Altered hematopoiesis in glypican-3-deficient mice results in decreased osteoclast differentiation and a delay in endochondral ossification.
Loss of function mutations in the gene encoding the heparan sulfate proteoglycan Glypican-3 (GPC3) causes an X-linked disorder in humans known as Simpson-Golabi-Behmel Syndrome (SGBS). This disorder includes both pre- and postnatal overgrowth, a predisposition to certain childhood cancers, and a complex assortment of congenital defects including skeletal abnormalities. In this study, we have identified a previously unrecognized delay in endochondral ossification associated with the loss of Gpc3 function. Gpc3 knockout animals show a marked reduction in calcified trabecular bone, and an abnormal persistence of hypertrophic chondrocytes at embryonic day 16.5 (E16.5). These hypertrophic chondrocytes down-regulate Type X collagen mRNA expression and undergo apoptosis, suggesting a normal progression of hypertrophic chondrocyte cell fate. However, replacement of these cells by mineralized bone is delayed in association with a marked delay in the appearance of osteoclasts in the bone in vivo. This delay in vivo correlates with a significant reduction in the capacity to form osteoclasts from bone marrow macrophage precursors in vitro in response to M-CSF and RANKL, and with a reduction in the numbers of bone-marrow-derived cells expressing the markers CD11b and Gr-1. Together, these results indicate selective impairment in the development of the common hematopoietic lineage from which monocyte/macrophages and PMNs are derived. This is the first report of a requirement for heparan sulfate, and specifically Gpc3, in the lineage-specific differentiation of these cell types in vivo.


Bimetallic C-C Bond-Forming Reductive Elimination from Nickel.
Ni-catalyzed cross-coupling reactions have found important applications in organic synthesis. The fundamental characterization of the key steps in cross-coupling reactions, including C-C bond-forming reductive elimination, represents a significant challenge. Bimolecular pathways were invoked in early proposals, but the experimental evidence was limited. We present the preparation of well-defined (pyridine-pyrrolyl)Ni monomethyl and monophenyl complexes that allow the direct observation of bimolecular reductive elimination to generate ethane and biphenyl, respectively. The sp(3)-sp(3) and sp(2)-sp(2) couplings proceed via two distinct pathways. Oxidants promote the fast formation of Ni(III) from (pyridine-pyrrolyl)Ni-methyl, which dimerizes to afford a bimetallic Ni(III) intermediate. Our data are most consistent with the subsequent methyl coupling from the bimetallic Ni(III) to generate ethane as the rate-determining step. In contrast, the formation of biphenyl is facilitated by the coordination of a bidentate donor ligand.


Serum deprivation induces a unique hypercontractile phenotype of cultured smooth muscle cells.
Chronic asthma is characterized by hypertrophy and hyperplasia of airway smooth muscle cells (SMC) that limit airflow by a geometric effect. Whether contractility of airway SMC is altered is not clear. Cultured cells were used as a model of hyperplasia. Phenotypic changes seen indicated conversion to a synthetic, weakly contractile type. At confluence, although limited reversal of protein changes was seen, no restoration in contractility occurred. Phenotypic modulation of postconfluent cultured airway SMC under prolonged serum deprivation (arrested cells) is reported here. Two phenotypically distinct groups of cells were identified in primary airway SMC cultures: 1) elongated spindle-shaped cells, which expressed large amounts of smooth muscle contractile and regulatory proteins, and 2) flat and stellate cells, which expressed very little. The first group showed a surprising shortening capacity and a velocity that was even greater than that of the freshly isolated cells, whereas the second group became spherical and noncontractile. Even more surprising was that the myosin heavy chain (MHC) isoform (SM-B) generally said to be associated with the higher shortening velocity disappeared from the cell, while the content of the key rate-limiting regulating enzyme, myosin light chain kinase (MLCK), increased 30-fold. We conclude that a functional, contractile phenotype of airway SMC can be obtained by prolonged serum deprivation. We speculate that the increased contractility could be the result of increased phosphorylation of the 20-kDa myosin light chain resulting from increased content of smooth muscle MLCK rather than any increase in endogenous MHC ATPase activity. This model may be useful for study of SMC differentiation and contraction.


CLINICAL TRIALS OF THE ABDOMINAL LEFT VENTRICULAR ASSIST DEVICE (ALVAD): PROGRESS REPORT.
An abdominal left ventricular assist device (ALVAD) is undergoing controlled clinical trials in our institution. The ALVAD is pneumatically-actuated, synchronously or asynchronously with an external console and is interposed between the apex of the left ventricle and the infrarenal abdominal aorta. It is an order of magnitude more effective than conventional intraaortic balloon pumping. Thus far, we have implanted this pump in 21 patients (15 males and six females). The average age has been 50. The duration of cardiopulmonary bypass with intensive pharmacologic support and IABP until ALVAD implantation has been nearly 4 hours. The plasma hemoglobins prior to ALVAD implantation have averaged 168 mg%. The platelet counts at implantation have averaged 68,000 mm(3). The average duration of ALVAD support has been in excess of one day and the longest trial extended for one week. We have been able to remove the pump after ventricular recovery in two instances and effected cardiac allografting in one instance of ALVAD dependency. We have found that (1) the profoundly depressed left (and right) ventricles can recover if totally supported with this device; (2) the device can function in the presence of ventricular fibrillation and/or standstill; (3) the device can effectively replace both left and right ventricular function in the presence of normal pulmonary vascular resistance and microcirculatory hemodynamics; and (4) in the presence of impending multiple organ failure, procrastination in use is to be avoided.


Hypercalcemia of malignancy.
Malignancy-associated hypercalcemia is a common and important clinical problem. Two major pathogenic mechanisms appear to be operative in this disorder: local osteolytic hypercalcemia and humoral hypercalcemia of malignancy. The clinical and biochemical features that distinguish these two processes are reviewed.


Clinical use and mechanisms of infliximab treatment on inflammatory bowel disease: a recent update.
The pathogenesis and treatment of inflammatory bowel disease (IBD) have been recently advanced, while it is still challenged with high morbidity and poor prognosis. Infliximab, a monoclonal antibody of tumor necrosis factor (TNF), has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and IBD patient life quality improvement. However, the biological effects of infliximab on IBD need to be elucidated. This paper reviewed the clinical use and recently advanced biological action of infliximab on IBD. By forming the stable complex with the soluble or the membrane form of TNF in fluid environment or on cell surface of immune cell, fibroblast, endothelium, and epithelium, infliximab quenches TNF activity and performs the important biological actions which lead to amelioration and remission of immune responses. The mechanisms of infliximab treatment for IBD were intensively discussed. The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed.


Immunological demonstration of protein kinase C mu in murine tissues and various cell lines. Differential recognition of phosphorylated forms and lack of down-regulation upon 12-O-tetradecanoylphorphol-13-acetate treatment of cells.
13 murine tissues and 12 cell lines were tested for the expression of the novel protein kinase C (PKC) isoenzyme mu. Using two different PKC mu antibodies (sc-639 and P26720), PKC mu was detected in all tissues and cells and thus proved to be an ubiquitous PKC isotype. However, in some tissues, PKC mu was recognized only by the antibody P26720 and not by sc-639. Thymus, lung and peripheral blood mononuclear cells expressed the greatest amount of PKC mu. Recognition of PKC mu by the antibody sc-639 was drastically impaired when treating keratinocytes or mouse skin in vivo with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), thus mimicking down-regulation of PKC mu. The lack of a decrease in the PKC mu amount and, thus, the lack of down-regulation could be proved using the antibody P26720. This antibody was able to recognize PKC mu in extracts of untreated as well as TPA-treated tissues or cells. Phosphorylation of proteins in a cell-free system (cell or tissue extracts) in the presence and absence of TPA or other PKC activators and various protein kinase inhibitors indicated that phosphorylation of activated PKC mu caused its reduced interaction with the antibody sc-639. Therefore, this antibody might present a well suited tool for the detection of activated PKC mu in vivo. Moreover, our results clearly show that some antibodies, such as sc-639, might be able to selectively detect non-phosphorylated or phosphorylated forms of a protein, and that such properties of an antibody have to be studied carefully before the latter can be used for reliable quantitative determination of this protein. We consider this information important to avoid misinterpretation of data concerning the immunological quantification of proteins such as PKC mu.


DimLift: Interactive Hierarchical Data Exploration Through Dimensional Bundling.
The identification of interesting patterns and relationships is essential to exploratory data analysis. This becomes increasingly difficult in high dimensional datasets. While dimensionality reduction techniques can be utilized to reduce the analysis space, these may unintentionally bury key dimensions within a larger grouping and obfuscate meaningful patterns. With this work we introduce DimLift, a novel visual analysis method for creating and interacting with dimensional bundles. Generated through an iterative dimensionality reduction or user-driven approach, dimensional bundles are expressive groups of dimensions that contribute similarly to the variance of a dataset. Interactive exploration and reconstruction methods via a layered parallel coordinates plot allow users to lift interesting and subtle relationships to the surface, even in complex scenarios of missing and mixed data types. We exemplify the power of this technique in an expert case study on clinical cohort data alongside two additional case examples from nutrition and ecology.


