Incidence and Characteristics Associated with Hospital Readmission after Discharge to Home Hospice.
Background: Home hospice is designed to provide comfort to patients at the end of their life and hospital readmission is incongruent with this goal. Objective: The purpose of this study was to investigate the incidence of and characteristics associated with hospital readmissions from home hospice over a two-year period. Design/Subjects: This was a retrospective cohort study of 705 inpatients discharged from a quaternary academic medical center to home hospice from January 1, 2016 to December 31, 2017. Measures: The primary outcome was incidence of hospital readmission after discharge to home hospice. Multivariate regression with stepwise forward selection was used to identify characteristics associated with readmission. Results: The incidence of readmission was found to be 10.50% (n = 74), and the median days from discharge to readmission were 32.50 days (interquartile range = 14.00, 75.00). Reasons for readmission were: unanticipated new medical issue (n = 33, 44.59%), uncontrolled symptoms (n = 25, 33.78%), misunderstanding of hospice status (n = 12, 16.22%), and caregiver distress (n = 4, 5.41%). The following characteristics were associated with readmission: female versus male (odds ratio [OR] = 1.96; 95% confidence interval [CI]: 1.16-3.32), non-white versus white (OR = 2.40; 95% CI: 1.36-4.24), and hospice diagnosis of cardiac disease versus all other diagnoses (OR = 4.40; 95% CI: 2.06-9.37). Conclusions: Compared with prior studies, our findings showed a lower incidence of readmission, 10.50%, from home hospice. In addition, those who are female, non-white, or have a hospice diagnosis of cardiac disease are more likely to be readmitted.


Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics.
Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide (F eNO), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in F eNO The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of "alarmins" thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.


Fractal Spiking Neural Network Scheme for EEG-Based Emotion Recognition.
Electroencephalogram (EEG)-based emotion recognition is of great significance for aiding in clinical diagnosis, treatment, nursing and rehabilitation. Current research on this issue mainly focuses on utilizing various network architectures with different types of neurons to exploit the temporal, spectral, or spatial information from EEG for classification. However, most studies fail to take full advantage of the useful Temporal-Spectral-Spatial (TSS) information of EEG signals. In this paper, we propose a novel and effective Fractal Spike Neural Network (Fractal-SNN) scheme, which can exploit the multi-scale TSS information from EEG, for emotion recognition. Our designed Fractal-SNN block in the proposed scheme approximately simulates the biological neural connection structures based on spiking neurons and a new fractal rule, allowing for the extraction of discriminative multi-scale TSS features from the signals. Our designed training technique, inverted drop-path, can enhance the generalization ability of the Fractal-SNN scheme. Sufficient experiments on four public benchmark databases, DREAMER, DEAP, SEED-IV and MPED, under the subject-dependent protocols demonstrate the superiority of the proposed scheme over the related advanced methods. In summary, the proposed scheme provides a promising solution for EEG-based emotion recognition.


Oxygen-sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension.
Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.


Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.
We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.


Speeding up backpropagation using multiobjective evolutionary algorithms.
The use of backpropagation for training artificial neural networks (ANNs) is usually associated with a long training process. The user needs to experiment with a number of network architectures; with larger networks, more computational cost in terms of training time is required. The objective of this letter is to present an optimization algorithm, comprising a multiobjective evolutionary algorithm and a gradient-based local search. In the rest of the letter, this is referred to as the memetic Pareto artificial neural network algorithm for training ANNs. The evolutionary approach is used to train the network and simultaneously optimize its architecture. The result is a set of networks, with each network in the set attempting to optimize both the training error and the architecture. We also present a self-adaptive version with lower computational cost. We show empirically that the proposed method is capable of reducing the training time compared to gradient-based techniques.


Mechanical reinforcement of tracheids compromises the hydraulic efficiency of conifer xylem.
Wood structure and function of juvenile wood from 18 conifer species from four conifer families (Araucariaceae, Cupressaceae, Pinaceae and Podocarpaceae) were examined for a trade-off between wood reinforcement and hydraulic efficiency. Wood density and tracheid 'thickness-to-span' ratio were used as anatomical proxies for mechanical properties. The thickness:span represented the ratio of tracheid double wall thickness to lumen diameter. Hydraulic resistivity (R) of tracheids on a cross-sectional area basis (RCA) increased over 50-fold with increasing density and thickness:span, implying a strength versus efficiency conflict. The conflict arose because density and thickness:span were increased by narrowing tracheid diameter rather than by thickening walls, which may be developmentally difficult. In the Pinaceae and Cupressaceae species, density and thickness:span correlated strongly with protection from drought-induced embolism, suggesting that mechanical strength was required in part to withstand tracheid collapse by negative sap pressure. These species showed a corresponding trade-off between increasing RCA and embolism protection. In contrast, species of Podocarpaceae and Araucariaceae were overbuilt for their embolism protection and were hydraulically inefficient, having greater density, thickness:span and RCA, none of which were correlated with vulnerability to embolism.


Vimentin knockdown decreases corneal opacity.
Wound induced corneal fibrosis can lead to permanent visual impairment. Keratocyte activation and differentiation play a key role in fibrosis, and vimentin, a major structural type III intermediate filament, is a required component of this process. The purpose of our study was to develop a nonviral therapeutic strategy for treating corneal fibrosis in which we targeted the knockdown of vimentin. To determine the duration of plasmid expression in corneal keratocytes, we injected a naked plasmid expressing green fluorescent protein (GFP; pCMV-GFP) into an unwounded mouse corneal stroma. We then injected pCMV-GFP or plasmids expressing small hairpin RNA in the corneal wound injury model (full-thickness corneal incision) to evaluate opacification. GFP expression peaked between days 1 and 3 and had prominent expression for 15 days. In the corneal wound injury model, we found that the GFP-positive cells demonstrated extensive dendritic-like processes that extended to adjacent cells, whereas the vimentin knockdown model showed significantly reduced corneal opacity. These findings suggest that a nonviral gene therapeutic approach has potential for treating corneal fibrosis and ultimately reducing scarring.


Homologous and heterologous enhancers modulate spatial expression but not cell-type specificity of the murine gamma F-crystallin promoter.
Previous studies have shown that mouse gamma F-crystallin sequences -759 to +45, which include the core promoter and two upstream enhancer elements, contain sufficient information for directing gene expression to terminally differentiated fiber cells of the ocular lens. To investigate the role that proximal sequences of the mouse gamma F-crystallin promoter play in the developmental regulation of gene expression, we generated transgenic mice containing the lacZ gene driven by either mouse gamma F-crystallin sequences -171 to +45, which lack functional enhancers, or a hybrid hamster alpha A-/mouse gamma F-crystallin promoter, which contains the hamster alpha A-crystallin enhancer instead of operational gamma F-crystallin enhancers. In situ analysis of lacZ expression in these mice revealed that the mouse gamma F-crystallin promoter segment -171 to +45, which shows low activity in vitro, is able to direct gene expression to the fiber cells in the nucleus of the lens. However, animals expressing gamma 171-lacZ show both a lower level of expression of the lacZ gene and a narrower pattern of staining in the lens nucleus than mice expressing gamma 759-lacZ, which contains the two enhancer elements located between -392 and -278 and -226 to -123.(ABSTRACT TRUNCATED AT 250 WORDS)


The human cytomegalovirus (HCMV) tegument protein UL94 is essential for secondary envelopment of HCMV virions.
Human cytomegalovirus (HCMV) virions are structurally complex, and the mechanisms by which they are assembled are poorly understood. However, several tegument proteins are known to be essential for proper particle assembly and maturation. Despite intense investigation, the function of many tegument proteins remains unknown. The HCMV UL94 gene is conserved among all herpesviruses and encodes a virion protein of unknown function. We demonstrate here that UL94 is a tegument protein that is expressed with true-late kinetics and localizes to the viral assembly complex during infection. To elucidate the function of UL94, we constructed a UL94-null mutant, designated UL94stop. This mutant is completely defective for replication, demonstrating that UL94 is essential. Phenotypic analysis of the UL94stop mutant shows that in the absence of UL94, viral gene expression and genome synthesis occur at wild-type levels. However, analysis of the localization of viral proteins to the cytoplasmic assembly complex shows that the essential tegument protein UL99 (pp28) exhibits aberrant localization in cells infected with the UL94stop mutant. Finally, we show that there is a complete block in secondary envelopment in the absence of UL94. Taken together, our data suggest that UL94 functions late in infection to direct UL99 to the assembly complex, thereby facilitating secondary envelopment of virions.


