Avoiding harm: Tackling problematic polypharmacy through strengthening expert generalist practice.
Problematic polypharmacy is a growing challenge. Medication that is intended to improve patients' health and wellbeing is instead becoming part of the problem. The way we practice medicine has become a driver for the problem. Dealing with the challenge will need us to think differently about how we do clinical care. A 2013 Kings Fund report stated that tackling problematic polypharmacy requires us to actively build a principle of compromise into the way we use medicines. There are implications for how we consult and make decisions with patients, in how we design health practice and systems to support that decision making, and, in our understanding of the process of research, how we generate the knowledge that informs practice. This review considers the current state of play in all 3 areas and identifies some of the work we still need to do in order to generate the practice-based evidence needed to tackle this most challenging problem. Finding a way to redesign practice to address problematic polypharmacy could offer a template for tackling other related complex issues facing medical practice such as multimorbidity, chronic pain and complex mental health.


Design of Binary Nb2O5-SiO2 Self-Standing Monoliths Bearing Hierarchical Porosity and Their Efficient Friedel-Crafts Alkylation/Acylation Catalytic Properties.
Alkylation of aromatic hydrocarbons is among the most industrially important reactions, employing acid catalysts such as AlCl3, H2SO4, HF, or H3PO4. However, these catalysts present severe drawbacks, such as low selectivity and high corrosiveness. Taking advantage of the intrinsic high acid strength and Lewis and Brønsted acidity of niobium oxide, we have designed the first series of Nb2O5-SiO2(HIPE) monolithic catalysts bearing multiscale porosity through the integration of a sol-gel process and the physical chemistry of complex fluids. The MUB-105 series offers efficient solvent-free heterogeneous catalysis toward Friedel-Crafts monoalkylation and -acylation reactions, where 100% conversion has been reached at 140 °C while cycling. Alkylation reactions employing the MUB-105(1) catalyst have a maximum turnover number (TON) of 104 and a turnover frequency (TOF) of 9 h-1, whereas for acylation, MUB-105(1) and MUB-105(2) yield maximum TON and TOF values of 107 and 11 h-1, respectively. Moreover, the catalysts are selective, producing equal amounts of ortho- and para-substituted alkylated products and greater than 90% of the para-substituted acylated product. The highest catalytic efficiencies are obtained for the MUB-105(1) catalyst, bearing the smallest Nb2O5 particle sizes, lowest Nb2O5 content, and the highest amorphous character. The catalysts presented here are in a monolithic self-standing state, offering easy handling, reusability, and separation from the final products.


Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?
Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. "Real-world" experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T - cytokine release syndrome and immune-cell-associated neurotoxicity syndrome - have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40-50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19- or CD19+ disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.


Negative effect of photocopier toner on alveolar macrophages determined by in vitro magnetometric evaluation.
Photocopier toner has been implicated in the etiology of some pulmonary diseases. We examined here the in vitro toxicity of toner particles to alveolar macrophages. Cell magnetometry revealed that relaxation was not delayed in macrophages exposed to toner, which represents a rapid decrease in the remaining magnetism emitted by phagocytosed magnetite. However, relaxation was delayed in macrophages exposed to silica (positive controls). The release of intracellular LDH enzyme activity to the extracellular space was negligible in cells exposed to toner compared with negative and positive controls. Morphological examinations by light and electron microscopy revealed no abnormal findings in the exposed cells. A histochemical study using TUNEL staining and the electrophoretic profile of DNA obtained from cells exposed to toner and to silica were negative for apoptosis. The results of the present and other investigations into animal exposure indicate that photocopier toner is toxicologically inert. However, although the present study examined only effects in vitro, exposure to toner should be minimized because lung overloading in animals has been reported.


Evolutionary genomics of Salmonella: gene acquisitions revealed by microarray analysis.
The presence of homologues of Salmonella enterica sv. Typhimurium LT2 genes was assessed in 22 other Salmonella including members of all seven subspecies and Salmonella bongori. Genomes were hybridized to a microarray of over 97% of the 4,596 annotated ORFs in the LT2 genome. A phylogenetic tree based on homologue content, relative to LT2, was largely concordant with previous studies using sequence information from several loci. Based on the topology of this tree, homologues of genes in LT2 acquired by various clades were predicted including 513 homologues acquired by the ancestor of all Salmonella, 111 acquired by S. enterica, 105 by diphasic Salmonella, and 216 by subspecies 1, most of which are of unknown function. Because this subspecies is responsible for almost all Salmonella infections of mammals and birds, these genes will be of particular interest for further mechanistic studies. Overall, a high level of gene gain, loss, or rapid divergence was predicted along all lineages. For example, at least 425 close homologues of LT2 genes may have been laterally transferred into Salmonella and then between Salmonella lineages.


[The ecology of Cryptosporidium parvum infection in small rodent populations].
The prevalence and abundance of Cryptosporidium parvum were studied over a three year period (1997-1999) in three species of rodents sampled from forest and abandoned fields in the Mazury Lake District, Poland. The overall prevalence was consistently higher in voles compared with Apodemus flavicollis (70.6% in Clethrionomys glareolus, 73.0% in Microtus arvalis and 27.8% in A. flavicollis). The prevalence and abundance of infection also varied across the 3 years of the study with 1998 being the year of higher prevalence and abundance of the parasite. Fewer older animals carried the infection, and their infections were relatively mild. We found no consistent pattern of seasonal changes despite the significance of seasonal differences. Host sex did not influence either the prevalence or abundance of infection with C. parvum. A great proportion of recaptured voles developed chronic infections between consecutive trapping sessions and only a small number of animals recovered. However, yellow-necked mice seem to be much more resistant to infection that became self-limiting. Our results firmly establish that the common woodland and grassland wild rodents in the Mazury Lake District constitute a significant and hazardous reservoir of C. parvum for animals and humans.


Universal health care coverage for children: impact on pediatric health care providers.
A Northern California county expanded health coverage to cover nearly all children in the state through a new insurance program. In two years, 75,500 children entered a health care system near capacity. We hypothesized that the influx of thousands of previously uninsured children into the health system would affect providers in many ways. This cross-sectional study sought to investigate how this influx affected provider practices, job satisfaction, access to specialists, and overarching views about the program. Qualitative analyses of expert interviews were performed. Providers reported improved access to health care, specialists, and medications for patients. They cited increased job satisfaction for providers due to fewer limits on care, improved referral process, and decreased patient family financial stress. Providers noted the persistence of long appointment wait times for specialist care. After moving to near universal coverage, safety net providers described increased job satisfaction. Because this study examined safety-net providers, future research requires a more representative sample of providers.


Angioimmunoblastic T cell lymphoma: an unusual presentation of posttransplant lymphoproliferative disorder in a pediatric patient.
Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy.


Academic health sciences library Website navigation: an analysis of forty-one Websites and their navigation tools.
The analysis included forty-one academic health sciences library (HSL) Websites as captured in the first two weeks of January 2001. Home pages and persistent navigational tools (PNTs) were analyzed for layout, technology, and links, and other general site metrics were taken. Websites were selected based on rank in the National Network of Libraries of Medicine, with regional and resource libraries given preference on the basis that these libraries are recognized as leaders in their regions and would be the most reasonable source of standards for best practice. A three-page evaluation tool was developed based on previous similar studies. All forty-one sites were evaluated in four specific areas: library general information, Website aids and tools, library services, and electronic resources. Metrics taken for electronic resources included orientation of bibliographic databases alphabetically by title or by subject area and with links to specifically named databases. Based on the results, a formula for determining obligatory links was developed, listing items that should appear on all academic HSL Web home pages and PNTs. These obligatory links demonstrate a series of best practices that may be followed in the design and construction of academic HSL Websites.


Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study.
There is growing evidence linking time in range (TIR), an emerging metric for assessing glycemic control, to diabetes-related outcomes. We aimed to investigate the association between TIR and mortality in patients with type 2 diabetes. A total of 6,225 adult patients with type 2 diabetes were included from January 2005 to December 2015 from a single center in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline, and the participants were stratified into four groups by TIR: >85%, 71-85%, 51-70%, and ≤50%. Cox proportional hazards regression models were used to estimate the association between different levels of TIR and the risks of all-cause and cardiovascular disease (CVD) mortality. The mean age of the participants was 61.7 years at baseline. During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD. The multivariable-adjusted hazard ratios associated with different levels of TIR (>85% [reference group], 71-85%, 51-70%, and ≤50%) were 1.00, 1.23 (95% CI 0.98-1.55), 1.30 (95% CI 1.04-1.63), and 1.83 (95% CI 1.48-2.28) for all-cause mortality (P for trend <0.001) and 1.00, 1.35 (95% CI 0.90-2.04), 1.47 (95% CI 0.99-2.19), and 1.85 (95% CI 1.25-2.72) for CVD mortality (P for trend = 0.015), respectively. The current study indicated an association of lower TIR with an increased risk of all-cause and CVD mortality among patients with type 2 diabetes, supporting the validity of TIR as a surrogate marker of long-term adverse clinical outcomes.


Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic Oncology Group study.
This Gynecologic Oncology Group (GOG) study was designed to estimate the activity of goserelin acetate as treatment for advanced and recurrent endometrial carcinoma. Forty evaluable patients received monthly treatment with goserelin acetate at a dose of 3.6 mg, given subcutaneously. Standard GOG response and adverse effects criteria were used. The median age of patients was 71 years. Seventy-one percent of patients had received prior radiation therapy; 18% of patients were reported to have received prior progestational therapy for endometrial cancer. One patient had received prior chemotherapy. There were two complete responses (5%) and three partial responses (7%). One response occurred in a patient who previously did not respond to progestin therapy after having achieved a response. The overall response rate was 11% (95% CI: 4-27%). Median progression-free survival was 1.9 months and median overall survival was 7.3 months. No severe or life-threatening toxicities occurred because of goserelin. Deep venous thrombosis developed in two patients. This study confirmed the limited activity of goserelin acetate in endometrial carcinoma, with only one response in a patient previously treated with hormonal therapy. The activity is insufficient to warrant further study of the single agent at this time. Elucidation of the mechanism of action of this drug may allow more effective use in conjunction with other agents in the future.


Constructing Cell-Free Expression Systems for Low-Cost Access.
Cell-free systems for gene expression have gained attention as platforms for the facile study of genetic circuits and as highly effective tools for teaching. Despite recent progress, the technology remains inaccessible for many in low- and middle-income countries due to the expensive reagents required for its manufacturing, as well as specialized equipment required for distribution and storage. To address these challenges, we deconstructed processes required for cell-free mixture preparation and developed a set of alternative low-cost strategies for easy production and sharing of extracts. First, we explored the stability of cell-free reactions dried through a low-cost device based on silica beads, as an alternative to commercial automated freeze dryers. Second, we report the positive effect of lactose as an additive for increasing protein synthesis in maltodextrin-based cell-free reactions using either circular or linear DNA templates. The modifications were used to produce active amounts of two high-value reagents: the isothermal polymerase Bst and the restriction enzyme BsaI. Third, we demonstrated the endogenous regeneration of nucleoside triphosphates and synthesis of pyruvate in cell-free systems (CFSs) based on phosphoenol pyruvate (PEP) and maltodextrin (MDX). We exploited this novel finding to demonstrate the use of a cell-free mixture completely free of any exogenous nucleotide triphosphates (NTPs) to generate high yields of sfGFP expression. Together, these modifications can produce desiccated extracts that are 203-424-fold cheaper than commercial versions. These improvements will facilitate wider use of CFS for research and education purposes.


Thyroid imaging: comparison of high-resolution real-time ultrasound and computed tomography.
High-resolution real-time ultrasound (US) and computed tomography (CT) were compared in 48 patients with a clinical diagnosis of thyroid abnormality and also correlated with biopsy or surgery. The modalities were considered comparable in 38 cases (79%), while CT was superior in 5 and US in 5. CT illustrated substernal extension of a goiter, demonstrated a 5-mm nodule not seen in US, showed 2 cases of thyroiditis better than US, and diagnosed a suspected thyroid mass as a lipoma anterior to the thyroid. US detected 4 nodules not seen on CT and resolved contiguous nodules that appeared to be a single nodule on CT. Both techniques lacked histopathological specificity. CT appears to be advantageous in detecting substernal thyroid extension and confirming thyroiditis, while the ability of US to detect small nodules makes it the procedure of choice in evaluating suspected intrinsic thyroid abnormalities.


Cell blotting: a new approach to quantify hormone secretion from individual rat pituitary cells.
A new technique is described for quantification of PRL secretion from individual pituitary cells incubated 1-6 h on ImmobilonTM, a high protein binding capacity transfer membrane. After incubation, the membrane is processed according to procedures commonly used in Western blotting. Individual cells and their "zone of secretion" can be seen by light microscopy. Purified hormone, incubated and processed in a similar fashion, is used to generate a PRL standard curve. An OasysTM Image Analysis System is used to measure area and intensity of released hormone. PRL release ranged from 0.1-1.5 pg/cell, depending upon time of incubation and cell donor. Heterogeneity of hormone release from single cells was obvious.


Research on the Effect of Pediococcus pentosaceus on Salmonella enteritidis-Infected Chicken.
Salmonella enteritidis can cause significant morbidity and mortality in humans and economic loss in the animal industry. Improving the innate immunity is an effective method to prevent S. enteritidis infection. Pediococcus pentosaceus is a Gram-positive coccus which had probiotics properties. Numerous previously published studies reported that probiotics were beneficial to gut microbiota by changing the intestinal flora structure and inhibiting the harmful microbial growth to enhance the innate immunity. We investigated the immunological effects of P. pentosaceus on Salmonella-infected chickens by the following experiment. A total of 120 broilers from AA line were fed and divided into 2 groups (treated and control groups) for the experiment from day 1. The control group was fed with the basic diet, while the treated group was fed with the basic diet adding P. pentosaceus microcapsule with the bacterial concentration of 1 g/kg in the feed and bacterial counts 2.5 × 109 CFU/g. All the birds were given with 0.5 ml of S. enteritidis bacterial suspension (109 CFU/ml) through oral cavity at day 9. The number of dead birds was recorded and used in the analysis. The bacterial culture method and quantitative real-time PCR analysis were used to evaluate the effects of P. pentosaceus on chickens infected with S. enteritidis and to ascertain the mechanism of the effect. The results showed that the P. pentosaceus could restrain the pathogenicity of S. enteritidis and reduce the death rate from 44.4% to 23.3%. The flora in the caecum exhibited "rising-declining" trends, and the gene (TLR4, MyD88, TRAF6 NF-κB, IFN-β, TNF-a, IL6, and IL8) expression pattern was different between the experimental and control group. P. pentosaceus as a probiotic may competitively inhibit the growth of S. enteritidis and control the inflammatory response through regulating the gene expression which involved in the toll-like receptor pathway and inflammation pathway.


Immediate-early expression of the herpes simplex virus type 1 ICP27 transcript is not critical for efficient replication in vitro or in vivo.
We constructed a promoter mutation altering the immediate-early expression of the herpes simplex virus type 1 (HSV-1) ICP27 transcript and its cognate wild-type rescue viruses in order to assess the role of the ICP27 protein in the earliest stages of viral infection by global transcriptional analysis with a DNA microarray. This mutant, ICP27/VP16, replaces the whole ICP27 promoter/enhancer with the VP16 promoter. It demonstrates loss of immediate-early expression of ICP27 according to the criteria expression in the absence of de novo protein synthesis and earliest expression in the kinetic cascade. Significant differences in relative transcript abundances between the mutant and wild-type rescue viruses were limited at the earliest times measured and not evident at all by 4 h after infection. Consistent with this observation, levels of some critical proteins were reduced in the mutant as compared to rescue virus infections at the earliest times tested, but were equivalent by 8 h postinfection. Further, both single and multistep levels of virus replication were equivalent with both mutant and rescue viruses. Thus, altering the immediate-early kinetics of ICP27 leads to a suboptimal quantitative lag phase in gene expression but without consequence for replication fitness in vitro. Infections in vivo also revealed equivalent ability of mutant and rescue viruses to invade the central nervous system of mice following footpad injections. Limitations to an immediate-early role of ICP27 in the biology of HSV are discussed in light of these observations.


Risk factors related to falling in stroke patients: a cross-sectional study.
[Purpose] The purpose of this study was to investigate a comprehensive understanding of the factors associated with falls in poststroke patients. [Subjects] Forty-eight stroke patients (22 males and 26 females; age 63.79 years) participated in this study. [Methods] This study applied a cross-sectional design. Fear of falling [Falls Efficacy Scale (FES)], balance function [Berg Balance Scale (BBS) and Modified Rivermead Mobility Index (MRMI)], ADL performance level [Modified Barthel Index (MBI)] and cognitive function [Loewenstein Occupational Therapy Cognitive Assessment for Geriatric Populations (LOTCA-G)] were assessed. [Results] Falls efficacy was moderately correlated with ADL performance, balance, and cognition. In addition, stepwise linear regression analysis revealed that ADL performance was the explanatory variable closely associated with falls efficacy in stroke patients. [Conclusion] ADL performance was the primary explanatory variable of falls efficacy according to regression analysis. Thus, we suggest that these results may be used as basic data for developing rehabilitation programs for prevention of falls in stroke patients.


Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability.
Our previous studies have shown that inflammatory mediators increase microvascular permeability through a phospholipase C-nitric oxide synthase (NOS)-guanylate cyclase cascade. The aim of this study is to delineate in more detail the signaling pathway leading to microvascular hyperpermeability. Endothelial cytosolic calcium and the apparent permeability coefficient of albumin (Pa) were measured in isolated and perfused coronary venules. Histamine stimulated a rapid increase in cytosolic calcium followed by a transient elevation in Pa. The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) and the guanosine 3',5'-cyclic monophosphate-dependent protein kinase G (PKG) inhibitor KT-5823 abolished the hyperpermeability but did not affect the calcium response to histamine. Similarly, the calcium ionophore ionomycin produced a calcium spike preceding venular hyperpermeability. Blockage of the NOS-PKG cascade inhibited the increase in Pa, whereas the endothelial calcium was still elevated on administration of ionomycin. Furthermore, the relationship between protein kinase C (PKC) and the calcium-NOS-PKG pathway in modulation of venular permeability was investigated. Stimulation of PKC with phorbol 12-myristate 13-acetate (PMA) dramatically increased basal Pa without significantly changing the cytosolic calcium level. The selective PKC inhibitor bisindolylmaleimide abolished the effect of PMA but did not alter the effect of histamines on Pa. In contrast, both L-NMMA and KT-5823 were able to greatly attenuate the increase in Pa caused by PMA. These results suggest that 1) elevation of endothelial cytosolic calcium is an early signaling event preceding nitric oxide (NO) synthesis in the transduction of endothelial hyperpermeability, and 2) activation of PKC may alter the endothelial barrier function partially through the modulation of NO production.


