattern of changes corresponded to that of the primary tuberculosis complex; in their presence, the tuberculous process ran with lymphogenic dissemination in 54.5% of cases and with bronchopulmonary involvement in 22.7%. In Group 2, a sputum culture was done in only 36.4% of the children and adolescents; microscopy was carried out in all. When computed tomography reveals the disseminated forms of primary tuberculosis with the concomitant involvement of lung tissue and intrathoracic lymph nodes in the presence of lung destructive changes, with the involvement of a few organs and systems in the pathological process, it is necessary to use all bacteriological studies, including culnolecular genetic methods, in order to establish the etiology of existing changes.


[The meaning of the Weber-Fechner Law IV. The psychometric curve, the interaction between inter hemisphere and the interaction in intrahemisphere].
The subject was presented with a pair of lines. One line was an objective referent line Ro and did not change its length. The other was a test line and changed the its length. The observer must report--where the longer line was--above or below in the pair. On the basis neurophysiological, psychophysical data and new type of the psychometrical curve a complex neuronal construction was built. The comparison of action of the neuronal construction with the psychophysical data on different stages of introduction the visual information showed that in both cases at first stages of introduction the information referent subjective stimulus Rs is not equal to Ro. But at the last stages, when Weber's fraction is obtained Rs = Ro. This result allows to suggest that the suggested neuronal contraction is near to the real constriction of the visual brain.


Blockade of Ghrelin Receptor Signaling Enhances Conditioned Passive Avoidance and Context-Associated cFos Activation in Fasted Male Rats.
Interoceptive feedback to the brain regarding the body's physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. Ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. GRA restored passive avoidance in fasted rats as measured by both latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before reexposure to the shock-paired context displayed more cFos activation of prolactin-releasing peptide (PrRP)-positive noradrenergic (NA) neurons in the caudal nucleus of the solitary tract, accompanied by more cFos activation in downstream target sites of PrRP neurons (i.e., bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus). These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive NA neurons and their downstream hypothalamic and limbic forebrain targets.


Surface markers of human lymphocytes.
The large accumulation of data on serum immunoglobulins (Igs) has made it possible to delineate readily the special membrane Ig receptors that respond to antigenic stimulation. B type lymphocytes are characterized by the selective presence of IgM and IgD. IgG, the main serum Ig, is rarely found and its previous reported presence was due to secondary adsorption. IgM and IgD occur together on the same lymphocytes and show similar or identical variable regions and antigen combining sites. The membrane Igs are positioned on the lymphocyte surface with a cosiderable part of the C-terminal portion of the heavy chains buried in the membrane. In addition to numerous other lymphocyte membrane markers, recent interest has centered on the new histocompatibility surface antigen, HL-B, which appears related to immune response genes and is selectively represented on B cells. Through the use of this group of lymphocyte markers considerable information on the character of the malignant cells in various leukemias and lymphomas has been obtained. Chronic lymphatic leukemia is essentially a proliferation of B cells. Acute lymphoblastic leukemia falls into two groups, a minor type that represents a proliferation of T cells and a major type that appears to show an immature cell type of probable B cells lineage. Various immunodeficiency syndromes have been clarified considerably through lymphocyte analyses and certain defects have been determined.


A family of Candida cell surface haem-binding proteins involved in haemin and haemoglobin-iron utilization.
The ability to acquire iron from host tissues is a major virulence factor of pathogenic microorganisms. Candida albicans is an important fungal pathogen, responsible for an increasing proportion of systemic infections. C. albicans, like many pathogenic bacteria, is able to utilize haemin and haemoglobin as iron sources. However, the molecular basis of this pathway in pathogenic fungi is unknown. Here, we identify a conserved family of plasma membrane-anchored proteins as haem-binding proteins that are involved in haem-iron utilization. We isolated RBT51 as a gene that is sufficient by itself to confer to S. cerevisiae the ability to utilize haemoglobin iron. RBT51 is highly homologous to RBT5, which was previously identified as a gene negatively regulated by the transcriptional suppressor CaTup1. Rbt5 and Rbt51 are mannosylated proteins that carry the conserved CFEM domain. We find that RBT5 is strongly induced by starvation for iron, and that deletion of RBT5 is by itself sufficient to significantly reduce the ability of C. albicans to utilize haemin and haemoglobin as iron sources. Iron starvation-inducible, antigenically cross-reacting haem-binding proteins are also present in other Candida species that are able to utilize haem-iron, underscoring the conservation of this iron acquisition pathway among pathogenic fungi.


Inhibitory effect of the anthelmintic drug pyrvinium pamoate on T315I BCR‑ABL‑positive CML cells.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the BCR‑ABL oncogene, which encodes a constitutively activated tyrosine kinase. Despite progress in controlling CML at the chronic phase by first and second generations of BCR‑ABL tyrosine kinase inhibitors (TKIs), effective drugs with good safety are not available for CML patients harboring T315I BCR‑ABL and those in advanced stages of CML. Therefore, there is an urgent requirement for the development of effective therapies against T315I BCR‑ABL. In the present study, it was demonstrated that pyrvinium pamoate, an anthelmintic drug approved by the Food and Drug Administration had potent inhibitory effects on growth and survival in CML cells with T315I BCR‑ABL. In addition, this agent was equally effective in inhibiting the Wnt/β‑catenin signaling in wild‑type and T315I BCR‑ABL CML cells. Thus, the clinical efficacy of pyrvinium pamoate in treating patients with CML bearing T315I BCR‑ABL should be further investigated.