Substance P: a putative sensory transmitter in mammalian autonomic ganglia.
Repetitive presynaptic stimulation elicited slow membrane depolarization in neurons of inferior mesenteric ganglia from guinea pigs. This response was not blocked by cholinergic antagonists but was specifically and reversibly inhibited by a substance P analog, (D-Pro2, D-Phe7, D-Trp9)-substance P, which also depressed the depolarization induced by exogenously applied substance P. The atropine-sensitive slow excitatory and slow inhibitory postsynaptic potentials evoked in neurons of rabbit superior cervical ganglia were not affected by the substance P analog. These and previous results provide strong support for the hypothesis that substance P or a closely related peptide is the transmitter mediating the slow depolarization. The latter may represent a sensory input from the gastrointestinal tract to neurons of the prevertebral ganglia.


Federated electronic health records for the European Health Data Space.
The European Commission's draft for the European Health Data Space (EHDS) aims to empower citizens to access their personal health data and share it with physicians and other health-care providers. It further defines procedures for the secondary use of electronic health data for research and development. Although this planned legislation is undoubtedly a step in the right direction, implementation approaches could potentially result in centralised data silos that pose data privacy and security risks for individuals. To address this concern, we propose federated personal health data spaces, a novel architecture for storing, managing, and sharing personal electronic health records that puts citizens at the centre-both conceptually and technologically. The proposed architecture puts citizens in control by storing personal health data on a combination of personal devices rather than in centralised data silos. We describe how this federated architecture fits within the EHDS and can enable the same features as centralised systems while protecting the privacy of citizens. We further argue that increased privacy and control do not contradict the use of electronic health data for research and development. Instead, data sovereignty and transparency encourage active participation in studies and data sharing. This combination of privacy-by-design and transparent, privacy-preserving data sharing can enable health-care leaders to break the privacy-exploitation barrier, which currently limits the secondary use of health data in many cases.


Bap, a Staphylococcus aureus surface protein involved in biofilm formation.
Identification of new genes involved in biofilm formation is needed to understand the molecular basis of strain variation and the pathogenic mechanisms implicated in chronic staphylococcal infections. A biofilm-producing Staphylococcus aureus isolate was used to generate biofilm-negative transposon (Tn917) insertion mutants. Two mutants were found with a significant decrease in attachment to inert surfaces (early adherence), intercellular adhesion, and biofilm formation. The transposon was inserted at the same locus in both mutants. This locus (bap [for biofilm associated protein]) encodes a novel cell wall associated protein of 2,276 amino acids (Bap), which shows global organizational similarities to surface proteins of gram-negative (Pseudomonas aeruginosa and Salmonella enterica serovar Typhi) and gram-positive (Enteroccocus faecalis) microorganisms. Bap's core region represents 52% of the protein and consists of 13 successive nearly identical repeats, each containing 86 amino acids. bap was present in a small fraction of bovine mastitis isolates (5% of the 350 S. aureus isolates tested), but it was absent from the 75 clinical human S. aureus isolates analyzed. All staphylococcal isolates harboring bap were highly adherent and strong biofilm producers. In a mouse infection model bap was involved in pathogenesis, causing a persistent infection.


The use of cell salvage during radical retropubic prostatectomy: does it influence cancer recurrence?
To assess whether there is a difference in the biochemical recurrence rate in patients who had radical retropubic prostatectomy (RRP) with or without cell salvage transfusion. The records of 769 consecutive patients undergoing RRP between 1992 and 1998 were retrospectively reviewed. Patients having adjuvant hormonal treatment, postoperative external beam radiotherapy, or a follow-up of < 1 year were excluded from the analysis. The remaining 408 patients were categorized into three groups: 87 who received cell-salvaged blood using a commercial cell saver; 264 receiving only autologous transfusion; and 57 with no transfusion. Disease recurrence was defined as a prostate-specific antigen (PSA) level of> 0.2 ng/mL. Bivariate and multivariate logistic regression analyses were used to assess and compare the risk of cancer recurrence in the three groups. Covariates used in the multivariate analyses included Gleason score, preoperative PSA level, seminal vesicle involvement and surgical margins. The mean (range) follow-up was 40.2 (12-104) months; there were no significant differences among the groups in initial PSA level and Gleason score. In the multivariate logistic regression analysis, the initial PSA, Gleason score, seminal vesicle involvement and surgical margins, but not transfusion group, were independent predictors of recurrence. Cell salvage during RRP does not influence the recurrence of prostate cancer. Cell salvage is a safe method of transfusion during RRP.


Effect of Aflatoxin B(1) on Cell Cultures.
Gabliks, J. (Massachusetts Institute of Technology, Cambridge), W. Schaeffer, L. Friedman, and G. Wogan. Effect of aflatoxin B(1) on cell cultures. J. Bacteriol. 90:720-723. 1965.-Aflatoxin B(1), a metabolite of the mold Aspergillus flavus, is toxic to cell cultures. The toxic effect is evidenced by an inhibition of growth followed by progressive granulation, rounding, and finally sloughing of the cells from the glass. In studies with embryonated eggs, duck embryos were found to be four to five times more susceptible than chick embryos. In studies on Chang liver cultures, there were decreases in cell number, protein, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA) per culture with increasing aflatoxin B(1) concentrations. Since the cell number decreased and the protein, RNA, and DNA content per cell increased with increasing concentrations of aflatoxin, enlarged cells were suggested. These data are consistent with in vivo data of other workers who have found hypertrophic cells with enlarged nuclei in histological studies on the tissues of rats and ducklings fed toxic peanut meal.


Anisotropic bidispersive convection.
This paper investigates thermal convection in an anisotropic bidisperse porous medium. A bidisperse porous medium is one which possesses the usual pores, but in addition, there are cracks or fissures in the solid skeleton and these give rise to a second porosity known as micro porosity. The novelty of this paper is that the macro permeability and the micro permeability are each diagonal tensors but the three components in the vertical and in the horizontal directions may be distinct in both the macro and micro phases. Thus, there are six independent permeability coefficients. A linear instability analysis is presented and a fully nonlinear stability analysis is inferred. Several Rayleigh number and wavenumber calculations are presented and it is found that novel cell structures are predicted which are not present in the single porosity case.


Low-level laser therapy improves vision in a patient with retinitis pigmentosa.
This case report describes the effects of low-level laser therapy (LLLT) in a single patient with retinitis pigmentosa (RP). RP is a heritable disorder of the retina, which eventually leads to blindness. No therapy is currently available. LLLT was applied using a continuous wave laser diode (780 nm, 10 mW average output at 292 Hz, 50% pulse modulation). The complete retina of eyes was irradiated through the conjunctiva for 40 sec (0.4 J, 0.333 W/cm2) two times per week for 2 weeks (1.6 J). A 55-year-old male patient with advanced RP was treated and followed for 7 years. The patient had complained of nyctalopia and decreasing vision. At first presentation, best visual acuity was 20/50 in each eye. Visual fields were reduced to a central residual of 5 degrees. Tritan-dyschromatopsy was found. Retinal potential was absent in electroretinography. Biomicroscopy showed optic nerve atrophy, and narrow retinal vessels with a typical pattern of retinal pigmentation. After four initial treatments of LLLT, visual acuity increased to 20/20 in each eye. Visual fields normalized except for a mid-peripheral absolute concentric scotoma. Five years after discontinuation of LLLT, a relapse was observed. LLLT was repeated (another four treatments) and restored the initial success. During the next 2 years, 17 additional treatments were performed on an "as needed" basis, to maintain the result. LLLT was shown to improve and maintain vision in a patient with RP, and may thereby have contributed to slowing down blindness.


Motion-invariant SRT treatment detection from direct M-scan OCT imaging.
Selective retina therapy (SRT) is a laser treatment targeting specific posterior retinal layers. It is focused on inducing damage to the retinal pigment epithelium (RPE), while sparing other retinal tissue compared to traditional photocoagulation. However, the targeted RPE layer is invisible with most imaging modalities and induced SRT lesions cannot be monitored. In this work, imaging scans acquired from an experimental setup that couples the SRT laser beam with an optical coherence tomography (OCT) beam are analyzed in order to evaluate the treatment as they occur. We isolated a small part of the time-resolved scan corresponding to the end of the treatment, for which we have microscopic evidence of the SRT outcome. We then use a convolutional neural network to correspond each scan to the treatment result. We explore which aspects of the scan convey more valuable information for a robust therapy evaluation. By only using this adequately small part, we can achieve an online estimation, while being resilient to eye movement. The available dataset consists of time- resolved OCT scans of 98 ex vivo porcine eyes, treated with different energy levels. The proposed method yields high performance in the task of predicting whether the applied energy was adequate for SRT treatment, by focusing on the immediate OCT signal acquired during treatment time. We propose a strategy toward online noninvasive SRT treatment assessment, able to provide a satisfying evaluation of a treatment status, that therefore could be used for the planning of the treatment continuation.


