Analysis of Correlation between Age and Satisfied Total Weight Loss Percentage Outcome at 1 Year after Bariatric Surgery using the Restricted Cubic Spline Function: A Retrospective Study in China.
This study aims to explore the relationship between age and whether the percentage of total weight loss (TWL%) is ≥ 25% or not at 1 year after bariatric surgery (BS). We aimed to provide evidence for the stratified treatment of spatients with obesity at different ages. The primary outcome evaluated was whether TWL% was no less than 25% at 1 year after BS. A TWL% ≥ 25% was defined as a satisfied TWL% outcome. Logistic regression analysis and the restricted cubic spline (RCS) function were used to analyze the relationship between age and the satisfied TWL% outcome at 1 year after BS. Two hundred and ninety-one patients were included in our study. After adjusting for potential confounders, the odds ratios (ORs) of the corresponding quartiles of age associated with satisfied TWL% outcome were 1.00 (reference), 1.117 [95% confidence interval (95% CI) = 0.540-2.311], 1.378 (95% CI = 0.647-2.935), and 0.406 (95% CI = 0.184-0.895). RCS analysis revealed a non-linear inverted L-shaped association between age and satisfied TWL% outcome at 1 year after BS (non-linear P = 0.033). Age was an independent predictor of satisfied TWL% outcome one year following BS, and our study considered 32 years as a potential cut-off point. For Chinese patients over the age of 32 who are eligible for BS, it may be beneficial to do BS earlier as the probability of achieving a satisfied TWL% outcome may decrease with age.


Gemfibrozil decreases platelet reactivity in patients with hypercholesterolemia during physical stress.
The effects of the lipid-lowering drug gemfibrozil on platelet reactivity at rest and during submaximal exercise were investigated in 10 patients with serum cholesterol levels greater than 270 mg/dl. No significant changes were observed in platelet reactivity at rest after gemfibrozil treatment. However, a marked decrease in platelet reactivity was seen in almost all patients treated with gemfibrozil during exercise. The adrenaline concentration necessary to induce secondary aggregation increased in eight patients during exercise after gemfibrozil and in two after placebo treatment. When adenosine diphosphatase (2 to 4 mumol/L) was used to induce aggregation, 5-hydroxytryptamine (serotonin) and thromboxane B2 secretion by platelets decreased by 35% and 67%, respectively, during exercise in patients treated with gemfibrozil. The area under the aggregation curve decreased by 28% during exercise after gemfibrozil. No significant changes occurred in these variables during exercise after placebo. Thus, gemfibrozil seems to have antiplatelet effects that might have importance in the prevention of acute complications of atherosclerosis in patients with hypercholesterolemia.


Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic-Pharmacodynamic Modeling Approaches.
Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.


Structure and function of long-lived olfactory organotypic cultures from postnatal mice.
The first synapse in the olfactory pathway mediates a significant transfer of information given the restricted association of specific olfactory receptor neurons with specific glomeruli in the olfactory bulb. To understand better how this connection is made and what the functional capacities of the participating cells are, we created a long-lived culture system composed of olfactory epithelium and olfactory bulb tissues. Using the roller tube method of culturing, we grew epithelium-bulb cocultures, explanted from 1-4-day-old Swiss Webster mice, on Aclar for periods ranging from 18 hr to 68 days. The explants flattened so that in some areas the culture was only a few cells thick, making individual cells distinguishable. From 107 cultures studied, we identified the following cell types by expression of specific markers (oldest culture expressing marker, days in vitro, DIV): olfactory receptor neurons (neural cell adhesion molecule, 42 DIV); mature receptor neurons (olfactory marker protein, 28 DIV); postmitotic olfactory receptor neurons and olfactory bulb neurons (beta-tubulin, 68 DIV); astrocytes (glial fibrillary acidic protein, glutamate/aspartate transporter, 68 DIV); olfactory horizontal basal cells (cytokeratin, 22 DIV). Neuronal processes formed glomeruli in 2-4-week-old cultures. We also recorded electro-olfactography responses to puffs of vapor collected over an odorant mixture containing ethyl butyrate, eugenol, (+) carvone, and (-) carvone from cultures as old as 21 DIV. These features of our olfactory culture system make this model useful for studying properties of immature and mature olfactory receptor neurons, pathfinding strategies of receptor axons, and mechanisms of information transfer in the olfactory glomerulus.


Multifunctional nanoscale strategies for enhancing and monitoring blood vessel regeneration.
Nanomedicine has great potential in biomedical applications, and specifically in regenerative medicine and vascular tissue engineering. Designing nanometer-sized therapeutic and diagnostic devices for tissue engineering applications is critical because cells experience and respond to stimuli on this spatial scale. For example, nanoscaffolds, including nanoscalestructured or nanoscale surface-modified vascular scaffolds, can influence cell alignment, adhesion, and differentiation to promote better endothelization. Furthermore, nanoscale contrast agents can be extended to the field of biomedical imaging to monitor and track stem cells to better understand the process of neovascularization. In addition, nanoscale systems capable of delivering biomolecules (e.g. peptides and angiogenic genes/proteins) can influence cell behavior, function, and phenotype to promote blood vessel regeneration. This review will focus on nanomedicine and nanoscale strategies applied to vascular tissue engineering. In particular, some of the latest research and potential applications pertaining to nanoscaffolds, biomedical imaging and cell tracking using nanoscale contrast agents, and nanodelivery systems of bioactive molecules applied to blood vessel regeneration will be discussed. In addition, the overlap between these three areas and their synergistic effects will be examined as related to vascular tissue engineering.


Preoperative malnutrition increases odds of hospital admission and extended length of stay following arthroscopic rotator cuff repair.
Rotator cuff repair (RCR) is a common orthopedic procedure frequently performed in the outpatient setting. Malnutrition, as assessed by preoperative serum albumin <3.5 g/dL, has been independently associated with significantly higher risks of multiple adverse outcomes in several orthopedic procedures. The effect of preoperative hypoalbuminemia on short-term outcomes of RCR was previously unknown. we hypothesized that preoperative serum albumin <3.5 g/dL would be associated with higher odds of post-operative admission and prolonged length of stay. This study represents a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database (NSQIP) for patients undergoing RCR between 2011 and 2015. Multivariate regression analysis adjusted for sex, ASA classification, age, BMI, and diabetes status (Table 3) showed preoperative hypoalbuminemia conferred a significantly increased adjusted odds ratio of postoperative admission (adjusted odds ratio 1.711, CI 1.134-2.583, p = 0.011) and extended length of stay (adjusted odds ratio 2.073, CI 1.073-4.003, p = 0.030). Malnutrition as assessed by preoperative serum albumin <3.5 g/dL is significantly associated with increased odds of hospital admission and extended length of stay following arthroscopic RCR. This has clinical implications in surgical patient selection and risk stratification. III, Retrospective cohort study.


Special Issue "Bacillus subtilis as a Model Organism to Study Basic Cell Processes".
Bacillus subtilis has served as a model microorganism for many decades [...].


Oral immunization induces a novel CXCR6+ β7+ intraepithelial lymphocyte subset predominating in the small intestine.
Intestinal T cells form a central part of the front-line defence against foreign organisms and need to be situated in the mucosa where infection occurs. It is well accepted that immunization by a mucosal route favours localization of antigen-specific effector T cells in the mucosal epithelium, while systemic immunization does not. The aim of the study is to determine how homing receptors are specifically involved in retaining effector T cells in the small intestine after oral immunization. We here demonstrate that the chemokine receptor CXCR6, integrins β7 and CD29 contribute differentially to the epithelial retention phenotype of CD8+ T cells in the small intestine of mice. CD8+ intraepithelial lymphocytes (IELs) of unvaccinated mice are predominantly β7 single positives, and subcutaneous immunization-induced antigen-specific CD8+ effector IELs are mainly composed of CXCR6+ , CD29+ and CXCR6+ CD29+ cells. Strikingly, the majority of oral immunization-induced antigen-specific CD8+ effector IELs exhibit a distinct, tissue-specific CXCR6+ β7+ double-positive phenotype, cytotoxic potential and enhanced intraepithelial localization. Transfer of antigen-specific CD8+ T cells preactivated with certain immuno-stimuli (such as monophosphoryl lipid A) results in increased accumulation of donor IELs with the CXCR6+ β7+ phenotype. As β7 exclusively paired with αE on IELs, our results strongly suggest that CXCR6 may cooperate with the heterodimer αEβ7 to preferentially retain intestinally induced effector IELs in the epithelium. The identification of this novel IEL phenotype has significant implications for the development of vaccines and therapeutic strategies to enhance gut immunity.


Presence of covalently attached fatty acids in rat apolipoprotein B via thiolester linkages.
Thiolester linked lipids in rat apolipoprotein B (ApoB) were examined by incubating reduced and carboxymethylated ApoB in 6 M urea buffer with [14C]methylamine at pH 8.5, 30 degrees C. It was observed that [14C]methylamine was covalently incorporated into ApoB, and there was a [14C]methylamine modified product which was lipid in nature. After extraction with organic solvents, the [14C]methylamine labeled product showed its Rf on TLC to be similar to that of the synthetic N-methyl fatty acyl amide. After purification on TLC and transesterification with 3 N methanolic HC1, methyl esters of C16:0, C18:0 and C18:1 fatty acids were identified by gas-liquid chromatography. These results suggest that rat ApoB, similar to human ApoB, contained covalently linked fatty acids through the high energy, labile thiolester bonds.


Adaptive behavior of marine cellular clouds.
Shallow marine clouds appear in two formations - open cells that are weakly reflective and closed cells that are more reflective and hence more effective at cooling the climate system. Lagrangian satellite data analysis reveals that open cells oscillate, forming and disappearing with a periodicity of ~3 hours. In contrast, closed cells maintain rigid structures for periods of more than 10 hours, suggesting that self-organisation breaks the link between the lifetime and the scale of a convective entity. These dynamical states are linked to two theoretical solutions of population dynamics.