Epidemiology of Injuries in Women's Lacrosse: Implications for Sport-, Level-, and Sex-Specific Injury Prevention Strategies.
By the end of 2013, the United States had an estimated 278 000 female lacrosse players, with half of those participating at the youth level. The effects of the sport's rapid growth on injury rates have yet to be determined. The purpose of this clinical review is to synthesize the available published data on injuries that have occurred in the sport of women's lacrosse. Of particular interest was the risk of injury based on the level of play and position. A comprehensive literature search was performed in PubMed, High Wire Press, SPORTDiscus, Google Scholar, and Ovid using the keywords "Lacrosse Injuries," "Epidemiology Lacrosse Injuries," "Lacrosse Injury," "Lacrosse," and "Injury." The electronic search included material published during or after 1950. In addition, all bibliographies of electronically found sources were cross-referenced to identify any additional publications that were not produced in the electronic searches. All articles with data on women's injury rates were categorized by overall injury rates, rates by session (competition vs practice), nature of injury, location, type, severity, and player position. Injury rates increase with age: from youth leagues to high school and finally to the collegiate level. Rates of injury varied from 0.03 to 3.9 injuries/100 athletes. Women's game injury rates are consistently higher than practice injury rates (ranging from 0.2 to 7.1 vs 0.01 to 3.3). Injuries occur most frequently from stick-to-player or player-to-ball contact, rather than player-to-player contact. Women sustain a higher percentage of head and facial injuries relative to male lacrosse players. The most common types of injuries for women are concussions, sprains, contusions, and lacerations. More than half of all injuries are in the mild category resulting in players missing practice and games for 1 to 7 days. Offensive players had the most injuries, followed by defensive players and then midfielders, with goalies having the fewest number of injuries. In women's lacrosse, the rules and equipment used are substantially different than for the men's game. Face and hand injuries are more prevalent for women when compared with men, and ankle injuries are most prevalent in female youth. Medical professionals who treat lacrosse players can benefit from an improved understanding of the types and rates of the injuries they are likely to encounter. Improved awareness of lacrosse-specific injuries can assist these professionals to be more prepared to treat these athletes, which may lead to improved care and outcomes.


Inactivation of triosephosphate isomerase from Trypanosoma cruzi by an agent that perturbs its dimer interface.
We characterized by crystallographic, calorimetric and biochemical methods the action of a low molecular weight compound, 3-(2-benzothiazolylthio)-1-propanesulfonic acid (compound 8) that binds to the dimer interface of triosephosphate isomerase from Trypanosoma cruzi (TcTIM) and thereby abolishes its function with a high level of selectivity. The kinetics of TcTIM inactivation by the agent and isothermal titration calorimetry experiments showed that the binding of two molecules of the compound per enzyme is needed for inactivation. The binding of the first molecule is endothermic, and that of the second exothermic. Crystals of TcTIM in complex with one molecule of the inactivating agent that diffracted to a resolution of 2A were obtained. The compound is at the dimer interface at less than 4A from residues of the two subunits. Compound 8 is more effective at low than at high protein concentrations, indicating that it perturbs the association between the two TcTIM monomers. Calorimetric and kinetic data of experiments in which TcTIM was added to a solution of the inactivating agent showed that at low concentrations of the compound, inactivation is limited by binding, whereas at high concentrations of the agent, the events that follow binding become rate-limiting. The portion of the interface of TcTIM that binds the benzothiazole derivative and its equivalent region in human TIM differs in amino acid composition and hydrophobic packing. Thus, we show that by focusing on protein-protein interfaces, it is possible to discover low molecular weight compounds that are selective for enzymes from parasites.


Antithrombin-heparin covalent complex: a possible alternative to heparin for arterial thrombosis prevention.
The anticoagulant effect of heparinoids is attributed to their cofactor activity for antithrombin (AT) and heparin cofactor II. In patients with thrombosis, however, thrombin is often protected from AT-dependent, heparin-mediated inactivation. The purpose of this study was to compare the properties of unfractionated/standard heparin (UFH/SH) and those of a novel covalent AT-heparin complex (ATH) in a rabbit arterial thrombosis prevention and bleeding model. Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored with a flow probe placed distal to the constrictor. Rabbits were given doses of SH (62.5 to 187.5 IU x kg(-1) x 90 min(-1)) or ATH (16 to 65 IU x kg(-1) x 90 min(-1)). Cumulative blood loss from skin incisions was used to assess drug safety. The antithrombotic effects of ATH were greater than those of SH as measured by clot weight, blood flow, and vessel patency; eg, complete thrombus resolution was achieved with ATH (33 to 65 IU/kg), but not SH (125.0 to 187.5 IU/kg). At doses that produced equivalent vessel patency (50% to 60%), blood loss induced by ATH (60.2 microL) was 2.6-fold lower (P<0.05) than that induced by SH (154.6 microL). In our experimental system, ATH was able to control arterial thrombosis more effectively than its SH precursor, without pronounced bleeding.


[Determination of the biological activity of aminoglycoside antibiotics on a dry nutrient medium of Soviet manufacture].
Possible use of the dry nutrient medium manufactured in the USSR for the assay of aminoglycoside antibiotic activity with the agar diffusion method was studied. The optimal conditions for the antibiotic activity assay on this medium were developed. The dry nutrient medium may be used for the activity assay of the aminoglycoside antibiotics, i. e. streptomycin sulfate, dihydrostreptomycin sulfate, neomycin sulfate, monomycin and gentamicin sulfate.