Approximating subcellular organisation of carbohydrate metabolism during cold acclimation in different natural accessions of Arabidopsis thaliana.
Accessions of Arabidopsis thaliana originating from climatically different habitats show different levels of cold acclimation when exposed to low temperatures. The central carbohydrate metabolism plays a crucial role during this acclimation. Subcellular distribution of carbohydrates over the compartments cytosol, vacuole and plastids, and putative interactions of the compartments, are analyzed in three differentially cold-tolerant accessions of Arabidopsis thaliana, originating from the Iberian Peninsula (C24), Russia (Rschew) and Scandinavia (Tenela), respectively. Subcellular carbohydrate concentrations were determined by applying the nonaqueous fractionation technique. Mathematical modeling and steady-state simulation was used to analyse the metabolic homeostasis during cold exposure. In all accessions, the initial response to cold exposure was a significant increase of plastidial and cytosolic sucrose concentrations. Raffinose accumulated in all cellular compartments of cold-tolerant accessions with a delay of 3 d, indicating that raffinose accumulation is a long-term component of cold acclimation. Minimal rates of metabolite transport permitting steady-state simulations of metabolite concentrations correlated with cold tolerance, indicating an important role of subcellular re-distribution of metabolites during cold acclimation. A highly regulated interplay of enzymatic reactions and intracellular transport processes appears to be a prerequisite for maintaining carbohydrate homeostasis during cold exposure and allowing cold acclimation in Arabidopsis thaliana.


Combination of canstatin and arsenic trioxide suppresses the development of hepatocellular carcinoma.
Complication of arsenic trioxide (ATO) and other drugs in cancer treatment has attracted much focus, but is limitedly investigated in hepatocellular carcinoma (HCC). This study aimed to explore the role of ATO combined with canstatin in HCC. HepG2 cells were treated with different concentrations of ATO with or without canstatin, CCK-8, flow cytometry, Transwell assays were conducted to determine cell proliferation, apoptosis, adhesion, migration, and invasion abilities. Besides, the protein expression or mRNA level of caspase-3, PCNA, and MMP-2 was measured using western blotting or qRT-PCR. BALB/c-nu/nu mice were used to establish nude mouse transplantation tumor model, and received ATO or canstatin treatment for 3 weeks. The results showed that ATO inhibited cell proliferation, adhesion, migration and invasion, and promoted cell apoptosis with a concentration-dependent way. Canstatin had a significantly inhibitory effect on cell proliferation, but had limited effects on the other cellular behaviors. Besides, combination with ATO and canstatin strengthened the effects of ATO alone on cell proliferation inhibition and cell apoptosis promotion. Moreover, both of ATO and canstatin increased the protein expression of caspase-3, while decreased PCNA and MMP-2, which was further strengthened upon their combination. Furthermore, both of ATO and canstatin inhibited tumor growth in vivo, which was also strengthened upon their combination. Collectively, we found that combined canstatin and ATO significantly inhibited cell proliferation, migration and adhesion abilities, and promoted cell apoptosis, and inhibited tumor growth, thus suppressed the progression of HCC.


Are Gap and Cast Indices Predictors of Efficacy of Reduction in Fractures of Both Bones of the Leg? A Cohort Study.
Introduction: Non-operative management has successfully been practised for long in diaphyseal fractures of both bones of the leg. This study attempts to establish an acceptability criteria for plaster cast in order to predict future loss of reduction and its adequacy. Materials and Methods: A total of forty subjects were included as per inclusion-exclusion criteria. Gap and cast indices were calculated in the immediate post reduction phase and at third week follow-up visit. Results: The mean values of gap and cast indices in the immediate post-reduction phase were 0.35±0.220 and 0.99±0.08 respectively and at the third week follow-up the mean value for both the parameters in those without loss of reduction were 1.11±0.50 and 1.03±0.09 respectively and in those with loss of reduction were 0.84±0.44 and 1.01±0.06 respectively. Conclusion: Gap and cast indices are not informative in assessing adequacy of reduction in diaphyseal fractures of both bones of the leg.


One year follow-up after operative ankle fractures: a prospective gait analysis study with a multi-segment foot model.
Ankle fractures are one of the most common lower limb traumas. Several studies reported short- and long-term post-operative results, mainly determined by radiographic and subjective functional evaluations. Three-dimensional gait analysis with a multi-segment foot model was used in the current study to quantify the inter-segment foot motions in 18 patients 1 year after surgically treated ankle fractures. Data were compared to that from gender- and age-matched healthy controls. The correlations between Olerud/Molander ankle score and kinematics were also evaluated. Patients with ankle fractures showed less plantarflexion and smaller range of motion in the injured talocrural joint, which were believed to be a sign of residual joint stiffness after surgery and immobilization. Moreover, the forefoot segment had smaller sagittal and transverse ranges of motion, less plantarflexion and the hallux segment had less dorsiflexion and smaller sagittal range of motion. The deviations found in the forefoot segment may contribute to the compensation mechanisms of the injured ankle joint. Findings of our study show that gait analysis with a multi-segment foot model provides a quantitative and objective way to perform the dynamic assessment of post-operative ankle fractures, and makes it possible to better understand not only how the injured joint is affected, but also the surrounding joints.


A profile of nurses who requested the removal of their names from the SAINC's registers during 1996. South African Interim Nursing Council.
Annually a number of nurses request to have their names removed from the registers and rolls of the South African Nursing Council (SANC-currently called the South African Interim Nursing Council or SAINC). Having their names removed from the SAINC's registers/rolls implies that they cannot practise their nursing profession. A total of 1,139 persons requested the removal of their names from SAINC's registers and roles at the beginning of 1996 (statistics supplied by SAINC). Name and address stickers were obtained for all persons who requested the removal of their names from SAINC's registers/rolls. A total of 71 persons supplied permanent addresses in foreign countries and were excluded from the study. The research population consisted of 1,068 persons, from which 20%, or 214 persons, was selected using a table of random numbers to comprise the research sample. Questionnaires, based on literature studies, and on previous studies undertaken by the researcher, were posted to 214 persons. The first part of the questionnaire requested autobiographic information, including the respondents' ages, marital status, qualifications and involvement in further studies. Other sections of the questionnaire endeavoured to obtain information about the reasons why the respondents requested the removal of their names from SAINC's registers and thus by implication why they left nursing; under what conditions they would consider re-entering the nursing profession; and whether they considered doing a re-entry course. Although this research could be regarded as being an exploratory descriptive survey, the research results do provide information which nurse researchers, educators and managers can use.


Predictors of idiopathic pulmonary fibrosis in absence of radiologic honeycombing: A cross sectional analysis in ILD patients undergoing lung tissue sampling.
Idiopathic pulmonary fibrosis (IPF) can be diagnosed confidently and non-invasively when clinical and computed tomography (CT) criteria are met. Many do not meet these criteria due to absence of CT honeycombing. We investigated predictors of IPF and combinations allowing accurate diagnosis in individuals without honeycombing. We utilized prospectively collected clinical and CT data from patients enrolled in the Lung Tissue Research Consortium. Included patients had no honeycombing, no connective tissue disease, underwent diagnostic lung biopsy, and had CT pattern consistent with fibrosing ILD (n = 200). Logistic regression identified clinical and CT variables predictive of IPF. The probability of IPF was assessed at various cut-points of important clinical and CT variables. A multivariable model adjusted for age and gender found increasingly extensive reticular densities (OR 2.93, CI 95% 1.55-5.56, p = 0.001) predicted IPF, while increasing ground glass densities predicted a diagnosis other than IPF (OR 0.55, CI 95% 0.34-0.89, p = 0.02). The model-based probability of IPF was 80% or greater in patients with age at least 60 years and extent of reticular density one-third or more of total lung volume; for patients meeting or exceeding these clinical thresholds the specificity for IPF is 96% (CI 95% 91-100%) with 21 of 134 (16%) biopsies avoided. In patients with suspected fibrotic ILD and absence of CT honeycombing, extent of reticular and ground glass densities predict a diagnosis of IPF. The probability of IPF exceeds 80% in subjects over age 60 years with one-third of total lung having reticular densities.


Effects of Static and Dynamic Stretching on the Isokinetic Peak Torques and Electromyographic Activities of the Antagonist Muscles.
The aim of this study was to investigate if static and dynamic stretching exercises of the knee muscles (quadriceps and hamstring muscles) have any effects on concentric and eccentric isokinetic peak torques and electromyographic amplitudes (EMG) of the antagonist muscles. Twenty healthy male athletes (age between 18-30 years) voluntarily participated in this study. All of the subjects visited the laboratory to complete the following intervention in a randomized order on 5 separate days; (a) non-stretching (control), (b) static stretching of the quadriceps muscles, (c) static stretching of the hamstring muscles, (d) dynamic stretching of the quadriceps muscles, and (e) dynamic stretching of the hamstring muscles. Static stretching exercises either for the quadriceps or the hamstring muscles were carried out at the standing and sitting positions. Subjects performed four successive repetitions of each stretching exercises for 30 seconds in both stretching positions. Similar to static stretching exercises two different stretching modes were designed for dynamic stretching exercises. Concentric and eccentric isokinetic peak torque for the non-stretched antagonist quadriceps or hamstring muscles at angular velocities of 60°/sec and 240°/sec and their concurrent electromyographic (EMG) activities were measured before and immediately after the intervention. Isokinetic peak torques of the non-stretched agonist hamstring and quadriceps muscles did not represent any significant (p > 0.05) differences following static and dynamic stretching of the antagonist quadriceps and hamstring muscles, respectively. Similarly, the EMG activities of the agonist muscles exhibited no significant alterations (p > 0.05) following both stretching exercises of the antagonist muscles. According to the results of the present study it is possible to state that antagonist stretching exercises either in the static or dynamic modes do not affect the isokinetic peak torques and the EMG activities of the non-stretched agonist quadriceps or hamstring muscles.