Thermodynamic properties of agonist interactions with the beta adrenergic receptor-coupled adenylate cyclase system. I. High- and low-affinity states of agonist binding to membrane-bound beta adrenergic receptors.
The properties associated with ligand interactions with membrane-bound beta adrenergic receptors prepared from L6 myoblasts were examined at five temperatures between 10 degrees and 30 degrees C. The interactions of antagonists with membrane-bound receptors were insensitive to temperature, whereas the interactions of agonists were temperature-dependent. The affinity constants for the low-affinity binding states of agonists (KL) decreased slightly with decreasing assay temperature. The small temperature-dependent changes in KL values were similar to the changes in Kd values observed in studies of the binding of agonists in the presence of GTP. The high-affinity dissociation constants (KH) for binding of full agonists to membrane-bound receptors in the absence of GTP were approximately 50-fold lower at 10 degrees than at 30 degrees C. The KH values for partial agonists also decreased with decreasing temperature, but the changes were smaller in magnitude. Thermodynamically, the binding of antagonists was primarily entropy-driven, whereas the binding of agonists was enthalpy-driven. The energetics of the low-affinity component of agonist binding to membrane-bound receptors were similar to the energetics for binding of agonists to membrane-bound receptors in the presence of GTP. Under these conditions, standard enthalpy change (delta H degree) and standard entropy change (delta S degree) values for binding of agonists were more negative than the corresponding values for binding of antagonists, possibly reflecting a conformational change in the receptor or an increased ordering of the lipids surrounding the receptor. The interaction of the receptor with the guanine nucleotide-binding protein to form the high-affinity component of agonist binding was thermodynamically described by larger negative changes in enthalpy and entropy than the values for formation of the low-affinity component of agonist binding. There was a correlation between the efficacies of ligands in activating adenylate cyclase and the delta H degree and delta S degree values for high-affinity binding of agonists. Thus, the extent or nature of the interaction between the guanine nucleotide-binding protein and the receptor may determine the efficacies of ligands.


Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA.
The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the "enteric nervous system-vagus nerve-brain" axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.


Association between older age and more successful aging: critical role of resilience and depression.
There is growing public health interest in understanding and promoting successful aging. While there has been some exciting empirical work on objective measures of physical health, relatively little published research combines physical, cognitive, and psychological assessments in large, randomly selected, community-based samples to assess self-rated successful aging. In the Successful AGing Evaluation (SAGE) study, the authors used a structured multicohort design to assess successful aging in 1,006 community-dwelling adults in San Diego County, ages 50-99 years, with oversampling of people over 80. A modified version of random-digit dialing was used to recruit subjects. Evaluations included a 25-minute telephone interview followed by a comprehensive mail-in survey of physical, cognitive, and psychological domains, including positive psychological traits and self-rated successful aging, scaled from 1 (lowest) to 10 (highest). The mean age of the respondents was 77.3 years. Their mean self-rating of successful aging was 8.2, and older age was associated with a higher rating, despite worsening physical and cognitive functioning. The best multiple regression model achieved, using all the potential correlates, accounted for 30% of the variance in the score for self-rated successful aging and included resilience, depression, physical functioning, and age (entering the regression model in that order). Resilience and depression had significant associations with self-rated successful aging, with effects comparable in size to that for physical health. While no causality can be inferred from cross-sectional data, increasing resilience and reducing depression might have effects on successful aging as strong as that of reducing physical disability, suggesting an important role for psychiatry in promoting successful aging.


A Cross-Sectional Analysis of Students' Intuitions When Interpreting CIs.
We explored how students interpret the relative likelihood of capturing a population parameter at various points of a CI in two studies. First, an online survey of 101 students found that students' beliefs about the probability curve within a CI take a variety of shapes, and that in fixed choice tasks, 39% CI [30, 48] of students' responses deviated from true distributions. For open ended tasks, this proportion rose to 85%, 95% CI [76, 90]. We interpret this as evidence that, for many students, intuitions about CIs distributions are ill-formed, and their responses are highly susceptible to question format. Many students also falsely believed that there is substantial change in likelihood at the upper and lower limits of the CI, resembling a cliff effect (Rosenthal and Gaito, 1963; Nelson et al., 1986). In a follow-up study, a subset of 24 post-graduate students participated in a 45-min semi-structured interview discussing the students' responses to the survey. Analysis of interview transcripts identified several competing intuitions about CIs, and several new CI misconceptions. During the interview, we also introduced an interactive teaching program displaying a cat's eye CI, that is, a CI that uses normal distributions to depict the correct likelihood distribution. Cat's eye CIs were designed to help students understand likelihood distributions and the relationship between interval length, C% level and sample size. Observed changes in students' intuitions following this teaching program suggest that a brief intervention using cat's eyes can reduce CI misconceptions and increase accurate CI intuitions.


Bcl-2 inhibits retinoic acid-induced apoptosis during the neural differentiation of embryonal stem cells.
We report here that all trans-retinoic acid (RA), a classical morphogen, induces apoptosis during the neural differentiation of the embryonic stem cell line P19. The apoptotic cells showed, in addition to DNA cleavage, typical morphological changes including chromatin condensation, nuclear fragmentation, and cytoplasmic vacuolation. These apoptotic changes became obvious by 12 h after the addition of RA. The endogenous expression of bcl-2 in surviving cells was down-regulated during this process, and the compelled expression of bcl-2 by retroviral vectors reduced the number of apoptotic cells. Apoptosis was partially inhibited by adding antisense oligonucleotides against RA receptors (RARs) simultaneously or by transfecting a plasmid vector flanked with a RA-responsive element. Antisense oligonucleotides against retinoid X receptors (RXRs), the receptors for 9 cis-RA, did not inhibit apoptosis induced by all trans-RA. Cycloheximide and actinomycin D, inhibitors of protein and RNA syntheses, respectively, suppressed apoptosis. No changes were seen in the expression of tumor necrosis factors, their receptors, Fas, FasL, p53, or c-myc, molecules which have been suggested to participate in the apoptotic process. Addition of neurotrophins to the culture medium did not affect apoptosis. These findings suggest that the signals themselves, promote expression of molecules essential for apoptosis. Furthermore, we observed that RA induced apoptosis of cerebral neurons from murine embryos in primary culture, which suggests that RA might participate in cell death which occurs during neural development.


Analysis of measurements from the first Swedish universal neonatal hearing screening program.
This study analyses results from the first Swedish UNHS program. It includes over 33 000 measurement files from 14 287 children at two maternity wards. The screening program uses a two-stage TEOAE test procedure. A database was created in MedLog after data transformation in Word and Excel. The coverage rate was 99.1%. Bilateral pass rate after retesting was 97.0%. A unilateral pass criterion would have resulted in 1268 fewer children (9.0% of target group) for retesting and 231 fewer children (1.6% of target group) for diagnostic evaluation. When the first test was performed on the day the child was born, the pass rate was 64.8%; the pass rate increased to 89.2% when testing> or =3 days after birth. High coverage rates and pass rates were found to be possible, independent of the number of children born at the maternity ward. Learning curves were observed in the program with improvements distributed over time. Test performance was clearly better when the children were tested day two after birth or later.


Oral indomethacin and ranitidine in advanced melanoma: a phase II study.
As a result of preclinical data demonstrating the antitumour and antimetastatic efficiency of indomethacin in murine models, and the clinical observation of occasional tumour regression in patients with advanced melanoma treated with indomethacin together with ranitidine, a Phase II study was performed of prolonged administration of these two oral agents in combination. Seventeen patients were entered into the study and commenced on indomethacin 50 mg three times daily; the dose was escalated to a maximum of 75 mg three times daily in patients who tolerated the starting dose. Ranitidine was administered concurrently at a dose of 150 mg twice daily. One patient with uveal melanoma metastatic to the liver achieved a partial response, with slow shrinkage of a biopsy-proved liver metastasis (objective response rate 6 percent; 95 percent CI0-29). Another patient demonstrated a minor response in pelvic lymph nodes. The combination of indomethacin and ranitidine has negligible activity in advanced malignant melanoma; a response may require months to be achieved.


