Excitation of mouse superficial dorsal horn neurons by histamine and/or PAR-2 agonist: potential role in itch.
Recent studies have suggested the existence of separate transduction mechanisms and sensory pathways for histamine and nonhistaminergic types of itch. We studied whether histamine and an agonist of the protease-activated receptor (PAR)-2, associated with nonhistaminergic itch, excite murine dorsal horn neurons. Single units were recorded in superficial lumbar dorsal horn of adult ICR mice anesthetized with pentobarbital. Unit activity was searched using a small intradermal hindpaw injection of histamine or the PAR-2 agonist SLIGRL-NH2. Isolated units were subsequently challenged with intradermal histamine followed by SLIGRL-NH2 (each 50 microg/1 microl) or reverse order, followed by mechanical, thermal, and algogenic stimuli. Forty-three units were classified as wide dynamic range (62%), nociceptive specific (22%), or mechano insensitive (16%). Twenty units gave prolonged (mean, 10 min) discharges to intradermal injection of histamine; 76% responded to subsequent SLIGRL-NH2, often more briefly. Units additionally responded to noxious heat (63%), cooling (43%), topical mustard oil (53%), and intradermal capsaicin (67%). Twenty-two other units gave prolonged (mean, 5 min) responses to initial intradermal injection of SLIGRL-NH2; 85% responded to subsequent intradermal histamine. They also responded to noxious heat (75%), mustard oil (93%), capsaicin (63%), and one to cooling. Most superficial dorsal horn neurons were excited by both histamine and the PAR-2 agonist, suggesting overlapping pathways for histamine- and non-histamine-mediated itch. Because the large majority of pruritogen-responsive neurons also responded to noxious stimuli, itch may be signaled at least partly by a population code.


Inter-Comparison of ASTER and MODIS Surface Reflectance and Vegetation Index Products for Synergistic Applications to Natural Resource Monitoring.
Synergistic applications of multi-resolution satellite data have been of a great interest among user communities for the development of an improved and more effective operational monitoring system of natural resources, including vegetation and soil. In this study, we conducted an inter-comparison of two remote sensing products, namely, visible/near-infrared surface reflectances and spectral vegetation indices (VIs), from the high resolution Advanced Thermal Emission and Reflection Radiometer (ASTER) (15 m) and lower resolution Moderate Resolution Imaging Spectroradiometer (MODIS) (250 m - 500 m) sensors onboard the Terra platform. Our analysis was aimed at understanding the degree of radiometric compatibility between the two sensors' products due to sensor spectral bandpasses and product generation algorithms. Multiple pairs of ASTER and MODIS standard surface reflectance products were obtained at randomly-selected, globally-distributed locations, from which two types of VIs were computed: the normalized difference vegetation index and the enhanced vegetation indices with and without a blue band. Our results showed that these surface reflectance products and the derived VIs compared well between the two sensors at a global scale, but subject to systematic differences, of which magnitudes varied among scene pairs. An independent assessment of the accuracy of ASTER and MODIS standard products, in which "in-house" surface reflectances were obtained using in situ Aeronet atmospheric data for comparison, suggested that the performance of the ASTER atmospheric correction algorithm may be variable, reducing overall quality of its standard reflectance product. Atmospheric aerosols, which were not corrected for in the ASTER algorithm, were found not to impact the quality of the derived reflectances. Further investigation is needed to identify the sources of inconsistent atmospheric correction results associated with the ASTER algorithm, including additional quality assessments of the ASTER and MODIS products with other atmospheric radiative transfer codes.


The course of depressive symptoms in early Parkinson's disease.
Little is known about the course of depressive symptoms in Parkinson's disease (PD). We studied the course of clinically significant depressive symptoms using data from two clinical trials that followed 413 early, untreated PD subjects for 12 to 18 months. We measured depressive symptoms with the 15-item geriatric depression scale (GDS-15); a score of > or =5 indicates clinically significant depressive symptoms. We used a time-dependent Cox model to examine the association between demographic variables, PD severity, and medication use on the time to resolution of depressive symptoms. One hundred fourteen of 413 (27.6%) subjects were screened positive for depression during the study, with a median GDS-15 score of 6, indicating mild symptoms. Within 6 months, 47% of subjects experienced remission of clinically significant depressive symptoms. Subjects with mild depressive symptoms were more likely to develop moderate to severe depressive symptoms (GDS > or = 10) than those without prior symptoms (relative risk = 6.16). Increasing severity of depressive symptoms, older age, and longer PD duration predicted a lower likelihood of symptom resolution (hazard ratios 0.83-0.92). Mild depressive symptoms have a variable course, with remission and development of more sustained and severe symptoms occurring over time. More severe depressive symptoms may herald a protracted course.


Mechanical regulation of auxin-mediated growth.
The phytohormone auxin is a primary regulator of growth and developmental pattern formation in plants. Auxin accumulates at specific sites (e.g., organ primordia) and induces localized growth within a tissue. Auxin also mediates developmental responses to intrinsic and external physical stimuli; however, exactly how mechanics influences auxin distribution is unknown. Here we show that mechanical strain can regulate auxin transport and accumulation in the tomato shoot apex, where new leaves emerge and rapidly grow. Modification of turgor pressure, application of external force, and artificial growth induction collectively show that the amount and intracellular localization of the auxin efflux carrier PIN1 are sensitive to mechanical alterations. In general, the more strained the tissue was, the more PIN1 was present per cell and the higher the proportion localized to the plasma membrane. Modulation of the membrane properties alone was sufficient to explain most of the mechanical effects. Our experiments support the hypothesis that the plasma membrane acts as a sensor of tissue mechanics that translates the cell wall strain into cellular responses, such as the intracellular localization of membrane-embedded proteins. One implication of this fundamental mechanism is the mechanical enhancement of auxin-mediated growth in young organ primordia. We propose that growth-induced mechanical strain upregulates PIN1 function and auxin accumulation, thereby promoting further growth, in a robust positive feedback loop.


Toll-like receptor 4 is involved in a protective effect of rhein on immunoglobulin A nephropathy.
The objective was to investigate the protective effects of rhein on renal histology change and the effects of rhein on renal tissue toll-like receptor (TLR) 4, TLR9, transforming growth factor-β1 (TGF-β1) expression in immunoglobulin A nephropathy (IgAN) rats. Bovine serum albumin-lipopolysaccharide-carbon tetrachloride 4 method was used to establish IgAN model. Thirty-two male sprague dawley rats were randomly divided into the control group, IgAN model group, rhein-prevented group, and rhein-treated group. 24-h urinary protein (UP), creatinine, urea, alanine aminotransferase (ALT), total protein (TP) contents in the serum of rats were detected with automatic biochemical analyzer and renal pathological changes were observed by the hematoxylin and eosin and periodic acid-Schiff staining. The glomerular deposition of IgA was measured by immunofluorescence staining. Real-time polymerase chain reaction and immunohistochemistry were used to detect renal tissue contents of TLR4, TLR9, TGF-β1 messenger ribonucleic acid and protein expression. The biochemical parameters results of IgAN model rats showed that the 24-h UP excretion and ALT concentration were much higher, and TP concentration was much lower than those of the control group (P < 0.05). Granule-like or mass-like IgA depositions in the mesangial area, glomerular hypercellularity, hyperplasia of mesangial matrix, and tubulointerstitial fibrosis were found in IgAN group. Rhein-prevented and rhein-treated both improved the biochemical parameters and relieved renal pathological injury. The expressions of renal tissue TLR4, TGF-β1, but not TLR9 were significantly elevated in IgAN model rats (P < 0.05). Rhein-prevented and rhein-treated both inhibited TLR4 and TGF-β1 expressions. Rhein significantly improved the serum and urine biochemical parameters, and attenuated the glomerular pathological changes and tubulointerstitial fibrosis in IgAN rats. The mechanism may involve inhibition of renal TLR4 and TGF-β1 secretion.


Organic single molecular structures for light induced spin-pump devices.
We present theoretical results on molecular structures for realistic spin-pump applications. Taking advantage of the electron spin resonance concept, we find that interesting candidates constitute triplet biradicals with two strongly spatially and energetically separated singly occupied molecular orbitals (SOMOs). Building on earlier reported stable biradicals, particularly bis(nitronyl nitroxide) based biradicals, we employ density functional theory to design a selection of potential molecular spin-pumps which should be persistent at ambient conditions. We estimate that our proposed molecular structures will operate as spin-pumps using harmonic magnetic fields in the MHz regime and optical fields in the infrared to visible light regime.


A minimal C-peptide sampling method to capture peak and total prehepatic insulin secretion in model-based experimental insulin sensitivity studies.
Model-based insulin sensitivity testing via the intravenous glucose tolerance test (IVGTT) or similar is clinically very intensive due to the need for frequent sampling to accurately capture the dynamics of insulin secretion and clearance. The goal of this study was to significantly reduce the number of samples required in intravenous glucose tolerance test protocols to accurately identify C-peptide and insulin secretion characteristics. Frequently sampled IVGTT data from 12 subjects [5 normal glucose-tolerant (NGT) and 7 type 2 diabetes mellitus (T2DM)] were analyzed to calculate insulin and C-peptide secretion using a well-accepted C-peptide model. Samples were reduced in a series of steps based on the critical IVGTT profile points required for the accurate estimation of C-peptide secretion. The full data set of 23 measurements was reduced to sets with six or four measurements. The peak secretion rate and total secreted C-peptide during 10 and 20 minutes postglucose input and during the total test time were calculated. Results were compared to those from the full data set using the Wilcoxon rank sum to assess any differences. In each case, the calculated secretion metrics were largely unchanged, within expected assay variation, and not significantly different from results obtained using the full 23 measurement data set (P < 0.05). Peak and total C-peptide and insulin secretory characteristics can be estimated accurately in an IVGTT from as few as four systematically chosen samples, providing an opportunity to minimize sampling, cost, and burden.