A comprehensively validated IVRT method reliably discriminates sameness and differences between several topical clotrimazole creams.
In vitro release testing (IVRT) has gained increasing acceptance for use as a biowaiver for topical products intended for local action. Whereas the United States Food and Drug Administration (US FDA) has issued product specific guidances (PSGs) recommending IVRT for several products, the PSG for clotrimazole cream does not include an IVRT option. However, an important requirement to include supplemental selectivity in the validation process as described in the recent FDA draft guidance on IVRT studies for topical drug products has generally been conspicuously absent in the published literature describing the application of IVRT as a biowaiver. Supplemental selectivity involves the comparison of a reference product and altered formulations containing the same strength of the active pharmaceutical ingredient (API). In order to demonstrate supplemental selectivity, cream formulation containing the same API (clotrimazole), at the same strength (1 %) and in the same dosage form (cream) but manufactured using different excipients were used. This will help assess the impact that excipients may have on the release rate of clotrimazole and whether the method is capable of identifying differences in the microstructure and arrangement of matter (Q3) as an important performance parameter. In addition, products containing <30 % or >40 % clotrimazole to serve as negative controls were also included for the discriminatory power assessment. Hence, the primary objective was to develop and validate a simple, reliable, reproducible, and cost-effective in vitro technique in accordance with the recent draft FDA guidance to assess the "sameness" of topical creams containing 1 % clotrimazole. An in vitro release testing (IVRT) system was used and an IVRT method was developed and accordingly validated. The validated IVRT method showed the potential to accurately measure the release from 1 % clotrimazole creams and demonstrated supplemental selectivity and appropriate discriminatory power to identify "sameness" and/ or differences.


Opto-electronic feedback control of membrane potential for real-time control of action potentials.
To unlock new research possibilities by acquiring control of action potential (AP) morphologies in excitable cells, we developed an opto-electronic feedback loop-based system integrating cellular electrophysiology, real-time computing, and optogenetic approaches and applied it to monolayers of heart muscle cells. This allowed accurate restoration and preservation of cardiac AP morphologies in the presence of electrical perturbations of different origin in an unsupervised, self-regulatory manner, without any prior knowledge of the disturbance. Moreover, arbitrary AP waveforms could be enforced onto these cells. Collectively, these results set the stage for the refinement and application of opto-electronic control systems to enable in-depth investigation into the regulatory role of membrane potential in health and disease.


A randomized controlled trial comparing traditional training in cardiopulmonary resuscitation (CPR) to self-directed CPR learning in first year medical students: The two-person CPR study.
The primary purpose of this study was to compare two, shorter, self-directed methods of cardiopulmonary resuscitation (CPR) education for healthcare professionals (HCP) to traditional training with a focus on the trainee's ability to perform two-person CPR. First-year medical students with either no prior CPR for HCP experience or prior training greater than 5 years were randomized to complete one of three courses: 1) HeartCode BLS System, 2) BLS Anytime, or 3) Traditional training. Only data from the adult CPR skills testing station was reviewed via video recording by certified CPR instructors and the Laerdal PC Skill Reporter software program (Laerdal Medical, Stavanger, Norway). There were 180 first-year medical students who met inclusion criteria: 68 were HeartCode BLS System, 53 BLS Anytime group, and 59 traditional group Regarding two-person CPR, 57 (84%) of Heartcode BLS students and 43 (81%) of BLS Anytime students were able to initiate the switch compared to 39 (66%) of traditional course students (p = 0.04). There were no significant differences in the quality of chest compressions or ventilations between the three groups. There was a trend for a much higher CPR skills testing pass rate for the traditional course students. However, failure to "clear to analyze or shock" while using the AED was the most common reason for failure in all groups. The self-directed learning groups not only had a high level of success in initiating the "switch" to two-person CPR, but were not significantly different from students who completed traditional training.


Systemic sarcoidosis presenting as a rare combination of interstitial nephritis with necrotizing vasculitis and urinary retention due to prostate involvement: a case report.
Sarcoidosis affects multiple organs and exhibits diverse clinical manifestations. Although tubulointerstitial nephritis is a known feature of renal involvement, necrotizing vasculitis is rare. Furthermore, prostate involvement with urinary retention is unusual in patients with sarcoidosis. Here, we report a case of systemic sarcoidosis with a rare combination of manifestations and different acute kidney injuries. A 66-year-old man developed sudden urinary retention and fever. He was diagnosed with prostatitis and admitted to our hospital. An indwelling urethral catheter was inserted, and antimicrobial therapy was initiated; however, the prostatitis was refractory. Computed tomography revealed enlarged mediastinal lymph nodes. Analysis of transbronchoscopic lymph node and prostate biopsies showed epithelioid cell granulomas, suggesting systemic sarcoidosis. During the clinical course, the serum creatinine level rapidly increased to 2.36 mg/dL without oliguria. A kidney biopsy revealed tubulointerstitial injury with moderate lymphohistiocytic infiltration and small-vessel vasculitis in the interstitium. Following oral administration of 60 mg/day prednisolone, the patient's renal function immediately improved, and urinary retention did not recur. To the best of our knowledge, this is the first reported case of sarcoidosis with two unusual complications. Given its clinical course and pathology, this case is clinically valuable.


Laparoscopic testicular denervation for chronic orchalgia.
No specific cause is identified in most cases of chronic orchialgia. Nonsurgical therapies, including management at a chronic pain clinic, are generally recommended. Only when multiple conservative measures fail are patients offered surgical intervention, such as orchiectomy. We evaluate laparoscopic testicular denervation as an organ preserving and minimally invasive surgical alternative. Since 1993, 9 patients with chronic orchialgia have undergone transperitoneal laparoscopic testicular denervation after nonsurgical modalities failed. Using 1, 10 mm. and 1 or 2, 5 mm. ports, the gonadal vessels were isolated circumferentially and divided cephalad to the vas deferens and its vasculature. Preoperative treatment modalities, morbidity and outcome were documented. A cord block provided temporary relief in all 9 patients. Analog scales were used to assess long-term pain relief (0 no pain to 100 worst pain) and activity levels (0 bedrest to 100 no restrictions). Average symptom duration before laparoscopic testicular denervation was 4.1 years. Of 9 patients 8 had undergone prior scrotal surgery. Failed nonsurgical modalities included anti-inflammatory drugs in 7 patients, antibiotics in 6, pain clinic consultations in 4 and antidepressant medications in 2. Mean pain score decreased from 69.4 (range 35 to 90) preoperatively to 30.6 at a mean followup of 25.1 months. Excluding the 2 cases that had no pain relief (less than 10-point reduction), average pain score decreased from 69 to 19 postoperatively (mean reduction 71%). Activity levels improved in all cases. There were no significant complications, including testis atrophy. One patient who had no pain relief underwent subsequent hydrocelectomy for pain, which also failed. Laparoscopic testicular denervation can provide significant long-term pain relief and appears to be a reasonable alternative in select cases with chronic orchialgia refractory to medical therapy. Larger series and prospective evaluations are necessary.


Traumatic Microbleeds in the Hippocampus and Corpus Callosum Predict Duration of Posttraumatic Amnesia.
Radiologic predictors of posttraumatic amnesia (PTA) duration are lacking. We hypothesized that the number and distribution of traumatic microbleeds (TMBs) detected by gradient recalled echo (GRE) magnetic resonance imaging (MRI) predicts PTA duration. Academic, tertiary medical center. Adults with traumatic brain injury (TBI). We identified 65 TBI patients with acute GRE MRI. PTA duration was determined with the Galveston Orientation and Amnesia Test, Orientation Log, or chart review. TMBs were identified within memory regions (hippocampus, corpus callosum, fornix, thalamus, and temporal lobe) and control regions (internal capsule and global). Regression tree analysis was performed to identify radiologic predictors of PTA duration, controlling for clinical PTA predictors. TMB distribution, PTA duration. Sixteen patients (25%) had complicated mild, 4 (6%) had moderate, and 45 (69%) had severe TBI. Median PTA duration was 43 days (range, 0-240 days). In univariate analysis, PTA duration correlated with TMBs in the corpus callosum (R = 0.29, P = .02) and admission Glasgow Coma Scale (GCS) score (R = -0.34, P = .01). In multivariate regression analysis, admission GCS score was the only significant contributor to PTA duration. However, in regression tree analysis, hippocampal TMBs, callosal TMBs, age, and admission GCS score explained 26% of PTA duration variance and distinguished a subgroup with prolonged PTA. Hippocampal and callosal TMBs are potential radiologic predictors of PTA duration.


Depolarization reverses age-related decrease of spontaneous transmitter release.
The effect of increasing extracellular Ca concentration on spontaneous transmitter release was studied at soleus nerve terminals of young (10 mo) and old (24 mo) C57BL/6J mice depolarized by high extracellular K concentration ([K]o). By using intracellular recording, miniature end-plate potentials (MEPPs) were first recorded in a normal [K]o Krebs solution. Subsequently, MEPPs were recorded in high [K]o Krebs solutions with four different Ca concentrations: Ca-free/ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and 0.5, 1.5, and 2.5 mM Ca. In both the normal [K]o Krebs and the Ca-free-high [K]o Krebs solutions, MEPP frequency was lower at old than at young nerve terminals. In the three high [K]o Krebs solutions with Ca, MEPP frequency was progressively higher at old than at young nerve terminals with higher Ca concentrations. Periodic oscillations were observed in MEPP frequency of depolarized nerve terminals. The period of oscillation was inversely proportional to spontaneous transmitter release. These results demonstrate that when the nerve terminal is depolarized, permeability of the terminal membrane to Ca increases because of opening of voltage-dependent Ca channels. In the present study resting MEPP frequency was lower at old than at young terminals. On depolarization, MEPP frequency became higher at old than at young terminals. The study demonstrates that voltage-dependent Ca entry increases during aging at the soleus nerve terminal.