Effect of atomicity on the oxidation of cationic copper clusters studied using thermal desorption spectrometry.
The resistivity to oxidation of small copper clusters, Cun+ (n ≤ 5), in the gas phase with a precise atomicity at the molecular level was investigated using a combination of thermal desorption spectrometry and mass spectrometry. Oxide clusters, CunOm+, with more O atoms than those present with a stoichiometry of n : m = 1 : 1 were produced at room temperature in the presence of O2, and the weakly bound excess oxygen atoms involved in the clusters were removed by post heating. Non-oxidized Cu2+ and Cu3+ clusters were formed in the range of 323-923 K, whereas partially oxidized clusters, Cu4O2+ and Cu5O2+, were generated for n = 4 and 5. Considering the fact that CunOm+ (m = n/2 + 1) tends to be generated for n ≥ 6, the small copper clusters were concluded to be resistive to oxidation. The possible reaction paths for the oxidation of Cu2+ and Cu4+ clusters were obtained by density functional calculations, which were consistent with the experimental findings. The oxidation states of the Cu atoms in the clusters were discussed based on the natural charges of the atoms.


Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.
Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.


First record of Megaselia scalaris (LOEW) (DIPTERA: PHORIDAE) infesting a spinose ear tick, Otobius megnini, colony in Sri Lanka.
Megaselia scalaris (Loew) is a cosmopolitan polyphagous small fly with the ability of exploiting variety of ecological niches. Different life history stages act as detritivore, parasite, and parasitoid of wider spectrum of plant and animal matter under natural and laboratory conditions. Here, for the first time we present the opportunistic parasitism of M. scalaris on Otobius megnini, which act as a vector of Q fever and is capable of causing paralysis, toxic conditions, otoacariasis and otitis in humans and other animals. Tick samples from the ear canals of 14 thoroughbred horses were brought to the laboratory and several days later, larvae of M. scalaris were found feeding on immature stages of O. megnini. When the development was completed pupae were found attached to adult ticks and all nymphs were found dead. This context reveals the capability of M. scalaris surviving on O. megnini and the risk of their invading ear canals of horses.


An on-demand nanofluidic concentrator.
Preconcentration of biomolecules by electrokinetic trapping at the nano/microfluidic interface has been extensively studied due to its significant efficiency. Conventionally, sample preconcentration takes place in continuous flow and therefore suffers from diffusion and dispersion. Encapsulation of the preconcentrated sample into isolated droplets offers a superior way to preserve the sample concentration for further analysis. Nevertheless, the rationale for an optimal design to obviate the sample dilution prior to encapsulation is still lacking. Herein, we propose a pressure-assisted strategy for positioning the concentrated sample plug directly at the ejecting nozzle, which greatly eliminates the concentration decline during sample ejection. A distinctive mechanism for this plug localization was elucidated by two-dimensional numerical simulations. Based on the simulation results, we developed an on-demand nanofluidic concentrator in which the nanochannels were facilely generated through lithography-free nanocracking on a polystyrene substrate. By wisely implementing an on-demand droplet generation module, our system can adaptively encapsulate the highly concentrated sample and effectively enhance the long-term stability. We experimentally demonstrated the preconcentration of a fluorescently labelled biomolecule, bovine serum albumin (BSA), by using an amplification factor of 10(4). We showed that, by adjusting the applied voltage, accumulation time, and pulsed pressure imposed on the control microchannel, our system can generate a droplet of the desired volume with a target sample concentration at a prescribed time. This study not only provides insights into the previously unidentified role of assisted pressure in sample positioning, but also offers an avenue for varied requirements in low-abundance biomolecule detection and analysis.


Pediatric interventional cardiac catheterization.
Interventional cardiac catheterization has become a standard part of the practice of pediatric cardiology. In this review, articles on pediatric interventional catheterization that have been published over the past 2 years are summarized. The interventional procedures have been divided into the following: lesions, pulmonary valve, aortic valve, mitral valve, coarctation of the aorta, branch pulmonary artery stenosis, device closure of septal defects, and miscellaneous lesions. In addition, within these lesions the articles have been further categorized in the following manner: 1) large collaborative studies defining the short-term efficacy and complications associated with many of the interventional procedures; 2) follow-up studies that now define the intermediate (1 to 8 years) hemodynamic results and complications associated with the various interventional procedures; 3) the reports of new cardiac lesions that can be treated within the catheterization laboratory; and 4) the description of new technologies that have improved the results or expanded the scope of interventional pediatric cardiology.


Can PEI microgels become biocompatible upon betainization?
Polyethylene imine (PEI) microgels prepared via micro emulsion polymerization technique were treated with 1,3-propane sultone to obtained betainized PEI (b-PEI) microgels. The betainization reaction generated zwitterions on PEI microgel that are positive charges from quarternized amine groups of PEI, and the newly formed negative charges from SO3- groups from the modifying agent, 1,3-propane sultone offered interesting properties. The smaller size of b-PEI microgels that are obtained by simple filtration were increased with betainization from 512±14 to 1114±86nm. Also, the betainization of PEI microgel provided negative zeta potential values at high pH values as 9, 10, 11, and 12. Moreover, the b-PEI microgels render more effective dye absorption capabilities for anionic or cationic organic dyes such as Methyl Orange (MO) and Methylene Blue (MB) separately with the significant increase dye adsorption capacity of 354±31 and 274±19mg/g respectively. Moreover, antibacterial properties of b-PEI microgels tested on the E. coli ATCC 8739 and S. aureus ATCC 6538 were diminished whereas bare PEI has low MIC and MBC values (strong antibacterial properties). Interestingly, the PEI microgels known for their strong antibacterial and toxic nature found to be biocompatible upon betainization reaction. The biocompatibility test were carried with WST-1 tests and double staining methods. The cytotoxicity, apoptotic and necrotic cell tests were shown that PEI microgels induce no cytotoxicity up to 400μg/mL whereas PEI microgels possessed 50% toxicity at this concentration, suggesting that b-PEI microgels become biocompatible upon betainization with, 3-propane sultone.


Characterization of the dextran-binding domain in the glucan-binding protein C of Streptococcus mutans.
Streptococcus mutans produces multiple glucan-binding proteins (Gbps), among which GbpC encoded by the gbpC gene is known to be a cell-surface-associated protein involved in dextran-induced aggregation. The purpose of the present study was to characterize the dextran-binding domain of GbpC using bioinformatics analysis and molecular techniques. Bioinformatics analysis specified five possible regions containing molecular binding sites termed GB1 through GB5. Next, truncated recombinant GbpC (rGbpC) encoding each region was produced using a protein expression vector and five deletion mutant strains were generated, termed CDGB1 through CDGB5 respectively. The dextran-binding rates of truncated rGbpC that included the GB1, GB3, GB4 and GB5 regions in the upstream sequences were higher than that of the construct containing GB2 in the downstream region. In addition, the rates of dextran-binding for strains CDGB4 and CD1, which was entire gbpC deletion mutant, were significantly lower than for the other strains, while those of all other deletion mutants were quite similar to that of the parental strain MT8148. Biofilm structures formed by CDGB4 and CD1 were not as pronounced as that of MT8148, while those formed by other strains had greater density as compared to that of CD1. Our results suggest that the dextran-binding domain may be located in the GB4 region in the interior of the gbpC gene. Bioinformatics analysis is useful for determination of functional domains in many bacterial species.


Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses.
Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational design method that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.


The Relationship between Maxillary Sinus Volume and Different Cephalometric Characteristics in Orthodontics.
This study aimed to evaluate the maxillary sinus volume (MSV) in both genders in a Saudi sample and among different skeletal patterns. This retrospective cross-sectional study included 52 cone-beam computed tomography (CBCT) scans of 18 years or older individuals with complete dentition and healthy medical history. MSV was measured as the mean value of both sides in cubic millimeters (mm3) using OnDemand three-dimensional™ Dental. Cephalometric tracings were conducted on cephalograms obtained from CBCT scans. The beta, A × B, and Frankfort-mandibular plane angles were selected to determine the sagittal and vertical skeletal patterns of the study subjects. Descriptive statistics and other tests were conducted. The significance level was set at P < 0.05. Fifty-two CBCT scans were included in this study (23 males and 29 females), with a mean age of 36 (±14) years. The mean MSV was 14887 (±5030.79) mm3. Males had statistically significantly larger MSV (16517 ± 5335 mm3) compared with females (13595 ± 4,452 mm3) (P = 0.036). There was no statistically significant difference in MSV among all other cephalometric measurements (P > 0.05). The MSV in the studied Saudi sample was larger among males. However, different skeletal patterns have no statistically significant differences in MSV.