Effect of vasopressin on adrenal steroidogenesis.
The direct effect of vasopressin on adrenal steroidogenesis and its effect on angiotensin II- and adrenocorticotropic hormone (ACTH)-stimulated steroidogenesis was evaluated by using an isolated perfused canine adrenal gland preparation. Infusions of vasopressin alone (50, 100, or 250 pg/ml perfusate) had no significant effect on the secretion of either aldosterone or cortisol. Infusions of vasopressin at 75 or 250 pg/ml perfusate during stimulation of steroidogenesis by angiotensin II or by ACTH did not cause a consistent increase in aldosterone secretion. In contrast, infusion of 250 but not 75 pg vasopressin/ml perfusate caused a consistent enhancement of ACTH-stimulated cortisol secretion. The infusion of a vasopressin V1-receptor agonist, but not of either a vasopressin V2-receptor agonist or oxytocin, also caused a significant enhancement of ACTH-stimulated cortisol secretion. These results suggest that the sensitivity of fasciculata cells to vasopressin is greater than that of glomerulosa cells. Finally, levels of vasopressin reported to occur in plasma during severe hemorrhage appear to be capable of enhancing cortisol secretion by a direct action on the adrenal gland via a V1-receptor mechanism.


Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha.
Anti-tumour necrosis factor alpha (TNF-alpha) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis (RA), and on theoretical grounds large differences in the effective dose between patients can be expected. Together with the high costs, these differences warrant new approaches to the way patients are dosed. We used the Disease Activity Score (DAS28), a composite disease activity index, to titrate the dose of anti-TNF-alpha (adalimumab, D2E7; Knoll) in 21 patients with low disease activity in an open extension study lasting 40 weeks. The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable. Disease activity and flares were assessed using the DAS28. Patients who flared received the previous effective dose. Dose reduction was accomplished in 15 patients. The total amount of anti-TNF-alpha given to the patients was reduced by 67%. At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA. Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy. This approach will save costs and possibly prevent long-term side-effects.


Primary Ewing Sarcoma of the Cervical Spine: A Case Report and Literature Review.
Ewing sarcoma is a rare neoplasm that mostly grows in bones or soft tissues around bones. Most cases of Ewing sarcoma occur in intra-skeletal locations (long bones, pelvis, or ribs) and rarely in extra-skeletal regions such as paravertebral or epidural space, whereas a primary intradural extramedullary Ewing sarcoma (IEES) is extremely rare. Fifty cases of primary IEES including our case were identified in the literature, so far, of which two-thirds are in the lumbosacral region, while only 12 reports described a cervical location of the tumor. Herein, we are presenting a case of C7-T1 primary IEES for a 24-year-old male, followed by a review of updated literature about the primary IEES in the cervical spine.


A Novel Approach for Studying the Physiology and Pathophysiology of Myelinated and Non-Myelinated Axons in the CNS White Matter.
Advances in brain connectomics set the need for detailed knowledge of functional properties of myelinated and non-myelinated (if present) axons in specific white matter pathways. The corpus callosum (CC), a major white matter structure interconnecting brain hemispheres, is extensively used for studying CNS axonal function. Unlike another widely used CNS white matter preparation, the optic nerve where all axons are myelinated, the CC contains also a large population of non-myelinated axons, making it particularly useful for studying both types of axons. Electrophysiological studies of optic nerve use suction electrodes on nerve ends to stimulate and record compound action potentials (CAPs) that adequately represent its axonal population, whereas CC studies use microelectrodes (MEs), recording from a limited area within the CC. Here we introduce a novel robust isolated "whole" CC preparation comparable to optic nerve. Unlike ME recordings where the CC CAP peaks representing myelinated and non-myelinated axons vary broadly in size, "whole" CC CAPs show stable reproducible ratios of these two main peaks, and also reveal a third peak, suggesting a distinct group of smaller caliber non-myelinated axons. We provide detailed characterization of "whole" CC CAPs and conduction velocities of myelinated and non-myelinated axons along the rostro-caudal axis of CC body and show advantages of this preparation for comparing axonal function in wild type and dysmyelinated shiverer mice, studying the effects of temperature dependence, bath-applied drugs and ischemia modeled by oxygen-glucose deprivation. Due to the isolation from gray matter, our approach allows for studying CC axonal function without possible "contamination" by reverberating signals from gray matter. Our analysis of "whole" CC CAPs revealed higher complexity of myelinated and non-myelinated axonal populations, not noticed earlier. This preparation may have a broad range of applications as a robust model for studying myelinated and non-myelinated axons of the CNS in various experimental models.


New species of Cortinarius sect. Austroamericani, sect. nov., from South American Nothofagaceae forests.
In this study, we document and describe the new Cortinarius section Austroamericani. Our results reveal high species diversity within this clade, with a total of 12 recognized species. Of these, only C. rufus was previously documented. Seven species are described as new based on basidiomata collections. The four remaining species are only known from environmental sequences. All examined species form ectomycorrhizal associations with species of Nothofagaceae and are currently only known from Argentinean and Chilean Patagonia. The phylogenetic analysis based on the nuc rDNA internal transcriber spacer (ITS1-5.8S-ITS2 = ITS) and partial 28S gene (28S) sequences shows that this section is related to other taxa from the Southern Hemisphere. Species in this group do not belong to subg. Telamonia, where C. rufus was initially placed. Cortinarius rufus and the newly described C. subrufus form a basal clade within sect. Austroamericani that has a weakly supported relationship with the core clade. Because the two species are morphologically similar to species from the core clade and share their distribution and Nothofagaceae associations, we include them here as part of sect. Austroamericani sensu lato (s.l.) until more material is available to refine the delimitation.


Flexible computation offloading in a fuzzy-based mobile edge orchestrator for IoT applications.
In the Internet of Things (IoT) era, the capacity-limited Internet and uncontrollable service delays for various new applications, such as video streaming analysis and augmented reality, are challenges. Cloud computing systems, also known as a solution that offloads energy-consuming computation of IoT applications to a cloud server, cannot meet the delay-sensitive and context-aware service requirements. To address this issue, an edge computing system provides timely and context-aware services by bringing the computations and storage closer to the user. The dynamic flow of requests that can be efficiently processed is a significant challenge for edge and cloud computing systems. To improve the performance of IoT systems, the mobile edge orchestrator (MEO), which is an application placement controller, was designed by integrating end mobile devices with edge and cloud computing systems. In this paper, we propose a flexible computation offloading method in a fuzzy-based MEO for IoT applications in order to improve the efficiency in computational resource management. Considering the network, computation resources, and task requirements, a fuzzy-based MEO allows edge workload orchestration actions to decide whether to offload a mobile user to local edge, neighboring edge, or cloud servers. Additionally, increasing packet sizes will affect the failed-task ratio when the number of mobile devices increases. To reduce failed tasks because of transmission collisions and to improve service times for time-critical tasks, we define a new input crisp value, and a new output decision for a fuzzy-based MEO. Using the EdgeCloudSim simulator, we evaluate our proposal with four benchmark algorithms in augmented reality, healthcare, compute-intensive, and infotainment applications. Simulation results show that our proposal provides better results in terms of WLAN delay, service times, the number of failed tasks, and VM utilization.


Adult protective services and animal welfare: should animal abuse and neglect be assessed during adult protective services screening?
Past research has examined links among animal abuse, child maltreatment, and intimate partner violence and demonstrated the importance of addressing the needs of both human and animal victims. We hypothesized that there might be a similar link between animal abuse and older adult welfare issues. As a first step in the earlier research was the development of a screening protocol that shed light on the link between domestic violence and animal abuse, we decided to follow a similar route to explore this new topic by asking state government representatives about their experiences, if any, with this topic. Here we report the results of a national survey of state Adult Protective Services agencies regarding their protocols for assessing animal welfare issues in the context of older adult maltreatment. We also describe a model assessment protocol we developed in collaboration with the Utah Division of Aging and Adult Services.


Cultural factors related to smoking in San Francisco's Irish bars.
California's Smoke-Free Workplace Act was extended to include bars in 1998. While the majority of bars in the state have become smoke free, in many bars patrons and staff continue to smoke despite the law. The authors present findings from a study which assessed cultural factors related to continued smoking in bars in the city of San Francisco. In bars serving primarily Irish migrants, tight-knit relations within the local Irish bar community together with a reluctance to be the first Irish bar to ban smoking were found to contribute to continued indoor smoking. The findings illustrate challenges to implementing tobacco control policies within ethnic subpopulations and particularly highlight the importance of considering how cultural dynamics within subpopulations may help or hinder such policies.