Declining Prevalence of Methicillin-Resistant Staphylococcus aureus Septic Arthritis and Osteomyelitis in Children: Implications for Treatment.
This study sought to assess clinical characteristics and differences in outcomes between children with Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA) osteomyelitis or septic arthritis and whether initial antibiotic regimen affects patient outcomes. We analyzed records of children ages 15 days to 18 years admitted between 2009 and 2016 to two tertiary children's hospitals who were diagnosed with an osteoarticular infection and had a microorganism identified. A total of 584 patients met inclusion criteria, of which 365 (62.5%) had a microbiological diagnosis. MSSA was the most common pathogen identified (45.5%), followed by MRSA (31.2%). Compared to MSSA, patients with MRSA had a higher initial C-reactive protein and longer hospitalization. Patients whose initial antibiotic regimens included vancomycin had a longer hospitalization than those initiated on clindamycin without vancomycin, even after removing sicker patients admitted to the pediatric intensive care unit. While MRSA was associated with increased severity of osteoarticular infections compared to MSSA, the incidence of MRSA has been declining at our institution. Patients with longer lengths of stay were more likely to be on vancomycin. Clindamycin should be considered in the initial antibiotic regimen for osteomyelitis and septic arthritis with ongoing surveillance of local microbiology and outcomes.


Sex differences in the perpetrator-victim relationship among emergency department patients presenting with nonfatal firearm-related injuries.
I examine whether female and male emergency department (ED) patients are equally likely to have been nonfatally shot or struck with a gun by someone they know versus by a stranger. This case-control study examined patient records from US hospital EDs from 1993 to 1999. The records of patients aged 15 years or older who presented with nonfatal firearm-related injuries were accessed from the National Electronic Injury Surveillance System. Patients were classified according to 2 firearm-related injury types (penetrating or nonpenetrating [eg, struck with gun] trauma) and 5 perpetrator types (injury inflicted by spouse or ex-spouse, other relative, friend or acquaintance, self, or stranger). Compared with male patients, female patients were 3.6 times (95% confidence interval [CI] 2.5 to 5.3) more likely to have been shot and 3.9 times (95% CI 1.6 to 9.4) more likely to have been struck with a gun wielded by a spouse or ex-spouse than by a stranger. Conversely, women were considerably less likely than men to have been struck with a gun or shot by another relative, to have been struck with a gun by a friend or acquaintance, or to have a gunshot injury that was self-inflicted. The cause of firearm-related injuries varies by sex. Before releasing firearm-injury victims from the ED, health care providers should consider 2 important factors: (1). the patient's relationship to the perpetrator, and (2). the availability and previous use of firearms in the victim's home. This information may be helpful in formulating posttreatment plans to enhance the victim's safety.


Evaluation of Mycobacterium leprae immunogenicity via adoptive transfer studies.
The immune response of mice to live, heat-killed, or autoclaved Mycobacterium leprae was investigated. After sensitization with 10(7) organisms in each group, recipient mice were transfused with the sensitized splenocytes 28 days later. A selected number of these mice were infected with 5 X 10(3) M. leprae, and the remaining animals were sacrificed at scheduled intervals for evidence of cell-mediated immunity to the M. leprae cell extract. Data from these and the bacteriological assays showed that all three materials induce cell-mediated immunity and also extend protection against the M. leprae challenge but not against a Listeria monocytogenes challenge. Adoptive immunity against M. leprae was expressed equally effectively in both non-irradiated animals and those sublethally (500 R) irradiated. This study reveals that, after adoptive transfer of immunity, a bacillary restriction occurs with concomitant onset of delayed hypersensitivity and that the protection observed could be specifically directed against an M. leprae challenge.


Ground truth hardware phantoms for validation of diffusion-weighted MRI applications.
To quantitatively validate diffusion-weighted MRI (DW-MRI) applications, a hardware phantom containing crossing fibers at a sub-voxel level is presented. It is suitable for validation of a large spectrum of DW-MRI applications from acquisition to fiber tracking, which is an important recurrent issue in the field. Phantom properties were optimized to resemble properties of human white matter in terms of anisotropy, fractional anisotropy, and T(2). Sub-voxel crossings were constructed at angles of 30, 50, and 65 degrees, by wrapping polyester fibers, with a diameter close to axon diameter, into heat shrink tubes. We show our phantoms are suitable for the acquisition of DW-MRI data using a clinical protocol. The phantoms can be used to successfully estimate both the diffusion tensor and non-Gaussian diffusion models, and perform streamline fiber tracking. DOT (Diffusion Orientation Transform) and q-ball reconstruction of the diffusion profiles acquired at b = 3000 s/mm(2) and 132 diffusion directions reveal multimodal diffusion profiles in voxels containing crossing yarn strands. The highly purpose adaptable phantoms provide a DW-MRI validation platform: applications include optimisation of acquisition schemes, validation of non-Gaussian diffusion models, comparison and validation of fiber tracking algorithms, and quality control in multi-center DWI studies.


Development of a clinical severity index for dogs with acute pancreatitis.
To establish a clinical severity index that correlates severity of body system abnormalities with outcome in dogs with acute pancreatitis (AP) and determine the usefulness of serum C-reactive protein (C-RP) concentration as an objective measure of AP severity. Retrospective cohort study. 61 client-owned dogs with ultrasonographically or histologically confirmed AP. Medical records of AP-affected dogs were reviewed, and signalment, physical examination findings, clinicopathologic data, and outcome (death or discharge from the hospital) were evaluated. The correlation of specific abnormalities in endocrine, hepatic, renal, hematopoietic, cardiovascular, and respiratory systems; local pancreatic complications; and intestinal integrity were evaluated, and a clinical severity index was developed for AP in dogs. The severity index score was compared with outcome and, for 12 dogs, with serum C-RP concentration. The clinical severity index had a good correlation with outcome and interval from hospital admission until end point (days until outcome), but there was no difference in days until outcome between survivors and nonsurvivors. All 12 dogs evaluated had high serum C-RP concentration, but this variable was not related to outcome; however, within a 2-day period after onset of clinical signs, serum C-RP concentration in survivors and nonsurvivors differed significantly. Among AP-affected dogs, the clinical severity index may be useful for treatment comparisons and prediction of intensive management requirements. Serum C-RP concentration was best related to AP severity within a 2-day period after onset of clinical signs, but daily measurement may be more useful for monitoring progress.


UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme.
Ubiquitin-dependent proteolysis by the 26S proteasome plays a pivotal role in cell cycle progression as well as in tumorigenesis. In this pathway, ubiquitin-conjugating enzyme (E2), together with ubiquitin ligase (E3), transfers ubiquitin to the specific substrate protein(s); however, little is known about the potential contribution of E2 to tumorigenesis. In this study, we examined the expression levels of 17 E2 genes in 25 different human normal tissues and 24 human cancerous cell lines by using a quantitative real-time reverse transcription-PCR. Among the E2 gene family, the expression level of UbcH10 was extremely low in many of the normal tissues but prominent in the majority of cancerous cell lines. Intriguingly, UbcH10 was expressed at high levels in primary tumors derived from the lung, stomach, uterus, and bladder as compared with their corresponding normal tissues, suggesting that UbcH10 is involved in tumorigenesis or progression of the tumor. To further investigate a possible contribution of UbcH10 to malignant transformation and tumor cell proliferation, NIH3T3 cells were transfected with the expression plasmid encoding UbcH10, and stable transfectants were subsequently established. UbcH10-overexpressing cells exhibited an increased incorporation of bromodeoxyuridine, an enhanced growth rate, an increase in saturation density, and a promotion of colony formation in soft agar medium as compared with parental NIH3T3 cells and the control transfectants. Collectively, our present results provide the first evidence that UbcH10 is highly expressed in various human primary tumors and that UbcH10 has an ability to promote cell growth and malignant transformation.


Some clinical aspects of superficial temporal-middle cerebral artery bypass surgery.
Carotid occlusive disease may occur at the base of the skull and siphon without evidence of atheroma in the neck. Careful search for lesions in this location should be undertaken in any patients with TIAs or neurologic deficit when the extracranial carotid arteries appear normal. Unilateral frontotemporal headache may be an early symptom of stenosis in this location. Inaccessible lesions are often bilateral, although the symptoms may be unilateral. Superficial temporal-middle cerebral artery bypass on the symptomatic side affords relief of symptoms. Bypass on the contralateral side should be considered when and if symptoms subsequently develop related to the lesion on that side. The configuration of a carotid thrombus may enable one to determine that it is a retrograde rather than antegrade occlusion and hence is not amenable to endarterectomy, even in the acute situation. The use of a Fogarty catheter in such a setting would be ill-advised and potentially hazardous. Current experience suggests that risk of subsequent stroke is reduced after EC-IC bypass operation.


Ultrastructure of gonococci in acute, chronic, and asymptomatic gonorrhoea.
The authors have made an electron microscope study of material from patients with acute, chronic, and asymptomatic gonorrhoea both before and during treatment with penicillin and kanamycin. Some features of the structure of the gonococcus, e.g. the six-layered cell wall, and of the reactions of the organism in different forms of gonorrhoeae before and during treatment with antibiotics were demonstrated using Ruthenium red staining. Thus, in chronic gonorrhoea, the presence of structures similar to gonococcal L-forms was found to be characteristic, while in asymptomatic gonorrhoea the formation was observed of multimembrane phagosomes hampering the penetration of drugs and antibodies. The positioning of gonococci round epithelial cells was noted (cellular energy). The possibility of changing treatment procedures is examined in the light of these observations.