Comparison of two microemulsion of cyclosporine A in healthy volunteers.
This study evaluated the bioequivalence of a new Cyclosporine A microemulsion formulation in comparison to the reference market standard. Twenty-four adult healthy volunteers were randomised to receive the two Cyclosporin A microemulsion formulations, at a dose of 2.5 mg/kg, according to a cross-over design. Blood samples were taken before drug administration and at 12 points within 24 hours. Cyclosporine A whole blood concentrations were determined by HPLC. The pharmacokinetic parameters AUC0-t and AUC0-infinity were calculated by the trapezoidal rule, Cmax and Tmax were obtained directly from blood data. AUCs and Cmax were tested for bioequivalence after log transformation of data, differences for Tmax were evaluated by the rank test of Wilcoxon for paired data. The 90% confidence interval ratio between tested/reference drug was 0.98 for AUC0-t, 0.96 for AUC0-infinity and 1.01 for Cmax. All of them were within the range of bioequivalence. Tmax was 1.60 +/- 0.44 hours after test drug and 1.67 +/- 0.48 after reference drug (p = 0.27, Wilcoxon test). According to these results the two Cyclosporine A microemulsion formulations can be considered bioequivalent.


Transfer of specific unresponsiveness to organ allografts by thymocytes. Specific unresponsiveness by thymocyte transfer.
Prolonged survival of vascularized organ allografts has been produced in unmodified inbred rats by transfer of thymocytes from enhanced, engrafted, syngeneic animals. For these thymocytes to increase significantly the survival of test allografts they must be harvested 6-9 d after transplantation. Thymectomy of the enhanced, engrafted animals during the same critical period causes acute rejection of othewise long surviving grafts. For optimal effect, the enhanced thymocyte donor must be actively and passively immunized and receive a cardiac allograft. The necessity for erythrocytes in the initial active immunization regimen is noted. Additionally, the antigenic specificity of the suppressor effect has been established with two histoincompatible donor rat strains. Cellular and humoral host responses mounted by test graft recipients after thymocyte transfer from enhanced, engrafted donors are different from those mounted either by unmodifed animals acutely rejecting their grafts or by enhanced rats bearing well-functioning grafts. Numbers of T lymphocytes are reduced in the grafted hearts and in the spleens of test graft recipients, a finding paralleled by the complete absence of specific direct lymphocyte-mediated cytotoxicity. In contrast, cytotoxic antibody production, although delayed, is increased in magnitude, peaking around the time of graft rejection. These studies provide evidence that different biological manipulations can modify separate pathways in the complex cellular and humoral responses towards organ allografts. They demonstrate that cellular immunity is critically involved in immunological enhancement of vascularized organ allografts, a phenomenon hitherto considered primarily humoral. It seems clear that cells with suppressor activity are present within the thymus during the early phases of immunological enhancement.


Tissue expression of angiopoietin-like protein 4 in cattle.
Angiopoietin-like protein 4 (ANGPTL4; also known as fasting-induced adipose factor) is a plasma protein that stimulates oxidation of fatty acids and inhibits fat accumulation. The gastrointestinal tract appears to play an important role in regulating plasma ANGPTL4 concentration in some situations and may be influenced by microbes within the gastrointestinal tract. Our aim was to determine which tissues express ANGPTL4 in the bovine. Rumen, omasum, abomasum, duodenum, jejunum, ileum, colon, pancreas, liver, and subcutaneous adipose tissue samples were collected postmortem from 2 steers. Abundance of ANGPTL4 messenger RNA was quantified by quantitative real-time PCR, and was most abundant in liver and adipose tissue (P < 0.05). We also detected ANGPTL4 messenger RNA throughout the gastrointestinal tract, although its abundance was approximately 10% of that found in liver and adipose tissue. Western blot analysis revealed that ANGPTL4 protein was most abundant in liver and adipose tissue (P < 0.05), but omasal, abomasal, and ileal samples contained at least 60% as much ANGPTL4 protein as the liver and adipose tissue samples, and the protein was detected in all tissues. Finally, cross-sections of the liver, pancreas, and rumen wall were used for indirect immunofluorescent detection of ANGPTL4. Despite the low abundance of ANGPTL4 measured by quantitative real-time PCR and Western blot in ruminal tissue, immunofluorescence demonstrated that expression of ANGPTL4 in ruminal epithelial cells was equivalent to or greater than that in liver hepatocytes. These findings indicate that, as in other species studied, liver and adipose tissue are key sources of ANGPTL4 in cattle. However, the protein was also highly abundant in ruminal epithelium, making it possible that commensal microbes may influence ANGPTL4 synthesis and secretion in the ruminant gastrointestinal tract.


Be smart, exercise your heart: exercise effects on brain and cognition.
An emerging body of multidisciplinary literature has documented the beneficial influence of physical activity engendered through aerobic exercise on selective aspects of brain function. Human and non-human animal studies have shown that aerobic exercise can improve a number of aspects of cognition and performance. Lack of physical activity, particularly among children in the developed world, is one of the major causes of obesity. Exercise might not only help to improve their physical health, but might also improve their academic performance. This article examines the positive effects of aerobic physical activity on cognition and brain function, at the molecular, cellular, systems and behavioural levels. A growing number of studies support the idea that physical exercise is a lifestyle factor that might lead to increased physical and mental health throughout life.


Delivery of siRNA mediated by histidine-containing reducible polycations.
Histidine containing reducible polycations based on CH(6)K(3)H(6)C monomers (His6 RPCs), are highly effective DNA transfection agents combining pH buffering endosomal escape mechanisms with rapid unpackaging following reduction in the cytoplasm. We examined their ability to mediate siRNA uptake into cells focusing on hepatocyte delivery. Co-delivery of EGFP siRNA with pEGFP plasmid DNA reduced reporter gene expression by 85%. However while DNA transfection efficiency increased with polymer size, with 162 k His6 RPCs proving the most effective, delivery of siRNA alone to EGFP stably expressing cells was only possible using 36-80 k polymers. Analysis of particle sizes showed that 80 k polymers formed more compact siRNA complexes than 162 k polymers. The reducible nature of the polymer was necessary for siRNA activity, since siRNA combined with non-reducible polylysine showed little activity. Incorporation of a targeting peptide from the Plasmodium falciparum circumsporozoite (CS) protein onto His6 RPCs, significantly improved transfection of plasmid DNA and siRNA activity in hepatocytes, but not in most non-liver cells tested. siRNA targeted to the hepatitis B virus surface antigen delivered by CS-His6 RPC, mediated falls in both mRNA and protein expression, suggesting that this delivery system could be developed for potential therapies for viral hepatitis.


The expression of genes encoding lipodepsipeptide phytotoxins by Pseudomonas syringae pv. syringae is coordinated in response to plant signal molecules.
Specific plant signal molecules are known to induce syringomycin production and expression of syrB1, a syringomycin synthetase gene, in Pseudomonas syringae pv. syringae. This report demonstrates that syringopeptin production likewise is activated by plant signal molecules and that the GacS, SalA, and SyrF regulatory pathway mediates transmission of plant signal molecules to the syr-syp biosynthesis apparatus. Syringopeptin production by BR132 was increased two-fold by addition of arbutin (100 microM) and D-fructose (0.1%) to syringomycin minimal medium (SRM). Among 10 plant phenolic compounds tested, only the phenolic glucosides arbutin, salicin, and phenyl-beta-D-glucopyranoside induced substantially the beta-glucuronidase (GUS) activity of a sypA::uidA reporter from 242 U per 10(8) CFU without plant signal molecules up to 419 U per 10(8) CFU with plant signal molecules. Syringopeptin production was found to be controlled by the SalA/SyrF regulon because no toxin was detected from cultures of B301DSL7 (i.e., salA mutant) and B301DSL1 (i.e., syrF mutant), and the expression of sypA::uidA was decreased approximately 99 and 94% in salA (B301DSL30) and syrF (B301DNW31) mutant backgrounds, respectively. Subgenomic analysis of transcriptional expression with a 70-mer oligonucleotide microarray demonstrated that the syr-syp genes are induced 2.5- to 10.5-fold by addition of arbutin and D-fructose to SRM. This study establishes that plant signal molecules are transmitted through the GacS, SalA/SyrF pathway to activate the coordinated transcriptional expression of the syr-syp genes.


Emergency procedures for patients with a continuous flow left ventricular assist device.
The number of ventricular assist devices (VADs) being implanted for terminal heart failure is rising at an exponential rate. These implanted patients have a decreased mortality, but still have significant morbidities, as the prevalence of these patients increases in the community. When VAD patients are discharged to home, they will very likely require emergency medical services (EMSs) and emergency medical doctors (EDs) with their future care. The interface of these patients with the community would suggest an increasing prevalence of encounters requiring the need for acute medical care. This will place the initial responsibility of these patients in the hands of EMS first responders and emergency room providers. To date, there is very little literature published on out-of-hospital or ED care for VAD patients. Most EMS personnel and ED feel uncomfortable treating a patient with a VAD because they have not had sufficient exposure. The cardiovascular treatment of VAD patients in the field can pose different challenges typically encountered including difficulties measuring a pulse and sometimes undetectable BP. Despite these unique challenges, official guidelines or even standard operating procedures regarding the emergency treatment of VAD patients are still lacking. We present a basic overview of the most commonly used left VAD systems and propose guidelines that should be followed in the event of an emergency with a VAD patient out of hospital.