Comparison of Thessaly Test with Joint Line Tenderness and McMurray Test in the Diagnosis of Meniscal Tears.
Meniscus injuries are the most frequent problem of the knee. The aim of this study was to investigate the accuracy of the Thessaly test and comparing it with those of McMurray and Joint-line tenderness tests for diagnosing meniscal tears.Materials and methods: This study was designed as a prospective observational one done in an outpatient clinic at a university hospital. 106 patients with knee pain and 82 age-matched control were included during study period (from February 2014 to January 2015). Each patient was clinically examined with McMurray, Thessaly, and joint line tenderness tests. Then, the findings were matched by MRI and arthroscopic findings. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated as main outcomes. Based on MRI, Thessaly was the most sensitive for medial meniscus tears (56.2%), while McMurray and joint-line tenderness were more specific (89.1% and 88.0%, respectively). For lateral meniscus tears, McMurray was the most sensitive (56.2%) and all were specific (McMurray 89.6%, Thessaly 88.4%, joint-line tenderness 90.2%). With arthroscopy, Thessaly was the most sensitive for medial meniscus (76.6%), while McMurray and joint-line tenderness were more specific (81.0%, and 81.0%). Agreement with arthroscopy was the highest with McMurray (for medial meniscus kappa=0.40, p<0.001, and for lateral meniscus kappa=0.38, p=0.002). The Thessaly can be used to screen for medial meniscus tears. McMurray and joint-line tenderness should be used for suspected medial meniscus tears. For lateral meniscus, McMurray is appropriate for screening and all the tests are useful in clinic.


Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults.
To further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC(0-12)s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC(0-12) in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥ 50 kg. Other adolescents should be dosed like adults.


beta-N-Oxalylamino-L-alanine: action on high-affinity transport of neurotransmitters in rat brain and spinal cord synaptosomes.
beta-N-Oxalylamino-L-alanine (BOAA) is a dicarboxylic diamino acid present in Lathyrus sativus (chickling pea). Excessive oral intake of this legume in remote areas of the world causes humans and animals to develop a type of spastic paraparesis known as lathyrism. BOAA is one of several neuroactive glutamate analogs reported to stimulate excitatory receptors and, in high concentrations, cause neuronal vacuolation and necrosis. The present study investigates the action of BOAA in vitro on CNS high-affinity transport systems for glutamate, gamma-aminobutyric acid (GABA), aspartate, glycine, and choline and in the activity of glutamate decarboxylase (GAD), the rate-limiting enzyme in the decarboxylation of glutamate to GABA. Crude synaptosomal fractions (P2) from rat brain and spinal cord were used for all studies. [3H]Aspartate transport in brain and spinal cord synaptosomes was reduced as a function of BOAA concentration, with reductions to 40 and 30% of control values, respectively, after 15-min preincubation with 1 mM BOAA. Under similar conditions, transport of [3H]glutamate was reduced to 74% (brain) and 60% (spinal cord) of control values. High-affinity transport of [3H]GABA, [3H]glycine, and [3H]choline, and the enzyme activity of GAD, were unaffected by 1 mM BOAA. While these data are consistent with the excitotoxic (convulsant) activity of BOAA, their relationship to the pathogenesis of lathyrism is unknown.


Association between marijuana use and kidney stone: a cross-sectional study of NHANES 2009 to 2018.
Objective: The purpose of this investigation is to determine whether regular marijuana use is related to history of kidney stones in the US population. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. Kidney stone and marijuana use data were collected from self-report questionnaires. Multivariate logistic regression and multiple sensitivity analyses were applied to examine the relationship between marijuana usage and kidney stones. Results: There are approximately 26.04% of the US population have admitted to using marijuana in their lifetime. Compared with none regular users, those with a higher frequency of marijuana use were more males, more non-Hispanic races, lower than high school education, overweight, no recreational activity, without diabetes mellitus, and more coronary heart disease. After adjusting for potential confounders, multivariate regression analysis demonstrated that marijuana use was inversely correlated to kidney stones in males (Odds ratio [OR] = 0.72, 95% Confidence interval [CI] = 0.54-0.97). One to seven times/week regular consumption of marijuana was associated with kidney stones in males (OR = 0.62, 95% CI = 0.43-0.89). Sensitivity analyses validated the robustness of our outcomes. Conclusion: Our findings revealed that regular marijuana male users were inversely associated with kidney stones. Marijuana use one to six times/week was inversely related to the risk of kidney stones in males. Further studies are required to explore the dose and type associations of marijuana with kidney stones.


Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels.
Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K(+) (K(ATP)) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive K(ATP) channel mutant [Kir6.2(deltaN2-30,K185Q)] under transcriptional control of the alpha-myosin heavy chain promoter. Strikingly, myocyte contraction amplitude was increased in TG myocytes (15.68 +/- 1.15% vs. 10.96 +/- 1.49%), even though K(ATP) channels in TG myocytes are very insensitive to inhibitory ATP. Under normal metabolic conditions, steady-state outward K(+) currents measured under whole cell voltage clamp were elevated in TG myocytes, consistent with threshold K(ATP) activation, but neither the monophasic action potential measured in isolated hearts nor transmembrane action potential measured in right ventricular muscle preparations were shortened at physiological pacing cycles. Taken together, these results suggest that there is a compensatory remodeling of excitation-contraction coupling in TG myocytes. Whereas there were no obvious differences in other K(+) conductances, peak L-type Ca(2+) current (I(Ca)) density (-16.42 +/- 2.37 pA/pF) in the TG was increased compared with the wild type (-8.43 +/- 1.01 pA/pF). Isoproterenol approximately doubled both I(Ca) and contraction amplitude in wild-type myocytes but failed to induce a significant increase in TG myocytes. Baseline and isoproterenol-stimulated cAMP concentrations were not different in wild-type and TG hearts, suggesting that the enhancement of I(Ca) in the latter does not result from elevated cAMP. Collectively, the data demonstrate that a compensatory increase in I(Ca) counteracts a mild activation of ATP-insensitive K(ATP) channels to maintain the action potential duration and elevate the inotropic state of TG hearts.


Tractography Navigated Endoscopic En-Bloc Excision of Pediatric Giant Choroid Plexus Tumor.
Giant choroid plexus (CP) tumors in children pose a formidable surgical challenge due to extensive vascularity/blood loss, tumor size impeding early visualization of the pedicle, hydrocephalus/mass effect distorting cerebral localization, considerable prevalence of atypical tumors and carcinoma demanding excision without tumor spillage, and retraction-associated morbidity. However, total resection of CP papilloma has excellent potential for cure. This is probably the first report in the literature of diffusion tensor imaging navigation-guided tumor pedicle targeting, endoscopic devascularization and division of pedicle followed by en bloc delivery in optimally tackling most of these challenges in a 6-year-old girl presenting with a giant lateral ventricular CP tumor. Giant CP tumors pose a formidable challenge. Extensive vascularity can cause life-threatening blood loss in children.1 Large tumor size makes it impractical during microsurgery to achieve early visualization of pedicle.2 Hydrocephalus and mass effect can distort sulcal anatomy, with potentially devastating deficits.3 Still, prevalence of atypical tumors and carcinoma warrants excision without tumor spillage.4 In Video 1, we demonstrate our "10-D" steps of en-bloc excision, exploiting panoramic visualization of endoscope5: 1. Diagnosis, 2. Diffusion tensor imaging guided pedicle targeting, 3. Design position & exposure, 4. Durotomy, 5. Dissection of sulcus, 6. Delineation of pedicle, 7. Devascularization, 8. Division of pedicle, 9. Delivery of tumor, and 10. Dural & skin closure. The conventional superior parietal lobule approach to get the tumor en-bloc would have been from the posterosuperior direction, where the tumor is likely to conceal the pedicle. The trajectory to first get to the pedicle must be from an anterosuperior direction but will violate corticospinal fibers. Hence entry point was chosen in between, just posterior to the post-central sulcus. To accommodate the 'en-bloc' excision avoiding ventricular seedlings, a 5 cm mini-craniotomy was fashioned centered on the entry point planned in the navigation system. Ventricle was entered perpendicular to the sulcus through the roof of the atrium, with least cortical transgression and avoiding injury to laterally placed optic radiation and speech areas.6 A 30-degree, 4-mm endoscope was inserted anterolateral to the tumor and fixed. The wide-angled vision offered by endoscopes enhancing meticulous dissection is the likely cause of better neurological outcomes, as noted in other ventricular lesions.7 Pedicular attachment of the tumor is coagulated thoroughly and cut, ensuring initial sparing of venous drainage. The draining vein is then coagulated and divided. 'En-bloc' excision is also known in other vascular lesions to decrease the risk of bleeding.8 The angled optics & panoramic visualization helps to identify any possible tumor seedlings.9 This is probably the first report of endoscopic en-bloc excision of a giant choroid plexus tumor in literature.