Natural history of chronic hepatitis B in co-infected patients.
HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.


Quantification of Chlamydia trachomatis elementary bodies in urine by ligase chain reaction.
Modification of the standard Chlamydia trachomatis ligase chain reaction (LCR) detection assay resulted in a quantitative test. Sample rates from C. trachomatis standards ranging from 32 to 1,048,576 elementary bodies (EB)/ml of urine exhibited a linear correlation with concentration. Quantitative LCR (qLCR) was used to measure the number of EB per milliliter in 158 urine samples from women in Madagascar that tested positive for C. trachomatis by the standard LCR detection assay. C. trachomatis concentrations displayed an apparent bimodal distribution, with approximately one-third of samples (37%) in a peak ranging from 32 to 1,015 EB/ml (median = 297 EB/ml) and the remainder (63%) in a grouping with relatively higher concentrations, ranging from 1,086 to 218,670 EB/ml (median = 7,389 EB/ml). qLCR will be useful for studies of chlamydial infection aimed at understanding the associations of organism burden with clinical manifestations and transmission.


Efficient solubilization, activation, and purification of recombinant Cry45Aa of Bacillus thuringiensis expressed as inclusion bodies in Escherichia coli.
A cytotoxic protein Cry45Aa of Bacillus thuringiensis expressed as inclusion bodies in Escherichia coli was solubilized in 10 mM HCl. Protein concentration of saturated solution of the recombinant Cry45Aa in 10 mM HCl was about 25 times higher than that in the buffer of previous method (in 50 mM sodium carbonate buffer, pH 10.5, containing 1 mM EDTA, and 10 mM dithiothreitol). The Cry45Aa solubilized in the acidic solution was activated by pepsin as an alternative to proteinase K in the previous method. Cytotoxic activity against CACO-2 cells of the pepsin-treated Cry45Aa was almost identical to the proteinase K-treated protein. The pepsin-treated Cry45Aa was purified by cation-exchange chromatography. The concentration of the purified protein was 539 microg/ml, which was 27-fold higher than that of the activated Cry45Aa by the previously method. The cytotoxic activity of the purified protein was stable in broad pH region (pH 2.0-11.0) for 3 days, and 97% cytotoxic activity remained after incubation at 30 degrees C for 360 min.


Bis-triazolylchalcogenium-Functionalized Benzothiadiazole Derivatives as Light-up Sensors for DNA and BSA.
A range of bis-triazolylchalcogenium-BTD 3 was synthesized by a copper-catalyzed azide-alkyne cycloaddition of azido arylchalcogenides 1 and 4,7-diethynylbenzo[c][1,2,5]thiadiazole 2. Eight new compounds were obtained in moderate to good yields using 1 mol % of copper(II) acetate monohydrate under mild reaction conditions. In addition, the synthesized bis-triazolylchalcogenium-BTD 3a-3h were investigated regarding their photophysical, electrochemical, and biomolecule binding properties in solution. In general, compounds presented strong absorption bands at the 250-450 nm region and cyan to green emission properties. The redox process attributed to the chalcogen atom was observed by electrochemical analysis (CV techniques). In addition, spectroscopic studies by UV-vis, steady-state emission fluorescence, and molecular docking calculations evidenced the ability of each derivative to establish interactions with calf-thymus DNA (CT-DNA) and bovine serum albumin (BSA). The behavior presented for this new class of compounds makes them a promising tool as optical sensors for biomolecules.


Tonsillectomy for the treatment of halitosis.
Halitosis, or oral malodor, is a term used to describe noticeably unpleasant odors exhaled in breathing whether the smell is from an oral source or not. Oral causes have been proposed to be responsible for the majority of halitosis complaints. The study aims to investigate the tonsils as an origin of halitosis and to assess the efficacy of tonsillectomy for the treatment of oral bad breath caused by chronic tonsillitis. After excluding dental, periodontal, sinonasal, oral, pulmonary, and gastroenterological diseases as the origin of halitosis, forty-four patients with halitosis caused by chronic tonsillitis which proved by positive Finkelstein's tonsil smelling test (pressing the tonsils and smelling the squeezed discharge), were included in the study. All patients were treated by tonsillectomy. Subjective and objective postoperative assessment was based on self-and-family report and clinical assessment. Patients were reviewed after 4 and 8 weeks postoperatively. Complete improvement of halitosis occurred in 31 patients (70.4%) after 4 weeks, this value increased to 35 patients (79.5%) in the second review after 8 weeks. Tonsillectomy is significantly effective procedure for the treatment of halitosis caused by chronic tonsillitis.


Upper limb corticomotor projections and physiological changes that occur with botulinum toxin-A therapy in children with hemiplegic cerebral palsy.
To investigate the corticomotor projection to the upper limb in children with hemiplegic cerebral palsy (CP) and the changes that occur with botulinum toxin (BTX)-A. The study design is a pilot prospective randomized trial. Twenty-two children with hemiplegic CP aged 7 years to 13 years 11 months were recruited. Treatment group (12) received one series of BTX-A injections into the upper limb. Control group (10) did not receive upper limb BTX-A. All participants except one treatment group participant also received lower limb BTX-A. Transcranial magnetic stimulation (TMS) was performed at baseline, and 1, 3 and 6 months post-injection. Outcome measures were: change in position of affected and unaffected side first dorsal interosseous optimal site of stimulation (OPTx). A shift in affected and unaffected side OPTx was observed for both treatment and control groups, and there was no statistically significant difference between groups at 1, 3 or 6 months. Poor tolerance of TMS cortical stimuli >80% was observed. Corticomotor projections associated with the upper limb in children with hemiplegic CP show significant variability over a 6-month period. This variability may reflect central motor reorganization because of systemic BTX-A effect or developmental changes. Upper limb BTX-A therapy is associated with reorganization of both affected and unaffected projections. Poor tolerance of the TMS procedure, in conjunction with higher cortical thresholds, may limit the usefulness of TMS as an investigatory tool in young children with movement disorders.


NEUROFIT: software for fitting Hodgkin-Huxley models to voltage-clamp data.
I introduce publicly available software for accurate fitting of Hodgkin-Huxley models to voltage-clamp data. I describe the model and non-linear fitting procedure employed by the software and compare its results with the usual method of fitting such models using potassium A-current data from a pyloric dilator cell of the lobster Panulirus interruptus and sodium current data from an electrocyte cell of the electric fish Sternopygus macrurus. The set of parameter values for the model determined by this software yield current traces that are substantially closer to the observed data than those determined from the usual fitting method. This improvement is due to the fact that the software fits all of the parameters simultaneously utilizing all of the data rather than fitting steady-state and time constant parameters disjointly using peak currents and portions of the rising and falling phases. I analyze the convergence properties of the software's fitting algorithm using simulated data showing that accurate parameter values are obtained for most of the parameters using any reasonable initial values. The software also incorporates a linear pre-estimation procedure to help in determining reasonable initial values for the full non-linear algorithm. I illustrate and discuss some of the inadequacies of voltage-clamp data.


Dynamic DNA Methylation Changes in the COMT Gene Promoter Region in Response to Mental Stress and Its Modulation by Transcranial Direct Current Stimulation.
Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. We investigated dynamic DNA methylation changes in whole blood of 42 healthy male individuals in response to a stressful cognitive task, its association with concentration changes in cortisol, and its modulation by transcranial direct current stimulation (tDCS). We observed a continuous increase in COMT promotor DNA methylation which correlated with higher saliva cortisol levels and was still detectable one week later. However, this lasting effect was suppressed by concurrent activity-enhancing anodal tDCS to the dorsolateral prefrontal cortex. Our findings support the significance of gene-specific DNA methylation in whole blood as potential biomarkers for stress-related effects. Moreover, they suggest alternative molecular mechanisms possibly involved in lasting behavioral effects of tDCS.


Proximal migration and compaction of an Enterprise stent into a coiled basilar apex aneurysm: a posterior circulation phenomenon?
A patient with a giant partially thrombosed basilar apex aneurysm was treated with balloon-assisted coil embolization. At the conclusion of the embolization, an Enterprise stent was placed from the upper basilar artery to the left P1 segment. Follow-up angiography 4 months later showed that the distal stent had pulled out of the posterior cerebral artery and was in the coil mass within the aneurysm. Angiography clearly showed that the stent had migrated down the basilar artery and that the artery was now kinked proximal to the stent. Nonetheless, the left posterior cerebral artery and the basilar artery were still widely patent. This is the first documented case in which a stent 'compacted' into a completed coiled aneurysm in a delayed fashion.


[Investigation of reproductive health status and service needs among unmarried young men in Changshu].
To investigate the status of pre-marital reproductive health education, sexual psychology behavior, contraception and pre-marital abortion in unmarried young men to get the correct way for pre-marital guidence and education. The survey adopted the society-psychology-behavior methodology. Five hundred and ten objects who had pre-marital sexual living history were investigated randomly. The reasons of making sexual pre-marital relations were thinking marriage and curiosity. 81.2% of them thought the best way of contraception is to use the condom. 34.8% of them used the prevenception when they had the first sexual experience. 39.7% of the objects adopted contraceptions every time, and 27.1% of the objects made the women pregnancy which resulted 22.4% women using the IUD for contraception. 63.6% of them thought the main reason of not using contraception was the fear to get trouble. The main source of contraceptives was pharmacy (59.8%). This survey suggested that the prevalence of pre-marital sexual behavior is relatively high in Changshu. It should be taken several methods to give unmarried young men the reproductibe education.