Heterogeneity of primary and secondary peristalsis in systemic sclerosis: A new model of "scleroderma esophagus".
Although esophageal dysmotility is common in systemic sclerosis (SSc)/scleroderma, little is known regarding the pathophysiology of motor abnormalities driving reflux severity and dysphagia. This study aimed to assess primary and secondary peristalsis in SSc using a comprehensive esophageal motility assessment applying high-resolution manometry (HRM) and functional luminal imaging probe (FLIP) Panometry. A total of 32 patients with scleroderma (28 female; ages 38-77; 20 limited SSc, 12 diffuse SSc) completed FLIP Panometry and HRM. Secondary peristalsis, i.e., contractile responses (CR), was classified on FLIP Panometry by pattern of contractility as normal (NCR), borderline (BCR), impaired/disordered (IDCR), or absent (ACR). Primary peristalsis on HRM was assessed according to the Chicago classification. The manometric diagnoses were 56% (n = 18) absent contractility, 22% (n = 7) ineffective esophageal motility (IEM), and 22% (n = 7) normal motility. Secondary peristalsis (CRs) included 38% (n = 12) ACR, 38% (n = 12) IDCR, 19% (n = 6) BCR, and 15% (n = 5) NCR. The median (IQR) esophagogastric junction (EGJ) distensibility index (DI) was 5.8 mm2 /mmHg (4.8-10.1) mm2 /mmHg; EGJ-DI was >8.0 mm2 /mmHg in 31%, and >2.0 mm2 /mmHg in 100% of patients. Among 18 patients with absent contractility on HRM, 11 had ACR, 5 had IDCR, and 2 had BCR. Among 7 patients with IEM, 1 had ACR, 5 had IDCR, and 1 NCR. All of the patients with normal peristalsis had NCR or BCR. This was the first study assessing combined HRM and FLIP Panometry in a cohort of SSc patients, which demonstrated heterogeneity in primary and secondary peristalsis. This complementary approach facilitates characterizing esophageal function in SSc, although future study to examine clinical outcomes remains necessary.


One-year study of polycyclic aromatic compounds at an urban site in Grenoble (France): Seasonal variations, gas/particle partitioning and cancer risk estimation.
21 PAHs, 27 oxy-PAHs and 32 nitro-PAHs were measured every third day over a year in both gaseous (G) and particulate PM10 (P) phases in ambient air of Grenoble (France). Mean total concentrations (G+P) of PAHs and oxy-PAHs were in the same range and about 10ngm(-3). Nitro-PAHs were 50 to 100 times less concentrated averaging 100pgm(-3). Polycyclic aromatic compound (PAC) concentrations were 5 to 7 times higher in "cold" period (October to March) than in "warm" period (April to September). Seasonal variations may be explained by higher primary emissions from residential heating, especially biomass burning in "cold" season. Meteorological conditions and influence of the geomorphology around Grenoble, with the formation of thermal inversion layers leading to the stagnation of pollutants, were additional key parameters. Maximum individual PAC concentrations were observed during two PM10 pollution events in December and February-March. Chemical processes and secondary formation of oxy- and nitro-PAH were probably enhanced by the accumulation of the pollutants during these events. PAC gas/particle partitioning depended on compound molecular weight and vapour pressure. Gas/particle partitioning of oxy- and nitro-PAHs were evaluated using a multi-phase poly-parameter linear free energy relationship model. The PAC cancer risk was assessed using toxic equivalency factors available in the literature (19 PAHs, 10 nitro-PAHs and 1 oxy-PAH). Overall, particle-bound PACs contributed about 76% of the cancer risk. While PAHs accounted for most of the total PAC cancer risk, oxy- and nitro-PAHs could account for up to 24%. The risk quantification across substance classes is limited by toxicological data availability.


Effects of short-term exposure to particulate matters on heart rate variability: A systematic review and meta-analysis based on controlled animal studies.
Exposure to particulate matters (PM) is recognized as an important risk factor for cardiovascular disease. A change in cardiac autonomic function is one postulated mechanism leading to PM related cardiovascular events. This study therefore evaluated the associations of short-term exposure to PM and heart rate variability (HRV) parameters, which can reflect the cardiac autonomic function. Four electronic databases were searched for controlled studies of rodents published prior to December 2018. A systematic review and meta-analysis was conducted. Effect sizes were calculated for five main HRV parameters, including standard deviation of normal-to-normal intervals (SDNN), square root of mean squared differences between successive normal-to-normal intervals (rMSSD), low frequency (LF), high frequency (HF), and the ratio of LF and HF (LF/HF). The review included 23 studies with 401 animals. Short-term exposure to PM by instillation yielded statistically significant effects on SDNN (Standardized Mean Difference [SMD] = -1.11, 95% Confidence Intervals [CI] = -2.22 to -0.01, P = 0.05), LF (SMD = -1.19, 95% CI = -1.99 to -0.40, P = 0.003) and LF/HF (SMD = -1.05, 95% CI = -2.03 to -0.07, P = 0.04). Short-term exposure to PM by inhalation only yielded statistically significant effect on LF/HF (SMD = -0.83, 95% CI = -1.39 to -0.27, P = 0.004). There was no evidence that animal model and exposure frequency influenced the relationship of PM and HRV. Short-term exposure to PM can decrease HRV of rodents, affecting cardiac autonomic function. Exposure methods can influence the relationships of PM and HRV parameters. Further studies should focus on the effects of long-term PM exposure, on human beings, and potential influential factors of PM-HRV associations.


The force of the myosin motor sets cooperativity in thin filament activation of skeletal muscles.
Contraction of striated muscle is regulated by a dual mechanism involving both thin, actin-containing filament and thick, myosin-containing filament. Thin filament is activated by Ca2+ binding to troponin, leading to tropomyosin displacement that exposes actin sites for interaction with myosin motors, extending from the neighbouring stress-activated thick filaments. Motor attachment to actin contributes to spreading activation along the thin filament, through a cooperative mechanism, still unclear, that determines the slope of the sigmoidal relation between isometric force and pCa (-log[Ca2+]), estimated by Hill coefficient nH. We use sarcomere-level mechanics in demembranated fibres of rabbit skeletal muscle activated by Ca2+ at different temperatures (12-35 °C) to show that nH depends on the motor force at constant number of attached motors. The definition of the role of motor force provides fundamental constraints for modelling the dynamics of thin filament activation and defining the action of small molecules as possible therapeutic tools.


Regulation of hepatic lipogenesis by the zinc finger protein Zbtb20.
Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease.


Immunoproteomics to identify tumor-associated antigens eliciting humoral response.
Proteome analysis has rapidly developed in the post-genome era and is widely accepted as a complementary technology to genetic profiling. Sera from tumor patients contain tumor specific antibodies directly against antigenic proteins. Immunoproteomics, which defines the subset of proteins involved in the immune response, holds considerable promise for the discovery of tumor-associated antigens, suggesting that this approach may be a useful tool for identification of prognostic, diagnostic markers and novel therapeutic targets. Recently, various different approaches are developed to identify tumor-associated antigens by autoantibodies from tumor patients' sera. More than one hundred tumor-associated antigens have been found in various tumors by with antibody-based strategy nowadays. However, some autoantibodies are also found in health subjects, even some of them with high antibody occurrence. So, it is necessary to undergo sufficiently detailed validation schemes for these novel tumor-associated antigens.


Cost-effectiveness of edoxaban versus rivaroxaban for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the US.
Understanding the value of new anticoagulation therapies compared with existing therapies is of paramount importance in today's cost-conscious and efficiency-driven health care environment. Edoxaban and rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥2 have been evaluated in pivotal trials versus warfarin. The relative value of edoxaban versus rivaroxaban would be of interest to health care stakeholders and patients who prefer a once-daily treatment option for long-term stroke prevention in NVAF. To evaluate the relative cost-effectiveness of two once-daily regimens of novel oral anticoagulation therapy - edoxaban (60 mg/30 mg dose-reduced) versus rivaroxaban (20 mg/15 mg dose-reduced) - for stroke prevention in NVAF patients from a US health-plan perspective. A Markov model simulated lifetime risk and treatment of stroke, systemic embolism, major bleeding, clinically relevant nonmajor bleeding, myocardial infarction, and death in NVAF patients treated with edoxaban or rivaroxaban. Efficacy and safety data were derived from a network meta-analysis that utilized data from patients enrolled in ENGAGE AF-TIMI 48 and ROCKET-AF. Health care cost and utility data were obtained from published sources. Incremental cost-effectiveness ratios of <US$50,000, $50,000-$150,000, and >$150,000 per quality-adjusted life year (QALY) gained were used as thresholds for "highly cost-effective", "cost-effective", and "not cost-effective" treatment options, respectively, as per American Heart Association/American College of Cardiology guidelines. Edoxaban was dominant relative to rivaroxaban, such that it was associated with lower total health care costs and better effectiveness in terms of QALYs in the base-case analysis. Results were supported by probabilistic sensitivity analyses that showed edoxaban as either dominant or a highly cost-effective alternative (incremental cost-effectiveness ratio <$50,000) to rivaroxaban in 88.4% of 10,000 simulations. Results of this study showed that the once-daily edoxaban (60 mg/30 mg dose-reduced) regimen is a cost-saving or highly cost-effective treatment relative to rivaroxaban (20 mg/15 mg dose-reduced) for stroke prevention in NVAF patients with CHADS2 ≥2.