Systems biophysics of gene expression.
Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses.


Molecular tuning of electroreception in sharks and skates.
Ancient cartilaginous vertebrates, such as sharks, skates and rays, possess specialized electrosensory organs that detect weak electric fields and relay this information to the central nervous system1-4. Sharks exploit this sensory modality for predation, whereas skates may also use it to detect signals from conspecifics 5 . Here we analyse shark and skate electrosensory cells to determine whether discrete physiological properties could contribute to behaviourally relevant sensory tuning. We show that sharks and skates use a similar low threshold voltage-gated calcium channel to initiate cellular activity but use distinct potassium channels to modulate this activity. Electrosensory cells from sharks express specially adapted voltage-gated potassium channels that support large, repetitive membrane voltage spikes capable of driving near-maximal vesicular release from elaborate ribbon synapses. By contrast, skates use a calcium-activated potassium channel to produce small, tunable membrane voltage oscillations that elicit stimulus-dependent vesicular release. We propose that these sensory adaptations support amplified indiscriminate signal detection in sharks compared with selective frequency detection in skates, potentially reflecting the electroreceptive requirements of these elasmobranch species. Our findings demonstrate how sensory systems adapt to suit the lifestyle or environmental niche of an animal through discrete molecular and biophysical modifications.


Methyldopa and propranolol or practolol in moderate hypertension.
The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.


Clinimetric properties of the alberta infant motor scale in infants born preterm.
The Alberta Infant Motor Scale (AIMS) is a standardized motor assessment for young infants. This study aimed to examine the reliability of the AIMS in a group of infants born at or before 29 weeks of gestation. Fifty-nine infants born preterm were recruited. Two experienced pediatric physical therapists participated in this reliability study. Infants were assessed at 4, 8, 12, and 18 months corrected age (CA). Intrarater reliability was high (intraclass correlation coefficient [ICC] > or =0.99). The ICC for interrater reliability varied from 0.85 to 0.97. The ICC was low at 4 and 18 months CA. The AIMS is reliable in evaluating motor development in infants born preterm. Clinicians should be cautious about using the AIMS in infants at very young ages and those approaching independent ambulation. Accurate placement of the window on a movement repertoire is crucial. Attention is required when using the AIMS in infants developing atypically.


Bile duct malignancies.
Bile duct malignancies include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gall bladder carcinoma (GC) and carcinoma of Vater's ampulla (ampulloma). Bile duct neoplasms are rare tumours with overall poor prognosis. The overall incidence affects up to 12.5 per 100,000 persons in the Czech Republic. The mortality rate has risen recently to 9.5 per 100,000 persons. The incidence and mortality have been remarkably stable over the past 3 decades. The survival rate of patients with these tumours is poor, usually not exceeding 12 months. The diagnostic process is complex, uneasy and usually late. Most cases are diagnosed when unresectable, and palliative treatment is the main approach of medical care for these tumours. The treatment remains very challenging. New approaches have not brought much improvement in this field. Standards of palliative care are lacking and quality of life assessments are surprisingly not common. From the scarce data it seems, however, that multimodal individually tailored treatment can prolong patients'survival and improve the health-related quality of life. The care in specialized centres offers methods of surgery, interventional radiology, clinical oncology and high quality supportive care. These methods are discussed in the article in greater detail. Improvements in this field can be sought in new diagnostic methods and new procedures in surgery and interventional radiology. Understanding the tumour biology on the molecular level could shift the strategy to a more successful one, resulting in more cured patients. Further improvements in palliative care can be sought by defining new targets and new drug development. The lack of patients with bile duct neoplasms has been the limiting factor for any improvements. A new design of larger randomized international multicentric clinical trials with prompt data sharing could help to overcome this major problem. Defining standards of palliative care is a necessity. Addressing health-related quality of life could help to assess the real benefit of palliative treatment.


Arterial pulse wave velocity, Fourier pulsatility index, and blood lipid profiles.
Increased arterial pulse wave velocity (PWV) and decreased Doppler-shifted Fourier pulsatility index (PI) have been utilized clinically to diagnose the presence and severity of peripheral vascular disease. We have examined the relationships between these two diagnostic indices and several lipoprotein atherogenic risk factors, e.g., serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipo-protein-cholesterol (LDL-C) among 74 healthy male volunteers, aged 20 to 56 yr. The Doppler signal from the radial artery was digitized and processed with the Hamming window and 512-point fast Fourier transform to obtain frequency power spectra and PI index by a desktop computer. PWV was determined on the computer by dividing the distance between two pressure transducers placed over the radial and carotid arteries by the transit time difference between the maximal first derivatives (dP/dt) of the recorded arterial pulse waves. The results indicated that PI was inversely related to TC, LDL-C, and TG (r = -0.50, -0.41, -0.54, respectively, P less than 0.001), but evidenced a positive relationship with the HDL-C/TC ratio (r = 0.69, P less than 0.001). PWV was also significantly correlated to TC (r = 0.40) and TG (r = 0.42), but was inversely associated with the HDL-C/TC ratio (r = -0.45, P less than 0.001). These findings are consistent with the current theory relating lipids to the pathology of atherosclerosis.


An anion-conjugated polyelectrolyte designed for the selective and sensitive detection of silver(I).
A novel conjugated polyelectrolyte P1, having a meta-substituted monopyridyl in the backbone, is designed and synthesized for Ag(+) detection in aqueous solution. As a chemosensor, P1 shows high sensitivity, low detection limit, and excellent selectivity for Ag(+) over other metal ions. The sensing mechanism is based on the specific interaction between Ag(+) and the pyridyl group of P1. The aggregated state of the polymer in water can amplify its quenching efficiency.


Influence of insurance status and vaccine cost on physicians' administration of pneumococcal conjugate vaccine.
In 2000, heptavalent pneumococcal conjugate vaccine (PCV7) was recommended for children younger than 2 years, but its high cost relative to other universally recommended childhood immunizations and variability in insurance coverage for the vaccine raised concerns. We investigated the influence of PCV7 cost and insurance coverage on physician recommendation of PCV7 to their patients and administration of PCV7 in their practices. We conducted a mail survey from April to July 2001 of a random sample of 833 pediatricians and 788 family physicians in 24 states with different vaccine financing strategies (Vaccines for Children [VFC]-only; enhanced VFC; universal purchase). Physicians specified the proportion of children in their practice with insurance coverage for PCV7, where they recommend administering PCV7, and whether they have concerns about the cost of PCV7. The response rate was 60%. Overall, 87% of physicians recommend PCV7 for children younger than 2 years (99% pediatricians; 68% family physicians). Among physicians who recommend PCV7, 98% said that they would administer the vaccine in their own practices for children whose insurance covers the vaccine. However, only 56% of physicians who recommend PCV7 reported that all children in their practices had insurance coverage for the vaccine, whereas 24% of physicians reported 86% to 99% of children with coverage and 20% reported <or=85% of children with coverage. Among physicians in the last group with the lowest PCV7 insurance coverage rates in their practices, only 44% said that they would administer the vaccine in their own practices to children without PCV7 coverage, compared with 62% of physicians who provide care to children with higher rates of PCV7 coverage. Physicians in states with VFC-only vaccine financing strategies for PCV7 are less likely to administer PCV7 in their own practices to children without coverage than physicians in states with enhanced VFC and universal purchase strategies (48% vs 64% vs 74%). Almost one third of physicians who recommend PCV7 are concerned about the cost of PCV7; those with cost concerns are more likely to recommend that children without insurance coverage for PCV7 receive the vaccine at a public health clinic rather than in their own practices (45% vs 29%). Physicians with cost concerns are also more likely to say that they now screen children for insurance coverage more than for previously recommended vaccines (52% vs 21% for physicians without cost concerns). Nationwide, physician adoption of PCV7 recommendations is high, but where physicians recommend that PCV7 be administered differs significantly by children's variable insurance coverage for the vaccine and by state vaccine financing strategies. Physicians' concerns about the cost of PCV7 may foreshadow their responses to future children's vaccines that may be even more expensive.