Ex Ovo Culture System for Avian Embryos and its Application.
Ex ovo culture of avian embryos can be applied not only to embryology but also to various fields of basic research such as embryo manipulation, toxicology, and regenerative medicine. The windowing method, which facilitates various manipulations and observations by opening a hole in one part of the eggshell, and culture systems using surrogate eggshells, are widely used. Despite this, biology lessons in high schools cover shell-less culture systems, which involve the development of avian embryos in artificial vessels, such as rice bowls, without using surrogate eggshells. However, as embryo development stops at its early stages in this method, it is not possible to continuously observe the development of the embryo. This led to attempts to develop an embryo culture method using a complete artificial culture vessel that does not use surrogate eggshells, and Kamihira et al. (1998) succeeded in hatching quail embryos in an artificial culture vessel using polytetrafluoroethylene membranes. In addition, Tahara succeeded in hatching chick embryos in artificial culture vessels that used cling film made of polymethylpentene and reported their detailed methodology (Tahara and Obara, 2014). These technologies are being applied not only to school education but also to various fields of research.


[Analysis of human papillomavirus type 16 E6/E7 mRNA in cervical cancers and precancerous lesions by means of the polymerase chain reaction with reverse transcriptase reaction].
We analyzed HPV-16 E6/E7 mRNA in human uterine cervical carcinomas and cervical intraepithelial neoplasias (CINs) by polymerase chain reaction (PCR) with reverse transcription (RT-PCR). Simultaneously total RNA and DNA were extracted from 6 cervical carcinomas, 14 CINs and 2 normal cervical tissues by the guanidium isothiocyanate/CsCl method. HPV-16 DNA was detected in 3 cervical carcinomas and 6 CINs. HPV-16 E6/E7 transcripts were detected in all HPV-16 DNA positive cervical carcinomas and CINs. In 2 cervical carcinomas and 5 CINs, 2 spliced E6 mRNA (E6*I and E6*II) and full length E6 mRNA were detected. In one cervical carcinoma and in one CIN, only full length E6-E7 mRNA was detected. Sequence analysis of cloned PCR products showed that both transcripts were generated by splicing out an intron in E6, from nucleotides (nt) 226 to 409 in E6*I and from nt 226 to 526 in E6*II. There was no significance difference in HPV-16 E6/E7 mRNA patterns between cervical carcinomas and CINs. This sensitive RT-PCR technique was available for analysis of HPV-16 mRNA in the small specimens.


Screen-printing ink transfer in a sexual assault case.
Yellow plastic-like particles were discovered on the clothing and body of a sexual assault victim. These particles were later associated to an athletic jersey with flaking yellow screen-printed numbers and letters, worn by the suspect. Depending on its intended substrate, screen-print ink can vary in color and composition. Particles dislodged from screen-printed garments may exhibit fabric impressions. Screen-printed clothing, commonly encountered in forensic casework, should be viewed as a potential source of trace evidence.


Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes.
Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers--of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19--received three 6-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60-mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC(0-infinity) of lansoprazole by 3.8-fold (P < .01) in homozygous EMs and by 2.5-fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine-mediated percentage increase in the AUC(0-infinity) of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.


[Utility of the L-alanine-aminopeptidase test for differentiating the cell wall structure of bacteria].
Evaluation of a detection test for L-alanine-aminopeptidase enzyme (Bactident Aminopeptidase) for determining the structure of bacterial cell wall. In a total of 246 clinical isolates of aerobic, microaerophilic and anaerobic bacteria, we detect the presence or absence of L-alanine-aminopeptidase using commercial kits (Bactident Aminopeptidase, Merck Diagnostica). We also identify and further classified the 246 strains. In nearly all gram-negative bacteria L-alanine-aminopeptidase was found, with the exception of Campylobacter spp and gram-negative anaerobic bacilli. All gram-positive and gram-variable bacteria were negative for the L-alanine-aminopeptidase presence. The results suggest a good correlation between the presence or absence of L-alanine-aminopeptidase and Gram stain method.


Interval estimation of quantile ratios applied to anti-cancer drug screening by xenograft experiments.
The current practice in analyzing data from anti-cancer drug screening by xenograft experiments lacks statistical consideration to account for experimental noise, and a sound inference procedure is necessary. A novel confidence bound and interval procedure for estimating quantile ratios developed in this paper fills the void. Justified by rigorous large-sample theory and a simulation study of small-sample performance, the proposed method performs well in a wide range of scenarios involving right-skewed distributions. By providing rigorous inference and much more interpretable statistics that account for experimental noise, the proposed method improves the current practice of analyzing drug activity data in xenograft experiments. The proposed method is fully nonparametric, simple to compute, performs equally well or better than known nonparametric methods, and is applicable to any statistical inference of a 'fold change' that can be formulated as a quantile ratio.


Evaluation of a welfare assessment tool to examine practices for preventing, recognizing, and managing pain at companion-animal veterinary clinics.
Successful prevention, recognition, and treatment of pain are integral to ensuring veterinary patient welfare. A canine and feline welfare assessment tool, incorporating verbal interviews with veterinarians using open-ended questions, was developed to assess pain management practices that safeguard and improve patient welfare. The tool was evaluated in 30 companion- and mixed-animal veterinary clinics in Ontario in order to assess its reliability, feasibility, and validity, while also benchmarking current practices. Responses were analyzed according to a scoring scheme developed based on published literature and expert opinion. Based on weighted kappa statistics, interview scoring had substantial inter-observer (Kw = 0.83, 0.73) and near-perfect intra-observer (Kw = 0.92) agreement, which suggests that the tool reliably collects information about pain management practices. Interviews were completed at all recruited clinics, which indicates high feasibility for the methods. Validity could not be assessed, as participants were reluctant to share information about analgesic administration from their clinical records. Descriptive results indicated areas for which many veterinarians are acting in accordance with best practices for pain management, such as pre-emptive and post-surgical analgesia for ovariohysterectomy patients, and post-surgical care instructions. Areas that offer opportunity for enhancement were also highlighted, e.g., training veterinary staff to recognize signs of pain and duration of analgesia in ovariohysterectomy patients after discharge. Overall, based on this limited sample, most veterinarians appear to be effectively managing their patients' pain, although areas with opportunity for enhancement were also identified. Further research is needed to assess trends in a broader sample of participants.


Reprogramming of CTLs into natural killer-like cells in celiac disease.
Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.


The role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus.
The aim of this study was to determine the yield of magnetic resonance imaging (MRI) after an episode of childhood convulsive status epilepticus (CSE) and to identify the clinical predictors of an abnormal brain scan. Children were recruited following an episode of CSE from an established clinical network in north London. Eighty children (age range 1mo-16y; 39 males; 41 females) were enrolled and seen for clinical assessment and brain MRI within 13 weeks of suffering from an episode of CSE. Scans were reviewed by two neuroradiologists and classified as normal (normal/normal-variant) or abnormal (minor/major abnormality). Factors predictive of an abnormal scan were investigated using logistic regression. Eighty children were recruited at a mean of 31.8 days (5-90d) after suffering from CSE. Structural abnormalities were found in 31%. Abnormal neurological examination at assessment (odds ratio [OR] 190.46), CSE that was not a prolonged febrile seizure (OR 77.12), and a continuous rather than an intermittent seizure (OR 29.98) were all predictive of an abnormal scan. No children with previous neuroimaging had new findings that altered their clinical management. Brain MRI should be considered for all children with a history of CSE who have not previously undergone MRI, especially those with non-prolonged febrile seizure CSE, those with persisting neurological abnormalities 2 to 13 weeks after CSE, and those with continuous CSE.


Professional autonomy - is it the future of general practice?
Internationally, rising financial costs and increasing expectations of health care delivery have increased regulation and decreased the autonomy of general practitioners and other health care professionals. This article explores professional autonomy within Australian general practice, and outlines the importance of autonomy in systems approaches to organisational change in general practice.


Surveillance recommendations for patients with Lynch syndrome and FAP : a monocentric study.
The most important causes of hereditary colorectal cancer are Lynch syndrome (LS) and the adenomatous polyposis syndromes (familial adenomatous poly- posis syndrome or FAP, attenuated FAP or AFAP and MUTYH associated polyposis syndrome or MAP). The aim of this study was to investigate whether all patients with a hereditary syndrome within one center receive uniform advice regarding surveillance and treatment. A retrospective analysis was performed of all electronic patient health records of patients with LS, FAP, AFAP and MAP who received genetic counselling or were followed by a health care specialist at the University Hospital in Ghent. Data from 122 patients were collected. For all patients, recommendations from the medical genetics department were highly consistent. Adherence to their recommendations was good within the center for the management of colon polyps. There was a lack of consistency in the screening and surveillance advice for other tumors in departments other than gastroenterology. Only 33 patients had systematic follow-up consultations to check results and organize surveillance. Previously, small studies have suggested that patients with hereditary gastrointestinal cancer syndromes infrequently have surveillance as specified in the guidelines. This study shows almost uniform recommendations and good adherence for surveillance of the colon, but incomplete or contradictory advice for surveillance of other organs. The need for an integrated approach from a multidisciplinary team will only increase in the future, because more families with hereditary cancer are likely to be found due to the increased use of next generation sequencing in cancer diagnostics.