[Economic aspects of surgical wound therapies].
Health care insurers in Germany pay 5 billion Euros annually in materials alone for pressure ulcers, diabetic foot ulcers, and ulcus cruris. With such figures it is necessary to consider, economic aspects of treatment. Due to the lack of evidence-based data on wound treatment costs, we investigated available studies for an effect on treatment costs when standard moist wound therapy was compared with alternative methods. Suited medical parameters are calculated and compared. Daily costs and length of treatment are correlated and compared. Published data show that alternative wound therapies may lead to an earlier wound closure, fewer complications, and reduction in hospital admissions and length of stay. Despite higher daily costs, some alternative wound therapies turn out to be more cost effective, when all economical factors are considered. In this respect a move towards alternative wound therapies could possibly lead to major savings. At present there is insufficient evidence to prove the efficacy of various treatment modalities for chronic wounds. This is due to numerous factors such as comorbidities and frequent multimorbidity. Nevertheless critical evaluation of one innovative treatment alone already uncovered an enormous potential for savings in a wider economic context, despite the comparatively higher cost of a single treatment. It is of utmost importance that conservative wound care become firmly embedded in surgical concepts.


A uniform LMI formulation for tuning PID, multi-term fractional-order PID, and Tilt-Integral-Derivative (TID) for integer and fractional-order processes.
In this paper first the Multi-term Fractional-Order PID (MFOPID) whose transfer function is equal to [Formula: see text] , where kj and αj are unknown and known real parameters respectively, is introduced. Without any loss of generality, a special form of MFOPID with transfer function kp+ki/s+kd1s+kd2sμ where kp, ki, kd1, and kd2 are unknown real and μ is a known positive real parameter, is considered. Similar to PID and TID, MFOPID is also linear in its parameters which makes it possible to study all of them in a same framework. Tuning the parameters of PID, TID, and MFOPID based on loop shaping using Linear Matrix Inequalities (LMIs) is discussed. For this purpose separate LMIs for closed-loop stability (of sufficient type) and adjusting different aspects of the open-loop frequency response are developed. The proposed LMIs for stability are obtained based on the Nyquist stability theorem and can be applied to both integer and fractional-order (not necessarily commensurate) processes which are either stable or have one unstable pole. Numerical simulations show that the performance of the four-variable MFOPID can compete the trivial five-variable FOPID and often excels PID and TID.


Protective roles of vitamin C and 5-aminosalicylic acid on reproduction in acrylamide intoxicated male mice.
Serious health risks have been connected to ongoing, escalating exposure to environmental toxins and one of them is acrylamide (ACR), an organic compound. Although there are many published reports on ACR toxicity, limited information is available regarding the use of two potential antioxidants against ACR-instigated reproductive toxicity. The study focused on investigating the protective effects of vitamin C and 5-ASA against ACR-incited reproductive toxicity. A total of 50 male mice aged 4 weeks old were treated for 90 days with different concentrations either of ACR or ACR and vitamin C or ACR and 5- ASA or ACR, vitamin C, and 5- ASA. ACR significantly reduced serum testosterone level (p = 0.0037), sperm concentration (p = 0.0004), and percentage of sperm motility (p = 0.003), as well as increased sperm abnormality; head (p = 0.0058), tail (p = 0.001), and midpiece (p = 0.0339). Besides, the weight (p = 0.0006) and length (p = 0.0105) of testes, as well as weight (p = 0.0001) and length (p = 0.0021) of epididymis were decreased along with atrophy of seminiferous tubules of the testis, and disintegration of the tubular epithelium of epididymis on ACR exposed mice which were improved by vitamin C and 5-ASA administration. Vitamin C and 5-ASA can potentially mitigate the negative effects of ACR on male reproduction; however, combined application is recommended for better performance. In Bangladesh, this work is anticipated to address the health benefits of vitamin C and 5-ASA, particularly in improving the reproductive health of males against ACR toxicity.


Psoriatic Alopecia and Paradoxical Psoriasis Induced by Adalimumab Successfully Treated with Certolizumab: Clinical, Trichoscopic, and in vivo Reflectance Confocal Microscopy Features.
Psoriatic alopecia is considered a type of hair loss occurring in patients with psoriasis. Adalimumab is a fully humanized recombinant anti-TNF-alpha monoclonal antibody approved for treatment of psoriasis and psoriatic arthritis (PsA), rarely related to the occurrence of dermatological disorders. We report the case of a 56-year-old female with PsA developing psoriatic alopecia and paradoxical psoriasis induced by adalimumab and successfully treated switching to certolizumab, evaluating response at both thrichoscopy and in vivo reflectance confocal microscopy. Among anti-TNF-α agents, certolizumab is the least involved in the development of paradoxical reactions such as psoriatic alopecia and showed to be an effective and safe alternative therapeutic options to manage psoriasis and PsA minimizing the risk of paradoxical reactions.


Impact of ancestral sequence reconstruction on mechanistic and structural enzymology.
Ancestral sequence reconstruction (ASR) provides insight into the changes within a protein sequence across evolution. More specifically, it can illustrate how specific amino acid changes give rise to different phenotypes within a protein family. Over the last few decades it has established itself as a powerful technique for revealing molecular common denominators that govern enzyme function. Here, we describe the strength of ASR in unveiling catalytic mechanisms and emerging phenotypes for a range of different proteins, also highlighting biotechnological applications the methodology can provide.


Benign partial epilepsy in infancy long-term outcome and marginal syndromes.
Benign partial epilepsy in infancy (BPEI) is an infantile epilepsy with excellent seizure and developmental outcome proposed by Watanabe et al. Our telephone interview survey revealed that the long-term outcome of patients with BPEI was also excellent over 8 years of age. Six of 39 patients did not fulfill the criteria of BPEI by the last follow-up. Two patients had a recurrence of unprovoked seizure beyond 2 years of age, three had cognitive problems (mild mental retardation in two and Asperger syndrome in one) and the other had both a recurrence of seizure and mild mental retardation. These results indicates that a large majority of patients diagnosed as possible BPEI at 2 years of age did not have a recurrence of unprovoked seizures and mental problems beyond 8 years of age. Our study also suggested a presence of some marginal syndromes of BPEI. An association of paroxysmal kinesigenic choreoathetosis was observed in three patients. Another three patients had experienced seizures with mild gastroenteritis. The seizure outcome of three patients with mild cognitive problems was quite excellent. These patients can be grouped as a marginal syndrome of BPEI.


[Injury to the upper limbs and prevention in equestrian sports].
The upper limb is one of the most frequently injured body regions in equestrian sports, but it is unclear which injuries are involved, and there are no data on the associated accident mechanism. The present study is aimed at evaluating the accident mechanisms, injuries of the upper limbs, and the circumstances of the accident in equestrian sports. We included 218 patients who were all treated between 2006 and 2014 at the level I trauma center at the Medical University in Hannover because of equestrian-related accidents. The most frequent injuries were fractures and bruising in the shoulder area, fingers and hands, and the distal area of the lower arm, which were mostly caused by the horse kicking. To prevent hand injuries it is recommended that gloves are worn; the potential introduction of strengthened materials could protect the bones from severe bumping. Training in falling techniques to prevent serious injury to the upper limb would be useful. In general, primary prevention in equestrian sports should be extended to counteract the increasing neglect of protective equipment.


The sodium-glucose cotransporter-2 inhibitor canagliflozin does not increase risk of non-genital skin and soft tissue infections in people with type 2 diabetes mellitus: A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials.
To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.


Fluorimetric assay of acid lipase in human leukocytes.
A fluorimetric assay for leukocyte acid lipase, the enzyme defect in Wolman disease, is described. The method requires a smaller volume of blood and can be performed more rapidly than the present colorimetric assay for the leukocyte enzyme.


[Not Available].
To study the levels of deoxynivalenol (DON) in retail cereal products, wheat and rye samples were purchased in 1999 from supermarkets and "organic food" shops in Munich, Germany. DON was analysed by an enzyme immunoassay (EIA), 78 of these samples were additionally analysed by HPLC. The following contamination rates (%) and mean DON levels were found: wheat flour type 405 (n=42): 71%, 200 µg/kg; flour type 550 (n=9): 33%, 410 µg/kg; flour type 1050 (n=11): 91%, 370 µg/kg; bread-baking wheat premixes (n=14): 79%, 210 µg/kg; whole grain flour (n=20): 65%, 300 µg/kg; whole grain wheat (n=8): 75%, 280 µg/kg, wheat bran (n=20): 85%, 830 µg/kg; rye flour and grits (n=7): 29%, 120 µg/kg. HPLC confirmed the results obtained by EIA. Further analysis of 16 wheat flour (405) samples in May 2000 showed a similar frequency (69%) and mean DON level (270 µg/kg) as for samples from 1999. It is concluded that with DON levels in wheat for human consumption ranging from 200-400 µg/kg, the intake of DON has to be taken seriously in the light of the temporary tolerable daily intake of 1 µg DON per kg body weight as proposed within the European Union.


Suicidal ideation and attempts in trichotillomania.
Trichotillomania is characterized by chronic pulling out of one's hair. Given the negative sequelae of trichotillomania, we examined rates of suicidal ideation and suicide attempts. Of the 219 adults (mean age = 29.5 years; 88% female) recruited, 40 (18.3%) reported lifetime suicidal ideation, and 5 (2.3%) reported a lifetime suicide attempt. Those with histories of suicidal ideation were significantly more likely to have major depressive disorder. Our findings suggest that suicidal ideation and attempts are common in trichotillomania and support the idea that comorbid depression should be considered a risk factor for suicidality.