Effects of acute exercise on liver function and blood redox status in heavy drinkers.
Excessive alcohol consumption can induce oxidative stress, resulting in the development of several diseases. Exercise has been reported to prevent and/or improve a number of health issues through several mechanisms, including an improvement in redox status. It has also been previously suggested that exercise can help individuals with alcohol use disorders reduce their alcohol intake; however, research in this field is limited. The aim of the present study was to investigage the effects of acute exercise of moderate intensity on the liver function and blood redox status in heavy drinkers. For this purpose, a total of 17 heavy drinkers [age, 31.6±3.2 years; body mass index (BMI), 27.4±0.8 kg/m2; experimental group (EG)] and 17 controls [age, 33.5±1.3 years; BMI, 26.1±1.4 kg/m2; control group (CG), who did not exceed moderate alcohol consumption], underwent one trial of acute exercise of moderate intensity (50-60% of the heart rate reserve) for 30 min on a cycle ergometer, following an overnight fast, and abstaining from smoking and alcohol consumption. Blood samples were obtained before and immediately after exercise for later determination of the indices of liver function and blood redox status. The subjects in the EG had significantly higher (p<0.05) baseline γ-glutamyl transferase (γ-GT) levels compared to the subjects in the CG. Exercise thus resulted in significantly higher γ-GT levels (p<0.005) only in the EG. No significant differences in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) baseline levels were observed between the 2 groups. Following exercise, the AST levels increased significantly (p<0.001) in both groups, whereas the ALT levels increased significantly (p<0.01) only in the EG. The baseline glutathione (GSH) levels were significantly lower (p<0.05) and remained low following exercise in the EG. In addition, we observed a trend for higher (p=0.07) baseline levels of thiobarbituric acid-reactive substances (TBARS), which remained elevated post-exercise in the EG compared to the CG. Significantly increased post-exercise total antioxidant capacity (TAC; p<0.01) and uric acid (UA; p<0.05) levels were noted in the CG, whereas the TAC (p=0.06) and UA (p=0.08) levels increased and approached significance post-exercise in the EG. No significant differences in the baseline levels of total bilirubin and protein carbonyl were observed between the 2 groups, even post-exercise. Thus, the findings of the present study indicate that even though heavy drinkers may be prone to oxidative stress, their exercise-induced antioxidant response is similar to that of individuals who do not drink heavily.


Rituximab Therapy for Systemic Rheumatoid Vasculitis: Indications, Outcomes, and Adverse Events.
To characterize the indication, outcomes, and adverse effects of rituximab (RTX) treatment in a large single-center cohort of patients with systemic rheumatoid vasculitis (RV). We retrospectively reviewed the medical charts of 17 patients treated with RTX for systemic RV from 2000 to 2017. Clinical characteristics, outcomes, and adverse effects were analyzed. At RV diagnosis, mean age was 59 years, 59% were female, 94% were white, and 82% had positive rheumatoid factor. At the time of initiating RTX, median Birmingham Vasculitis Activity Score for rheumatoid arthritis was 4.0 (interquartile range 2.0-7.5). RV presented in the skin in 8 patients (47%), as mononeuritis multiplex in 2 (12%), inflammatory ocular disease in 2 (12%), and affected multiple organ systems in 5 (29%). RTX was used for induction therapy in 8 patients (47%), relapsing RV in 4 (24%), second-line therapy in 2 (12%), and salvage therapy or in combination with another agent in 3 (18%). At 3 months, 2 (13%) of 15 patients with available followup information achieved complete remission (CR), and 10 (67%) achieved partial response (PR). At 6 months, 6 patients (40%) achieved CR, 8 (53%) achieved PR, and one had no response. At 12 months, 8 of 13 patients with available records (62%) had CR and 5 patients (38%) had PR. Systemic RV is difficult to treat effectively. CR of RV was achieved in 62% and PR in 38% of patients within 12 months of RTX use. Further evidence is needed to inform treatment for patients with RV.


Traumatic brain injuries evaluated in U.S. emergency departments, 1992-1994.
To describe the incidence and patient characteristics of traumatic brain injuries (TBIs) treated in U.S. emergency departments (EDs). A secondary analysis was performed on data from the National Hospital Ambulatory Medical Care Survey administered from 1992 to 1994. An ED visit was determined to represent a case of TBI if the case record contained ICD-9-CM codes of 800.0-801.9, 803.0-804.9, or 850.0-854.1. The average annual estimate of new TBI treated in U.S. EDs was 1,144,807, equaling 444 per 100,000 persons (95% CI = 390 to 498), which represents approximately 3,136 new cases of TBI per day and accounts for 1.3% of all ED visits. Males were 1.6 times as likely as females to suffer TBI until the age of 65 years, when the female rate exceeded the male. The rate for blacks was 35% higher than that for whites. The highest overall incidence rate of TBI occurred in the less-than-5-year age group (1,091 per 100,000), closely followed by the more-than-85-year age group (1,026 per 100,000). Falls represented the most common mechanism of TBI injury, followed by motor vehicle-related trauma. This study underscores the ongoing need for effective surveillance of all types of TBI and evaluation of prevention strategies targeting high-risk individuals. It serves as a clinically grounded and ED-based corroboration of prior survey research, providing a basis for comparison of incidence rates over time and a tool with which to measure the efficacy of future interventions.


Agreement between Programmed Cell Death Ligand-1 Diagnostic Assays across Multiple Protein Expression Cutoffs in Non-Small Cell Lung Cancer.
Purpose: Immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) demonstrate encouraging antitumor activity and manageable tolerability in non-small cell lung cancer (NSCLC), especially in patients with high tumor PD-L1 expression, as detected by companion or complementary diagnostic assays developed for individual agents. A laboratory is unlikely to use multiple assay platforms. Furthermore, commercially available diagnostic assays are not standardized, and different assay methods could lead to inappropriate treatment selection. This study establishes the extent of concordance between three validated, commercially available PD-L1 IHC diagnostic assays for NSCLC patients [Ventana SP263 (durvalumab), Dako 22C3 (pembrolizumab), and Dako 28-8 (nivolumab)].Experimental Design: Five hundred formalin-fixed, paraffin-embedded archival NSCLC samples were obtained from commercial sources. Stained slides were read in batches on an assay-by-assay basis by a single pathologist trained in all methods, in a Clinical Laboratory Improvements Amendments program-certified laboratory. An additional pathologist performed an independent review of 200 stained samples for each assay.Results: PD-L1 expression was evaluable with all assays in 493 samples. The three assays showed similar patterns of tumor membrane staining, with high correlation between percent PD-L1 staining. An overall percentage agreement of >90% was achieved between assays at multiple expression cutoffs, including 1%, 10%, 25%, and 50% tumor membrane staining.Conclusions: This study builds optimism that harmonization between assays may be possible, and that the three assays studied could potentially be used interchangeably to identify patients most likely to respond to anti-PD-1/PD-L1 immunotherapies, provided the appropriate clinically defined algorithm and agent are always linked. Clin Cancer Res; 23(14); 3585-91. ©2017 AACR.


Mind bomb 1 is essential for generating functional Notch ligands to activate Notch.
The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis, vasculogenesis and cardiogenesis. The Mib1-/- embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1-/- mutants, Dll1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1-/- embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2, as well as Dll1, Dll3 and Dll4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling.


Membrane scission by the ESCRT-III complex.
The endosomal sorting complex required for transport (ESCRT) system is essential for multivesicular body biogenesis, in which cargo sorting is coupled to the invagination and scission of intralumenal vesicles. The ESCRTs are also needed for budding of enveloped viruses including human immunodeficiency virus 1, and for membrane abscission in cytokinesis. In Saccharomyces cerevisiae, ESCRT-III consists of Vps20, Snf7, Vps24 and Vps2 (also known as Did4), which assemble in that order and require the ATPase Vps4 for their disassembly. In this study, the ESCRT-III-dependent budding and scission of intralumenal vesicles into giant unilamellar vesicles was reconstituted and visualized by fluorescence microscopy. Here we show that three subunits of ESCRT-III, Vps20, Snf7 and Vps24, are sufficient to detach intralumenal vesicles. Vps2, the ESCRT-III subunit responsible for recruiting Vps4, and the ATPase activity of Vps4 were required for ESCRT-III recycling and supported additional rounds of budding. The minimum set of ESCRT-III and Vps4 proteins capable of multiple cycles of vesicle detachment corresponds to the ancient set of ESCRT proteins conserved from archaea to animals.


Effect of autogenous harvest site location on the outcome of ridge augmentation for implant dehiscences.
Treatment planning for the placement of an implant in a site with a thin crestal ridge should address the probability that a buccal dehiscence will result. The aim of the present investigation was to perform guided bone regeneration (GBR) around implants with buccal dehiscences and evaluate the outcomes of using autogenous bone grafts harvested from three different intraoral sites. Forty-six Osseotite implants, 4 mm in diameter, were placed in thin crestal ridges, resulting in an uncovered implant surface from the buccal aspect. The lengths of the buccal dehiscences ranged from 3 to 7 mm as measured from the implant cervix to the most apical extent of the uncovered threads. A standard GBR technique was carried out to augment the bone defect around the buccal implant surface immediately after implant placement. The cases were divided into three groups according to receipt of an autogenous bone graft from the ramus, tuberosity, or mandibular symphysis. In all cases, e-PTFE membranes were used to cover the grafted areas. Grafted sites were exposed after 6 months, membranes were removed, and residual distance between the implant cervix and most uncovered thread was recorded. All grafting materials were able to produce a certain degree of bone regeneration. In terms of bone change level, the three groups were not equal. The mandibular symphysis group exhibited the highest mean bone growth level, followed by the ramus group. The tuberosity produced the poorest result. Mandibular and ramus autogenous bone grafts represent the best choice in materials for GBR procedures around implants, while tuberosity bone grafts can be used as an alternative.