[Research on laser spectrum detecting technology based on static Mach-Zehnder interferometer].
It is the key content of laser warning to reliably and real-time detect the type and characteristic parameters of incident laser. Coherent detection technology detects the information based on the coherence of laser, and is a kind of effective detection technology. In order to detect the incident laser's spectrum, a kind of device for laser detecting and real time spectrum measurement was designed, which measures the laser spectrum on the bases of coherent detecting technology, Fourier optics and optical signal processing. Using compact and static Mach-Zehnder interferometer as the coherent detection components, it can restrain the background light efficiently. The non-scanning mechanical parts allow fast spectrum detection, and narrow laser pulse can be detected. The real-time signal processing is realized by DSP and multi-channel frame subtraction technology to wipe off the background light, detect the laser and measure its spectrum. The result indicates that, using Mach-Zehnder interferometer and multi-channel frame subtraction technology can realize the laser pulse detection, and improve the measuring precision efficiently; 10 ns laser pulse can be detected and the wavelength measuring error is less than 10 nm.


Pigmented villonodular synovitis of the temporomandibular joint.
Pigmented villonodular synovitis (PVNS) is a proliferative disorder that affects synovium-lined joints, bursae, and tendon sheaths. It appears in both diffuse and localized forms, depending on the extent of synovial involvement. PVNS rarely involves the temporomandibular joint (TMJ); when it does, it manifests clinically as a slowly growing and painless preauricular mass that resembles a parotid tumor. TMJ dysfunction, paresthesia, and/or hearing loss can result. We present a case of a large extra-articular PVNS of the TMJ, and we review the literature.


MRS-lateralisation index in patients with epilepsy and focal cortical dysplasia or a MEG-focus using bilateral single voxels.
To evaluate if single voxel proton magnetic resonance spectroscopy (SV-MRS) can help in lateralising and sometimes in localizing an epileptogenic focus. The assumption is that in MRI negative patients the underlying pathology most often is focal cortical dysplasia (FCD). Several studies have shown that in the presence of FCD there are also (1)H-MRS abnormalities on the contralateral side. However, in most cases the studied group was not homogeneous and included different forms of dysplasias, including band heterotopias and polymicrogyria, and the studies used different spectroscopy protocols. In the present study, using bilateral SV-MRS we investigated the presence of a lateralisation index in two groups of patients with localisation related epilepsy: patients with focal cortical dysplasia on MRI and patients without MRI abnormalities with a focus identified by MEG. Aim of the study was to show that in both groups the expected epileptogenic side shows more pronounced metabolic alterations, making MRS a possible screening tool for clarifying lateralisation questions in patients with cryptogenic localisation related epilepsy. In ten patients a single voxel was placed over the FCD and in nine patients over the region of interest (ROI) as indicated by MEG. In all patients a voxel was also placed in the contralateral homologus location. We used metabolite concentrations as peak ratios relative to the creatine (Cr) peak to calculate a lateralisation index. In both groups NAA/Cr was significantly lower on the affected side whereas the results for Cho/Cr were more diverse. There were no significant differences between the two groups. The limitations of the used methods and the implications of the findings are discussed.


Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations.
Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia via induction of differentiation and programmed cell death (apoptosis). We investigated the effects of As2O3 on a panel of malignant lymphocytes to determine whether growth-inhibitory and apoptotic effects of As2O3 can be observed in these cells at clinically achievable concentrations. Eight malignant lymphocytic cell lines and primary cultures of lymphocytic leukemia and lymphoma cells were treated with As2O3, with or without dithiothreitol (DTT) or buthionine sulfoximine (BSO) (an inhibitor of glutathione synthesis). Apoptosis was assessed by cell morphology, flow cytometry, annexin V protein level, and terminal deoxynucleotidyl transferase labeling of DNA fragments. Cellular proliferation was determined by 5-bromo-2'-deoxyuridine incorporation into DNA and flow cytometry and by use of a mitotic arrest assay. Mitochondrial transmembrane potential (delta psi(m)) was measured by means of rhodamine 123 staining and flow cytometry. Protein expression was assessed by western blot analysis or immunofluorescence. Therapeutic concentrations of As2O3 (1-2 microM) had dual effects on malignant lymphocytes: 1) inhibition of growth through adenosine triphosphate (ATP) depletion and prolongation of cell cycle time and 2) induction of apoptosis. As2O3-induced apoptosis was preceded by delta psi(m) collapse. DTT antagonized and BSO enhanced As2O3-induced ATP depletion, delta psi(m) collapse, and apoptosis. Caspase-3 activation, usually resulting from delta psi(m) collapse, was not always associated with As2O3-induced apoptosis. As2O3 induced PML (promyelocytic leukemia) protein degradation but did not modulate expression of cell cycle-related proteins, including c-myc, retinoblastoma protein, cyclin-dependent kinase 4, cyclin D1, and p53, or expression of differentiation-related antigens. Substantial growth inhibition and apoptosis without evidence of differentiation were induced in most malignant lymphocytic cells treated with 1-2 microM As2O3. As2O3 may prove useful in the treatment of malignant lymphoproliferative disorders.


Aneurysm growth occurs at region of low wall shear stress: patient-specific correlation of hemodynamics and growth in a longitudinal study.
Evolution of intracranial aneurysmal disease is known to be related to hemodynamic forces acting on the vessel wall. Low wall shear stress (WSS) has been reported to have a negative effect on endothelial cells normal physiology and may be an important contributor to local remodeling of the arterial wall and to aneurysm growth and rupture. Seven patient-specific models of intracranial aneurysms were constructed using MR angiography data acquired at two different time points (mean 16.4+/-7.4 months between the two time points). Numeric simulations of the flow in the baseline geometries were performed to compute WSS distributions. The lumenal geometries constructed from the two time points were manually coregistered, and the radial displacement of the wall was calculated on a pixel-by-pixel basis. This displacement, corresponding to the local growth of the aneurysm, was compared to the time-averaged wall shear stress (WSS TA) through the cardiac cycle at that location. For statistical analysis, radial displacement was considered to be significant if it was larger than half of the MR pixel resolution (0.3 mm). Mean WSS TA values obtained for the areas with a displacement smaller and greater than 0.3 mm were 2.55+/-3.6 and 0.76+/-1.5 Pa, respectively (P<0.001). A linear correlation analysis demonstrated a significant relationship between WSS TA and surface displacement (P<0.001). These results indicate that aneurysm growth is likely to occur in regions where the endothelial layer lining the vessel wall is exposed to abnormally low wall shear stress.


Validating the European randomised study for screening of prostate cancer (ERSPC) risk calculator in a contemporary South African cohort.
Numerous prostate cancer predictive tools have been developed to help with decision-making in men needing prostate biopsy. However, they have been modelled and validated almost exclusively in Caucasian cohorts, hence limiting their use in other population groups. The aim of this study was to assess the validity of the ERSPC risk calculator in a South African cohort. Patients who have had a transrectal ultrasound (TRUS)-guided prostate biopsy at Groote Schuur Hospital from January 2008 to August 2017 were reviewed. Predictor variables were entered into the ERSPC risk calculator and results were compared with prostate biopsy pathology results. Predictive accuracy of the ERSPC risk calculator for these patients was derived using receiver operator characteristics (ROC) Area under the curve and is expressed as a percentage. 516 prostate biopsy sessions in 475 different men were analysed. The predictive accuracy of the ERSPC risk calculator was better than a PSA/DRE strategy for the presence of cancer-0.738 (95% CI 0.695-0.781) vs 0.686 (95% CI 0.639-0.732), and for significant PCa-0.833 (95% CI 0.789-0.876) vs 0.793 (95% CI 0.741-0.846). This translated into 50 less biopsies when compared to a PSA > 4/abnormal DRE strategy. Use of the ERSPC RC would have missed eight non-significant cancers [Significant cancer being defined as having a tumour stage T2b (> 1/2 lobe involved with prostate cancer) and/or a Gleason Score equal to or greater than 7]. Our results confirm the validity of the ERSPC RC in a South African cohort. Application of this calculator to the wider South African population would allow better selection of patients for prostate biopsy and spare a significant number its adverse consequences.


Choosing an opioid analgesic for cancer patients.
The following is a supplement to the article on the management of cancer pain which appeared in the January edition of AFP. It will provide some more detailed information on the choice and prescribing of opioid analgesics other than morphine for cancer patients. One should, of course, bear in mind many of the comments made in the original article regarding the holistic assessment of patients and their pain, the use of adjuvant therapies and alternatives. For more complete information regarding their use and pharmacokinetics one may need to consult product information, MIMS or one of the excellent short books designed for GPs.