MEK inhibitor effective against proliferation in breast cancer cell.
The targeted small-molecule drug AZD6244 is an allosteric, ATP-noncompetitive inhibitor of MEK1/2 that has shown activity against several malignant tumors. Here, we report that AZD6244 repressed cell growth and induced apoptosis and G1-phase arrest in the breast cancer cell lines MDA-MB-231 and HCC1937. Using microRNA (miRNA) arrays and quantitative RT-PCR, we found that miR-203 was up-regulated after AZD6244 treatment. In accordance with bioinformatics and luciferase activity analyses, CUL1 was found to be the direct target of miR-203. Furthermore, miR-203 inhibition and CUL1 overexpression reversed the cytotoxicity of AZD6244 on the MDA-MB-231 and HCC1937 cells. Collectively, our data indicate that miR-203 mediates the AZD6244-induced cytotoxicity of breast cancer cells and that the MEK/ERK/miR-203/CUL1 signaling pathway may participate in this process.


[Pharmacological and pharmaceutical foundation of nanodrugs].
Literary data and results of own investigations about pharmacological and pharmaceutical grounds of nanodrugs are analyzed in the article. Main requirements to nanodrugs are summarized. (1) To have much more expressed effect in comparison with drugs used in a medicinal practice. (2) New nanodrug mustn't have adverse reactions. (3) Nanodrugs must decrease adverse effects of other drugs. (4) Nanodrugs mustn't negatively influence on clinic-pharmacological properties of drugs used in medicinal practice forthe treatment of different disorders. (5) One of the requirements to nanodrugs is positive pharmacoeconomic parameters. (6) Medicinal form of nanodrug must be usable for different ways of drug administration. (7) Technology of drug production should be inexpensive, without negative influence on ecology. Comprehensive experimental researches of nanoparticle pharmacodynamics and pharmacokinetics in the human body and its influence on environment should be done. A new technology of obtaining nanoparticles of iron oxide, silver, copper and their composites has been developed in the laboratory of electron-beam nanotechnology of nonorganic materials for medicine. It was shown, that nanoparticles of iron and silver oxide have more significant antimicrobial activity than oxides of these metals in normal size.


Treatment with gefitinib or lapatinib induces drug resistance through downregulation of topoisomerase IIα expression.
The EGF receptor (EGFR) is therapeutically targeted by antibodies and small molecules in solid tumors including lung, colorectal, and breast cancer. However, chemotherapy remains important, and efforts to improve efficacy through combination with targeted agents is challenging. This study examined the effects of short and long durations of exposure to the EGFR- and HER2-targeted tyrosine kinase inhibitors (TKI) gefitinib and lapatinib, on induction of cell death and DNA damage by topoisomerase IIα (Topo IIα) poisons, in the SK-Br-3 HER2-amplified breast cancer cell line. Short exposure to either gefitinib or lapatinib for 1 hour did not affect the induction of apoptosis by the Topo IIα poisons doxorubicin, etoposide, and m-AMSA. In contrast, cells treated for 48 hours were resistant to all three drugs. Short exposure (1 hour) to TKI did not alter the number of DNA single- or double-strand breaks (DSB) induced, whereas longer exposure (48 hours) reduced the number of DNA DSBs and the formation of γ-H2AX foci. Both gefitinib and lapatinib reduced the expression and activity of Topo IIα at 48 hours. Studies using a cell line with inducible downregulation of Topo IIα showed that expression of Topo IIα, and not Topo IIβ, determined the number of DNA strand breaks induced by these chemotherapeutic agents. These results indicate that prolonged exposure to TKIs targeting EGFR and HER2 induce resistance to doxorubicin, etoposide, and m-AMSA through downregulation of Topo IIα. This may explain why their addition to chemotherapy regimens have not increased efficacy.


Sevoflurane reverses cisplatin resistance in neuroblastoma cells through the linc00473/miR-490-5p/AKT1 axis.
To determine whether sevoflurane regulates cisplatin resistance in neuroblastoma cells. The SH-SY5Y cell line with cisplatin-resistant phenotype (SH-SY5Y-SR) was generated. Cells were co-treated with sevoflurane and cisplatin to seek the sevoflurane function on cisplatin resistance. Key targets of sevoflurane treatment were determined using sequencing (ribonucleic acid [RNA-seq]). Cells were then transfected with specific vectors. Linc00473 and microRNA-490-5p (miR-490-5p) levels were detected using reverse transcriptase quantitative real-time reverse transcription PCR (RT-qPCR). Linc00473-miR-490-5p binding was confirmed using a luciferase reporter-gene assay. After treatment, cell proliferation, viability, and caspase-3 activity were measured to determine the effects of treatment on tumor cells. Each experimental result is based on three independent experiments. Co-treatment with sevoflurane and cisplatin markedly improved the sensitivity of SH-SY5Y-SR cells to cisplatin, which inhibited the occurrence of cisplatin resistance. The RNA-sequencing analysis and RT-qPCR showed that sevoflurane inhibited linc00473 expression. Overexpression of linc00473 promoted cell proliferation, inhibited apoptosis, and promoted cisplatin resistance. The linc00473/miR-490-5p/V-akt murine thymoma viral oncogene homolog 1 (AKT1) axis was found to mediate the regulatory effects of sevoflurane on cisplatin resistance. Sevoflurane has great clinical potential against cisplatin-resistant tumors. Further animal experiments and clinical trials are required to achieve this goal.