Bone Material Properties in Bone Diseases Affecting Children.
Metabolic and genetic bone disorders affect not only bone mass but often also the bone material, including degree of mineralization, matrix organization, and lacunar porosity. The quality of juvenile bone is moreover highly influenced by skeletal growth. This review aims to provide a compact summary of the present knowledge on the complex interplay between bone modeling and remodeling during skeletal growth and to alert the reader to the complexity of bone tissue characteristics in children with bone disorders. We describe cellular events together with the characteristics of the different tissues and organic matrix organization (cartilage, woven and lamellar bone) occurring during linear growth. Subsequently, we present typical alterations thereof in disorders leading to over-mineralized bone matrix compared to those associated with low or normal mineral content based on bone biopsy studies. Growth spurts or growth retardation might amplify or mask disease-related alterations in bone material, which makes the interpretation of bone tissue findings in children complex and challenging.


Genome-wide reinforcement of cohesin binding at pre-existing cohesin sites in response to ionizing radiation in human cells.
The cohesin complex plays a central role in genome maintenance by regulation of chromosome segregation in mitosis and DNA damage response (DDR) in other phases of the cell cycle. The ATM/ATR phosphorylates SMC1 and SMC3, two core components of the cohesin complex to regulate checkpoint signaling and DNA repair. In this report, we show that the genome-wide binding of SMC1 and SMC3 after ionizing radiation (IR) is enhanced by reinforcing pre-existing cohesin binding sites in human cancer cells. We demonstrate that ATM and SMC3 phosphorylation at Ser(1083) regulate this process. We also demonstrate that acetylation of SMC3 at Lys(105) and Lys(106) is induced by IR and this induction depends on the acetyltransferase ESCO1 as well as the ATM/ATR kinases. Consistently, both ESCO1 and SMC3 acetylation are required for intra-S phase checkpoint and cellular survival after IR. Although both IR-induced acetylation and phosphorylation of SMC3 are under the control of ATM/ATR, the two forms of modification are independent of each other and both are required to promote reinforcement of SMC3 binding to cohesin sites. Thus, SMC3 modifications is a mechanism for genome-wide reinforcement of cohesin binding in response to DNA damage response in human cells and enhanced cohesion is a downstream event of DDR.


Emerging directions in the genetics of atrial fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.


Clinical aerosols II. Therapeutic aerosols.
The current uses of clinical aerosols such as water, saline, mucolytics, bronchodilators, cromolyn sodium, corticosteroids, and antimicrobials have been reviewed. The benefits of water, saline, and detergent aerosols continue to be surrounded by uncertainty and controversy. Aerosolized mucolytic and proteolytic agents have not been conclusively shown to be of substantial value in the improvement of respiratory disorders. Favorable bronchodilator therapy is achieved with aerosols of certain sympathomimetic and anticholinergic agents. However, successful therapy depends on the dose administered and the site of aerosol deposition in the lung. The prophylactic use of cromolyn sodium in patients with asthma is another useful application of aerosols. Topically active corticosteroid aerosols are increasingly being used since they may reduce risks of systemic effects from corticosteroids. Research on uncommonly aerosolized agents has widened the spectrum of therapeutic applications of aerosols.


Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life.
Repeated or prolonged early life exposure to anesthesia is neurotoxic in animals and associated with neurocognitive impairment in later life in humans. We used electron microscopy with unbiased stereological sampling to assess synaptic ultrastructure in dorsolateral prefrontal cortex (dlPFC) and hippocampal CA1 of female and male rhesus monkeys, four years after three 4-h exposures to sevoflurane during the first five postnatal weeks. This allowed us to ascertain long-term consequences of anesthesia exposure without confounding effects of surgery or illness. Synapse areas were reduced in the largest synapses in CA1 and dlPFC, predominantly in perforated spinous synapses in CA1 and nonperforated spinous synapses in dlPFC. Mitochondrial morphology and localization changed subtly in both areas. Synapse areas in CA1 correlated with response to a mild social stressor. Thus, exposure to anesthesia in infancy can cause long-term ultrastructural changes in primates, which may be substrates for long-term alterations in synaptic transmission and behavioral deficits.


TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic.
Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the TBC domain-containing protein, TBC1D14, as a negative regulator of autophagy that controls delivery of membranes from RAB11-positive recycling endosomes to forming autophagosomes. In this study, we identify the TRAPP complex, a multi-subunit tethering complex and GEF for RAB1, as an interactor of TBC1D14. TBC1D14 binds to the TRAPP complex via an N-terminal 103 amino acid region, and overexpression of this region inhibits both autophagy and secretory traffic. TRAPPC8, the mammalian orthologue of a yeast autophagy-specific TRAPP subunit, forms part of a mammalian TRAPPIII-like complex and both this complex and TBC1D14 are needed for RAB1 activation. TRAPPC8 modulates autophagy and secretory trafficking and is required for TBC1D14 to bind TRAPPIII. Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. We propose a model whereby TBC1D14 and TRAPPIII regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.


Tumor necrosis factor-alpha in a porcine bronchial model of obliterative bronchiolitis.
In posttransplant obliterative bronchiolitis (OB), the major pathologic features are inflammation, epithelial cell injury, fibrosis, and obliteration of the small airways. Tumor necrosis factor (TNF)-alpha is a cytokine known to mediate and augment the inflammatory reaction and to enhance fibroblast proliferation. We assessed the role of TNF-alpha in the development of OB in our heterotopic porcine bronchial transplantation model. Three groups were formed: autografts, nontreated allografts, and allografts treated with preoperative anti-TNF-alpha monoclonal antibody (infliximab) infusion. The implants were harvested on days 2, 4, 7, 11, 14, 21, and 28 for histologic and immunohistochemical analysis. TNF-alpha inhibition reduced inflammation, rate of epithelial loss, fibrosis, and obliteration early in the development of OB. In the epithelium, the numbers of TNF-alpha-positive epithelial and inflammatory cells and macrophages were significantly lower in treated than in nontreated allografts on day 4; furthermore, in the epithelium and in the bronchial wall, invasion of CD8+ lymphocytes was significantly decreased during the first week. These results indicate that TNF-alpha promotes the development of OB, and inhibition of TNF-alpha may prove beneficial in a clinical setting.


Geographic variation in advertisement calls in a tree frog species: gene flow and selection hypotheses.
In a species with a large distribution relative to its dispersal capacity, geographic variation in traits may be explained by gene flow, selection, or the combined effects of both. Studies of genetic diversity using neutral molecular markers show that patterns of isolation by distance (IBD) or barrier effect may be evident for geographic variation at the molecular level in amphibian species. However, selective factors such as habitat, predator, or interspecific interactions may be critical for geographic variation in sexual traits. We studied geographic variation in advertisement calls in the tree frog Hyla japonica to understand patterns of variation in these traits across Korea and provide clues about the underlying forces for variation. We recorded calls of H. japonica in three breeding seasons from 17 localities including localities in remote Jeju Island. Call characters analyzed were note repetition rate (NRR), note duration (ND), and dominant frequency (DF), along with snout-to-vent length. The findings of a barrier effect on DF and a longitudinal variation in NRR seemed to suggest that an open sea between the mainland and Jeju Island and mountain ranges dominated by the north-south Taebaek Mountains were related to geographic variation in call characters. Furthermore, there was a pattern of IBD in mitochondrial DNA sequences. However, no comparable pattern of IBD was found between geographic distance and call characters. We also failed to detect any effects of habitat or interspecific interaction on call characters. Geographic variations in call characters as well as mitochondrial DNA sequences were largely stratified by geographic factors such as distance and barriers in Korean populations of H. japonica. Although we did not detect effects of habitat or interspecific interaction, some other selective factors such as sexual selection might still be operating on call characters in conjunction with restricted gene flow.