Significance of serum leptin and adiponectin levels in Egyptian patients with chronic hepatitis C virus associated hepatic steatosis and fibrosis.
To study serum levels of leptin and adiponectin in patients with chronic hepatitis C virus infection genotype-4 (HCV-4) related steatosis and fibrosis. We prospectively studied 45 untreated men with chronic HCV-4, with proven steatosis (group I, 30 patients), and fibrosis (group II, 15 patients), on liver biopsy. In addition, 15 healthy men (group III), matched for age, and body mass index were included. However, we excluded another five patients with steatohepatitis, and six patients with cirrhosis. We measured total serum leptin and adiponectin levels, as potential predictors for liver steatosis and fibrosis. Also, a correlation between these adipokines and various clinical and laboratory data were evaluated. All subjects were selected from Tropical and Internal medicine departments, Menoufiya University Hospital, Menoufiya, Egypt, during the period from February 2010 to August 2011. In group I, severity of hepatic steatosis was mild, moderate, and severe, in 19 patients (63.5%), 8 patients (26.5%), and 3 patients (10%), respectively. In contrast, in group II, hepatic fibrosis was found to be in stage 1, 2, and 3, in 6 patients (40%), in 6 patients (40%), and in 3 patients (20%), respectively. On comparing group I with group II, there was a significant decrease in serum adiponectin levels (131.4 ± 7.91 pg/mL vs 436 ± 9.75 pg/mL, P < 0.001), while there was no significant difference between both groups regarding serum leptin levels (34.69 ± 7.69 ng/mL vs 35.17 ± 1.06 ng/mL, P > 0.05). However, in the same group, when compared with group III, there was a significant increase in serum leptin levels (34.69 ± 7.69 ng/mL vs 10.69 ± 0.84 ng/mL, P < 0.001), while there was a significant decrease in serum adiponectin levels (131.4 ± 7.91 pg/mL vs 342.4 ± 44.48 pg/mL, P < 0.001). In contrast, in group II, when compared with group III, there was a significant increase in serum leptin and adiponectin levels (35.17 ± 1.06 ng/mL vs 10.69 ± 0.84 ng/mL, P < 0.001, and 436 ± 9.75 pg /mL vs 342.4 ± 44.48 pg/mL, P < 0.05, respectively), while there was no significant difference between both groups regarding serum creatinine (0.83 ± 0.34 vs 0.89 ± 0.24, P > 0.05). On the other hand, serum leptin was not correlated with serum adiponectin in group I and in group II (r = 0.09, P > 0.05, and r = -0.1, P > 0.05, respectively). However, serum adiponectin was significantly negatively correlated with serum aspartate transaminase in group I, but no correlation detected in group II (r =-0.39, P > 0.05, and r = -0.03, P > 0.05). In male patients with chronic HCV-4, serum adiponectin levels are elevated in hepatic fibrosis, but decreased in steatosis. Therefore, in contrast to leptin, adiponectin may be used as a non-invasive marker.


3D MRI of the cervical spine: low flip angle FISP vs. Gd-DTPA TurboFLASH in degenerative disk disease.
The authors undertook this study to compare bright and dark CSF three-dimensional (3D) gradient-echo (GE) MR techniques to answer the following questions: Could a single Gd-DTPA enhanced T1-weighted GE volume sequence (with multiplanar reformats) be diagnostically equivalent for degenerative cervical disk disease to a standard sequence consisting of sagittal T1-weighted spin echo and axial low flip angle volume GE images (with reformatted images)? Does performing oblique coronal reformats perpendicular to the course of exiting cervical nerve roots improve diagnostic confidence over axial images alone? Thirty-one consecutive patients received a "routine" MR examination consisting of a sagittal T1-weighted spin echo and axial low flip angle volume sequence (FISP) [(35/7/5), 64 slices, 2 mm slice thickness, 192 x 256 matrix, 7.2 min]. Each patient was then given 0.1 mmol/kg Gd-DTPA intravenously, and reimaged with a T1-weighted volume GE sequence [(13/6/12), acquired as 128-1.2 mm coronal partitions, 192 x 256 matrix, 5.5 min]. Sequences were reconstructed on the standard diagnostic console in 1 mm increments. Sets of examinations (routine vs T1-weighted volume) were independently interpreted by three neuroradiologists for location, type, and severity of extradural degenerative disease. There was no strong or consistent trend for increased detection of disease by one imaging sequence over the other. For lateral disk disease, only 3% of the observations were in discordance. For disk disease, there was close agreement in the severity scores. All readers indicated that additional information was provided by the reformatted images more frequently with TurboFLASH (fast low angle shot) than with FISP. All readers indicated that increased confidence was provided by the reformatted images more frequently with TurboFLASH than with FISP. A single 3D contrast-enhanced TurboFLASH sequence is diagnostically equivalent to a set of two-dimensional T1-weighted sagittal spin echo and 3D axial low flip angle sequences for assessing the location and degree of cervical extradural degenerative disease. A screening examination of the cervical spine could be performed with a single contrast-enhanced 5.2 min study, and then relying on computer postprocessing to provide additional imaging planes.


Isolation and characterization of a small heat shock protein gene from maize.
A maize (Zea mays L.) genomic clone (Zmempr 9') was isolated on the basis of its homology to a meiotically expressed Lilium sequence. Radiolabeled probe made from the maize genomic clone detected complementary RNA at high fidelity. Furthermore, it hybridized to RNA isolated from staged (an interval that is coincident with meiotic prophase) maize tassel spikelets. Complimentary RNA was strongly (at least 50-fold) induced during heat shock of maize somatic tissue and appeared as a single size class in Northern blot hybridizations. Sequencing of the complete coding region of Zmempr 9' confirmed the homology of the inferred amino acid sequence to other small heat shock proteins. Consensus sequences found in the flanking regions corresponded to the usual signals for initiation of RNA transcription, polyadenylate addition, and the induction of heat shock genes. The latter sequences conferred heat shock-specific transient expression in electroporated protoplasts when cloned into promoterless reporter gene plasmid constructs. Hybrid-selected translations revealed specific translation products ranging from 15 to 18 kilodaltons, providing evidence that this gene is a member of a related multigene family. We therefore conclude that this maize genomic DNA clone, recovered through its homology to clones for meiotic transcripts in lily, represents a genuine maize small heat shock protein gene.


Drug use in prisons in Kyrgyzstan: a study about the effect of health promotion among prisoners.
In Kyrgyzstan the prevalence of injecting drug behaviour is among the highest found throughout the world. Health promotion training, improved health care and needle/syringe exchange (NSE) programmes have been shown to decrease risk behaviour among injecting drug users. In Kyrgyzstan, an intervention study with training of prison staff and prisoners was performed in one prison. Before and after the training, a random selection of the prisoners answered a questionnaire about drug use, risk behaviour and health care. The survey was carried out in both the intervention prison and in a reference prison. The number of drug users, the use of drugs and risk behaviour were improved significantly within half a year and, especially, the injection and use of drugs decreased in the intervention group. The study clearly shows that increased focus, improved healthcare and training of prisoners and staff on drug use and harm reduction can reduce both use of drugs and risk behaviour.


An improved polychromatic graphs-based BOM multi-view management and version control method for complex products.
With the increasing complexity of modern engineering and wide application of intelligent manufacturing technology, the type and quantity of product data continue to climb, and the corresponding version iteration rate continues to accelerate. In order to achieve effective unified management and maintenance of product data and to track version evolution accurately, this paper proposes an improved polychromatic graphs-based BOM multi-view management and version control method for complex products. Firstly, the framework was established for BOM multi-view management and version control, whose mechanism was also elaborated. According to the model of multi-view-version product structure, the expression method of product structure was discussed at different stages of product life cycle. Furtherly, with multi-object constraints sets were introduced, a version control model was established based on the improved polychromatic graphs, whose definition and principle were also detailed. Finally, application cases were discussed to verify the feasibility and universality of the proposed models and methods.


Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder.
Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse. To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse. This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse. Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups. Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.


Oxidation-Responsive Nanoassemblies for Light-Enhanced Gene Therapy.
Microenvironment-responsive supramolecular assemblies have attracted great interest in the biomedical field due to their potential applications in controlled drug release. In this study, oxidation-responsive supramolecular polycationic assemblies named CPAs are prepared for nucleic acid delivery via the host-guest interaction of β-cyclodextrin based polycations and a ferrocene-functionalized zinc tetraaminophthalocyanine core. The reactive oxygen species (ROS) can accelerate the disassembly of CPA/pDNA complexes, which would facilitate the release of pDNA in the complexes and further benefit the subsequent transfection. Such improvement in transfection efficiency is proved in A549 cells with high H2 O2 concentration. Interestingly, the transfection efficiencies mediated by CPAs are also different in the presence or absence of light in various cell lines such as HEK 293 and 4T1. The single oxygen (1 O2 ), produced by photosensitizers in the core of CPAs under light, increases the ROS amount and accelerates the disassembly of CPAs/pDNA complexes. In vitro and in vivo studies further illustrate that suppressor tumor gene p53 delivered by CPAs exhibits great antitumor effects under illumination. This work provides a promising strategy for the design and fabrication of oxidation-responsive nanoassemblies with light-enhanced gene transfection performance.