Event-Specific Emotional Expression of Persons Living With Dementia in Long-term Care: A 6 Months Follow-up Study.
This longitudinal study aimed to explore the event-specific emotional expressions of persons living with dementia in long-term care during a 6-month period with repeated observations. Emotional expressions at three specific events (mealtime, personal care, and social activity) were videotaped at the beginning, month 3, and month 6. Thirty participants were enrolled, and nine observations were made for each participant. Mixed-effect models were used for statistical analysis. The type of care events, the person who provides care, and the facility type were associated with emotional expressions. Specifically, personal care, interaction with non-nursing providers, and facility type were associated with positive emotional expressions. Negative emotional expressions were related to personal care, interaction with family or volunteer, and facility type. This study provides a better understanding of event-specific emotional expressions and knowledge to support the development of emotion-oriented intervention programs to improve the psychological well-being of persons living with dementia.


[Experimental analysis and planning using the Salmonella/microsomes test].
A possible statistical treatment of the results obtained in Salmonella typhimurium TA1950, TA1535, TA1537, TA1538, TA98 and TA100 using the Salmonella/microsomes test was investigated. An analysis of independent repeated experiments pointed to the divergence of the data obtained. Consequently, it has been recommended to carry out the statistical treatment of experimental data within the limits of dispersion analysis with the subsequent use of the Scheffe's method for multiple comparisons. To stabilize the dispersion of experimental data, it is suggested to express the number of revertant colonies as lnX. A minimal volume of the data sample needed for resolving experimental tasks has been calculated. In standard experiments aimed at revealing the mutagenic activity of the compounds used, three Petri dishes should be used in each variant of experiments.


A paramagnetic chemical exchange-based MRI probe metabolized by cathepsin D: design, synthesis and cellular uptake studies.
Overexpression of the aspartyl protease cathepsin D is associated with certain cancers and Alzheimer's disease; thus, it is a potentially useful imaging biomarker for disease. A dual fluorescence/MRI probe for the potential detection of localized cathepsin D activity has been synthesized. The probe design includes both MRI and optical reporter groups connected to a cell penetrating peptide by a cathepsin D cleavable sequence. This design results in the selective intracellular deposition (determined fluorimetrically) of the MRI and optical reporter groups in the presence of overexpressed cathepsin D. The probe also provided clearly detectable in vitro MRI contrast by the mechanism of paramagnetic chemical exchange effects (OPARACHEE).


Analysis of False-negative Findings of the Incomparable Accuracy and Swiftness of Flow Cytometric Diagnosis of Primary Central Nervous System Lymphoma.
Primary central nervous system lymphoma (PCNSL), a relatively rare brain tumor, bears a dire prognosis. On occasion, the rapid progression of the tumor makes immediate diagnosis and initiation of therapy imperative. To achieve swift diagnosis, we adopt flow cytometry (FCM) in addition to conventional histopathology. This study aimed to reveal the utility of FCM diagnosis for PCNSL and the cause of false-negative results of FCM diagnosis. We investigated 33 patients with suspected PCNSL on neuroradiological findings and received both FCM and histological diagnosis. The patients' electronic medical records were investigated, and histological findings, results of FCM, and other clinical data were evaluated. Overall, 27 patients (14 males and 13 females) were diagnosed with PCNSL by histological confirmation. The median age at diagnosis was 68 years. FCM analysis showed lymphoma pattern in 24 cases; however, FCM results did not show lymphoma pattern (sensitivity: 88.9%, specificity: 100%) in the other three lymphoma cases (FCM discordant: FCM-D) and six nonlymphomatous tumor cases. Analysis of FCM-D cases showed the infiltration of T lymphocytes or astrocytes into the tumor tissue, indicating tumor microenvironmental reaction; it is assumed that these reactions deceived FCM diagnosis. The survival of FCM-D patients was superior to FCM concordant counterpart, although the difference was not significant (p = 0.459). The diagnosis of PCNSL by FCM is rapid and highly reliable. Some FCM-D cases are PCNSLs with strong tumor microenvironmental reactions.


Action of milk-clotting enzymes on beta-caseins from buffalo's and cow's milk.
beta-Caseins isolated from buffalo's and cow's milk were hydrolysed either with rennet or with microbial proteases from Mucor miehei, M. pusillus Lindt or Endothia parasitica. The degradation products were separated by polyacrylamide-gel electrophoresis and the residual beta-casein was determined quantitatively after various times. The electrophoretic patterns of the degradation products of buffalo and bovine beta-casein produced by the different enzymes were not identical. beta-Casein of buffalo's milk was hydrolysed by rennet and M. miehei protease at a slower rate than that of cow's milk. The reverse was found with E. parasitica and M. pusillus Lindt proteases. Carbamylation of buffalo beta-casein was found to retard its proteolysis by all the enzymes but particularly by rennet and M. miehei protease.


The Association Between Service Connection and Treatment Outcome in Veterans Undergoing Residential PTSD Treatment.
The Department of Veterans Affairs has invested significant time and resources into the treatment of posttraumatic stress disorder (PTSD). Despite concerted efforts, a significant portion of patients do not respond optimally to trauma-focused treatment. One of the factors that has been hypothesized to be associated with treatment response is participation in the Veterans Benefits Administration service-connected disability process. This factor may be particularly relevant in the residential treatment setting, where most participants are engaged in the compensation seeking process. We conducted a retrospective chart review of 105 veterans who completed Cognitive Processing Therapy (CPT) in a residential rehabilitation program. ANCOVAs that adjusted for baseline PTSD severity compared symptom change between those who were and were non-compensation seeking at the time of treatment. Compensation seeking status was associated with significantly less symptom improvement over the course of CPT after adjusting for baseline PTSD severity (F(1, 102) = 4.29, p < .001, η2 = .03). Sensitivity analyses did not detect a similar effect during a prior coping skills phase of treatment. During CPT, clinically significant change was met by 66.7% of non-compensation seeking veterans (M = -15, SD = 14.56) and by 40.1% of the compensation seeking group (M = -7.1, SD = 12.24). Compensation-seeking may be associated with reduced response to trauma-focused treatment in certain settings. Future research is needed to better understand the mechanisms underlying this effect.


Preformed donor-specific HLA antibodies are associated with increased risk of early mortality after liver transplantation.
There is limited evidence for a negative impact of preformed, donor-specific HLA antibodies (DSA) identified by cross-matching on outcomes after liver transplantation. Three recent studies have suggested an association between preformed DSA detected by Luminex and reduced graft or recipient survival in liver transplant cohorts with a high prevalence of hepatitis C. This study investigated the impact of preformed DSA identified by Luminex in the Scottish liver transplant population. All recipients of liver transplants in Scotland between 2007 and 2015 with samples available for day of transplant antibody testing and donor HLA typing were included (n=459); 96% of the cohort were white and 19% had a primary diagnosis of hepatitis C. The median follow-up time was 36 months. Preformed DSA were detected in 88 recipients. In multivariate analysis, preformed DSA with a median fluorescent intensity ≥10 000 were associated with recipient mortality at 1 year. There was no association between DSA and overall graft or recipient survival. This study adds to the growing body of evidence supporting a detrimental impact of preformed, high-level DSA in a subset of liver transplant recipients by identifying an association in an ethnically and demographically distinct liver transplant population.


New Gram-positive antibiotics: better than vancomycin?
Despite concerns about vancomycin use in the treatment of multidrug-resistant Gram positives, evidence for better therapeutic outcomes with alternative antibiotics is lacking. This review focuses on recent advances. Combination therapy with vancomycin-rifampin, although associated with better cure rates, resulted in the emergence of high rates of rifampin resistance. Of the newer anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotics, ceftopibrole, ortivancin and dalbavancin require further development prior to a further assessment by the United States Food and Drug Administration. Ceftaroline, telavancin and daptomycin were associated with comparable clinical cure rates compared with vancomycin in the treatment of complicated MRSA skin and soft tissue infections. In the treatment of hospital-acquired pneumonia, both telavancin and linezolid resulted in significantly greater clinical cure rates compared with vancomycin. Despite greater clinical cure rates, no difference in overall or infection-related mortality was detected. Of concern is the appearance of daptomycin and linezolid resistance following increased use. Toxicity profiles (especially of linezolid) are comparable to vancomycin provided short-duration therapy is prescribed. The first reports of daptomycin-induced acute eosinophillic pneumonia were described in 2010. Based on current evidence, greater microbiological and clinical cure rates are achieved with alternative agents. However, these differences do not translate into mortality benefits compared with vancomycin for the treatment of S. aureus infections.


Immunotherapy for melanoma: current status and perspectives.
Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease.


Association between vitiligo and spondyloarthritis.
To establish if spondyloarthritis (SpA) and vitiligo occur together more frequently than by chance. All consecutive patients with SpA seen in a 6 month period were evaluated for vitiligo by an experienced dermatologist. The control group included the 2 consecutive patients without SpA seen after each patient with SpA. Two hundred thirty-four patients with SpA (131 men, 103 women; mean age 59 +/- 18.3 yrs) were seen in the study period. Of these, 43 had ankylosing spondylitis (AS), 112 psoriatic arthritis (PsA), 14 SpA associated with inflammatory bowel disease, 64 undifferentiated SpA, and one reactive arthritis. The 468 control patients (360 women, 108 men; mean age 68.5 +/- 2 yrs) had various degenerative and inflammatory rheumatic diseases. Eight (3.4%) patients out of 234 with SpA had type A vitiligo. In the control group, 5 (1.06%) out of 468 had type A vitiligo. The difference was statistically significant (p < 0.05). Of the 8 patients with coexisting vitiligo and SpA, 4 had PsA, 2 primary AS, one AS associated with Crohn's disease, and one undifferentiated SpA. Of the 5 patients with vitiligo in the control group, one had rheumatoid arthritis, one S ogren's syndrome, one palindromic rheumatism, one crystal arthropathy, and one osteoarthritis. Our results suggest that vitiligo and SpA do not coexist by chance and that vitiligo should be included in the list of diseases associated with SpA.