Conversation focused aphasia therapy: investigating the adoption of strategies by people with agrammatism.
Background: A recent review of interaction (or conversation)-focused therapy highlighted the potential of programmes targeting the person with aphasia (PWA) directly. However, it noted the key limitations of current work in this field to be a reliance on single case analyses and qualitative evidence of change, a situation that is not unusual when a complex behavioural intervention is in the early stages of development and evaluation. Aims: This article aims to evaluate an intervention that targeted a PWA and their conversation partner (CP), a dyad, as equals in a novel conversation therapy for agrammatic aphasia, using both quantitative and qualitative evidence of change. The intervention aimed to increase the insight of a dyad into facilitator and barrier conversation behaviours, to increase the understanding of the effect of agrammatism on communication, and to support each speaker to choose three strategies to work on in therapy to increase mutual understanding and enhance conversation. Methods & Procedures: Quantitative and qualitative methods are used to analyse multiple pre-therapy and follow up assessments of conversation for two dyads. Outcomes & Results: Results show that one person with severe and chronic agrammatic aphasia was able to select and practise strategies that led to qualitative and quantitative changes in his post-therapy conversations. The other PWA showed a numerical increase in one of his three strategies post therapy, but no significant quantitative change. Although both CPs significantly reduced barrier behaviours in their post-therapy conversations, neither showed a significant increase in the strategies they chose to work on. For one CP, there was qualitative evidence of the use of different turn types. Conclusions: Individually tailored input from a speech and language therapist can assist some people with chronic agrammatism to develop conversational strategies that enhance communication. Outcomes are influenced by the severity and extent of language deficits affecting, for example, single word writing. In terms of behaviour change for CPs, it appears that it may be easier to reduce barrier behaviours rather than to increase the use of facilitatory strategies. The results have implications for collaborative goal setting with clients undergoing conversation therapy.


Use of structural allografts in spinal osteomyelitis: a review of 47 cases.
The use of structural allografts in spinal osteomyelitis remains controversial because of the perceived risk of persistent infection related to a devitalized graft and spinal hardware. The authors have identified 47 patients over the last 3.5 years who underwent a surgical decompression and stabilization procedure in which fresh-frozen allografts were used after aggressive removal of infected and devitalized tissue. The patients subsequently underwent 6 weeks of postoperative antibiotic therapy (12 months for those with tuberculosis [TB]). Follow-up data included results of serial clinical examinations, radiography, laboratory analysis (erythrocyte sedimentation rate and white blood cell count), and clinical outcome questionnaires. Of the original 47 patients (14 women and 33 men, aged 14-83 years), 39 were available for follow up. The average follow-up period at the time this article was submitted was 17 +/- 9 months (median 14 months, range 6-45 months). In the majority of cases (57%), a Staphylococcus species was the infectious organism. Predisposing risk factors included intravenous drug abuse (IVDA), previous surgery, diabetes, TB, and concurrent infections. During the follow-up period only two patients suffered recurrent infection at a contiguous level; both had a history of IVDA and one also had a chronic excoriating skin condition. No other recurrent infections have been identified, and no patient has required reoperation for persistent infection or allograft/hardware failure. It is the authors' opinion that the use of structural allografts in combination with aggressive tissue debridement and adjuvant antibiotic therapy provide a safe and effective therapy in cases of spinal osteomyelitis requiring surgery.


Young-adult carriers of Neisseria meningitidis in Puglia (Italy): will the pattern of circulating meningococci change following the introduction of meningococcal serogroup C conjugate vaccines?
Studies of meningococcal carriage are essential in improving knowledge of the epidemiology of meningococcal disease. The aim of this study is to ascertain the carrier rate and the serogroups of Neisseria Meningitidis circulating in a sample of students from the University of Bari. The population consisted of university students from the University of Bari - School of Medicine, who were invited to take a nasopharyngeal swab. The swabs were plated on selective plate medium; cultural and MLST tests were performed. Of 583 university students 12 carriers were identified (2%). 9 isolates proved auto-agglutinable. The other strains belonged to serogroups B, W135 and Y. Auto-agglutinable strains belonged to different clonal complexes, of which ST-53 was the most common. Only one strain, that belonged to ST-23/cluster A3 clonal complex, could cause meningococcal disease. No type C serogroup strain was detected and this could be directly related to immunization policies that provided meningococcal serogroup C conjugate vaccines for newborns and adolescents. The changing pattern of circulating serogroups of Neisseria meningitidis in healthy carriers could support a new immunization strategy which could provide quadrivalent meningococcal conjugate vaccines to pre-adolescents and adults.


Assessment of spinal movement reduction by thoraco-lumbar-sacral orthoses.
Bracing is a common modality in treating spinal fractures. Its objective is to reduce spinal movements and to stabilize the fracture. Until now, factual insight into the movement-reducing properties of Thoraco-Lumbar-Sacral Orthoses (TLSOs) has been missing. Two common TLSOs (e.g., Jewett and Voigt-Bähler) were tested for their movement-reducing properties in two small groups of healthy subjects. In the first study, maximal gross spinal movements, with and without a TLSO, were measured by means of a Portable Posture Registration Set (PPRS) in three different planes. In the second study, maximal segmental vertebral movements in the regions T10 to L4 were measured via X-rays. With few notable exceptions, wearing a TLSO, as measured by the PPRS and X-ray techniques, significantly reduced the segmental as well as gross spinal movements. However, the amount of movement reduction varied greatly from subject-to-subject and was sometimes small. Unfortunately, data are lacking on the amount of movement reduction that is clinically relevant.