On the mechanism of inhibition of cytochrome c oxidase by nitric oxide.
The mechanism of inhibition of cytochrome (cyt) c oxidase by nitric oxide (NO) has been investigated by stopped flow transient spectroscopy and singular value decomposition analysis. Following the time course of cyt c oxidation at different O2/NO ratios, we observed that the onset of inhibition: (i) is fast and at a high NO concentration is complete during the first turnover; (ii) is sensitive to the O2/NO ratio; and (iii) is independent of incubation time of the oxidized enzyme with NO. Analysis of the reaction kinetics and computer simulations support the conclusion that inhibition occurs via binding of NO to a turnover intermediate with a partially reduced cyt a3-CuB binuclear center. The inhibited enzyme has the optical spectrum typical of NO bound to reduced cyt a3. Reversal of inhibition in the presence of O2 does not involve a direct reaction of O2 with NO while bound at the binuclear center, since recovery of activity occurs at the rate of NO dissociation (k = 0.13 s-1), as determined in the absence of O2 using hemoglobin as a NO scavenger. We propose that removal of NO from the medium is associated with reactivation of the enzyme via a relatively fast thermal dissociation of NO from the reduced cyt a3-CuB center.


Robotic Pelvic Exenteration for Gynecologic Malignancies, Anatomic Landmarks, and Surgical Steps: A Systematic Review.
Pelvic exenteration represents the last resort procedure for patients with advanced primary or recurrent gynecological malignancy. Pelvic exenteration can be divided into different subgroup based on anatomical extension of the procedures. The growing application of the minimally invasive surgical approach unlocked new perspectives for gynecologic oncology surgery. Minimally invasive surgery may offer significant advantages in terms of perioperative outcomes. Since 2009, several Robotic Assisted Laparoscopic Pelvic Exenteration experiences have been described in literature. The advent of robotic surgery resulted in a new spur to the worldwide spread of minimally invasive pelvic exenteration. We present a review of the literature on robotic-assisted pelvic exenteration. The search was conducted using electronic databases from inception of each database through June 2021. 13 articles including 53 patients were included in this review. Anterior exenteration was pursued in 42 patients (79.2%), 2 patients underwent posterior exenteration (3.8%), while 9 patients (17%) were subjected to total exenteration. The most common urinary reconstruction was non-continent urinary diversion (90.2%). Among the 11 women who underwent to total or posterior exenteration, 8 (72.7%) received a terminal colostomy. Conversion to laparotomy was required in two cases due to intraoperative vascular injury. Complications' report was available for 51 patients. Fifteen Dindo Grade 2 complications occurred in 11 patients (21.6%), and 14 grade 3 complications were registered in 13 patients (25.5%). Only grade 4 complications were reported (2%). In 88% of women, the resection margins were negative. Pelvic exenteration represents a salvage procedure in patients with recurrent or persistent gynecological cancers often after radiotherapy. A careful patient selection remains the milestone of such a mutilating surgery. The introduction of the minimally invasive approach has led to advantages in terms of perioperative outcomes compared to classic open surgery. This review shows the feasibility of robotic pelvic exenteration. An important step forward should be to investigate the potential equivalence between robotic approaches and the laparotomic one, in terms of long-term oncological outcomes.


Results of the Putti-Platt operation for recurrent anterior dislocation of the shoulder.
Between 1973 and 1981, 101 patients had a Putti-Platt repair for recurrent dislocation of the shoulder; 89 of them were followed up and 43 underwent a clinical examination, 23 being assessed with the Cybex dynamometer. The 46 who did not attend were interviewed by telephone. The mean follow up time was 8 +/- 2 years (range 5-14 years). Redislocation occurred in 18 patients (20%), but this was twice as high in patients who were aged under 26 years at the time of operation compared with those who were older (29% versus 13%). The time of recurrence was between 1 and 11 years after operation. A decrease in strength and power of abduction, internal and external rotation, was found in the affected shoulder. Restriction of all measured movements, particularly external rotation, was also found in all patients. Nevertheless most had a high functional score and relatively few symptoms. We conclude that the Putti-Platt procedure has a high recurrence rate in younger patients, and we hesitate to recommend it for young active individuals.


Neuroinflammatory priming to stress is differentially regulated in male and female rats.
Exposure to stressors can enhance neuroinflammatory responses, and both stress and neuroinflammation are predisposing factors in the development of psychiatric disorders. Females suffer disproportionately more from several psychiatric disorders, yet stress-induced changes in neuroinflammation have primarily been studied in males. Here we tested whether exposure to inescapable tail shock sensitizes or 'primes' neuroinflammatory responses in male and female rats. At 24 h post-stress, male and female rats exposed to a peripheral immune challenge enhanced neuroinflammatory responses and exacerbated anxiety- and depressive-like behaviors. These changes are likely glucocorticoid dependent, as administering exogenous CORT, caused a similar primed inflammatory response in the hippocampus of male and female rats. Further, stress disinhibited anti-inflammatory signaling mechanisms (such as CD200R) in the hippocampus of male and female rats. In males, microglia are considered the likely cellular source mediating neuroinflammatory priming; stress increased cytokine expression in ex vivo male microglia. Conversely, microglia isolated from stressed or CORT treated females did not exhibit elevated cytokine responses. Microglia isolated from both stressed male and female rats reduced phagocytic activity; however, suggesting that microglia from both sexes experience stress-induced functional impairments. Finally, an immune challenge following either stress or CORT in females, but not males, increased peripheral inflammation (serum IL-1β). These novel data suggest that although males and females both enhance stress-induced neuroinflammatory and behavioral responses to an immune challenge, this priming may occur through distinct, sex-specific mechanisms.


Role of a care transition pharmacist in a primary care resource center.
The role of a care transition pharmacist (CTP) in a primary care resource center is described. A CTP role was implemented as part of a primary care resource center team to provide medication therapy management services for patients at high risk for readmission, including patients with chronic obstructive pulmonary disease, with heart failure, or with complex medication regimens and taking more than nine medications. Patients were initially identified upon admission and were seen by the CTP who conducted a medication therapy review, provided patient education, and ensured that any medication-related issues were addressed before discharge. In addition, the CTP followed up with patients by telephone within 72 hours of discharge. CTP interventions included reinforcement of the plan of care (67%), medication-related interventions in which specific issues were addressed (9%), contacting of the physician for treatment plan clarification or care gap (9%), reinforced scheduling of the primary care physician follow-up appointment (8%), and referral of the patient to another caregiver (6%). Patients who received postdischarge follow-up from the CTP were significantly less likely to have an acute care visit within 30 days of discharge compared with patients not contacted by the CTP and had improved Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores. Patients discharged from a community hospital who received a follow-up telephone call from a CTP were less likely to be admitted to the hospital or have an emergency department visit within 30 days of an acute care admission. HCAHPS patient satisfaction scores also improved in medication-related and discharge preparation question domains after CTP services were implemented.


Bone turnover in hyperparathyroidism.
A narrow serum calcium level which is essential for many metabolic processes is regulated by the calcium-sensing receptor which regulates parathyroid hormone (PTH) release. Primary hyperparathyroidism is supposed to be the third most common endocrine disorder. Besides nephrolithiasis and an increased incidence of cardiovascular symptoms it is associated with bone loss and an increased risk of fracture. Several different classical bone turnover markers have been shown to be increased. However, there are many uncertainties in pathophysiology of PHPT. Hardly any conclusive data exist on the RANK (receptor activator of nuclear factor-kB)/RANKL (receptor activator of nuclear factor-kB ligand)/OPG (osteoprotegerin) system, cathepsin K, sclerostin, FGF-23 (Fibroblast growth factor-23), Klotho, and DKK 1 (Dickkopf 1) in patients suffering from PHPT.


A qualitative study of barriers to consistent condom use among HIV-1 serodiscordant couples in Kenya.
This study explored barriers to consistent condom use among heterosexual HIV-1 serodiscordant couples who were aware of the HIV-1 serodiscordant status and had been informed about condom use as a risk reduction strategy. We conducted 28 in-depth interviews and 9 focus group discussions among purposively selected heterosexual HIV-1 serodiscordant couples from Thika and Nairobi districts in Kenya. We analyzed the transcribed data with a grounded theory approach. The most common barriers to consistent condom use included male partners' reluctance to use condoms regardless of HIV-1 status coupled with female partners' inability to negotiate condom use, misconceptions about HIV-1 serodiscordance, and desire for children. Specific areas of focus should include development of skills for women to effectively negotiate condom use, ongoing information on HIV-1 serodiscordance and education on safer conception practices that minimize risk of HIV-1 transmission.