Foliar contamination of Phaseolus vulgaris with aerosols of 137Cs, 85Sr, 133Ba and 123mTe: influence of plant development stage upon contamination and rain.
As part of a requirement to improve the assessment of the impact of radioactive fallout on consumed agricultural products, bean plants at four development stages (seedlings, preflowering, late flowering and mature plants) were contaminated by dry deposition of (137)Cs, (85)Sr, (133)Ba and (123m)Te aerosols. The influence of two rain scenarios and of the development stage upon contamination on interception, retention, and translocation to pods was studied. Interception of the four radionuclides was almost identical and varied from 30 to 60% with increasing development stage. The most important rain parameter was the time which elapsed between contamination and the first rain. Whatever the development stage, rain washed off more cesium from the leaves when it occurred 2 days after the deposit (37% at the seedling stage, for example) rather than later on (6 days, 27%), due to rapid migration of Cs in the plant. The first rain washed off nearly 40% of Ba whatever the scenario. For later stages, Sr and Ba were more washed off by heavy weekly rains than by weak twice-a-week rains, perhaps because of the Sr/Ba-contaminated material loss associated with wash off (desquamation of cuticles). Te showed little wash off (less than 5%). Wash off decreased with an older development stage for a weak rain intensity, due to the superimposition of leaves. Heavy rains removed this shelter effect. At harvest, rain effect was no longer detectable as foliar activity was similar for both rain scenarios. Translocation factors (TF) for strontium and barium increased from 6 x 10(-3) to 1 x 10(-1) with the plant development stage upon contamination, whereas those for cesium remained almost unchanged between 2 x 10(-1) and 4 x 10(-1). Flowering is the most critical stage towards residual contamination in pods at harvest, with the exception of direct deposit on pods at the mature stage (TF values are one order of magnitude higher). TF value for Te was 6.5 x 10(-2) and was due to direct deposit. Modelling reflected the trends, through the differential values of the wash off and absorption coefficients, of what was reported for experimental results.


Innovations in Intraoperative Tumor Visualization.
In the surgical management of solid tumors, adequacy of tumor resection has implications for local recurrence and survival. The standard method of intraoperative identification of tumor margin is frozen section pathologic analysis, which is time-consuming with potential for sampling error. Intraoperative tumor visualization has the potential to significantly improve surgical cancer care across disciplines, by guiding accuracy of biopsies, increasing adequacy of resections, directing adjuvant therapy, and even providing diagnostic information. We provide an outline of various methods of intraoperative tumor visualization developed to aid in the real-time assessment of tumor extent and adequacy of resection.


A new Schiff-base chemosensor for selective detection of Cu2+ and Co2+ and its copper complex for colorimetric sensing of S2- in aqueous solution.
A new Schiff-base colorimetric chemosensor 1 was developed for the detection of Cu2+, Co2+ and S2-. Sensor 1 could simply monitor Cu2+ and Co2+ by a color change from colorless to yellow. The binding modes of 1 to Cu2+ and Co2+ were determined to be a 2 : 1 complexation stoichiometry through Job's plot and ESI-mass spectrometry analysis. The detection limits (0.02 μM and 0.63 μM) for Cu2+ and Co2+ were lower than the recommended values (31.5 μM and 1.7 μM) by the World Health Organization (WHO) for Cu2+ and the Environmental Protection Agency (EPA) for Co2+, respectively. Importantly, 1 could detect and quantify Cu2+ in real water samples. In addition, the Cu2+-2·1 complex could be used as a highly selective colorimetric sensor for S2- in the presence of other anions without any interference. Moreover, the sensing mechanisms of Cu2+ and Co2+ by 1 were explained by theoretical calculations.


Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) with postural orthostatic tachycardia syndrome after silicone breast implantation: Case report.
This study illustrates two patients who developed autoimmune/inflammatory syndrome induced by adjuvants (ASIA) with postural orthostatic tachycardia syndrome (POTS) after silicone breast implant (SBI) and improved after SBI extraction.


Comparing Dermabond PRINEO versus Dermabond or staples for wound closure: a randomized control trial following total shoulder arthroplasty.
The method of surgical incision closure after total shoulder arthroplasty is an important factor to consider, as it affects operating room time, procedure cost, cosmetic outcomes, and patient satisfaction. The optimal method of wound management is unknown, but should be cost-effective, reproducible, and provide a reliable clinical result. This study aimed to compare the following wound closure methods after total shoulder arthroplasty: staples, Dermabond, and Dermabond PRINEO. We hypothesized that wound closure time for Dermabond PRINEO would be faster than Dermabond and comparable to that of staples, and Dermabond PRINEO would be more cost-effective than Dermabond and staples, and provide equal or superior closure outcomes to Dermabond and staples. A randomized, prospective clinical trial comparing wound closure time and cost for 2 surgeons' traditional technique with that of Dermabond PRINEO was conducted. This study included at least 18 subjects in each group. Surgeon 1's patients were randomized to traditional Dermabond or Dermabond PRINEO, whereas surgeon 2's patients were randomized to staples or Dermabond PRINEO. Cosmetic outcomes and satisfaction scores were collected at 6 weeks and 3 months, postoperatively. Incisions were photographed, at both the 6-week and 3-month visits, and subsequently evaluated by a plastic surgeon blinded to the treatment method. The wound closure time for surgeon 1 was significantly faster for Dermabond PRINEO vs. Dermabond, and surgeon 2 closed significantly faster with staples vs. Dermabond PRINEO. The mean cost of closure was significantly less with Dermabond PRINEO compared with Dermabond, whereas the mean cost of staples was significantly less than Dermabond PRINEO. For both surgeons 1 and 2, there were no significant differences in patient satisfaction at 6 weeks or 3 months. In addition, the wound closure methods did not produce differing cosmetic outcomes. Although significant, the closing time for each method did not differ by a clinically relevant amount. Staples were the most cost-effective closing method, followed by Dermabond PRINEO. As neither method was superior over the other in terms of patient satisfaction, adverse events, and cosmetic outcomes, cost-effectiveness may be the greatest differentiator between the 3 methods.


Female genital mutilation in Nigeria.
To determine the prevalence and distribution of female genital mutilation (FGM) procedures in a Nigerian population. Five hundred consecutive women were evaluated for evidence of FGM. The WHO classification system was utilized. Demographic and sociocultural information was collected. Thirty-four percent of women were found to have some type of FGM. Type I and Type II procedures were the most common. Fifty-five percent of women were unaware they had FGM and 62% with FGM did not know the reason. Twenty-one percent of women said they were going to have FGM on their daughters. FGM is still broadly practiced among ethnic and religious groups in Nigeria. Educational efforts need to be directed at eliminating this practice.


A rare MRI finding of NF-1: perineural arachnoidal gliomatosis.
Optic pathway gliomas are the most common central nervous system neoplasms in patients with neurofibromatosis type 1. Perineural arachnoidal gliomatosis is a rare and distinctive growth pattern of optic nerve glioma, in which the tumor infiltrates through the pia mater and pre-dominantly involves the subarachnoid space around the optic nerve. Here, we report an 8-year-old girl with perineural arachnoidal gliomatosis associated with neurofibromatosis type 1.


Schizosaccharomyces pombe exo1 is involved in the same mismatch repair pathway as msh2 and pms1.
Besides the MutLS-like system, Schizosaccharomyces pombe has an additional pathway of mismatch repair. This minor pathway, producing short excision tracts, repairs C/C and, with lower efficiency, other mismatches also. We investigated the involvement of the exo1+, msh2+ and pms1+ genes in the two pathways. The exo1+ gene encodes a 5' to 3' exonuclease, while msh2+ and pms1+ are homologs of Escherichia coli mutS and mutL, respectively. Intragenic two-factor crosses showed that exo1+, msh2+ and pms1+ are involved in the major, but not in the C/C-correcting, pathway. Post-meiotic segregation frequencies and mitotic mutation rates in single and double mutants supported this finding. Furthermore, msh2 delta was epistatic over exo1 delta, and the ExoI enzyme is likely to be redundant with other exonucleases.


Family of origin history, psychological distress, quality of childhood memory, and content of first and recovered childhood memories.
Individual differences in quality of childhood memory and recovered memories from childhood remain poorly understood. Therefore, this study tested several hypotheses which may help account for the large amount of variation that individuals report in the general quality of their childhood memory and the valence of the memories that many individuals report recovering from their childhoods. It was hypothesized that family of origin dysfunction would be associated with poorer childhood memory, that current depressed mood would be associated with impaired childhood recall and the recall of negative memories, and that the content of recovered childhood memories would be disproportionately negative because they include a significant number of memories which had been repressed or dissociated. Questionnaires were administered to 553 college students, 27% of whom reported a history of child abuse. The participants reported substantial variation in the general quality of their childhood memories and also a wide variety of different types of experiences for both their first childhood memories and the recovered memories that most of them had from their childhoods. Weak associations were found between family of origin dysfunction and poorer general quality of childhood memory, but the study as a whole resulted in few significant findings. Only weak support was found for some of the factors that have been hypothesized to distort autobiographical memory. The substantial individual variation in childhood memory that has been reported by college student samples remains poorly understood.


Robot-Assisted Surgery for Upper Tract Urothelial Carcinoma.
Upper tract urothelial carcinoma is a rare malignancy for which surgery provides definitive management. Open radical nephroureterectomy was the gold standard treatment, but laparoscopic and robot-assisted approaches are alternative options. Kidney-sparing approaches are feasible for carefully selected patients with ureteral cancer. This article discusses the evaluation of patients with upper tract urothelial carcinoma and definitive management using robot-assisted surgical approaches. Patients with urothelial carcinoma of the upper tract can be treated with robot-assisted nephroureterectomy, distal ureterectomy, and segmental ureterectomy.


Effect of prostacyclin on coronary occlusion in acute myocardial infarction.
Prostacyclin is a powerful inhibitor of platelet aggregation and induces relaxation of vascular smooth muscle. We have studied the coronary effects of high local concentrations of prostacyclin in 17 patients during the early stages of acute myocardial infarction. We infused graded concentrations of intracoronary prostacyclin and compared the effects to those of intracoronary isosorbide dinitrate before and after an intracoronary infusion of streptokinase. Considerable dilation of the infarct-related stenosis may follow local infusions of prostacyclin in some patients. In general, however, dilation of the infarct-related stenosis or coronary recanalization did not result from infusion of prostacyclin.


[Toxic retinopathies].
Toxic retinopathies are most frequently induced by external stimulants (e.g. nicotine, poppers, methanol) and are less frequently undesired side effects of systemic drugs (e.g. hydroxychloroquine, ethambutol, MEK, ERK, FLT3 or checkpoint inhibitors, didanosine, pentosan polysulfate sodium) or intravitreally applied drugs. The clinical symptoms of undesired side effects of drugs are often similar to retinal diseases from other causes, which interferes with the recognition of the undesired side effects of drugs. Clinical findings, pathophysiological mechanisms and if advisable strategies for screening are discussed. The focus is on the presentation of confirmed undesirable side effects with established associations for medications which have long been approved. For novel medications, in addition potential but not proven associations are presented to facilitate the recognition of additional cases with side effects for these medications.