A simple chemical method reduces ochratoxin A in contaminated cocoa shells.
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species, which contaminates cocoa among other food commodities. It has been previously demonstrated that the toxin is concentrated in cocoa shells. The aim of this study was to assay a simple chemical method for ochratoxin A reduction from naturally contaminated cocoa shells. In order to determine the efficiency of the method, a high-performance liquid chromatography method with fluorescence detection was set up beforehand and validated. Ochratoxin A was extracted from cocoa shells with methanol-3% sodium bicarbonate solution and then purified with immunoaffinity columns. The recovery attained was 88.7% (relative standard deviation = 6.36%) and the limits of detection and quantification were 0.06 and 0.2 kg/kg, respectively. For decontamination experiments, the solvent extractor ASE 200 was used. First, aqueous solutions of 2% sodium bicarbonate and potassium carbonate were compared under the same conditions (1,500 lb/in2 at 40 degrees C for 10 min). Higher ochratoxin A reduction was obtained with potassium carbonate (83 versus 27%). Then, this salt was used under different conditions of pressure, temperature, and time. The greatest ochratoxin A reduction was achieved with an aqueous potassium carbonate solution (2%), at 1,000 lb/in2 at 90 degrees C for 10 min. This method could probably be applicable to the cocoa industry because it is fast and relatively economic. From the point of view of human health, the use of potassium carbonate, partially eliminated by rinsing the sample with water, does not likely represent a risk for human health.


Regression analysis and transfer function in estimating the parameters of central pulse waves from brachial pulse wave.
This study mainly analyzed the parameters such as ascending branch slope (A_slope), dicrotic notch height (Hn), diastolic area (Ad) and systolic area (As) diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), subendocardial viability ratio (SEVR), waveform parameter (k), stroke volume (SV), cardiac output (CO) and peripheral resistance (RS) of central pulse wave invasively and non-invasively measured. These parameters extracted from the central pulse wave invasively measured were compared with the parameters measured from the brachial pulse waves by a regression model and a transfer function model. The accuracy of the parameters which were estimated by the regression model and the transfer function model was compared too. Our findings showed that in addition to the k value, the above parameters of the central pulse wave and the brachial pulse wave invasively measured had positive correlation. Both the regression model parameters including A_slope, DBP, SEVR and the transfer function model parameters had good consistency with the parameters invasively measured, and they had the same effect of consistency. The regression equations of the three parameters were expressed by Y'=a+bx. The SBP, PP, SV, CO of central pulse wave could be calculated through the regression model, but their accuracies were worse than that of transfer function model.


Simulation-based evaluation of the linear-mixed model in the presence of an increasing proportion of singletons.
Data in medical sciences often have a hierarchical structure with lower level units (e.g. children) nested in higher level units (e.g. departments). Several specific but frequently studied settings, mainly in longitudinal and family research, involve a large number of units that tend to be quite small, with units containing only one element referred to as singletons. Regardless of sparseness, hierarchical data should be analyzed with appropriate methodology such as, for example linear-mixed models. Using a simulation study, based on the structure of a data example on Ceftriaxone consumption in hospitalized children, we assess the impact of an increasing proportion of singletons (0-95%), in data with a low, medium, or high intracluster correlation, on the stability of linear-mixed models parameter estimates, confidence interval coverage and F test performance. Some techniques that are frequently used in the presence of singletons include ignoring clustering, dropping the singletons from the analysis and grouping the singletons into an artificial unit. We show that both the fixed and random effects estimates and their standard errors are stable in the presence of an increasing proportion of singletons. We demonstrate that ignoring clustering and dropping singletons should be avoided as they come with biased standard error estimates. Grouping the singletons into an artificial unit might be considered, although the linear-mixed model performs better even when the proportion of singletons is high. We conclude that the linear-mixed model is stable in the presence of singletons when both lower- and higher level sample sizes are fixed. In this setting, the use of remedial measures, such as ignoring clustering and grouping or removing singletons, should be dissuaded.


Interval estimation of the proportion ratio in repeated binary measurements under a stratified randomized clinical trial with noncompliance.
The proportion ratio (PR) of a positive response between an experimental treatment and a standard treatment (or placebo) is often used to measure the relative treatment efficacy in a randomized clinical trial (RCT). For ethical reasons, it is almost inevitable to encounter some patients not complying with their assigned treatment. Furthermore, when there are confounders in a RCT or meta-analysis, we commonly employ stratified analysis to control the confounding effects on interval estimation of the PR. On the basis of a general risk multiplicative model, we focus our discussion on interval estimation of the PR in repeated binary data under a stratified RCT with noncompliance. We develop seven asymptotic closed-form interval estimators for the PR. We apply Monte Carlo simulation to study the finite-sample performance of these interval estimators in a variety of situations. We note that the two interval estimators with the logarithmic transformation based on the commonly used weighted least squares (WLS) approach can be liberal, while the three interval estimators with the Mantel-Haenszel (MH) weight derived from various methods can consistently perform well. We also note that the two estimators with the estimated optimal weight defined in the context using Fieller's Theorem and a randomization-based approach may not necessarily produce a confidence interval preferable to the MH-type interval estimators for the PR with respect to accuracy and precision.


Effects of chronic levodopa therapy on dopa pharmacokinetics.
We reevaluate here the effects of chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon. The peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC) were markedly increased after long-term levodopa therapy, whereas the time to the peak concentration (Tmax) and the elimination half-life (T(1/2)) were decreased. These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. Furthermore, the wearing-off group had a markedly higher Cmax and AUC, and a shorter Tmax and T(1/2) than the stable group. We speculate that the clinical expression of 'stable' or 'wearing-off' depends on the absorption of levodopa as well as the presynaptic terminal and postsynaptic receptors.


Ureteral obstruction due to retroperitoneal fibrosis secondary to a solitary internal iliac aneurysm.
We report a case of ureteral obstruction due to retroperitoneal fibrosis secondary to a solitary left internal iliac aneurysm. It has been reported that as a cause of ureteral obstruction, an internal iliac aneurysm without aortic and/or common iliac aneurysms is very rare. In the present case, magnetic resonance imaging was a useful modality to diagnose retroperitoneal fibrosis secondary to an internal iliac aneurysm as a direct cause of ureteral obstruction.


Vesicular acetylcholine transporter (VAChT): a cellular marker in rat retinal development.
A polyclonal goat antiserum against the C-terminal end of the rat vesicular acetylcholine transporter (VAChT) was used to examine the postnatal expression of this protein in the rat retina. The transporter protein was localized in choline acetyltransferase (ChAT)-positive, cholinergic interneurones (so-called starburst amacrine cells) in the inner retina. During postnatal development the VAChT was expressed from postnatal day 1 onward by the two subsets of these cholinergic amacrine cells. The immunocytochemical detection of the VAChT provides a specific marker for the study of developing cholinergic neurones in the rat retina, which so far has only been monitored by ChAT immunoreactivity in the second postnatal week.


Effective Diagnosis and Treatment through Content-Based Medical Image Retrieval (CBMIR) by Using Artificial Intelligence.
Medical-image-based diagnosis is a tedious task' and small lesions in various medical images can be overlooked by medical experts due to the limited attention span of the human visual system, which can adversely affect medical treatment. However, this problem can be resolved by exploring similar cases in the previous medical database through an efficient content-based medical image retrieval (CBMIR) system. In the past few years, heterogeneous medical imaging databases have been growing rapidly with the advent of different types of medical imaging modalities. Recently, a medical doctor usually refers to various types of imaging modalities all together such as computed tomography (CT), magnetic resonance imaging (MRI), X-ray, and ultrasound, etc of various organs in order for the diagnosis and treatment of specific disease. Accurate classification and retrieval of multimodal medical imaging data is the key challenge for the CBMIR system. Most previous attempts use handcrafted features for medical image classification and retrieval, which show low performance for a massive collection of multimodal databases. Although there are a few previous studies on the use of deep features for classification, the number of classes is very small. To solve this problem, we propose the classification-based retrieval system of the multimodal medical images from various types of imaging modalities by using the technique of artificial intelligence, named as an enhanced residual network (ResNet). Experimental results with 12 databases including 50 classes demonstrate that the accuracy and F1.score by our method are respectively 81.51% and 82.42% which are higher than those by the previous method of CBMIR (the accuracy of 69.71% and F1.score of 69.63%).


Surgery of the adrenal metastases.
Adrenal metastases are the most common malignant lesions of the adrenal glands and the second most common tumor after adenomas. The location of the primary tumor is described: lung (39%), breast (35%), gastrointestinal tract, among other. Several studies show that surgery improves survival in selected cases. Retrospective and single-center observational study of patients operated for adrenal metastasis over a period of 11 years. The characteristics of the disease and surgical results were described. 14 suprarenalectomies were performed. The average age was 65.85 years. The primary tumors described: non-small cell lung carcinoma (42.8%) and clear cell renal carcinoma (14.20%). In 92.8% the injury was unilateral. In 64.2% it was metachronous. An initial laparoscopic approach was performed in 85.71%. The morbidity of our series was 14.28%. The median overall survival was 30 months. Survival was 75% per year, 55.5% at 3 years and 40% at 5 years. Age, primary location, degree of differentiation, histological type, size greater, laterality, disease-free interval, chemotherapy and surgical technique are not associated with changes in survival. In the presence of a single adrenal mass, surgical evaluation is mandatory and surgery could play a role in patients with metastases in other locations with control of the primary disease.