High-frequency steering maneuvers mediated by tactile cues: antennal wall-following in the cockroach.
Cockroaches (Periplaneta americana) use their antennae to detect a wall and to maintain a constant distance from it as they walk or run along it. The faster they run, the closer they position themselves to the wall. They also use their antennae to detect and follow multiple accordion-like projections in the wall. They can make up to 25 body turns s-1 for short periods during rapid running to follow such wall projections. Each turn apparently involves a change in stepping direction. These turns help to avoid collisions with the outward projections, while keeping the body close to the wall. Sensory inputs from the flagellum of the antenna, and not from its base, appear to evoke the turns in response to wall projections. These flagellar inputs appear to report the position along the antenna of its contact with the wall and/or the position of the consequent antennal bend. This flagellar information constitutes a one-dimensional sensory map, with location along the map indicating the distance to the wall.


Neuromuscular recovery in ACL reconstruction with Bone-Tendon-Patellar-Bone and Semitendinosus-Gracilis autograft.
Several different types of grafts have been used in ACL rupture. The purpose of the study was to compare the recovery of lower limbs muscle strength and proprioception in athletes, who underwent ACL reconstruction with Bone-Patellar-Tendon-Bone (BPTB) versus semitendinosus and gracilis (HS) autografts. We enrolled 30 male amateur athletes. Each patient was evaluated by isokinetic test, triaxial accelerometer test and balance test with stabilometric platform. Isokinetic test evaluated quadriceps and hamstrings Peak Torque. Accelerometer test evaluated squat jump test (SJT) and stiffness test (ST). The recording on the balance platform was performed with open and closed eyes and evaluated medio-lateral and anterior-posterior pathways. 30 patients were selected (15 in group BPTB and 15 in group HS). In SJT we noticed a statistically significant difference in height of jump in the involved side in favour of Group BPTB (p=0.037) and not significant difference in the other parameters. In the ST, we did not observe significant statistical differences in the parameters of the test. The stabilometric platform data and isokinetic peak torque parameters did not show a significant difference. Little high quality researches are available to help determine when patients can safely return to full activity and sport. Included evaluation criteria were a combination of factors regarding knee motion, muscles strength and neuromuscular function. In our study, despite a not full recovery of explosive strength in HS group , the balance and the other parameters after one year are comparable between the two graft. In our findings there isn't clinical difference between the two grafts. We suggest that the evaluation of explosive strength and proprioception are the priority parameters in neuromuscular recovery after ACL reconstruction.


Physiological and flesh quality consequences of pre-mortem crowding stress in Atlantic mackerel (Scomber scombrus).
In commercial wild capture pelagic fisheries it is common practice to crowd catches to high densities to allow efficient pumping onboard. Crowding during the final stages of purse seine capture for small pelagic species often results in intense and sustained behavioural escape responses. Such a response may trigger a shift in energy production from aerobic to anaerobic pathways and result in metabolic acid accumulation and exhaustion of intracellular reserves of ATP. Where there is insufficient time or opportunity to recover to physiological equilibrium before death, pre-mortem stress may be an important determinant of fillet quality, as has been shown for a variety of farmed fish species. However, there is currently a lack of knowledge related to the flesh quality implications of capture stress for wild captured species in European waters. Here we show that crowding results in a physiological stress response that has consequences for flesh quality in the wild captured species Atlantic mackerel (Scomber scombrus). Using small schools in tanks and aquaculture net pens in three separate experiments, we found crowding results in physiological changes in mackerel consistent with an acute stress response and anaerobic metabolism. Consequently, we found crowded fish had more acidic pre- and post-mortem muscle pH as well as indications of faster onset and strength of rigor mortis and increased cathepsin B & L activity. We examined fillet flesh quality after two and seven days of ice storage and found reduced green colouration, increased gaping (separation of muscle myotomes) and reduced textural firmness associated with fish which had been crowded. However, the effects on quality were dependant on experiment and/or storage time. These results indicate the potential of crowding capture stress to influence the flesh quality of an economically important species and may have important implications for the wild capture pelagic fishing industry.


Identification and characterization of a novel gene, hshB, in Xanthomonas oryzae pv. oryzicola co-regulated by quorum sensing and clp.
Virulence factors of Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak in rice, are regulated by a diffusible signal factor (DSF)-dependent quorum-sensing (QS) system. In this study, a novel pathogenicity-related gene, Xoryp_010100018570 (named hshB), of X. oryzae pv. oryzicola was characterized. hshB encodes a hydrolase with a putative signal peptide, which is a homolog of imidazolonepropionase. Bioinformatic analysis showed that hshB is relatively conserved in the genus Xanthomonas but the homologous gene of hshB was not found in X. oryzae pv. oryzae. Reverse-transcription polymerase chain reaction (PCR) analysis showed that hshB and its upstream gene, Xoryp_010100018565 (named hshA), are co-transcribed in X. oryzae pv. oryzicola. Subsequent experimental results indicated that mutation of hshB remarkably impaired the virulence, extracellular protease activity, extracellular polysaccharide production, growth in minimal medium, and resistance to oxidative stress and bismerthiazol of X. oryzae pv. oryzicola. Mutation of clp, encoding a global regulator, resulted in similar phenotypes. Real-time PCR assays showed that hshB transcription is positively regulated by clp and DSF, and induced by poor nutrition. Our study not only found a novel gene hshB regulated by DSF-dependent QS system and clp but also showed that hshB was required for virulence of X. oryzae pv. oryzicola.


The price of information: Increased inspection costs reduce the confirmation bias in visual search.
In visual search, there is a confirmation bias such that attention is biased towards stimuli that match a target template, which has been attributed to covert costs of updating the templates that guide search [Rajsic, Wilson, & Pratt, 2015. Confirmation bias in visual search. Journal of Experimental Psychology: Human Perception and Performance. Advance online publication. doi:10.1037/xhp0000090]. In order to provide direct evidence for this speculation, the present study increased the cost of inspections in search by using gaze- and mouse-contingent searches, which restrict the manner in which information in search displays can be accrued, and incur additional motor costs (in the case of mouse-contingent searches). In a fourth experiment, we rhythmically mask elements in the search display to induce temporal inspection costs. Our results indicated that confirmation bias is indeed attenuated when inspection costs are increased. We conclude that confirmation bias results from the low-cost strategy of matching information to a single, concrete visual template, and that more sophisticated guidance strategies will be used when sufficiently beneficial. This demonstrates that search guidance itself comes at a cost, and that the form of guidance adopted in a given search depends on a comparison between guidance costs and the expected benefits of their implementation.


In Vitro Derivation of Melanocytes from Embryonic Neural Crest Stem Cells.
During development, melanocyte progenitors originate from the neural crest, a transient embryonic structure in vertebrates that gives rise to a variety of cell types including neurons and glia of the peripheral nervous system, smooth muscle cells of the cardiovascular system, chondrocytes and osteoblasts of the craniofacial elements, and pigment cells in the skin. In this chapter, we describe a method for the differentiation of multipotent embryonic neural crest stem cells into differentiated pigmented melanocytes by using in vitro explant culture system. This protocol allows the dissection of genetic and cellular mechanisms regulating neural crest stem cell and melanocyte development. Based on this knowledge it is possible to make predictions about processes that might also be implicated in melanoma initiation and progression.


Does preparedness planning improve attitudes and completion of advance directives in patients with symptomatic heart failure?
There is little evidence to support whether interventions that engage patients with symptomatic heart failure (HF) in preparedness planning impacts completion of advance directives (ADs). This study was conducted to assess the impact of a palliative care intervention on health perceptions, attitudes, receipt of information and knowledge of ADs, discussion of ADs with family and physicians, and completion of ADs in a cohort of patients with symptomatic HF. Thirty-six patients hospitalized for HF decompensation were recruited and referred for an outpatient consultation with a palliative care specialist in conjunction with their routine HF follow-up visit after discharge; telephone interviews to assess health status and attitudes toward ADs were conducted before and 3 months after the initial consultation using an adapted version of the Advance Directive Attitude Survey (ADAS). Information pertaining to medical history and ADs was verified through medical chart abstraction. The current study found support for enhancing attitudes and completion of ADs following a palliative care consultation in patients with symptomatic HF. Despite a significant increase in attitudes toward completion of ADs following the intervention, only 47% of the participants completed ADs. This finding suggests that although education and understanding of ADs is important and can result in more positive attitudes, it does not translate to completion of ADs in all patients.


Illusions of visual motion elicited by electrical stimulation of human MT complex.
Human cortical area MT(+) (hMT(+)) is known to respond to visual motion stimuli, but its causal role in the conscious experience of motion remains largely unexplored. Studies in non-human primates demonstrate that altering activity in area MT can influence motion perception judgments, but animal studies are inherently limited in assessing subjective conscious experience. In the current study, we use functional magnetic resonance imaging (fMRI), intracranial electrocorticography (ECoG), and electrical brain stimulation (EBS) in three patients implanted with intracranial electrodes to address the role of area hMT(+) in conscious visual motion perception. We show that in conscious human subjects, reproducible illusory motion can be elicited by electrical stimulation of hMT(+). These visual motion percepts only occurred when the site of stimulation overlapped directly with the region of the brain that had increased fMRI and electrophysiological activity during moving compared to static visual stimuli in the same individual subjects. Electrical stimulation in neighboring regions failed to produce illusory motion. Our study provides evidence for the sufficient causal link between the hMT(+) network and the human conscious experience of visual motion. It also suggests a clear spatial relationship between fMRI signal and ECoG activity in the human brain.