A Novel Prediction Tool for Endoscopic Intervention in Patients with Acute Upper Gastro-Intestinal Bleeding.
(1) Background: Predicting which patients with upper gastro-intestinal bleeding (UGIB) will receive intervention during urgent endoscopy can allow for better triaging and resource utilization but remains sub-optimal. Using machine learning modelling we aimed to devise an improved endoscopic intervention predicting tool. (2) Methods: A retrospective cohort study of adult patients diagnosed with UGIB between 2012−2018 who underwent esophagogastroduodenoscopy (EGD) during hospitalization. We assessed the correlation between various parameters with endoscopic intervention and examined the prediction performance of the Glasgow-Blatchford score (GBS) and the pre-endoscopic Rockall score for endoscopic intervention. We also trained and tested a new machine learning-based model for the prediction of endoscopic intervention. (3) Results: A total of 883 patients were included. Risk factors for endoscopic intervention included cirrhosis (9.0% vs. 3.8%, p = 0.01), syncope at presentation (19.3% vs. 5.4%, p < 0.01), early EGD (6.8 h vs. 17.0 h, p < 0.01), pre-endoscopic administration of tranexamic acid (TXA) (43.4% vs. 31.0%, p < 0.01) and erythromycin (17.2% vs. 5.6%, p < 0.01). Higher GBS (11 vs. 9, p < 0.01) and pre-endoscopy Rockall score (4.7 vs. 4.1, p < 0.01) were significantly associated with endoscopic intervention; however, the predictive performance of the scores was low (AUC of 0.54, and 0.56, respectively). A combined machine learning-developed model demonstrated improved predictive ability (AUC 0.68) using parameters not included in standard GBS. (4) Conclusions: The GBS and pre-endoscopic Rockall score performed poorly in endoscopic intervention prediction. An improved predictive tool has been proposed here. Further studies are needed to examine if predicting this important triaging decision can be further optimized.


Cutting seton for the treatment of cryptoglandular fistula-in-ano: a systematic review and meta-analysis.
The use of cutting seton (CS) for the management of cryptoglandular fistula-in-ano has remained controversial because of reports of fecal incontinence, postoperative pain, and extended healing time. The aim of this review was to provide the first synthesis of studies investigating the use of CS for the treatment of cryptoglandular fistula-in-ano. MEDLINE, Embase, and CENTRAL were searched up to October 2022. Randomized controlled trials and observational studies comparing CS with alternative interventions were included, along with single-arm studies evaluating CS alone. The primary outcome was fistula-in-ano recurrence, and secondary outcomes included incontinence, healing time, proportion with complete healing, and postoperative pain. Inverse variance random-effects meta-analyses were used to pool effect estimates. After screening 661 citations, 29 studies were included. Overall, 1513 patients undergoing CS (18.8% female, mean age: 43.1 years) were included. Patients with CS had a 6% (95% CI: 3-12%) risk of recurrence and a 16% (95% CI: 5-38%) risk of incontinence at 6 months. CS patients had an average healing time of 14.6 weeks (95% CI: 10-19 weeks) with 73% (95% CI: 48-89%) of patients achieving complete healing at 6 months postoperatively. There was no difference in recurrence between CS and fistulotomy, advancement flap, two-stage seton fistulotomy, or draining seton. Overall, this analysis shows that CS has comparable recurrence and incontinence rates to other modalities. However, this may be at the expense of more postoperative pain and extended healing time. Further comparative studies between CS and other modalities are warranted.


NursingQuest: supporting an analysis of nursing issues.
With the development and use of new strategies, practices, applications, and resources in technology, the teaching and learning context is shifting. Nurse educators are challenged to create instructional strategies that appeal to the newer generation of students and have the potential to enhance learning. Effective learning programs for these students require new digital communication skills, new pedagogies, and new practices. Nursing students should not be seeking the right answer as much as they should be seeking appropriate information and then developing approaches to issues or resolutions for problems. The focus of the teaching and learning context is shifting from the individual to the group, with the purpose of constructing new knowledge from available information. This article discusses the value of WebQuest activities as inquiry-oriented strategies and the process of adapting the WebQuest format for the development of a strategy called NursingQuest.


Spontaneous emergence of chirality in the limited enantioselectivity model: autocatalytic cycle driven by an external reagent.
The model of limited enantioselectivity (LES) in closed systems, and under experimental conditions able to achieve chemical equilibrium, can give rise to neither spontaneous mirror symmetry breaking (SMSB) nor kinetic chiral amplifications. However, it has been recently shown that it is able to lead to SMSB, as a stationary final state, in thermodynamic scenarios involving nonuniform temperature distributions and for compartmentalized separation between the two autocatalytic reactions. Herein, it is demonstrated how SMSB may occur in LES in a cyclic network with uniform temperature distribution if the reverse reaction of the nonenantioselective autocatalysis, which gives limited inhibition on the racemic mixture, is driven by an external reagent, that is, in conditions that keep the system out of chemical equilibrium. The exact stability analysis of the racemic and chiral final outcomes and the study of the reaction parameters leading to SMSB are resolved analytically. Numerical simulations, using chemical kinetics equations, show that SMSB may occur for chemically reasonable parameters. Numerical simulations on SMSB are also presented for speculative, but reasonable, scenarios implying reactions common in amino acid chemistry.


Photoacoustic Spectroscopy Gas Detection Technology Research Progress.
Photoacoustic spectroscopy (PAS) can be utilized as an ultrasensitive gas detection method. The basic principles of gas detection using PAS are discussed in this paper. First, the basic instrumentation for a PAS gas detection system is introduced focusing on the photoacoustic cell. The discussion includes non-resonant photoacoustic cells and the different types of resonant photoacoustic cells, including the longitudinal photoacoustic cell, the Helmholtz photoacoustic cell, the T-type photoacoustic cell, and the high-frequency resonant photoacoustic cell. The basic working principles of each of these, cells as well as the advantages and disadvantages of photoacoustic cells are discussed, and the development of newer types of photoacoustic cells in recent years is outlined in detail. This review provides detailed reference information and guidance for interested researchers who would like to design and build advanced photoacoustic cells for gas detection.


Improved side-chain torsion potentials for the Amber ff99SB protein force field.
Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data.