A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer.
To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.


Duodenal plasma cells correspond to serum IgA in common variable immunodeficiency.
Common variable immunodeficiency (CVID) can be associated with a range of serum IgA concentrations, from absent, to variably reduced, and in some patients classified as 'possible CVID', even normal. The aim of this study was to assess the proportion of duodenal plasma cells in patients with CVID and determine whether there was an association with serum IgA concentration. Duodenal biopsies obtained at upper endoscopy from 35 patients with CVID were assessed for the presence of plasma cells and compared with serum IgA concentrations. A reduction or absence of duodenal plasma cells in 60% of patients with CVID and an association between the proportions of duodenal plasma cells and serum IgA concentrations was demonstrated. The presence of duodenal plasma cells associated with numbers of isotype switched memory B cells in the peripheral blood. A reduction in serum IgA over time was observed in 19% of CVID patients. The gastrointestinal tract provides a window into the immune system in CVID, and these results reinforce the association between gastrointestinal plasma cells and serum IgA concentrations. Preservation of gastrointestinal plasma cells and serum IgA in some patients with CVID, and the sequential decline of both in others, highlight the heterogeneity of this disorder.


Chronic methadone administration to male rats: tolerance to adverse effects on sires and their progeny.
Previous studies have shown that acute administration of methadone to male rats prior to mating results in adverse effects on their progeny, particularly decreased birth weights and increased neonatal mortality. Rather than chronic administration accentuating these effects, results of the present study indicate that tolerance developed so that no adverse effects were found in offspring sired after 21--32 days of methadone administration. In the sire, maintenance of normal weights of accessory sex glands after 4 months of daily methadone suggests that tolerance developed to the CNS effect(s) responsible for the depressed serum LH and testosterone levels found after acute administration of narcotics. In contrast, tolerance did not develop to the inhibition of weight gain produced by methadone administration. No evidence for a dominant lethal effect could be found after chronic methadone administration, in contrast to suggestive evidence for this effect found in previous experiments after acute methadone administration.


Endophytic Bosea spartocytisi sp. nov. Coexists with rhizobia in root nodules of Spartocytisus supranubius growing in soils of Teide National Park (Canary Islands).
Two rod-shaped Gram negative strains, SSUT16T and SSUT22, were isolated from root nodules of Spartocytisus supranubius in soils of the Teide National Park (Tenerife, Spain). The 16S rRNA gene sequences of these two novel strains classified them within genus Bosea with similarity values ranging from 97.65 % to 99.54 % with respect to the other species of this genus. The MLSA analysis from a concatenation of the two housekeeping- genes, recA and gyrB, showed that Bosea thiooxidans LMG 26210T and B. robiniae LMG 26381T are the two closest relative species with which they share similarity sequences values of 94.42 % and 94.27 %, respectively. The genome sequence analysis of strain SSUT16T showed average nucleotide identity percentages (ANIb) and digital DNA-DNA hybridization (dDDH) below 84 % and 33 %, respectively, with the type strains of all sequenced species of genus Bosea. These values are much lower than the currently accepted cut-off values for these two parameters to delineate bacterial species, confirming that the novel strains constitute a novel Bosea species. In addition, they are also distinguished from the other closest species in their fatty acid composition and in other phenotypic characteristics. Genome sequence analysis showed the absence of the common nodulation and nitrogen fixation genes in the novel strains. Therefore, based on the results of phylogenetic, genomic, chemotaxonomic and phenotypic characterization, we propose a new species named Bosea spartocytisi sp. nov., with type strain SSUT16T (=LMG 32510T = CECT 30526T = HAMBI 3759T).


Family medicine residency training and burnout: a qualitative study.
Almost three-quarters of family practice residents in British Columbia (BC) meet criteria for burnout. We sought to understand how burnout is perceived and experienced by family medicine residents, and to identify both contributory and protective factors for resident burnout. Two semi-structured focus groups were conducted with ten family practice residents from five distinct University of British Columbia training sites. Participants completed the Maslach Burnout Inventory (MBI). The data were analyzed using a thematic analysis approach. Seventy percent of the focus group participants met criteria for burnout using the MBI. The experience of burnout was described as physical and emotional exhaustion, loss of motivation, isolation from loved ones, and disillusionment with the medical profession. Contributory factors included high workload, burned-out colleagues, perceived undervaluing of family medicine, lack of autonomy, and inability to achieve work-life balance. Protective factors included strong role models in medicine, feeling that one's work is valued and rotations in family medicine. The high level of burnout in family medicine residents in BC is a multifactorial and complex phenomenon. Training programs and faculty should be aware of burnout risk factors and strive to implement changes to reduce burnout, including allowing residents increased control over scheduling, access to counseling services and training for resident mentors.


Effect of cyclophosphamide and levan treatment on bone marrow and peripheral blood cells in B16-F10 melanoma-bearing mice.
Immunotherapeutic agents have often been found to provoke opposite effects on tumor growth--inhibitory or stimulatory--depending on dose, timing or route of administration. The reason for these opposite effects is not yet known. Levan (polyfructose), an immunomodulatory polysaccharide, has been found to exert opposite effects on the growth of the F10 variant of B16 melanoma. Low doses inhibit and high doses enhance the growth of this tumor. Cyclophosphamide (CY) augments the inhibitory effect of the polysaccharide. In order to elucidate the mechanism of these opposite effects, we tried to determine the changes induced by levan at inhibitory and stimulatory doses, alone or in conjunction with CY, on the lymphatic and hematopoietic systems of B16-F10 melanoma-bearing mice. In a previous study we reported the effect of these treatments on the morphology of spleen and lymph nodes (Leibovici, Kopel, Siegal & Gal-Mor (1986). Int. J. Immunopharmac., 8, 391). In the present study, we examined the effect of the treatments on bone marrow and peripheral blood composition. The growth of the tumor itself, as well as the various treatments, induced very marked changes in both bone marrow and blood. Tumor inoculation produced a sharp leukopenia and anemia followed by a restoration of both white and red blood cells. In the bone marrow, the tumor caused a gradual decrease in lymphocyte number. CY accentuated the severe leukopenia caused by the tumor. Lymphocyte depletion was prolonged, while restoration of granulocytes was achieved by day 7. A similar pattern of changes was observed in the bone marrow. With levan, opposite effects were observed in blood and bone marrow with the two doses in relation to the number of the cells of the lymphoid and myeloid lines: while 0.1 mg (tumor inhibitory) doses caused a more active restoration of lymphocytes as compared to 10 mg (tumor stimulatory) doses, an opposite effect was seen on the myeloid series--the high dose induced a more pronounced granulocytosis than the low dose. In the combined treatment, the low levan dose accelerated lymphocyte restoration in bone marrow compared to CY, while the high dose delayed the recovery of these cells. The results of the present study in conjunction with our previous study may explain the basis of the intriguing tumor inhibitory-stimulatory effects of some immunomodulators. Moderate increases in myeloid cell series appear to favor tumor inhibition and high increases favor tumor stimulation. In addition, the results of this study suggest that a regulatory relation might exist between the proliferation of the lymphoid and myeloid cell series.


[Coronary artery bypass grafting for cases which were not amenable to preoperative left ventriculogram].
We evaluated the coronary artery bypass grafting (CABG) for the cases which were not amenable to preoperative left ventriculograms (LVG). Between June 1970 and March 1996, we had 2045 cases of isolated CABG, and 52 cases of which were not amenable to preoperative LVG. The reasons of no preoperative LVG were during cardiopulmonary resuscitation (CPR) in 4 cases, shock state in 14, NYHA class IV or CCS class IV in 26, angina attack after coronary angiography in 3 and so on. Preoperative diagnoses were acute myocardial infarction in 28, angina after infarction in 13, unstable angina in 9 and effort angina in 2. Preoperative conditions were reoperation in 6, insertion of intra-aortic balloon pumping in 46, chronic renal failure in 15 (hemodialysis in 4) and arrhythmia (VT or Vf) in 12. Concerning the coronary lesions, left main trunk and triple vessel diseases occupied 75% of all. Surgical deaths were 5 cases (9.6%) and hospital deaths were 4 cases (7.7%). The all cases which needed preoperative CPR were died with brain injury. The result of the cases which were not amenable to preoperative LVG were worse than the cases with ischemic cardiomyopathies. In conclusion, no preoperative LVG is one of the highest risk factors of all.


Defect and structural evolution under high-energy ion irradiation informs battery materials design for extreme environments.
Understanding defect evolution and structural transformations constitutes a prominent research frontier for ultimately controlling the electrochemical properties of advanced battery materials. Herein, for the first time, we utilize in situ high-energy Kr ion irradiation with transmission electron microscopy to monitor how defects and microstructures evolve in Na- and Li-layered cathodes with 3d transition metals. Our experimental and theoretical analyses reveal that Li-layered cathodes are more resistant to radiation-induced structural transformations, such as amorphization than Na-layered cathodes. The underlying mechanism is the facile formation of Li-transition metal antisite defects in Li-layered cathodes. The quantitative mathematical analysis of the dynamic bright-field imaging shows that defect clusters preferentially align along the Na/Li ion diffusion channels (a-b planes), which is likely governed by the formation of dislocation loops. Our study provides critical insights into designing battery materials for extreme irradiation environments and understanding fundamental defect dynamics in layered oxides.


Congenital giant pigmented nevus and intracranial arteriovenous malformation.
We describe a case with congenital giant pigmented nevus and intracranial arteriovenous malformation. This association should be included in the spectrum of neurocutaneous syndromes related to congenital giant pigmented nevus.