Robot-assisted Sistrunk's operation, total thyroidectomy, and neck dissection via a transaxillary and retroauricular (TARA) approach in papillary carcinoma arising in thyroglossal duct cyst and thyroid gland.
Carcinomas arising in the thyroglossal duct cysts are rare, accounting only for about 0.7-1.5 % of all thyroglossal duct cysts. Synchronous occurrence of thyroglossal duct carcinoma and thyroid carcinoma is reported to be even rarer. Traditionally, surgical treatments of such coexisting thyroglossal duct cyst carcinoma (TGDCa) and papillary thyroid carcinoma (PTC) were typically performed through a single transverse or double incisions on the overlying skin. A longer, extended cervical incision might be required if neck dissection is necessary. Though this method provides the operator with the optimal surgical view, the detrimental cosmetic effect on the patient of possessing a scar cannot be avoided, despite the effort of the surgeon to camouflage the scar by placing the incision in natural skin creases. Recently, the authors have previously reported the feasibility of robot-assisted neck dissections via a transaxillary and retroauricular ("TARA") approach or modified face-lift approach in early head and neck cancers. On the basis of the forementioned surgical technique, we demonstrate our novel technique for robot-assisted Sistrunk's operation via retroauricular approach as well as robot-assisted neck dissection with total thyroidectomy via transaxillary approach. This is a case presentation of a 22-year-old woman with synchronous TGDCa and PTC with minimal lymph node metastasis who underwent resection of TGDCa and total thyroidectomy with left neck level III and IV lymph node dissection as well as central compartment lymph node dissection (CCND) via TARA approach with a robotic surgery system after approval from the institutional review board at Severance Hospital, Yonsei University College of Medicine. The incision was just like the TARA approach in head and neck cancer, which has been reported by our institute. The operation was proceeded as follows. First, excision of the TGDCa through the retroauricular incision was done followed by total thyroidectomy with CCND via transaxillary approach. Finally, neck dissection of left level III, IV was conducted via transaxillary approach. The da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA) was introduced via retroauricular or transaxillary port. A 30° dual-channel endoscope was used, and the two instrument arms were equipped with 5 mm Maryland forceps and a 5 mm spatula monopolar cautery for TGDCa excision via retroauricular approach. When conducting total thyroidectomy and neck dissection via transaxillary approach, three instrument arms were utilized, each equipped with 5 mm Maryland forceps, ProGrasp forceps and a 5 mm spatula monopolar cautery or Harmonic curved shears. The rest of the surgery was completed with the robotic system (see Video). The operative procedure was successfully completed utilizing the robotic surgical system with no conversion to open surgery. The operation time for TGDCa excision was 97 min, including the time for skin flap elevation (15 min), setting up the robotic system (5 min), and console time using the robotic system (77 min). Also, the total operation time for the consecutive total thyroidectomy with CCND and level III, IV dissection was 142 min including the time for skin flap elevation (27 min), setting up the robotic system (3 min), and console time using the robotic system (112 min). There were no intraoperative complications. The retroauricular approach for the removal of the TGDCa allowed for an excellent magnified surgical view revealing important structures of the local anatomy. It also created sufficient space for the cutting of the relevant portion of the hyoid bone. Handling of the robotic instruments through the incision was technically feasible and safe without any mutual collisions throughout the operation. The patient's postoperative parathyroid hormone (PTH) level was within normal range and functions of her both vocal cords were intact. The histopathologic results of the specimens revealed thyroglossal duct cyst with internal papillary carcinoma measuring 1.1 cm with infiltrative tumor margins and papillary microcarcinoma measuring 0.9 cm within the left thyroid lobe with extrathyroidal soft tissue extension. There was no evidence of tumor in the right lobe and the pyramidal lobe of the thyroid gland. As for the lymph nodes resected, 7 out of 9 paratracheal nodes and 2 out of 7 left level III, IV nodes revealed metastatic carcinomas. The patient was discharged on the 8th day after the operation with no complications. The patient was extremely satisfied with the cosmetic results. The patient has received high-dose radioiodine ablation (RAI) therapy and is currently doing well with no evidence of recurrence. Although there is still a great deal of controversy regarding the treatment of TGDCa, there is little debate that for the cases of synchronous TGDCa and PTC, total thyroidectomy in addition to the Sistrunk procedure must be performed. As for the patient in our case where left level IV lymph node metastasis was detected under preoperative ultrasonography (USG), if the usual method of surgical procedure was to be selected, double incisions or a single extended transverse incision must be adopted for the Sistrunk's operation and total thyroidectomy with lateral neck dissection. The conventional method to remove neck masses was to do so by placing an incision on the overlying skin. This 'open' approach to viewing the lesion has an advantage of providing the operator with the best surgical view, but the recognizable surgical scar that results from the surgery can be displeasing for patients. Therefore the surgeon can try to make a small incision and camouflage the scar by placing the incision in natural skin creases, yet the cosmetic results can still be displeasing for the patient due to its visibility and permanence. This can be an even greater problem if the patient is young and an active member of his/her society and if the lesion is benign or low-grade malignancy which can be simply dissected and excised. Therefore it is the surgeon's best interest to perform an operation successfully with a 'least obvious' or 'hidden' scar whenever possible. Accordingly, we have adopted a novel approach, the transaxillary and retroauricular approach, in view of our increasing surgical experience with various indications such as submandibular gland (SMG) resections and neck dissections in head and neck cancer or thyroid papillary carcinoma. Some investigators have demonstrated that robot-assisted neck dissections performed on patients with thyroid cancer and lateral neck node metastasis are feasible and safe. We conducted total thyroidectomy with bilateral CCND and level III and IV dissection using the same approach. Although the technical feasibility and safety of neck dissection or SMG resection via retroauricular approach has already been reported previously at our institute, Sistrunk's operation via retroauricular approach will be challenging. In spite of that, we were able to demonstrate successfully Sistrunk's operation including the hyoid bone resection through the retroauricular approach. There are however, certain areas of potential difficulties which must be considered with caution during the operation procedure. First, when removing the TGDCa through the retroauricular port, identification of the ipsilateral hyoid bone is primarily important and it is also crucial that dissection along the capsule must be done carefully so as not to rupture the tumor. It is essential that sufficient working space must be created for the comfortable movement of the robotic arms through the retroauricular port and in order to do so, sufficient skin flap elevation in both superior and inferior directions must be performed. It is necessary to elevate the superior skin flap up to the level of the inferior border of the mandible but during this process, the platysma muscle must be identified and meticulous dissection along the subplatysmal plane must be carried out so as not to damage the marginal mandibular branch of the facial nerve. Another area of potential pitfalls concerns the total thyroidectomy with neck dissection through the transaxillary port. Sufficient amount of working space must be secured in order to perform comfortably the contralateral thyroidectomy and neck dissection and in order to do so, skin flap elevation must be done at least 2 cm further based on the ipsilateral omohyoid muscle and the contralateral thyroid gland must be adequately exposed. Using the robotic surgical system in removing the thyroglossal duct cyst, the free movement of wristed instrumentation through the retroauricular incision allowed for efficient dissection and easy handling of the tissue. In this particular case we could not identify the tract beyond the hyoid and up to the foramen cecum, but we anticipate that there would be no technical problems of dissection and excision had it been so. To our knowledge, Sistrunk's operation and total thyroidectomy with lateral neck dissection via TARA approach utilizing the robotic surgical system has never been attempted before. It has some advantages over the conventional surgery in terms of cosmesis. However, careful consideration in selecting appropriate cases is required and prospective trials should be conducted to recognize long-term outcomes and to overcome potential limitations.


Developing a pediatric outpatient transplantation program. The Children's Memorial Hospital experience.
We describe the development of a pediatric outpatient transplant program and our initial experience with autologous and allogeneic transplants performed partially or completely in the outpatient setting. Forty-eight autologous and seven allogeneic transplants have been performed in our institution in the outpatient setting between June 1994 and July 2000. The ablation used for the autologous outpatient transplants was VP-16 1000 mg/m2/ day as a continuous infusion for 2 days and Carboplatinum 667mg/m2/day for 2 days. The autologous inpatient transplants received Thio-tepa 300-mg/ m2per day x 3 days and cyclophosphamide 60 mg/kg/day for 4 days. For those patients who received an immune-ablative allogeneic outpatient transplant, the regimen consisted of Fludarabine 30 mg/m2/day for 6 days, followed by busulfan for children less than five years of age 1 mg/kg/dose x 8 doses and for those five years and older 0.8 mg/kg/dose x 8 doses, followed by ATG 40mg/kg/day x 4 days. Engraftment was complete in all transplants achieving an ANC >500 for the outpatient transplant in 15 days (10-35) vs. the inpatient in 15 days (14-58). This was not statistically significant. They achieved un-sustained platelets >20.0 by day 19 (14-58) for the outpatients and day 32 10-64) for the inpatient. The allogeneic immune ablative transplants were considered engrafted when their VNTRs were greater that 30% which was achieved at a median of 13 days (10-27). The economic data showed a statistically significant decrease in charges and direct costs between the outpatient (median charges $30 775, direct costs $8 389) and the inpatient (median charges $99 838, direct costs $42 757) transplants (p0.001). There was no difference in morbidity and mortality between the two groups but the use of empiric amphotericin B was markedly decreased in the outpatient transplants. In conclusion it is feasible and less costly to perform autologous hematopoietic stem cell transplants in the outpatient setting with no increase in morbidity and mortality. For the allogeneic transplants there is not yet enough data to establish a similar conclusion.


A robust and representative lower bound on object processing speed in humans.
How early does the brain decode object categories? Addressing this question is critical to constrain the type of neuronal architecture supporting object categorization. In this context, much effort has been devoted to estimating face processing speed. With onsets estimated from 50 to 150 ms, the timing of the first face-sensitive responses in humans remains controversial. This controversy is due partially to the susceptibility of dynamic brain measurements to filtering distortions and analysis issues. Here, using distributions of single-trial event-related potentials (ERPs), causal filtering, statistical analyses at all electrodes and time points, and effective correction for multiple comparisons, we present evidence that the earliest categorical differences start around 90 ms following stimulus presentation. These results were obtained from a representative group of 120 participants, aged 18-81, who categorized images of faces and noise textures. The results were reliable across testing days, as determined by test-retest assessment in 74 of the participants. Furthermore, a control experiment showed similar ERP onsets for contrasts involving images of houses or white noise. Face onsets did not change with age, suggesting that face sensitivity occurs within 100 ms across the adult lifespan. Finally, the simplicity of the face-texture contrast, and the dominant midline distribution of the effects, suggest the face responses were evoked by relatively simple image properties and are not face specific. Our results provide a new lower benchmark for the earliest neuronal responses to complex objects in the human visual system.