Prevalence of alcohol and other drug problems among physicians.
Extreme statements regarding the prevalence of problems with alcohol and other drugs among physicians have often been made without firm empirical support. The data that are available can be categorized as follows: license and disciplinary actions, known or registered addicts, mortality rates, hospital admissions and treatment populations, and surveys of selected groups of physicians. Because of difficulties in interpreting each type of data, it must be concluded that the prevalence of drug problems among physicians is unknown. A previously unpublished survey of Ontario physicians found that the proportion who have been treated for problems with alcohol and other drugs is not greater than that in the general population. Indeed, when alcohol and other drugs are considered together, physicians may not be unusually likely to have such problems.


Histoenzymological mapping of acid phosphatase and 5-nucleotidase in the diencephalic and mesencephalic centers of Uromastix hardwickii.
The study deals with the histoenzymological mapping of acid phosphatase and 5-nucleotidase in the various nuclei of diencephalon and mesencephalon of Uromastix hardwickii. Almost all the nuclei and the fiber tracts reveal positive activity, both for acid phosphatase and 5-nucleotidase, althouh the intensity of the enzymatic activity presents great variations. Acid phosphatase preparations have generally revealed moderate or mild activity. On the contrary, the 5-nucleotidase preparations demonstrate the activity of a higher order. For this enzyme beside the nuclei, the commissures and fore-brain bundles are seen equipped with very intense activity. On the other hand, the commissures and fore-brain pundles present moderate activity for acid phosphatase. An attempt has been made to discuss the significance of the distribution of the enzymes at various locales.


Effect of gender (gilt and surgically and immunocastrated male) and ractopamine hydrochloride supplementation on growth performance, carcass, and pork quality characteristics of finishing pigs under commercial conditions.
This study evaluated the effects of gender and feeding of ractopamine on growth performance, carcass, and meat quality characteristics of pigs reared under commercial conditions. The study was performed as a randomized complete block design (blocking factor date of start on test) with a 3 × 2 factorial arrangement of treatments: 1) gender [gilt vs. surgical castrate vs. intact males immunocastrated] and 2) ractopamine level (0 vs. 5 g/ton). The study was conducted out over a fixed duration (126 d) from 1 wk after weaning (28 d of age; 8.04 ± 1.31 kg BW) to 154 d of age (111.44 ± 4.67 kg BW) in 3 growth periods: nursery (d 0 to 35 of the study), growing (d 35 to 70), and finishing (d 70 to 126). Ractopamine was fed for the final 28 d of the study (d 98 to 126). Pigs were kept in groups of 10 or 11 in the nursery phase and then moved to the growing-finishing facility where they were kept in groups of 22 to the end of the study. At the end of the growth study, pigs were harvested and carcass and pork quality were evaluated, including consumer evaluation of eating quality. During the nursery, there was no effect of gender (P > 0.05) on G:F, but surgical castrates grew faster (P < 0.05) than intact males and gilts and had greater (P < 0.05) ADFI than intact males. There was no effect of gender (P > 0.05) on ADG in the growing period; however, immunocastrated males had lower ADFI than surgical castrates and greater G:F than surgical castrates and gilts. In finishing, immunocastrated males and surgical castrates had similar ADG but grew faster than gilts; G:F was greater for immunocastrated males than the other genders. Feeding 5 compared to 0 g/ton ractopamine increased ADG and G:F but had no effect (P > 0.05) on carcass yield or fresh meat quality. Carcass yield was lower but percentage lean cut yield was greater for immunocastrated males than for surgical castrates. Longissimus muscle drip loss was greater (P = 0.05) for immunocastrated males than surgical castrates. Gender had no effect (P > 0.05) on consumer panel evaluation. Feeding ractopamine had no effect on pork flavor and tenderness but improved juiciness scores. Odor scores were similar (P > 0.05) for surgical castrates and immunocastrated males that were fed ractopamine. Consumers gave lower liking scores for odor for immunocastrated males than surgical castrates that were not fed ractopamine. This study highlights the feed efficiency and lean cut yield advantage for immunocastrated males compared to surgical castrates and suggests a similar growth response to feeding ractopamine in these genders. Although immunocastrated males had a lower carcass yield and higher drip loss, panelists were not able to detect differences in pork juiciness, flavor, and tenderness when compared to surgical castrate pigs.


Genetic programming in medical diagnosis.
The paper describes the results obtained for differential diagnostics of substantially complex disorders in the acid-base status. Since the first attempts of applying the genetic programming to this problem, presented by the authors at MIE 2000, proved promising, the investigation has been continued. The goal of the present study is to create computer genetic programs which, while taking into account a set of laboratory gasometric and electrolyte measurements, would be able to assist the diagnostics of acid-base disorders. Seven (7) single acid-base disorders, eleven (11) double acid-base disorders and six (6) triple complicated disorders with accompanying anion gap alterations are approached in the study. A set of simulated laboratory measurements has been prepared, providing 250 results for the evaluation of the fitness function of the designed genetic computer programs, plus some additional results for testing. The final results are presented in the form of a confusion matrix for the testing data, which shows that the developed system may be helpful in clinical practice.


Grouping of beta-haemolytic streptococci with group-specific antibodies absorbed to staphylococcal protein A.
A total of 245 isolates of beta-haemolytic streptococci was grouped by the counter current immunoelectrophoresis method and by co-agglutination with antibody-coated staphylococci. Co-agglutination was found to be simple and accurate, and many commercially available grouping sera were suitable for use in this test, though some of them had to be absorbed to remove cross-reactions.