The relationship between cell phone use, physical and sedentary activity, and cardiorespiratory fitness in a sample of U.S. college students.
Today's cell phones increase opportunities for activities traditionally defined as sedentary behaviors (e.g., surfing the internet, playing video games). People who participate in large amounts of sedentary behaviors, relative to those who do not, tend to be less physically active, less physically fit, and at greater risk for health problems. However, cell phone use does not have to be a sedentary behavior as these devices are portable. It can occur while standing or during mild-to-moderate intensity physical activity. Thus, the relationship between cell phone use, physical and sedentary activity, and physical fitness is unclear. The purpose of this study was to investigate these relationships among a sample of healthy college students. Participants were first interviewed about their physical activity behavior and cell phone use. Then body composition was assessed and the validated self-efficacy survey for exercise behaviors completed. This was followed by a progressive exercise test on a treadmill to exhaustion. Peak oxygen consumption (VO2 peak) during exercise was used to measure cardiorespiratory fitness. Hierarchical regression was used to assess the relationship between cell phone use and cardiorespiratory fitness after controlling for sex, self-efficacy, and percent body fat. Interview data was transcribed, coded, and Chi-square analysis was used to compare the responses of low and high frequency cell phone users. Cell phone use was significantly (p = 0.047) and negatively (β = -0.25) related to cardio respiratory fitness independent of sex, self-efficacy, and percent fat which were also significant predictors (p < 0.05). Interview data offered several possible explanations for this relationship. First, high frequency users were more likely than low frequency users to report forgoing opportunities for physical activity in order to use their cell phones for sedentary behaviors. Second, low frequency users were more likely to report being connected to active peer groups through their cell phones and to cite this as a motivation for physical activity. Third, high levels of cell phone use indicated a broader pattern of sedentary behaviors apart from cell phone use, such as watching television. Cell phone use, like traditional sedentary behaviors, may disrupt physical activity and reduce cardiorespiratory fitness.


Malaria infection status of European Robins seems to associate with timing of autumn migration but not with actual condition.
Avian malaria parasites can negatively affect many aspects of the life of the passerines. Though these parasites may strongly affect the health and thus migration patterns of the birds also during autumn, previous studies on avian malaria focused mainly on the spring migration and the breeding periods of the birds. We investigated whether the prevalence of blood parasites varies in relation to biometrical traits, body condition and arrival time in the European Robin (Erithacus rubecula) during autumn migration. We found no sex or age related differences in avian malaria prevalence and no relationship between infection status and body size or actual condition of the birds was found either. However, the timing of autumn migration differed marginally between infected and non-infected juveniles, so that parasitized individuals arrived later at the Hungarian stopover site. This is either because avian malaria infections adversely affect the migration timing or migration speed of the birds, or because later arriving individuals come from more distant populations with possibly higher blood parasite prevalence. The possible delay that parasites cause in the arrival time of the birds during autumn migration could affect the whole migratory strategy and the breeding success of the birds in the next season.


Aromatic amines contents of cigarette butts: Fresh and aged cigarette butts vs unsmoked cigarette.
Cigarette butts (CBs) are some of the most abundant waste items in the environment and may contain high levels of different toxic chemicals, such as aromatic amines (AAs). However, to this date, there is no comprehensive study on the role of CBs in the emission of AAs into the environment. The present study investigated for the first time the concentration levels of 10 primary aromatic amines (PAAs), including ANL, p-TOL, m-TOL, o-TOL, 2,6-DMA, o-ASD, 2-NA, 1-NA, 3-ABP, and 4-ABP that were measured and compared in unsmoked cigarette, freshly smoked CBs, and CBs collected from urban streets (named here aged CBs). The mean levels of ∑PAAs in different sample categories were statistically significantly different and the mean level order was as freshly smoked CBs > aged CBs > unsmoked cigarette with the values of 3.43, 2.12 μg g-1, and 0.28 μg g-1, respectively. The levels of ∑PAAs, ANL, o-ASD, 2,6-DMA, 2-NA, and ∑TOL dramatically increased by 12.26, 4.05, 8.46, 10.41, 4.78, and 28.84 times, respectively, right after smoking comparing the freshly smoked CBs samples and unsmoked cigarette. The results also showed a substantial decrease in the levels of PAAs (except o-ASD) in the aged CBs samples compared to freshly smoked CBs. The levels of ∑PAAs, o-ASD, 2,6-DMA, ∑TOL, ANL, 2-NA, 1-NA, and ∑ABP decreased 1.62, 1.09, 1.91, 3.20, 3.42, 2.63, 2.00, and 1.88 times, respectively. Considering the average PAAS content and estimated CBs littered worldwide every year, freshly smoked CBs can theoretically emit 2.9 tons of ∑PAAs into the environment annually. Considering other chemicals that may also be released into the environment via CBs (beside PAAs), we can consider CBs as a critical source of toxic compounds into the environment and water bodies.


Prevalence of terminal duct lobular units and frequency of neoplastic involvement of the nipple in mastectomy.
Breast cancer treatment has greatly evolved from radical mastectomy to more cosmetically acceptable and less-debilitating surgeries. Nipple-sparing mastectomy is increasingly done for both cancer treatment and risk reduction. The frequency of terminal duct lobular units (TDLUs) and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples (GUNs) is not well investigated. To describe frequency of TDLUs and occult and overt neoplastic nipple involvement. Nipples from 105 consecutive specimens (90 therapeutic, 15 prophylactic) were studied. Sixty-five nipples were entirely submitted to evaluate frequency of TDLUs; the rest had 1 vertical section submitted. Terminal duct lobular unit was seen in 17 GUNs (26%). Six had TDLU in the base, 6 had it in the papilla, and 5 in both. Four GUNs showed lobular carcinoma in situ (1), Paget disease (1), and pagetoid extension of underlying malignancy (2). Grossly/clinically abnormal nipples had Paget disease (2), lymphovascular invasion (2), invasive carcinoma (4), and pagetoid extension (5). Involved nipples were closer to tumor (mean, 1.1 versus 3.2 cm, P < .001), had larger underlying tumors (mean, 4.3 versus 2.6 cm, P = .03) and of higher grade (P = .04), and more often had lymph node metastases (91% versus 44%, P = .007). No pathologic abnormalities were found in prophylactic mastectomy nipples. Terminal duct lobular units were seen in 26% of nipples. They were frequently seen in the nipple papilla. Occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable therapeutic mastectomy nipples. Pagetoid extension was the dominant spread of underlying malignancy. Overall, the nipple was more often involved by larger and higher-grade tumors located closer to the nipple. All prophylactic mastectomies had unremarkable nipples. These findings should be considered while selecting patients for nipple-sparing mastectomy.


Noninvasive brain stimulation combined with exercise in chronic pain: a systematic review and meta-analysis.
Background: The use of noninvasive brain stimulation (NIBS) combined with exercise could produce synergistic effects on chronic pain conditions. This study aims to evaluate the efficacy and safety of NIBS combined with exercise to treat chronic pain as well as to describe the parameters used to date in this combination.Methods: The search was carried out in Medline, Central, Scopus, Embase, and Pedro until November 2019. Randomized clinical trials (RCTs) and quasi-experimental studies reporting the use of noninvasive brain stimulation and exercise on patients with chronic pain were selected and revised.Results: The authors included eight studies (RCTs), reporting eight comparisons (219 participants). Authors found a significant and homogeneous pain decrease (ES: -0.62, 95% CI:-0.89 to -0.34; I2 = 0.0%) in favor of the combined intervention compared to sham NIBS + exercise, predominantly by excitatory (anodal tDCS/rTMS) motor cortex stimulation. Regarding NIBS techniques, the pooled effect sizes were significant for both tDCS (ES: -0.59, 95% CI: -0.89 to -0.29, I2 = 0.0%) and rTMS (ES: -0.76, 95% CI: -1.41 to -0.11, I2 = 0.0%).Conclusions: This meta-analysis suggests a significant moderate to large effects of the NIBS and exercise combination in chronic pain. The authors discuss the potential theoretical framework for this synergistic effect.


Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial.
Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial. A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups. Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups.


Probing the stability of neutral and anionic transition-metal-doped golden cage nanoclusters: M@Au16 (M = Sc, Ti, V).
The golden Au16(q) (q = 0, -1) cage is doped systematically with an external atom of different valence electrons: Sc, Ti, and V. The structural, electronic, and magnetic properties of the doped clusters, M@Au16(q) (M = Sc, Ti and V; q = 0, -1) are investigated using the Saunders "Kick" (SK) global search technique combined with density-functional theory (DFT) calculations (SK-DFT). It is found that the closeness of the calculated vertical/adiabatic detachment energy for Ti-doped and V-doped (3.09/3.16 eV for Ti-doped, and 3.31/3.38 eV for V-doped) is consistent with the negligible geometry change between the anionic and neutral ground state structures. The characteristics of the Sc@Au16(-) cluster includes its remarkably high average binding energy and doping energy, which reflects its high stability. The different spectral features between doped M@Au16(-) and pure Au16(-) clusters indicate endohedral structures with larger distortion from the parent Au16(-) cage for the doped clusters. The s electrons of the Au16 cage are observed to transfer to Sc, Ti and V atom for doped M@Au16(q) clusters by natural population analysis (NPA). The magnetic moment of the impurity Sc/Ti/V atom is somewhat quenched. Furthermore, the electron localization function analysis does not reveal strong interactions. The current work shows that the electronic properties of the golden cage can be systematically tuned through doping.