Who or what do young adults hold responsible for men's drunken violence?
Men are more likely than women to perpetrate serious violence when they have consumed alcohol, but alcohol does not affect all men in the same way. This paper considers young adults' attribution about agency (the capacity to act) in men's drunken violence. Interviews about alcohol use in night-time venues, streets or private parties were conducted with 60 young adults aged 18-24 in Melbourne, Australia, and analysed thematically. Participants included seven men who identified as having initiated violence when drunk. Some interviewees stated that men chose to be violent, or that men's violence when they were drunk was purposeful and therefore involved some component of choice. However, much alcohol-related violence enacted by young men was understood (both by men who reported violence and by other young adults) as impelled by forces outside their control. These forces were: diffusely defined effects of drinking alcohol; proclivities of men and masculinity, and the interaction of alcohol and men's bodies to override capacity for judgement and produce an irresistible urge to fight. The latter was at times explained as caused by the mutually reinforcing actions of alcohol and testosterone, providing a particularly persuasive account of men's violence as biologically-determined. These categories encapsulate a set of discursive resources that contribute to the rationalisation, naturalisation and production of men's violence. Participants tended to regard alcohol, masculinities and testosterone as inciting violence predictably and consistently, suggesting that men themselves had relatively little agency over its occurrence. In contrast, research evidence indicates that these actors do not cause violence in any uniform way and that their effects are contingent on changing configurations of factors. Highlighting discrepancies between young adults' understandings of responsibility for men's drunken violence, and those expressed in research, presents additional opportunities for intervention.


Transport-theory-based stochastic image reconstruction of bioluminescent sources.
A stochastic image reconstruction methodology is proposed for solving the highly ill-posed inverse bioluminescent source problem in light-scattering media. The unknown source distribution is expressed in terms of a set of linearly independent source basis functions. The bioluminescent boundary flux originating from each source basis function is computed prior to image reconstruction by solving the equation of radiative transfer. The misfit between the measured and the predicted boundary flux is described by an error function, which is iteratively minimized by stochastically sampling the global parameter space of all basis functions. Selection and alteration mechanisms, which can be guided by evolutionary principles found in nature, lead to new stochastic samples of source distributions for the next iteration cycle. A least-squares-error solution, representing the sought image of the unknown source distribution, is obtained after convergence. Numerical experiments demonstrate the feasibility of reconstructing bioluminescent source distributions in tissuelike media.


Ethnic and gender differences in drinking, smoking and drug taking among adolescents in England: a self-report school-based survey of 15 and 16 year olds.
Concern has been mounting about the increasing numbers of adolescents who (ab)use drugs, alcohol and cigarettes. The aim of this study was to establish the prevalence according to gender and ethnicity of drinking, smoking and drug-use in a representative sample of 15 and 16 year olds. The sample consisted of 6020 15- and 16-year-old pupils from 41 schools in England who completed an anonymous self-report survey. There were clear gender and ethnic differences in self-reported substance use. For example, more males than females reported drinking and drug taking. More females reported smoking, but males were more likely to be heavy smokers. Asian, Black and other boys and Black and Asian girls were less likely to report drinking during a typical week compared to White participants. Asian females were less likely to report smoking compared to White females. Cannabis was the most commonly used drug for both genders. Black males were more likely than White males to have used cannabis, opiates and other drugs. However, Asian females were more likely than their White counterparts to have used opiates, but were significantly less likely to have used cannabis. Asian males were more likely than White males to have used ecstasy. The results confirm gender differences in substance use and demonstrate that there are different patterns of substance use between ethnic groups. These findings have implications for targeting prevention campaigns through the media and educational initiatives.


Caregiver awareness of reproductive health issues for women with intellectual disabilities.
Limited attention has been paid to the issue of reproductive health as it affects women with intellectual disabilities, despite reproductive health being a vital issue in public health policy for women in the general population. This paper describes caregiver awareness of reproductive health issues relative to women with intellectual disabilities who are being cared for in welfare institutions in Taiwan. The study employed a cross-sectional, questionnaire-based study which recruited 1,152 caregivers (response rate = 71.87%) from 32 registered disability welfare institutions in Taiwan. We classified their understanding/awareness of reproductive health issues into four domains: menstrual (1) and menopause (2) issues, sex education (3), and reproductive health services (4). Each domain had five associated yes/no questions and the total score for the four domains was out of a maximum of 20. Data were analyzed using SPSS 15.0 software. We found that most of the caregivers were familiar with matters concerning sex education, menopause, and reproductive health services, but they lacked adequate understanding of issues associated with menstruation in women with ID. Many aspects of reproductive health such as "menstrual pain", "age at menarche", "masturbation", "diet during perimenopause", and "publicly available reproductive health services" were issues in which caregivers lacked adequate knowledge and required further instruction. Logistic regression analysis revealed that female caregivers with a university degree, and those who had experience assisting with reproductive health care were more inclined to have higher reproductive health awareness scores than their counterparts. This study highlights that service providers should offer appropriate reproductive health education to institutional caregivers, and that more attention be focused on the personal experiences and concerns of intellectually disabled women in future research.


Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina.
Hematopoietic stem cell transplantation (HSCT) is an effective mode of consolidation therapy for children with high-risk acute leukemia. In high-income countries, match sibling donor (MSD) and match unrelated donor (MUD) HSCT have similar outcomes, but data are scarce in upper-middle-income countries. Our objective was to compare MSD and MUD HSCT outcomes for children with acute leukemia in Argentina. This was a single-institution retrospective cohort study. We included children with acute leukemia who underwent HSCT with either MSD or MUD between 2014 and 2019. The study included 45 patients who received MSD (n=27) or MUD (n=18) for acute leukemia. Event-free survival was not significantly different between MSD (62.3±10.7%) versus MUD (54.2±15.0%; P=0.54) at 5 years. Similarly, there was no significant difference in 5-year overall survival between MSD (71.9±9.8%) versus MUD (65.1±13.5%; P=0.38). The cumulative incidence of treatment-related mortality (P=0.31), cumulative incidence of relapse (P=0.99), and proportion with acute-graft-versus-host disease (P=0.76) and chronic-graft-versus-host disease (P=0.68) were also not significantly different. In Argentina, we did not show significant differences in outcomes between MSD and MUD HSCT for children with high-risk leukemia. Future work should focus on strategies to reduce the relapse risk in children with high-risk leukemia in upper-middle-income countries.


Management of atrial fibrillation in the acute setting.
The review aims to describe the scope of the problem and potential therapeutic intervention for the management and risk stratification of patients with atrial fibrillation in the emergency department and acute care setting. Atrial fibrillation is the most common arrhythmia prompting admission to the hospital. Management strategies include determining the trigger of the arrhythmia, rate control, and potential cardioversion. In the acute care setting the treatment is often dependent on the timing of the onset of arrhythmia. In those patients presenting with symptoms of less than 48 h of duration management may consist of rate control, pharmacologic, or electrical cardioversion. Recent studies suggest no difference in long-term outcomes with rate and rhythm control. In patients with symptoms greater that 48 h rate control is the initial option with potential for cardioversion as an outpatient. There are recent advances in ablation that provide additional options to patients with paroxysmal atrial fibrillation. An essential component of the treatment strategy for these patients is risk stratification for stroke and the initiation of long-term anticoagulation in appropriate patients. Management of atrial fibrillation is guided by underlying causes of the atrial fibrillation and duration of symptoms.


Seroprevalence of Brucellosis in Human Immunodeficiency Virus Infected Patients in Hamadan, Iran.
Brucellosis is a systemic disease with a wide spectrum of clinical manifestations. This study aimed to determine the seroprevalence of brucellosis in human immunodeficiency virus (HIV) infected patients in Hamadan Province in the west of Iran. A total of 157 HIV-infected patients were screened through standard serological tests, including Wright's test, Coombs' Wright test, and 2-mercaptoethanol Brucella agglutination test (2ME test), blood cultures in Castaneda media, and CD4 counting. Data were analyzed using Stata version 11. Wright and Coombs' Wright tests were carried out, and only 5 (3.2%) patients had positive serological results. However, all patients had negative 2ME results, and blood cultures were negative for Brucella spp. Moreover, patients with positive serology and a mean CD4 count of 355.8 ± 203.11 cells/μL had no clinical manifestations of brucellosis, and, and the other patients had a mean CD4 count of 335.55 ± 261.71 cells/μL. Results of this study showed that HIV infection is not a predisposing factor of acquiring brucellosis.


Staff acceptance of a telemedicine intensive care unit program: a qualitative study.
We conducted an evaluation to identify factors related to intensive care unit (ICU) staff acceptance of a telemedicine ICU (Tele-ICU) program in preimplementation and postimplementation phases. Individual or group semistructured interviews and site observations were conducted with staff from the Veterans Affairs Midwest Health Care Network Tele-ICU and affiliated ICUs. A qualitative content analysis of preimplementation and postimplementation transcripts and field notes was undertaken to identify themes positively and negatively influencing Tele-ICU acceptance. Telemedicine ICU training, Tele-ICU understanding, perceived need, and organizational factors emerged as influencing acceptance of the Tele-ICU before implementation. After implementation, Tele-ICU understanding, impact on work systems, perceived usefulness, and relationships were factors influencing acceptance and utilization. Barriers to implementation included confusion about how to use the Tele-ICU, disruptions to communication and workflows, unmet expectations, and discomfort with being monitored. Facilitators included positive experiences, discovery of new benefits, and recognition of Tele-ICU staff as complementing bedside care. Telemedicine ICU implementation is complex. Time and resources should be allocated for local coordination, continuous needs assessment for Tele-ICU support, staff training, developing interpersonal relationships, and systems design and evaluation. Such efforts are likely to be rewarded with more rapid staff acceptance of this new technology.