Innate immunity during Equid herpesvirus 1 (EHV-1) infection.
Intrinsic phagocytosis and killing of C. albicans by equine monocytes and polymorphonuclear leucocytes (PMN) was examined during Equid Herpesvirus 1 (EHV-1) (subtypes 1 or 2) and Adenovirus infections. Monocyte function increased during EHV-1 subtype 2 and Adenovirus infection. Conversely, there was an impairment of monocyte ingestion during EHV-1 subtype 1 infection which was ascribed to virus replication in peripheral blood mononuclear cells. PMN phagocytosis was not decreased in any of the infections studied. The raised levels of haemolytic complement in animals which subsequently developed EHV-1 subtype 1 induced paresis suggested an abnormality of complement turnover. Increased levels of interferon were evident in the nasal secretions of both subtype 1 and subtype 2 infected animals but only subtype 1 virus induced measurable levels of serum interferon. No intrinsic abnormality of interferon production by monocytes or lymphocytes was found.


Pulsed Electromagnetic Field Stimulation in Lumbar Spine Fusion for Patients With Risk Factors for Pseudarthrosis.
Lumbar spinal fusion surgeries are increasing steadily due to an aging and ever-growing population. Patients undergoing lumbar spinal fusion surgery may present with risk factors that contribute to complications, pseudarthrosis, prolonged pain, and reduced quality of life. Pulsed electromagnetic field (PEMF) stimulation represents an adjunct noninvasive treatment intervention that has been shown to improve successful fusion and patient outcomes following spinal surgery. A prospective, multicenter study investigated PEMF as an adjunct therapy to lumbar spinal fusion procedures in patients at risk for pseudarthrosis. Patients with at least 1 of the following risk factors were enrolled: prior failed fusion, multilevel fusion, nicotine use, osteoporosis, or diabetes. Fusion status was determined by radiographic imaging, and patient-reported outcomes were also evaluated. A total of 142 patients were included in the analysis. Fusion status was assessed at 12 months follow-up where 88.0% (n = 125/142) of patients demonstrated successful fusion. Fusion success for patients with 1, 2+, or 3+ risk factors was 88.5%, 87.5%, and 82.3%, respectively. Significant improvements in patient-reported outcomes using the Short Form 36, EuroQol 5 Dimension (EQ-5D) survey, Oswestry Disability Index, and visual analog scale for back and leg pain were also observed compared with baseline scores (P < 0.001). A favorable safety profile was observed. PEMF treatment showed a positive benefit-risk profile throughout the 6-month required use period. The addition of PEMF as an adjunct treatment in patients undergoing lumbar spinal surgery provided a high rate of successful fusion with significant improvements in pain, function, and quality of life, despite having risk factors for pseudarthrosis. PEMF represents a useful tool for adjunct treatment in patients who have undergone lumbar spinal surgery. Treatment with PEMF may result in improved fusion and patient-reported outcomes, regardless of risk factors. NCT03176303.


HIV: prevention of mother-to-child transmission.
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions. We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria. In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.


Identification of a novel regulatory sequence of actin nucleation promoting factor encoded by Autographa californica multiple nucleopolyhedrovirus.
Actin polymerization induced by nucleation promoting factors (NPFs) is one of the most fundamental biological processes in eukaryotic cells. NPFs contain a conserved output domain (VCA domain) near the C terminus, which interacts with and activates the cellular actin-related protein 2/3 complex (Arp2/3) to induce actin polymerization and a diverse regulatory domain near the N terminus. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) nucleocapsid protein P78/83 is a virus-encoded NPF that contains a C-terminal VCA domain and induces actin polymerization in virus-infected cells. However, there is no similarity between the N terminus of P78/83 and that of other identified NPFs, suggesting that P78/83 may possess a unique regulatory mechanism. In this study, we identified a multifunctional regulatory sequence (MRS) located near the N terminus of P78/83 and determined that one of its functions is to serve as a degron to mediate P78/83 degradation in a proteasome-dependent manner. In AcMNPV-infected cells, the MRS also binds to another nucleocapsid protein, BV/ODV-C42, which stabilizes P78/83 and modulates the P78/83-Arp2/3 interaction to orchestrate actin polymerization. In addition, the MRS is also essential for the incorporation of P78/83 into the nucleocapsid, ensuring virion mobility powered by P78/83-induced actin polymerization. The triple functions of the MRS enable P78/83 to serve as an essential viral protein in the AcMNPV replication cycle, and the possible roles of the MRS in orchestrating the virus-induced actin polymerization and viral genome decapsidation are discussed.


Selection of antibiotic resistance in pigs after exposure to feed cross-contaminated with oxytetracycline.
Due to possible cross-contamination of animal feedstuff with antibiotics, food-producing animals may be exposed to undesirable low concentrations of antimicrobials. These sub-therapeutic levels of antibiotics can lead to the selection of resistant bacteria in the animal gut. The goal of this study was to assess, through analysis of the faeces of treated and control pigs, the risk of resistant E. coli being selected after daily exposure for three weeks to feed contaminated with oxytetracycline at 1% of the therapeutic dose. Liquid Chromatography coupled to tandem Mass Spectrometry was used to determine the oxytetracycline concentrations in faecal samples. In the treated group, concentrations were in the range of 4481.9 - 8671.2 µg/kg. In the control group, these concentrations were either below the method's limit of quantification or up to 60.5 µg/kg. After a transient increase in resistance in both groups, microbiological analysis showed that the treated group had a significantly higher oxytetracycline resistance rate by the end of the study than the control group (p < 0.001). Furthermore, the treated animals were found to select co-resistances to nalidixic acid and ampicillin. Finally, at tolerated antibiotic contamination levels of feed, the treated group had a higher proportion of multidrug-resistant isolates at the end of the study than the control one (p < 0.05). The present study demonstrates that, at the tolerated contamination rates, both antimicrobial resistance and multidrug-resistant bacteria can be selected and evidenced in the gut microbiota.