Protective metabolic effects of propranolol during total myocardial ischemia.
Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37 degrees C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 +/- 1.4 minutes compared with 75.9 +/- 2.2 minutes in the propranolol-treated group (p less than 0.01). In addition to significantly delaying the onset of ischemic contracture, propranolol also decreased the rate of anaerobic glycolysis during ischemia. Ischemic contracture occurred in the control group with an average adenosine triphosphate level of 1.26 +/- 0.08 mumol compared to 0.91 +/- 0.08 mumol/gm wet weight for the beta blocked group (p less than 0.0025). These are the first data suggesting that the protective effects of beta blockade may be related to a beneficial effect on ischemic myocardial metabolism allowing myocardium to survive with lower levels of adenosine triphosphate.


Clinical characteristics of the BREATHE cohort - a real-life study on patients with asthma and COPD.
Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p < 0.001). Patients with asthma, asthma + COPD and Other had higher sputum eosinophilia (1.5%, 1.5%, 1.2% vs 0.75%, respectively, p < 0.001) but lower sputum neutrophilia (39.3, 43.5%, 40.8% vs 66.8%, p < 0.001) compared to patients with COPD. Conclusions: The BREATHE study provides a unique database and biobank with clinical information and samples from 1403 real-life patients with asthma, COPD, and overlap representing different severities of the diseases. This research platform is highly relevant for disease phenotype- and biomarker studies aiming to describe a broad spectrum of obstructive airway diseases.


Identification and characterisation of microRNAs and their target genes in phosphate-starved Nicotiana benthamiana by small RNA deep sequencing and 5'RACE analysis.
Phosphorus is an important macronutrient that is severely lacking in soils. In plants, specific microRNAs (miRNAs) essential for nutrient management and the regulation of stress responses are responsible for the control of many phosphate starvation responses. Further understanding of conserved and species-specific microRNA species has potential implications for the development of crops tolerant to soils with low phosphate. This study identified and characterised phosphate starvation-responsive miRNAs in the native Australian tobacco Nicotiana benthamiana. Small RNA libraries were constructed and sequenced from phosphate-starved plant leaves, stems and roots. Twenty-four conserved miRNA families and 36 species-specific miRNAs were identified. The majority of highly phosphate starvation-responsive miRNAs were highly conserved, comprising of members from the miR399, miR827, and miR2111 families. In addition, two miRNA-star species were identified to be phosphate starvation-responsive. A total of seven miRNA targets were confirmed using RLM-5'RACE to be cleaved by five miRNA families, including two confirmed cleavage targets for Nbe-miR399 species, one for Nbe-miR2111, and two for Nbe-miR398. A number of N. benthamiana-specific features for conserved miRNAs were identified, including species-specific miRNA targets predicted or confirmed for miR399, miR827, and miR398. Our results give an insight into the phosphate starvation-responsive miRNAs of Nicotiana benthamiana, and indicate that the phosphate starvation response pathways in N. benthamiana contain both highly conserved and species-specific components.


Temporal and spatial distribution of intracellular potentials during generation and spread of epileptogenic discharges.
This chapter addresses the characteristics and spatial distribution of intracellular potentials, the spread of paroxysmal depolarization shifts (PDSs) through the cortex, the extracellular field potentials in three dimensions, and the concentrations of penicillin in direct contact with elements in the epileptogenic focus. Data are presented that show that there are several types or gradations of PDS intensities within each focus; PDS types are distributed in groups related to their distance from the center of the focus and to the concentration of the epileptogenic drug; the morphology and repetition rate of electroencephalogram (EEG) spikes are related to features of the intracellular potentials; a mathematical model can estimate the distribution of concentrations of penicillin within the focus over long periods; no barriers impede diffusion of penicillin either at the cortical surface or at the boundary between gray and white matter; the potential field of the EEG spike is defined in three dimensions; and PDSs spread through the focus at the rate of 0.25 m/sec.


Characteristics of wet work in the cleaning industry.
Wet work is the main cause of occupational contact dermatitis in the cleaning industry. Dermatologists and occupational physicians need to base their primary and secondary prevention for workers in the cleaning industry on the characteristics of wet work exposures. We quantified the burden of wet work in professional office cleaning activities with a continuous standardized observation by trained observers of 41 office cleaners. Duration and frequency of wet work exposure and of different cleaning activities were assessed. Wet work made up 50% of such cleaning work. Within a typical 3-hr shift, a mean frequency of 68 episodes of wet work was observed, which classifies office cleaning as wet work. Skin exposure to irritants was markedly different among cleaners who did the same cleaning activities. Reduction in skin irritation can be achieved by training the workers. Because this group of workers, who have a low level of education, has a high risk of developing irritant hand dermatitis, a special effort on training and instruction should be made. A reduction of exposure can be achieved by: using gloves more often; using gloves for a shorter period of time; using gloves while doing activities that otherwise cause the skin to be in contact with water and cleaning substances and washing hands with water only, reserving soap for when the hands are visibly dirty.


Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies.
Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine. Methods: Here, we first tested the possibility of a novel circular RNA (circRNA) platform for protein expression and compare its duration with linear RNA. Then, we developed a lipid nanoparticle (LNP) system for circRNA delivery in vitro and in vivo. Next, the innate and adaptive immune response of circRNA-LNP complex was evaluated in vivo. The anti-tumor efficacy of circRNA-LNP was further confirmed in three tumor models. Finally, the possibility of combination therapy with circRNA-LNP and adoptive cell transfer therapy was further investigated in a late-stage tumor model. Results: We successfully increased the stability of the RNA vaccine by circularizing the linear RNA molecules to form highly stable circRNA molecules which exhibited durable protein expression ability. By encapsulating the antigen-coding circRNA in LNP enabling in vivo expression, we established a novel circRNA vaccine platform, which was capable of triggering robust innate and adaptive immune activation and showed superior anti-tumor efficacy in multiple mouse tumor models. Conclusions: Overall, our circRNA vaccine platform provides a novel prospect for the development of cancer RNA vaccines in a wide range of hard-to-treat malignancies.


Interspecies mixed-effect pharmacokinetic modeling of penicillin G in cattle and swine.
Extralabel drug use of penicillin G in food-producing animals may cause an excess of residues in tissue which will have the potential to damage human health. Of all the antibiotics, penicillin G may have the greatest potential for producing allergic responses to the consumer of food animal products. There are, however, no population pharmacokinetic studies of penicillin G for food animals. The objective of this study was to develop a population pharmacokinetic model to describe the time-concentration data profile of penicillin G across two species. Data were collected from previously published pharmacokinetic studies in which several formulations of penicillin G were administered to diverse populations of cattle and swine. Liver, kidney, and muscle residue data were also used in this study. Compartmental models with first-order absorption and elimination were fit to plasma and tissue concentrations using a nonlinear mixed-effect modeling approach. A 3-compartment model with extra tissue compartments was selected to describe the pharmacokinetics of penicillin G. Typical population parameter estimates (interindividual variability) were central volumes of distribution of 3.45 liters (12%) and 3.05 liters (8.8%) and central clearance of 105 liters/h (32%) and 16.9 liters/h (14%) for cattle and swine, respectively, with peripheral clearance of 24.8 liters/h (13%) and 9.65 liters/h (23%) for cattle and 13.7 liters/h (85%) and 0.52 liters/h (40%) for swine. Body weight and age were the covariates in the final pharmacokinetic models. This study established a robust model of penicillin for a large and diverse population of food-producing animals which could be applied to other antibiotics and species in future analyses.


Differential divergence in autosomes and sex chromosomes is associated with intra-island diversification at a very small spatial scale in a songbird lineage.
Recently diverged taxa showing marked phenotypic and ecological diversity provide optimal systems to understand the genetic processes underlying speciation. We used genome-wide markers to investigate the diversification of the Reunion grey white-eye (Zosterops borbonicus) on the small volcanic island of Reunion (Mascarene archipelago), where this species complex exhibits four geographical forms that are parapatrically distributed across the island and differ strikingly in plumage colour. One form restricted to the highlands is separated by a steep ecological gradient from three distinct lowland forms which meet at narrow hybrid zones that are not associated with environmental variables. Analyses of genomic variation based on single nucleotide polymorphism data from genotyping-by-sequencing and pooled RAD-seq approaches show that signatures of selection associated with elevation can be found at multiple regions across the genome, whereas most loci associated with the lowland forms are located on the Z sex chromosome. We identified TYRP1, a Z-linked colour gene, as a likely candidate locus underlying colour variation among lowland forms. Tests of demographic models revealed that highland and lowland forms diverged in the presence of gene flow, and divergence has progressed as gene flow was restricted by selection at loci across the genome. This system holds promise for investigating how adaptation and reproductive isolation shape the genomic landscape of divergence at multiple stages of the speciation process.


Effects of ipsilateral and bilateral auditory stimuli on audiovisual integration: a behavioral and event-related potential study.
We used event-related potential measures to compare the effects of ipsilateral and bilateral auditory stimuli on audiovisual (AV) integration. Behavioral results showed that the responses to visual stimuli with either type of auditory stimulus were faster than responses to visual stimuli only and that perceptual sensitivity (d') for visual detection was enhanced for visual stimuli with ipsilateral auditory stimuli. Furthermore, event-related potential components related to AV integrations were identified over the occipital areas at ∼180-200 ms during early-stage sensory processing by the effect of ipsilateral auditory stimuli and over the frontocentral areas at ∼300-320 ms during late-stage cognitive processing by the effect of ipsilateral and bilateral auditory stimuli. Our results confirmed that AV integration was also elicited, despite the effect of bilateral auditory stimuli, and only occurred at later stages of cognitive processing in response to a visual detection task. Furthermore, integration from early-stage sensory processing was observed by the effect of ipsilateral auditory stimuli, suggesting that the integration of AV information in the human brain might be particularly sensitive to ipsilaterally presented AV stimuli.