Comparison of 18FDG-PET with CT scans in the evaluation of patients with residual and recurrent Hodgkin's lymphoma.
The reliable assessment of residual masses after treatment as well as of new lesions suspected for relapse remains a diagnostic problem in patients with Hodgkin's disease (HD). The current study compares the results obtained by CT scan to FDG-PET imaging in a blind analysis with respect to the viability of residual masses and in case of suspected relapse. Between 1/94 and 10/99, 47 comparisons of PET and corresponding CT scans - 26 comparisons in 24 patients with residual tumors and 21 comparisons in 20 patients with suspected relapse of HD - were evaluated by independent reviewers blinded to he results of each other. Patients with primary diagnosis had been treated within trials of the German HD Trial study group. Relapsed patients received intensified salvage chemotherapy regimens. PET was assessed visually and by quantifying glucose uptake (SUV). Changes in size of tumor lesions as well as contrast medium enhancement served as criteria for assessment by CT scans. Results were validated either by histologic examination of a resected mass or biopsy (n=17) or by a clinical follow-up over 6 months following treatment (n=30). In 26 cases with residual lesions FDG-PET showed an increased tracer uptake in 8, 7 of which were true positive (TP) and 1 false positive (FP). Eighteen cases were classified as being negative (no viable HD), 17 true negative (TN) and 1 FN. In the blinded reading of the corresponding CT scans, 10 cases with residual lesions were considered to contain vital lymphoma (2 TP, 8 FP). Sixteen CT scans were classified as negative (10 TP, 6 FN). The resulting sensitivity and specificity of PET were 87.5% and 94.4% in contrast to only 25% and 56% for CT scans. The positive and negative predictive values of PET and CT scans were 87.5% and 94.4% and 20% and 62.5%, respectively. In patients with suspected relapse, sensitivity and positive predictive value for the diagnosis of the relapse were 100% and 86%, respectively, yielding the same results for both methods. FDG-PET performed in HD patients with residual masses appears to offer important additional information regarding the presence of viable HD in these residual lesions. In patients with suspected relapse of HD, FDG-PET seems not to offer any information over CT scans. Using SUVs is not superior to visual assessment of PET alone.


Objective assessment of cosmetic outcome after targeted intraoperative radiotherapy in breast cancer: results from a randomised controlled trial.
The international randomised targeted intraoperative radiotherapy (TARGIT) trial has demonstrated evidence of non-inferiority between the novel technique of TARGIT (intra-operative radiotherapy with Intrabeam(®)) and conventional external beam radiotherapy (EBRT) in women with early breast cancer in terms of the primary outcome measure of risk of local relapse within the treated breast. Cosmesis is an increasingly important outcome of breast conserving treatment with both surgery and radiotherapy contributing to this. It was unknown if the single high dose of TARGIT may lead to damaging fibrosis and thus impair cosmesis further, so we objectively evaluated the aesthetic outcome of patients within the TARGIT randomised controlled trial. We have used an objective assessment tool for evaluation of cosmetic outcome. Frontal digital photographs were taken at baseline (before TARGIT or EBRT) and yearly thereafter for up to 5 years. The photographs were analysed by BCCT.core, a validated software which produces a composite score based on symmetry, colour and scar. 342 patients were assessed, median age at baseline 64 years (IQR 59-68). The scores were dichotomised into Excellent and Good (EG), and Fair and Poor (FP). There were statistically significant increases in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group at year 1 (OR 2.07, 95 % CI 1.12-3.85, p = 0.021) and year 2 (OR 2.11, 95 % CI 1.0-4.45, p = 0.05). Following a totally objective assessment in a randomised setting, the aesthetic outcome of patients demonstrates that those treated with TARGIT have a superior cosmetic result to those patients who received conventional external beam radiotherapy.


The effects of the change in the NRMP matching algorithm. National Resident Matching Program.
Following 2 years of heated controversy about the resident match, the National Resident Matching Program (NRMP) recently voted to replace the existing matching algorithm with a newly designed applicant-proposing algorithm. To design an applicant-proposing algorithm for the match and compare it with the existing NRMP algorithm to determine how many applicants and residency programs could be expected to receive better or worse matches from the 2 algorithms, how the different algorithms influence the opportunity for strategic behavior, and what advice can be given to participants. Computational experiments compared the newly designed applicant-proposing algorithm with the existing NRMP algorithm on the rank order lists (ROLs) submitted by all applicants and residency programs in the 1987 and 1993 through 1996 NRMP matches. Differences in the matchings produced by the 2 algorithms are small: fewer than 1 in 1000 applicants would have received a different match. Most (but not all) of the few applicants who are matched to different positions by the 2 algorithms do better when the applicant-proposing algorithm is used; the opposite is true for programs. Opportunities for profitable strategic behavior are very rare for both applicants and programs under either algorithm. With either algorithm, both applicants and programs can be advised that trying to get a preferred match by behaving strategically is far more likely to harm than to help them. The existing NRMP algorithm and the newly designed applicant-proposing algorithm perform similarly. Both algorithms make it sensible for applicants and residency programs to arrange their ROLs based solely on their preferences for possible matches. The choice of algorithms will systematically affect the matches of only a small group of applicants (<0.1%). The NRMP's recent decision to use the applicant-proposing algorithm starting in 1998 reflects a judgment about the impact of this difference on applicants and programs.


Implementation of an acceptance- and mindfulness-based group for depression and anxiety in primary care: Initial outcomes.
Depression and anxiety disorders are highly prevalent among primary care patients. Group visits provide a way of delivering interventions to multiple patients at the same time. Group visits for depression and anxiety present an opportunity to expand the reach of behavioral health services for primary care patients. The goal of the current study was to evaluate the implementation of an acceptance and mindfulness-based group for primary care patients with depression and anxiety. Adult family medicine patients with Patient Health Questionnaire-9 (PHQ-9) and/or Generalized Anxiety Disorder Scale-7 (GAD-7) scores > 5 were eligible for the group. The group was held biweekly in the family medicine practice with rolling enrollment. The PHQ-9 and GAD-7 were administered at every visit, and changes in depression and anxiety symptoms were analyzed using multilevel modeling. We evaluated feasibility, acceptability/satisfaction, penetration, and sustainability. Over the course of 19 months, 50 patients were referred to the group, and 29 enrolled. The median number of visits attended was four among those who attended more than one group visit. Results revealed that depression and anxiety symptoms decreased significantly over the first four visits attended (d = -.26 and -.19, respectively). Patients who attended more than one group reported high satisfaction. The group was sustainable after the research funding ended; however, penetration was low. A rolling enrollment group for patients with depression and anxiety that utilized mindfulness- and acceptance-based treatment principles is feasible to implement in a primary care setting but is not without challenges. Recommendations for ways to enhance implementation and future research are provided. (PsycINFO Database Record


Evaluation of in vivo activation of protein kinase A under non-dissociable conditions through the overexpression of wild-type and mutant regulatory subunits in Saccharomyces cerevisiae.
BCY1-encoded protein kinase A (PKA) wild-type and mutant regulatory (R) subunits from Saccharomyces cerevisiae were inducibly overexpressed in their corresponding background strains containing the same mutation in the bcy1 gene. The aim of this approach was to shift the catalytic activity of PKA within the cell to the undissociated holoenzyme form(s) in order to evaluate whether the wild-type or the mutant forms of the holoenzyme could display catalytic activity. Two mutants of R subunits were used: bcy1-16, with a complete deletion of cAMP-binding domain B; and bcy1-14, with a small deletion in the carboxy terminus of cAMP-binding domain A. Their overexpression caused an increase in the level of R subunits in the range 40-90-fold, as detected by cAMP-binding activity, Coomasie-stained SDS-PAGE and Western blot analysis. The change in PKA activity attained by overexpression of R was assessed in three ways: (i) through the analysis of PKA-dependent phenotypes, and (ii, iii) by measurement of PKA activity -/+ cAMP using the specific substrate kemptide in crude extracts (ii) and permeabilized cells (iii). Upon overexpression of the R subunits, PKA-dependent phenotypes were less severe when compared with their own background. However, a gradient in the degree of severity of phenotypes bcy1-14>bcy1-16> wild-type was observed in the background strains and was maintained in the strains overexpressing the R subunits. cAMP levels measured in background and in R-overexpressing strains showed an increase of around two orders accompanying the overexpression of the R subunits. Three main conclusions could be drawn from the PKA activity measurements -/+ cAMP in crude extracts: (i) catalytic activity was not increased in compensation for the increase in R subunits in any of the three cases (wild-type, bcy1-16 or bcy1-14 overexpression); (ii) PKA activity assayed in the absence of cAMP was lower in the case of extracts from strains overexpressing wild-type or bcy1-16 R subunits when compared with the corresponding extracts without overexpression; and (iii) in these two cases, the great excess of R subunits in the crude extracts displayed additional inhibitory capacity towards exogenously added catalytic (C) subunits. To provide an estimate of the in vivo activation of PKA, permeabilized cells from control strains and strains transformed with either wild-type, bcy1-16 or bcy1-14 R subunits were used to measure PKA activity in the presence of variable concentrations of cAMP. There were two main observations from the results: (i) the activity of PKA detected in the absence of exogenous cAMP was decreased in the strains overexpressing the R subunits when compared to their corresponding backgrounds, and (ii) the sensitivity to activation by cAMP was decreased or almost nil. The biochemical and genetic results obtained are consistent with the hypothesis that within the cell it is possible to have catalytically active, cAMP-bound, undissociated PKA holoenzyme.