Spontaneous hypoglycemia: diagnostic evaluation and management.
Spontaneous hypoglycemia is a puzzling clinical problem and an important reason for referral to endocrinologists. Several clinical conditions such as insulinomas, non-insulinoma pancreatogenous hypoglycemia syndrome, insulin autoimmune syndrome, postprandial hypoglycemia (reactive hypoglycemia), non-islet cell tumor hypoglycemia, primary adrenal insufficiency, hypopituitarism, and critical illness can be associated with spontaneous hypoglycemia. Rarely, in patients with mental health issues, factious hypoglycemia from extrinsic insulin use or ingestion of oral hypoglycemic agents can obfuscate the clinical picture for clinicians trying to identify an organic cause. In those presenting with Whipple's triad (symptoms ± signs of hypoglycemia, low plasma glucose, and resolution symptoms ± signs after hypoglycemia correction), a 72-h supervised fast test with measurement of plasma insulin, c-peptide, pro-insulin, and beta-hydroxybutyrate levels, coupled with plasma/urine sulphonylurea screen, forms the first step in diagnostic evaluation. A mixed meal test is preferable for those with predominantly postprandial symptoms. Additional non-invasive and/or invasive diagnostic evaluation is necessary if an organic hypoglycemic disorder is suspected. With the aid of a few brief clinical case scenarios, we discuss the diagnostic evaluation and management of spontaneous hypoglycemia through this comprehensive article.


Impact of intracytoplasmic sperm injection in women with non-male factor infertility: A systematic review and meta-analysis.
The purpose of this study is to determine whether intracytoplasmic sperm injection (ICSI) is beneficial in patients with non-male factor infertility. This systematic review and meta-analysis included articles from inception to May 2022. Published studies of non-male factor infertile women undergoing ICSI or in vitro fertilization (IVF) included in PubMed, Embase, web of science, Wanfang Database, and CNKI were searched by computer, without language restrictions. A random-effect model was applied to calculate the risk ratios (RRs) and their 95% confidence intervals (CIs). Letters, case reports, and review articles including meta-analyses and expert opinions were excluded. The primary endpoints were laboratory outcomes and pregnancy outcomes. The Secondary endpoints were neonatal outcomes. Six randomized controlled studies and 20 retrospective cohort studies met the inclusion criteria. In meta-analytic forest plots, compared with IVF, those who received ICSI treatment were not different in fertilization rate (RR = 0.99, 95% CI [0.90-1.09], P = 0.88), total fertilization failure rate (RR = 1.30, 95% CI [1.17-1.45], P < 0.00001), and good quality embryo rate (RR = 0.94, 95% CI [ 0.86-1.02], P = 0.15), clinical pregnancy rate (RR = 0.84, 95% CI [0.70-1.01], P = 0.06), live birth rate (RR = 0.89, 95% CI [0.77-1.03], P = 0.13), miscarriage rate (RR = 1.06, 95% CI [0.78-1.43], P = 0.71), preterm neonatal delivery rate (RR = 0.92, 95% CI [0.67-1.26], P = 0.61), and low neonatal weight rate (RR = 1.13, 95% CI [0.80-1.61], P = 0.48). However, the implantation rate of IVF was better than ICSI (RR = 0.77, 95% CI [0.64-0.93], P = 0.005). In the subgroup analysis of the live birth rate of fresh embryo transfer, IVF performed in those ≥35 years had a higher live birth rate (RR = 0.82, 95% CI [0.78-0.83], P < 0.001). The findings of this study indicate that ICSI is not superior to IVF in the treatment of infertility related to non-male factors. In order to confirm this result, more high-quality clinical studies are needed.


Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis.
To investigate the host immunologic response to endometriosis in terms of killer inhibitory receptor (KIR) expression by natural killer (NK) cells. Case-control study of immunologic markers. University hospital. We compared cells from Japanese women with laparoscopically diagnosed endometriosis to cells from 40 women with other laparoscopic diagnoses. Peripheral venous blood sampling and laparoscopic peritoneal fluid collection. Flow cytometry was used to assess expression of KIR by NK cells in the cell samples. The percentage of cells that expressed KIR2DL1 among NK (KIR2DL1(+)NK) cells in peritoneal fluid and peripheral blood was significantly higher in women with endometriosis than in controls. The proportion of KIR2DL1(+)NK cells in peripheral blood NK cells before and 1 month after laparoscopic surgery did not differ significantly. The proportion of KIR2DL1(+)NK cells was increased in peritoneal fluid and peripheral blood in women with endometriosis; this difference is probably related to NK cell suppression in endometriosis. This increase in KIR2DL1 expression by NK cells may represent a risk factor in the pathogenesis of endometriosis.


COVID-19: A review of newly formed viral clades, pathophysiology, therapeutic strategies and current vaccination tasks.
Today, the world population is facing an existential threat by an invisible enemy known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) or COVID-19. It is highly contagious and has infected a larger fraction of human population across the globe on various routes of transmission. The detailed knowledge of the SARS-CoV-2 structure and clinical aspects offers an important insight into the evolution of infection, disease progression and helps in executing the different therapies effectively. Herein, we have discussed in detail about the genome structure of SARS-CoV-2 and its role in the proteomic rational spread of different muted species and pathogenesis in infecting the host cells. The mechanisms behind the viral outbreak and its immune response, the availability of existing diagnostics techniques, the treatment efficacy of repurposed drugs and the emerging vaccine trials for the SARS-CoV-2 outbreak also have been highlighted. Furthermore, the possible antiviral effects of various herbal products and their extracted molecules in inhibiting SARS-CoV-2 replication and cellular entry are also reported. Finally, we conclude our opinion on current challenges involved in the drug development, bulk production of drug/vaccines and their storage requirements, logistical procedures and limitations related to dosage trials for larger population.


Retinal vascular calibres are significantly associated with cardiovascular risk factors: the Tromsø Eye Study.
To describe the association between retinal vascular calibres and cardiovascular risk factors. Population-based cross-sectional study including 6353 participants of the Tromsø Eye Study in Norway aged 38-87 years. Retinal arteriolar calibre (central retinal artery equivalent) and retinal venular calibre (central retinal vein equivalent) were measured computer-assisted on retinal photographs. Data on blood pressure, body mass index (BMI), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, glycosylated haemoglobin (HbA1c) and smoking were collected. Association between retinal vessel calibre and the cardiovascular risk factors was assessed by multivariable linear and logistic regression analyses. Retinal arteriolar calibre was independently associated with age, blood pressure, HbA1c and smoking in women and men, and with HDL cholesterol in men only. Blood pressure had the strongest effect on arteriolar calibre, with a decrease in calibre of 3.6 μm (women)/4.1 μm (men) per standard deviation increase in mean arterial blood pressure. Retinal venular calibre was independently associated with age, blood pressure, BMI, HDL and LDL cholesterol and smoking in men and women. The effect of BMI and HDL cholesterol on venular calibre was sigifnicantly stronger in men than in women. Current smoking was the most important factor for venular calibre, where smokers had 13.2 μm (women)/15.2 μm (men) wider calibre than nonsmokers. All the explored cardiovascular risk factors were independently associated with retinal vascular calibre, with stronger effect of HDL cholesterol and BMI in men than in women. Blood pressure and smoking contributed most to the explained variance.


Trivalent Iron Is Responsible for the Yellow Color Development in the Nacre of Akoya Pearl Oyster Shells.
The gold and cream colors of cultured Akoya pearls, as well as natural yellow nacre of pearl oyster shells, are thought to arise from intrinsic yellow pigments. While the isolation of the yellow pigments has been attempted using a large amount of gold pearls, the substance concerned is still unknown. We report here on the purification and characterization of yellow pigments from the nacre of Akoya pearl oyster shells. Two yellow components, YC1 and YC2, were isolated from the HCl-methanol (HCl-MeOH) extract from nacreous organic matrices obtained by decalcification of the shells with ethylenediaminetetraacetic acid (EDTA). Energy-dispersive X-ray and infrared spectroscopy analyses suggested that YC1 and YC2 precipitated under basic conditions are composed of Fe-containing inorganic and polyamide-containing organic compounds, respectively. YC1 solubilized under acidic conditions exhibited positive reactions to KSCN and K4[Fe(CN)6] reagents, showing the same ultraviolet-visible absorption spectrum as those of Fe(III)-containing compounds. In addition, X-ray absorption fine structure analysis supported the compound in the form of Fe(III). The total amount of Fe was approximately 2.6 times higher in the yellow than white nacre, and most Fe was fractionated into the EDTA-decalcifying and HCl-MeOH extracts. These results suggest that Fe(III) coordinated to EDTA-soluble and insoluble matrix compounds are mainly associated with yellow color development not only in the Akoya pearl oyster shells but also in the cultured Akoya pearls.


Grading and staging mucinous neoplasms of the appendix: a case series and review of the literature.
The grading and staging of appendiceal mucinous neoplasms is challenging and fraught with terminology problems, but has critical prognostic and therapeutic implications. We utilized a small case series to examine the grading and staging systems of appendiceal mucinous neoplasms and outline the evidence for the new systems proposed in the upcoming 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual. We reviewed 33 cases of appendiceal mucinous neoplasms with available clinical follow-up data, 6 of which were widely disseminated in the peritoneum. An additional 4 cases with disseminated peritoneal involvement were also reviewed. A detailed review of the literature was performed with an emphasis on features associated with disease recurrence and correlation of grade with outcome. Recurrence was not seen in 64 low-grade appendiceal mucinous neoplasms (LAMNs) confined to the muscularis propria in our series (n=21) or in the literature (n=43). Of cases of LAMN with neoplastic epithelium present beyond the muscularis propria, 64% (57/89) had peritoneal disease at the time of diagnosis or follow-up. A majority of studies of disseminated appendiceal mucinous neoplasms showed significant five-year survival differences using a three-tier grading scheme. Thus, LAMNs confined to the muscularis propria are best considered as in situ tumors, as these are cured with complete excision. A three-tier system has prognostic significance and should be used for grading of disseminated appendiceal mucinous neoplasms. The conclusions of this case series and literature review provide evidence to support the changes proposed in the 8th edition of the AJCC Staging Manual.