Cerebral aspergillosis in adult critically ill patients: a descriptive report of 10 patients from the AspICU cohort.
An unexpectedly high incidence of invasive pulmonary aspergillosis (IPA) has been reported in non-neutropenic intensive care unit (ICU) patients. After the respiratory tract, the brain is most often affected by invasive aspergillosis. However, little is known about brain involvement by Aspergillus in critically ill patients. In this study, demographics, risk profile, diagnosis, treatment and outcome of proven cases of invasive cerebral aspergillosis (ICA) taken from a cohort of 563 adult patients with evidenced Aspergillus involvement during their ICU stay were reviewed. Ten patients with central nervous system aspergillosis were identified. All had one or more host factors predisposing for invasive aspergillosis. The clinical and radiological presentation was non-specific and exclusively pulmonary-related. All but one patient had proven or probable/putative IPA. On cerebral computed tomography, lesions appeared as either solitary and hyperdense or were multiple and randomly distributed throughout the brain. One patient presented with sole meningeal infestation. Aspergillus infection was confirmed by brain biopsy in three subjects. Voriconazole was used as primary treatment in only one-half of the patients. Mortality was 90%. ICA is not frequently observed in adult ICU patients. Diagnosis must be considered in patients at risk presenting with proven or probable/putative IPA in association with suggestive neuroradiological findings. The brain is most likely affected through haematogenous dissemination from the lungs. Current treatment recommendations are not always applied and outcome remains dismal.


[Surgical treatment of middle laryngostenoses of paralytic etiology via extralaryngeal approach].
A method of treatment of middle laryngostenosis of paralytic etiology with laterofixation of the vocal fold is proposed. The technique includes an extralaryngeal approach to the thyroid cartilage plate from the front, subpericartilaginous resection of the vocal process of the arytenoids cartilage with dissection of the internal cricothyroid muscle and most of the thyroarytenoid muscle; placement of a part of the autocartilage under the anterior third of the vocal fold; divertion of the elastic cone with the vocal fold by ligation and tightening ligatures on the autotransplant put on the plate of the thyroid cartilage. Laryngostereotopometry used by the authors allows three-dimensional localization of the necessary point in the larynx and its topometric characteristics of its position in persons with different figure and form of the neck.


Pharmacological and non-pharmacological treatments for insomnia: A protocol for a systematic review and network meta-analysis.
Although nonpharmacological therapies are recommended as first-line treatments for insomnia, they do not widely implement in practice owing to costly or time-consuming. As a result, pharmacotherapy remains to be commonly prescribed for patients with the sleep disorder. Pharmacotherapy for insomnia consists of different types of drugs. Few studies focused on comprehensively evaluating all available drugs for insomnia. Our review aims to compare efficacy and safety of pharmacological and nonpharmacological treatments by synthesizing direct evidence and indirect evidence to help clinicians and patients make informed decisions for insomnia. We will search the MEDLINE, EMBASE, and Cochrane Register of Controlled Trials between January 2000 and June 12, 2021. Randomized controlled trials of pharmacological and nonpharmacological interventions for insomnia will be included. Study quality will be assessed on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Eight network meta-analyses were conducted. A Bayesian network meta-analysis would be performed, and relative ranking of agents would be assessed. A node splitting method will be used to examine the inconsistency between direct and indirect comparisons when a loop connecting 3 arms exists. The results of this paper will be submitted to a peer-reviewed journal for publication. The conclusion of our study will provide updated evidence to rank the effectiveness and safety of pharmacological and nonpharmacological interventions for insomnia. Ethical approval is not applicable, as this study is a network meta-analysis based on published trials. INPLASY202160031.


Fecal Incontinence Diagnosed by the Rome IV Criteria in the United States, Canada, and the United Kingdom.
The diagnostic criteria for fecal incontinence (FI) were made more restrictive in the Rome IV revision. We aimed to determine the characteristics of FI patients defined by the Rome IV criteria, assess how FI frequency and amount affect quality of life, identify risk factors, and compare prevalence values among countries. We performed an internet-based survey of 5931 subjects in the United States, Canada, and the United Kingdom, from September to December 2015. Subjects were stratified by country, sex, and age. Responders answered questions about diagnosis, health care use, and risk factors. We performed multivariate linear regression analysis to identify risk factors for FI. FI was reported by 957 subjects (16.1%) but only 196 (3.3%) fulfilled the Rome IV criteria. Frequency of FI was less than twice a month for 672/957 subjects (70.2%) and duration was less than 6 months for 285/957 subjects (29.8%). Quality of life was significantly impaired in all subjects with FI compared to subjects with fecal continence. The strongest risk factors for FI were diarrhea, urgency to defecate, and abdominal pain. FI was more prevalent in the United States than in the United Kingdom. Between-country differences were due to less diarrhea and urgency in the United Kingdom. Rome IV FI prevalence is lower than previous estimates because the new criteria exclude many individuals with less frequent or short duration FI. These excluded patients have impaired quality of life. It might be appropriate to make a diagnosis of FI for all patients with FI ≥2 times in 3 months and to provide additional information on frequency, duration, and amount of stool lost to assist clinicians in treatment selection.


68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer.
Gallium-68 is a generator-produced radionuclide for positron emission tomography (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compounds [(68)Ga]3 and [(68)Ga]6 are high-affinity urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60% to 70% and radiochemical purities of more than 99%. Compound [(68)Ga]3 demonstrated 3.78 +/- 0.90% injected dose per gram of tissue (%ID/g) within PSMA+ PIP tumor at 30 min postinjection, while [(68)Ga]6 showed a 2 h PSMA+ PIP tumor uptake value of 3.29 +/- 0.77 %ID/g. Target (PSMA+ PIP) to nontarget (PSMA- flu) ratios were 4.6 and 18.3, respectively, at those time points. Both compounds delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with (68)Ga, a cyclotron-free isotope useful for clinical PET studies, with maintenance of target specificity.


Gene transfer into brain parenchyma elicits antitumor effects.
Gene therapy strategies for cancer currently aim at targeting gene delivery to the malignant cell. In a mouse model of intracerebral Lewis lung carcinoma (3LL), adenoviral vectors transduce not only 3LL cells but also brain parenchymal cells including endothelial cells, neurons, microglia, and astrocytes in vivo. Furthermore, transgene expression persists longer in brain than in tumor. Transfer of IFN-gamma into brain parenchymal cells rather than tumor is both necessary and sufficient to generate antitumor therapeutic benefits. Therefore, parenchymal cells represent an effective and necessary target for delivery of genes that render the brain uninhabitable by the tumor.


Diversity and Prevalence of Clostridium innocuum in the Human Gut Microbiota.
Clostridia are a polyphyletic group of Gram-positive, spore-forming anaerobes in the Firmicutes phylum that significantly impact metabolism and functioning of the human gastrointestinal tract. Recently, Clostridia were divided into two separate classes, Clostridia and Erysipelotrichia, based on phenotypic and 16S rRNA gene-based differences. While Clostridia include many well-known pathogenic bacteria, Erysipelotrichia remain relatively uncharacterized, particularly regarding their role as a pathogen versus commensal. Despite wide recognition as a commensal, the erysipelotrichial species Clostridium innocuum has recently been associated with various disease states. To further understand the ecological and potential virulent role of C. innocuum, we conducted a genomic comparison across 38 C. innocuum isolates and 194 publicly available genomes. Based on colony morphology, we isolated multiple C. innocuum cultivars from the feces of healthy human volunteers (n = 5). Comparison of the 16S rRNA gene of our isolates against publicly available microbiota data sets in healthy individuals suggests a high prevalence of C. innocuum across the human population (>80%). Analysis of single nucleotide polymorphisms (SNPs) across core genes and average nucleotide identify (ANI) revealed the presence of four clades among all available genomes (n = 232 total). Investigation of carbohydrate and protein utilization pathways, including comparison against the carbohydrate-activating enzyme (CAZyme) database, demonstrated inter- and intraclade differences that were further substantiated in vitro. Collectively, these data indicate genetic variance within the C. innocuum species that may help clarify its role in human disease and health. IMPORTANCE Clostridia are a group of medically important anaerobes as both commensals and pathogens. Recently, a new class of Erysipelotrichia containing a number of reassigned clostridial species has emerged, including Clostridium innocuum. Recent studies have implicated C. innocuum as a potential causative agent of diarrhea in patients from whom Clostridioides difficile could not be isolated. Using genomic and in vitro comparison, this study sought to characterize C. innocuum in the healthy human gut. Our analyses suggest that C. innocuum is a highly prevalent and diverse species, demonstrating clade-specific differences in metabolism and potential virulence. Collectively, this study is the first investigation into a broader description of C. innocuum as a human gut inhabitant.


Antigenic and antiheparin properties of human platelet factor 4 (PF4).
Platelet factor 4 (PF4, a heparin-neutralizing protein) was isolated from washed human platelets. It was found to be homogenous by SDS-polyacrylamide gel electrophoresis, immunodiffusion, and immunoelectrophoresis, when tested with monospecific antibody produced in rabbits. PF4 is a heat-stable protein, but its antiheparin activity and antigenicity are destroyed by trypsin. The molecular weight of PF4 as calculated by amino acid analysis is approximately 8000 and by SDS-polyacrylamide gel electrophoresis with beta-mercaptoethanol, 7100 daltons. PF4 migrated to the cathode at pH 8.6. The interaction of PF4 with heparin resulted in the formation of a complex which migrated to the anode, as tested by immunoelectrophoresis. Incubation of purified PF4 with its antibody at 37 degrees C resulted in a loss of antiheparin activity. The presence of antiheparin activity and of PG4 antigen in material released during platelet aggregation by various agents and at various stages of the preparative procedure closely correlated. It has been concluded that PF4 antigen and antiheparin activity are two properties of the same protein. Comparison of human and pig PF4 revealed significant biochemical and antigenic differences.