Audio-visual temporal perception in children with restored hearing.
It is not clear how audio-visual temporal perception develops in children with restored hearing. In this study we measured temporal discrimination thresholds with an audio-visual temporal bisection task in 9 deaf children with restored audition, and 22 typically hearing children. In typically hearing children, audition was more precise than vision, with no gain in multisensory conditions (as previously reported in Gori et al. (2012b)). However, deaf children with restored audition showed similar thresholds for audio and visual thresholds and some evidence of gain in audio-visual temporal multisensory conditions. Interestingly, we found a strong correlation between auditory weighting of multisensory signals and quality of language: patients who gave more weight to audition had better language skills. Similarly, auditory thresholds for the temporal bisection task were also a good predictor of language skills. This result supports the idea that the temporal auditory processing is associated with language development.


Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis.
Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.).


Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells.
Alterations of endothelial adhesive properties by cigarette smoke (CS) can progressively favor the development of atherosclerosis which may cause cardiovascular disorders. Modified risk tobacco products (MRTPs) are tobacco products developed to reduce smoking-related risks. A systems biology/toxicology approach combined with a functional in vitro adhesion assay was used to assess the impact of a candidate heat-not-burn technology-based MRTP, Tobacco Heating System (THS) 2.2, on the adhesion of monocytic cells to human coronary arterial endothelial cells (HCAECs) compared with a reference cigarette (3R4F). HCAECs were treated for 4h with conditioned media of human monocytic Mono Mac 6 (MM6) cells preincubated with low or high concentrations of aqueous extracts from THS2.2 aerosol or 3R4F smoke for 2h (indirect treatment), unconditioned media (direct treatment), or fresh aqueous aerosol/smoke extracts (fresh direct treatment). Functional and molecular investigations revealed that aqueous 3R4F smoke extract promoted the adhesion of MM6 cells to HCAECs via distinct direct and indirect concentration-dependent mechanisms. Using the same approach, we identified significantly reduced effects of aqueous THS2.2 aerosol extract on MM6 cell-HCAEC adhesion, and reduced molecular changes in endothelial and monocytic cells. Ten- and 20-fold increased concentrations of aqueous THS2.2 aerosol extract were necessary to elicit similar effects to those measured with 3R4F in both fresh direct and indirect exposure modalities, respectively. Our systems toxicology study demonstrated reduced effects of an aqueous aerosol extract from the candidate MRTP, THS2.2, using the adhesion of monocytic cells to human coronary endothelial cells as a surrogate pathophysiologically relevant event in atherogenesis.


Involvement of DNA polymerase mu in the repair of a specific subset of DNA double-strand breaks in mammalian cells.
The repair of DNA double-strand breaks (DSB) requires processing of the broken ends to complete the ligation process. Recently, it has been shown that DNA polymerase mu (polmu) and DNA polymerase lambda (pollambda) are both involved in such processing during non-homologous end joining in vitro. However, no phenotype was observed in animal models defective for either polmu and/or pollambda. Such observations could result from a functional redundancy shared by the X family of DNA polymerases. To avoid such redundancy and to clarify the role of polmu in the end joining process, we generated cells over-expressing the wild type as well as an inactive form of polmu (polmuD). We observed that cell sensitivity to ionizing radiation (IR) was increased when either polmu or polmuD was over-expressed. However, the genetic instability in response to IR increased only in cells expressing polmuD. Moreover, analysis of intrachromosomal repair of the I-SceI-induced DNA DSB, did not reveal any effect of either polmu or polmuD expression on the efficiency of ligation of both cohesive and partially complementary ends. Finally, the sequences of the repaired ends were specifically affected when polmu or polmuD was over-expressed, supporting the hypothesis that polmu could be involved in the repair of a DSB subset when resolution of junctions requires some gap filling.


Platelet and neutrophil distributions in pump oxygenator circuits. III. Influence of nitric oxide gas infusion.
The authors used quantitative gamma scintigraphy to evaluate the influence of nitric oxide gas on platelet and neutrophil deposition in Cobe Duo microporous oxygenators during cardiopulmonary bypass (CPB). The effects of nitric oxide gas on circulating platelet and neutrophil counts and platelet function also were assessed. Animals were prepared by standard methods. Cells were harvested, labeled (111 In platelet and 99mTc neutrophil), infused, and recirculated. Nitric oxide gas, a guanylate cyclase pathway promoter, was infused int he Duo gas port at 500 ppm (t = 0-60 min), increased to 1,000 (t = 60-80 min), and stopped (final, 10 min). Images were taken at 10-15 min intervals during CPB. Standard isotope image corrections were made. No differences between nitric oxide gas and control experiments were observed for flow, pressure, hematocrit, or replacement volume. Nitric oxide gas infusion significantly (p < 0.05) reduced both platelet adherence to the oxygenator and in vitro platelet aggregation. Neutrophil adhesion tended to be lower, and circulating platelet and neutrophil counts tended to be higher with nitric oxide gas infusion. Results of in vitro aggregometry studies using rabbit platelets indicate that the class V phosphodiesterase inhibitor zaprinast can strongly enhance the inhibitory effects of nitric oxide. The authors conclude nitric oxide gas is a promising platelet sparing agent in the setting of CPB.


Protective effects of polyphenol-rich blackcurrant preparation on biochemical and metabolic biomarkers of rats fed a diet high in fructose.
The purpose of the study was to compare in vivo effects of dietary supplementation with blackcurrant pomaces containing variable level of phenolic compounds on blood and internal organ parameters in rats. Forty-eight growing Wistar rats were allocated to six treatment groups in which they were fed ad libitum for 4 weeks the following diets: standard chow (group S), high-fructose diet (group F), standard chow supplemented with 7.7% of either rich in polyphenols unprocessed blackcurrant pomace (UB) or polyphenol-deprived processed pomace (PB) (groups SUB and SPB respectively), and high-fructose diet with 7.7% of either UB or PB (groups FUB and FPB respectively). Blackcurrant pomace, irrespective of its phenolic content, selectively modulated the enzymatic activity of the colon microflora, reducing the activity of enzymes with potentially harmful properties and promoting activities of enzymes that might increase the use of carbohydrates that escaped digestion in the upper gastrointestinal tract. Although both pomaces increased antioxidant status of the liver and blood serum, the unprocessed pomace showed a greater ability to inhibit lipid peroxidation in heart and kidney than the pomace that was less abundant in polyphenols. Both of the examined pomaces had a positive influence on serum lipid profile, but better hypocholesterolemic effect was observed after supplementation of the diet with unprocessed preparation. The biochemical action of unprocessed pomace in the normalization of fructose-induced disturbances was more distinct than those of pomace remaining after extraction.


The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes.
HIV enters the brain soon after virus exposure but elicits profound neurological deficits in infected humans years later usually during progressive immunosuppression and the development of the acquired immune deficiency syndrome. The neurological disease complex associated with virus infection occurs in a large proportion of infected patients and is commonly referred to as HIV-1 associated dementia complex. The neuropathogenesis of central nervous system/viral infection revolves around mononuclear phagocytes (brain macrophage/microglial) infection and immune activation in brain. Macrophages secrete neurotoxic factors that elicit neuronal injury and inevitably death leading to the constellation of cognitive and motor impairments common during progressive disease. Neurotoxic factor production requires virus entry and replication, the evolution/selection of neurovirulent HIV-1 strains and the production of viral and cellular immune factors injurious to human neurons. Interestingly, neurological deficits, the HIV-1 associated neuropathology and viral replication disease are not always associated. This has led to the notion that viral replication induces the autocrine/paracrine production of cellular/viral factors leading to a metabolic encephalopathy. Anti-retroviral and anti-inflammatory therapies should prove increasingly beneficial for treatment and, ultimately, reversal of HIV-1 associated dementia complex in the affected human host.


Typhoid fever at a resort hotel in New York: a large outbreak with an unusual vehicle.
The largest outbreak of typhoid fever in the United States since 1981 occurred in 1989 among guests and staff at a New York hotel. There were 43 culture-confirmed and 24 probable cases among guests, 1 culture-confirmed case and 1 asymptomatic culture-positive case among hotel employees, and 1 culture-confirmed secondary case. Twenty-one persons were hospitalized and 2 had bowel perforation. Breakfast on 13 June was the only meal consumed by all ill persons (relative risk, infinite; P = .004). In a case-control study, case-patients were more likely than controls to have consumed orange juice (odds ratio, 5.6; 95% confidence interval, 1.1-54.7), which had been prepared in a 208-L container with ample opportunity for hand contact. No other food was associated with illness. S. typhi was isolated from the stool of an asymptomatic food worker who handled orange juice but who was not known to be a typhoid carrier. S. typhi is a foodborne pathogen with continuing potential to cause large outbreaks in the United States.


A history of One Health.
One Health is not a new concept. It can be demonstrated that its origins and development literally run the gamut from A to Z, that is to say, from Aristotle to Zoobiquity. Indeed, the consequences of the interaction that occurs between ecosystems, animals and people have shaped, and continue to shape, the course of human events and history. A reasoned and evidence-based assessment of the history of One Health must first be founded on an agreed definition of the term, but, given the many disciplines and sciences involved, finding such a definition is no easy task. Furthermore, there is an extensive and growing list of visionary individuals who have, over the centuries, attempted to promote awareness and advance the conceptto improve the management of the risks and consequences that arise at the interface between animal, human and ecosystem health. The One Health ideas of the 21st Century constitute a re-conceptualisation of health management in response to the accelerating environmental changes of the past 100 years, changes that are associated with the parallel exponential growth and concentration of the global human population. Consequently, the concept of One Health must recognise the constantly evolving relationship between animals and humans and the planet they share.