Spermicidal effect of antagonists of platelet-activating factor.
A variety of antagonists of platelet-activating factor (PAF) have been examined for their ability to prevent pregnancy, by admixture with spermatozoa in vitro followed by insemination, or in vivo by administration to female rabbits. When the antagonists were added to the ejaculate at a concentration of 10(-4) M 30 minutes before insemination of the females, a significant failure of fertilization was seen only with CV-3988, U66985, and SRI 63-441--all structural analogs of PAF. Antagonists that were not structural analogs were not effective. All compounds to a lesser or greater extent caused some qualitative agglutination and loss of sperm motility, but these effects were not correlated with inhibition of fertilization. SRI 63-441 was the most effective compound and was subjected to further study. When given intravenously prior to ovulation (5 mg/kg at 1, 5, and 9 hours after the ovulating injection), no effect on fertilization was seen. If SRI 63-441 (40 mg in 0.5 ml aqueous solution) was instilled into the vagina 2 minutes before insemination, a highly significant reduction in the fertilization rate was achieved. It is concluded that these compounds act by an action on the sperm membrane rather than by direct PAF antagonism on spermatozoa.


Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma.
Lymph-nodal status is an important predictor of survival in intrahepatic cholangiocarcinoma (iCCA), but the need to perform lymphadenectomy in patients with clinically node-negative (cN0) iCCA is still under debate. The aim of this study was to determine whether adequate lymphadenectomy improves long-term outcomes in patients undergoing liver resection for cN0 iCCA. We performed a retrospective cohort study on consecutive patients who underwent radical liver resection for cN0 iCCA at five tertiary referral centers. A propensity score based on preoperative data was calculated and used to generate stabilized inverse probability of treatment weight (IPTW). Overall and recurrence-free survival of patients undergoing adequate (≥6 retrieved lymph nodes) vs. inadequate lymphadenectomy were compared. Interactions between adequacy of lymphadenectomy and clinical variables of interest were explored through Cox IPTW regression. The study includes 706 patients who underwent curative surgery for cN0 iCCA. Four-hundred and seventeen (59.1%) received adequate lymphadenectomy. After a median follow-up of 33 months (IQR 18-77), median overall survival was 39 months (IQR 23-109) and median recurrence-free survival was 23 months (IQR 8-74). After stratification according to nodal status at final pathology, node-positive patients had longer overall survival (28 vs. 23 months; hazard ratio 1.82; 95% CI 1.14-2.90; p = 0.023) and disease-free survival (13 vs. 9 months; hazard ratio 1.35; 95% CI 1.14-1.59; p = 0.008) after adequate lymphadenectomy. Adequate lymphadenectomy significantly improved survival outcomes in patients without chronic liver disease, and in patients with less-advanced tumors (solitary tumors, tumor size <5 cm, carbohydrate antigen 19-9 <200 U/ml). Adequate lymphadenectomy provided better survival outcomes for patients with cN0 iCCA who were found to be node-positive at pathology, supporting the routine use of adequate lymphadenectomy for cN0 iCCA. Lymphadenectomy is essential for the surgical staging of intrahepatic cholangiocarcinoma (iCCA). While its role in patients with preoperative suspicion of nodal metastases is implicit, the impact of lymphadenectomy on survival of patients with clinically node-negative (cN0) disease is still under debate. In this large retrospective study on patients who underwent surgical resection for cN0 iCCA, we show that adequate lymphadenectomy (i.e. retrieving ≥6 lymph nodes) significantly improves survival and lowers the risk of tumor recurrence. Lymphadenectomy during surgical resection of iCCA is actually underperformed by the surgical community, resulting in inadequate staging and possibly worse long-term outcomes. The results of this study should empower surgeons and clinicians to push for adequate lymphadenectomy even for cN0 iCCA. Since patients with no chronic liver disease and with less-advanced tumors receive a significant benefit from lymphadenectomy, our results might guide decision making in patients at high-risk of postoperative complications.


Fractionation of beta-glucosidases and related extracellular enzymes from Aspergillus niger.
Industrial concentrates from Aspergillus niger culture filtrates were fractionated by ion-exchange and adsorption chromatography. Several other types of hydrolases were completely removed. Eight partially purified components were obtained. Using specific activity as an estimate of purification, one aryl-beta-glucosidase was purified 35-fold. Another component showed 147-fold purification using a viscosimetric assay with carboxymethylcellulose as substrate. The aryl-beta-glucosidase was distinctly more thermolabile than the carboxymethylcellulase.


Kinetics of d-tubocurarine disposition and pharmacologic response in rats.
After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels less than or equal to 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of 3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses less than or equal to 0.15 mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (+/- SD) value was 30.5 (+/- 3.8). Plasma d-TC levels and pharmacologic response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range less than or equal to 0.15 mg/kg.


A direct high-performance liquid chromatography assay of the enzymatic activity of enterokinase (enteropeptidase).
Bovine enterokinase (enteropeptidase) activates trypsinogen to trypsin at pH 8.0. In the presence of chicken ovomucoid, a stable complex of ovomucoid-trypsin is produced, inactivating trypsin and eliminating autoactivation of trypsinogen. The molecular size of trypsin (24,000 Da) is increased twofold on forming the ovomucoid-trypsin complex (52,000 Da). Size-exclusion chromatography on a Toya Soda TSK G2000SW column in an HPLC system and with computer-assisted analyses gives a direct quantitative determination of the amount of substrate (trypsinogen) and product (ovomucoid-trypsin). The rate of disappearance of substrate is equal to the rate of formation of product in agreement with kinetic theory. The simultaneous determination of both rates increases the reliability of the assay. The HPLC assay has an extended linear range for the velocity of the activation process as a function of enzyme concentration. The assay is reliable and accurate for highly purified preparations, samples at different steps in the purification scheme, and for a direct assay of the intestinal contents. The assay should be useful in clinical analyses.


Macrophage deficiency in CSF1R-knockout rat embryos does not compromise placental or embryo development.
Macrophages are an abundant cell population in the placenta and developing embryo and appear to be involved in processes of vascularization, morphogenesis, organogenesis, and hematopoiesis. The proliferation, differentiation, and survival are dependent on signals from the macrophage colony-stimulating factor receptor, CSF1R. Aside from the role in macrophages, Csf1r mRNA is highly expressed in placental trophoblasts. To explore the function of macrophages and Csf1r in placental and embryonic development, we analyzed the impact of homozygous Csf1r null mutation (Csf1rko) in the rat. In late gestation, IBA1+ macrophages were abundant in control embryos in all tissues, including the placenta, and greatly reduced in the Csf1rko. CSF1R was also detected in stellate macrophage-like cells and in neurons using anti-CSF1R antibody but was undetectable in trophoblasts. However, the neuronal signal was not abolished in the Csf1rko. CD163 was most abundant in cells forming the center of erythroblastic islands in the liver and was also CSF1R dependent. Despite the substantial reduction in macrophage numbers, we detected no effect of the Csf1rko on development of the placenta or any organs, the relative abundance of vascular elements (CD31 staining), or cell proliferation (Ki67 staining). The loss of CD163+ erythroblastic island macrophages in the liver was not associated with anemia or any reduction in the proliferative activity in the liver, but there was a premature expansion of CD206+ cells, presumptive precursors of liver sinusoidal endothelial cells. We suggest that many functions of macrophages in development of the placenta and embryo can be provided by other cell types in their absence.


Estimated glomerular filtration rate by formulas in patients with cirrhosis: An unreliable procedure.
In cirrhosis, the reliability of formulas that estimate renal function, either those specifically developed in this population or the classic equations, has not been properly quantified. We studied the agreement between estimated (eGFR) and measured glomerular filtration rate (mGFR) in cirrhosis. Renal function was estimated with 56 formulas including specific equations: Glomerular Filtration Rate Assessment in Liver Disease (GRAIL), Royal Free Hospital Cirrhosis (RFHC) and Mindikoglu-eGFR, and measured with a gold standard procedure; plasma clearance of iohexol using dried blood spots sampling in a group of cirrhotics. The agreement eGFR-mGFR was evaluated with specific tests: total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). We defined acceptable agreement as values: TDI < 10%, CCC ≥ 0.9 and CP > 90%. A total of 146 patients (age 65 ± 9 years, 81% male) were evaluated; 61 (42%) Child A, 67 (46%) Child B and 18 (12%) Child C. Median MELD-Na was 14 (9-15). The agreement between eGFR and mGFR was poor: TDI averaged was of 73% (90% of the estimations ranged from ±73% of mGFR); CCC averaged was 0.7 indicating low concordance and CP averaged 22% indicating that 78% of the estimations have an error > 10%. Specific formulas showed also poor agreement: TDI was 82%, 70% and 37% for the GRAIL, RFHC and Mindikoglu equations, respectively. Overall, formulas poorly estimated renal function in cirrhotic patients. Specific formulas designed for cirrhosis did not outperform classic equations. eGFR must be considered with caution in cirrhotic patients.


How Is Family Medicine Engaging Patients at the Practice-Level?: A National Sample of Family Physicians.
Emerging policy consensus advocates that patient-centered care should include an active, practice-level patient role, but it is unknown how commonly these roles are implemented. We sought to understand current prevalence and predictors of practice-level patient engagement in US primary care settings. We assessed practice-level patient engagement by using 2016 American Board of Family Medicine Certification Examination registration data, restricted to ambulatory primary care site respondents randomly selected for a patient-centered medical home (PCMH) question module. Multivariate logistic regression models identified predictors of high-intensity patient engagement, defined as a patient advisory council or patient volunteers in quality improvement activities. A total of 6900 examinees reported practicing in primary care sites; 1368 randomly received PCMH questions. Practice-level patient engagement included patient surveys (76.5%; 95% CI, 74.3-78.8%), patient suggestion boxes (52.9%; 95% CI, 50.2-55.5%), patient board of director memberships (18.8%; 95% CI, 16.7-20.9%), patient advisory councils (23.8%; 95% CI, 21.5-26.0%), and patient participation in quality improvement (20.5%; 95% CI, 18.3-22.6%). High-intensity patient engagement was reported by 31.1% (95% CI, 28.7-33.6%); predictors included large practice size (OR, 3.30; 95% CI, 1.96-5.57), serving more vulnerable patient populations, (OR, 1.83; 95% CI, 1.18-2.84) and PCMH certification (OR, 2.19; 95% CI, 1.62-2.97). Nearly one-third of physicians reported working in settings with high-intensity practice-level patient engagement. An implementation science approach should examine why high-intensity activities are more common in some practice settings and whether these activities add value through improved patient experience and health outcomes.