[Acid-base equilibrium of blood in chicken with gout].
It is shown that visceral gout in chicken is accompanied by acute metabolic acidosis. The mentioned change in the acid-base equilibrium is supposed to aggravate the course of the disease.


Shaping anesthetic techniques to reduce post-operative delirium (SHARP) study: a protocol for a prospective pragmatic randomized controlled trial to evaluate spinal anesthesia with targeted sedation compared with general anesthesia in older adults undergoing lumbar spine fusion surgery.
Postoperative delirium is common in older adults, especially in those patients undergoing spine surgery, in whom it is estimated to occur in > 30% of patients. Although previously thought to be transient, it is now recognized that delirium is associated with both short- and long-term complications. Optimizing the depth of anesthesia may represent a modifiable strategy for delirium prevention. However, previous studies have generally not focused on reducing the depth of anesthesia beyond levels consistent with general anesthesia. Additionally, the results of prior studies have been conflicting. The primary aim of this study is to determine whether reduced depth of anesthesia using spinal anesthesia reduces the incidence of delirium after lumbar fusion surgery compared with general anesthesia. This single-center randomized controlled trial is enrolling 218 older adults undergoing lumbar fusion surgery. Patients are randomized to reduced depth of anesthesia in the context of spinal anesthesia with targeted sedation using processed electroencephalogram monitoring versus general anesthesia without processed electroencephalogram monitoring. All patients are evaluated for delirium using the Confusion Assessment Method for 3 days after surgery or until discharge and undergo assessments of cognition, function, health-related quality of life, and pain at 3- and 12-months after surgery. The primary outcome is any occurrence of delirium. The main secondary outcome is change in the Mini-Mental Status Examination (or telephone equivalent) at 3-months after surgery. Delirium is an important complication after surgery in older adults. The results of this study will examine whether reduced depth of anesthesia using spinal anesthesia with targeted depth of sedation represents a modifiable intervention to reduce the incidence of delirium and other long-term outcomes. The results of this study will be presented at national meetings and published in peer-reviewed journals with the goal of improving perioperative outcomes for older adults. Clinicaltrials.gov , NCT03133845. This study was submitted to Clinicaltrials.gov on October 23, 2015; however, it was not formally registered until April 28, 2017 due to formatting requirements from the registry, so the formal registration is retrospective.


The yeast Hansenula wingei U3 snoRNA gene contains an intron and its coding sequence co-evolved with the 5' ETS region of the pre-ribosomal RNA.
The 5' external transcribed spacer (ETS) region of the pre-rRNA in Saccharomyces cerevisiae contains a sequence with 10 bp of perfect complementarity to the U3 snoRNA. Base pairing between these sequences has been shown to be required for 18S rRNA synthesis, although interaction over the full 10 bp of complementarity is not required. We have identified the homologous sequence in the 5' ETS from the evolutionarily distant yeast Hansenula wingei; unexpectedly, this shows two sequence changes in the region predicted to base pair to U3. By PCR amplification and direct RNA sequencing, a single type of U3 snoRNA coding sequence was identified in H. wingei. As in the S. cerevisiae U3 snoRNA genes, it is interrupted by an intron with features characteristic of introns spliced in a spliceosome. Consequently, this unusual property is not restricted to the yeast genus Saccharomyces. The introns of the H. wingei and S. cerevisiae U3 genes show strong differences in length and sequence, but are located at the same position in the U3 sequence, immediately upstream of the phylogenetically conserved Box A region. The 3' domains of the H. wingei and S. cerevisiae U3 snoRNAs diverge strongly in primary sequence, but have very similar predicted secondary structures. The 5' domains, expected to play a direct role in pre-ribosomal RNA maturation, are more conserved. The sequence predicted to base pair to the pre-rRNA contains two nucleotide substitutions in H. wingei that restore 10 bp of perfect complementarity to the 5' ETS. This is a strong phylogenetic evidence for the importance of the U3/pre-rRNA interaction.


Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta.
Participation of human polymorphonuclear neutrophils in the inflammatory response is mediated, in part, by soluble factors such as chemotactic peptides and cytokines. Although the cytokine, transforming growth factor beta (TGF-beta), has been shown to recruit monocytes and promote the inflammatory process, its effects on neutrophils are unknown. In this investigation, [125I]TGF-beta 1 affinity binding studies were employed to show that neutrophils express TGF-beta receptors (350 +/- 20 receptors/cell), which exhibit high affinity for the ligand (dissociation constant, 50 pM). Affinity cross-linking studies identified the receptors to be primarily of the type I class. In contrast to the receptors on monocytes, neutrophil TGF-beta receptors were not down-regulated by exposure to specific inflammatory mediators. Additional studies examined whether exposure of neutrophils to TGF-beta could enhance specific functions, as occurs with monocytes. TGF-beta was shown to cause directed migration of neutrophils at femtomolar concentrations, thus it is the most potent neutrophil chemotactic factor yet identified. Neutrophil production of reactive oxygen intermediates was not stimulated by TGF-beta, nor did TGF-beta enhance or depress subsequent PMA- or FMLP-stimulated superoxide production. However, the stable expression of neutrophil TGF-beta receptors, and the capacity of this cytokine to stimulate neutrophil chemotaxis, suggest that the pro-inflammatory effects of TGF-beta are mediated by neutrophils in addition to monocytes.


Pediatric pharmacokinetic data: implications for environmental risk assessment for children.
Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children's age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children's risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children's abilities to metabolize and eliminate chemicals at various developmental stages.