Mesonephric adenocarcinoma of bladder.
Mesonephric adenocarcinoma of the bladder is an unusual tumor, with its origin unclear. Metaplasia of urothelium and anaplasia of embryonic cell rests appear to be the cause of this tumor. A patient is described with mesonephric adenocarcinoma, who is now apparently free of disease two years after a radical cystectomy and ileal conduit. This represents the second such report in the literature.


Clinical implications of scapular notching at 2 and 5-year follow-up after reverse total shoulder arthroplasty.
Scapular notching is a unique radiographic sequela of reverse total shoulder arthroplasty (rTSA) with unclear long-term clinical consequences. Our retrospective review of a single surgeon, single implant, primary rTSA database investigates the incidence of scapular notching at 2 and 5-year follow-up. Various patient outcome scores were also obtained. Of 158 primary rTSAs performed, 82 (52%) patients completed 2-year and subsequent 5-year follow-up. The incidence of scapular notching at 2 and 5-years was 11.9% and 19.5%, respectively. Scapular notching negatively affects validated post-operative outcome scores, active range of motion and total complications, and furthermore increases with time.


Isolation and molecular characterization of a novel broad-host-range plasmid from Bordetella bronchiseptica with sequence similarities to plasmids from gram-positive organisms.
A 2.6 kb plasmid, named pBBR1, was isolated from Bordetella bronchiseptica S87. After insertion of an antibiotic resistance marker, this plasmid could be transferred into Escherichia coli, Bordetella pertussis, B. bronchiseptica, Vibrio cholerae, Rhizobium meliloti, and Pseudomonas putida by transformation or conjugation. Conjugation was possible only when the IncP group transfer functions were provided in trans. As shown by incompatibility testing, pBBR1 does not belong to the broad-host-range IncP, IncQ or IncW groups. DNA sequence analysis revealed two open reading frames: one was called Rep, involved in replication of the plasmid, and the other, called Mob, was involved in mobilization. Both the amino-terminal region of Mob and its promoter region show sequence similarities to Mob/Pre proteins from plasmids of Gram-positive bacteria. In spite of these sequence similarities, pBBR1 does not replicate via the rolling-circle mechanism commonly used by small Gram-positive plasmids. We therefore speculate that pBBR1 may combine a mobilization mechanism of Gram-positive organisms with a replication mechanism of Gram-negative organisms. Determination of the plasmid copy number in E. coli and B. pertussis indicated that pBBR1 has a rather high copy number, which, in conjunction with its small size and broad host range, renders it particularly interesting for studies of broad-host-range replicons and for the development of new cloning vectors for a wide range of Gram-negative bacteria.


Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory.
We investigated whether spatial working memory (WM) is associated with functional specialization of the right prefrontal cortex (PFC) relative to WM for shapes. We designed spatial and shape WM tasks that are relatively easy to perform and that minimize both task-switching and manipulation demands. The tasks use identical stimuli and require the same motor response. We presented 12 subjects with target shapes that appeared in particular locations. Subjects maintained either the location or the shape of the targets in WM and responded to each probe by indicating whether it was a target. During a non-WM control task, subjects indicated whether the probe appeared on the right or left side of the screen. Subjects were scanned with a 3.0 T Siemens scanner and data were analyzed using SPM99. The WM tasks were compared to identify PFC activation that was different for spatial versus shape WM. Each WM task was also compared to the control task. compared with shape WM, spatial WM performance was faster and more accurate and was associated with increased right ventrolateral and frontopolar PFC activation. In contrast, compared to spatial WM, shape WM was associated with increased left ventrolateral PFC activity. These findings demonstrate hemispheric specialization for spatial versus shape WM in the ventrolateral PFC. The increased activity in the right PFC for spatial WM cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we propose that differences in performance and activation reflect the use of configural processing strategies for spatial WM.


The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel.
In vitro monolayer studies using Caco-2 cells were employed here to explore P-glycoprotein mediated transport of morphine. Bi-directional transport studies of 10-75 microM morphine showed efflux to be twofold higher than influx (4 x 10(-6) compared to 2 x 10(-6) cm/s) and cellular accumulation in the efflux direction was eightfold higher. The cyclosporin analogue (PSC-833) equilibrated morphine transport in both directions. Depletion of intracellular glutathione had a greater effect on increasing cellular morphine accumulation than P-glycoprotein inhibitors, suggesting a role for glutathione in morphine transport. P-glycoprotein had a substantially greater effect on paclitaxel accumulation, efflux and bi-directional transport than for morphine. Paclitaxel transport was below detection (<0.1 x 10(-6) cm/s) in the influx direction, yet efflux was very high (18.4 x 10(-6) cm/s) and P-glycoprotein inhibition increased accumulation >100-fold. These results reinforce the substantial role P-glycoprotein has in paclitaxel transport. Conversely, P-glycoprotein regulated morphine transport is weak. Nevertheless, morphine transport rates could be doubled when administered with P-glycoprotein substrates. Therefore, increased analgesia through P-glycoprotein inhibition should be possible.


Assessment of personal care and medical robots from older adults' perspective.
Demographic reports indicate that population of older adults is growing significantly over the world and in particular in developed nations. Consequently, there are a noticeable number of demands for certain services such as health-care systems and assistive medical robots and devices. In today's world, different types of robots play substantial roles specifically in medical sector to facilitate human life, especially older adults. Assistive medical robots and devices are created in various designs to fulfill specific needs of older adults. Though medical robots are utilized widely by senior citizens, it is dramatic to find out into what extent assistive robots satisfy their needs and expectations. This paper reviews various assessments of assistive medical robots from older adults' perspectives with the purpose of identifying senior citizen's needs, expectations, and preferences. On the other hand, these kinds of assessments inform robot designers, developers, and programmers to come up with robots fulfilling elderly's needs while improving their life quality.


Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma.
Recent reports by European investigators suggest that sentinel lymphadenectomy (SLND), a mainstay of melanoma diagnosis and treatment planning, increases the risk of in-transit metastasis (ITM) and should be abandoned. This study compared the incidence of ITM after wide local excision (WLE), WLE plus SLND (SLND), or WLE plus elective lymphadenectomy (ELND) for primary melanoma. Review of our prospective database identified 4,412 patients who underwent WLE (n = 2,771), SLND (n = 1,016), or ELND (n = 625) for stage I/II melanoma (1971 through 2002). The incidence of ITM overall and as a first recurrence was examined before and after computerized prognostic matching of treatment groups. Intergroup statistical comparisons used chi(2) analysis and log-rank test. The incidence of ITM increased with Breslow depth, Clark level, and T stage. Although overall incidence of ITM was significantly higher (P = .0008) after ELND (6.56%) versus WLE (3.36%) or SLND (3.64%), the ELND group had higher risk primaries. Treatment groups matched by T stage (1,875 patients; 625 per group) or by age, sex, Breslow depth, and primary location (1,680 patients; 560 per group), showed no significant differences in ITM overall or as a first recurrence. There is no relationship between SLND and ITM. Recent reports to the contrary reflect analysis of significantly smaller cohorts not matched for confounding variables such as T stage. The phase III Multicenter Selective Lymphadenectomy Trial will definitively settle the issue; until then, use of SLND, the most accurate staging procedure for early-stage melanoma, should continue.


Cross and ring-closing metathesis of 1,3-diynes: metallotropic [1,3]-shift of ruthenium carbenes.
The regio- and stereoselective enyne CM and RCM reactions involving 1,3-diynes have been developed. The ring-closing metathesis of enediynes induces a facile metallotropic [1,3]-shift of alkynyl ruthenium carbene species, thereby providing a unique entry into the synthesis of fully conjugated 1,5-diene-3-ynes.


Construct validation of the Nurse Cultural Competence Scale: a hierarchy of abilities.
The aim of this study was to describe the development of a Nurse Cultural Competence Scale using Mokken scaling. The psychometrics of the present cultural competence assessment tools has been questioned. The levels of competence measured by existing tools are not capable of indicating individual differences. This study employed a cross-sectional design. A convenience sample of 172 on-the-job nursing students in a college of technology in Taiwan was recruited. Based on previous literature, the Nurse Cultural Competence Scale comprising 41 items was developed to measure the concept of cultural awareness, cultural knowledge, cultural sensitivity and cultural skill. Mokken scaling analysis was conducted to investigate the unidimensionality and hierarchical nature of the scale. From the 41 items entered into the Mokken scaling procedure, 20 form a strong Mokken scale. The 20 items form a reliable and statistically significant scale which is negatively skewed. The ordering of the items from lowest to highest difficulty shows a hierarchy. Nursing managers and educators may use this scale to assess the levels of cultural competence of their members or students and then provide the education according to individual needs.


Ticagrelor.
Ticagrelor is one of the most recent antiplatelet agents used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It belongs to the non-thienopyridine class. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is usually used for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. This chapter include an overview on the physical properties, chemical properties, mode of action, pharmacokinetics and common uses of ticagrelor. In addition, the reported methods of ticagrelor assay will be discussed briefly in order to help analysts to find the most convenient method for its estimation in routine analysis. The methods of synthesis used for the preparation of ticagrelor will also be covered in this chapter. Moreover, the analytical and characterization techniques used to characterize ticagrelor row material are summarized herein.