Magnetization and electron paramagnetic resonance studies of reduced uteroferrin and its "EPR-silent" phosphate complex.
The exchange coupling of reduced uteroferrin has been measured (19.8(5) cm-1 S1.S2) using recently developed techniques for studying metalloprotein magnetization. A spin Hamiltonian describing the coupled binuclear Fe(II).Fe(III) center has been used to fit the low and high field magnetization data, the EPR g values, and the highly anisotropic effective hyperfine tensor of the ferric site. The exchange coupling of the phosphate complex of reduced uteroferrin has also been measured (6.0(5) cm-1 S1.S2) using the same techniques. The smaller exchange coupling of the phosphate complex is comparable with the zero field splittings of the iron sites. This results in increased sensitivity of the system g values (found by calculation from the spin Hamiltonian) to variations of the zero field splitting parameters arising from heterogeneities in the protein microenvironment. Consequently, there is a very significant (9-fold) increase in the "effective g strain" of the system compared to the situation in the absence of phosphate. This, together with the larger g anisotropy (g = (1.06, 1.51, 2.27)), gives rise to an EPR signal for the phosphate complex of reduced uteroferrin which is extremely broad and difficult to detect but which has now been identified for the first time.


First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer.
A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.


Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes.
Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity.


Testing sleeping bags according to EN 13537:2002: details that make the difference.
The European Standard on sleeping bag requirements (EN 13537:2002) describes a procedure to determine environmental temperature limits for safe usage of sleeping bags regarding their thermal insulation. However, there are several possible sources of error related to this procedure. The main aim of this work was to determine the influence of the various measuring parameters on the acuity of the respective parameters in order to judge the requirements. The results indicated that air velocity, mattress insulation and time between unpacking the bag and measurement had a significant impact on the result, with a difference of up to 5-15% in thermal insulation between minimum and maximum allowable parameter levels. On the other hand, manikin weight, thickness of the artificial ground and presence of a face mask were found to have a negligible influence. The article also discusses more general aspects of the standard including the calculation methods used.


Flow cytometric evaluation of bone marrow plasma cells using CD19, CD45, CD56, CD38, and CD138 and correlation with bone marrow infiltration ratio in multiple myeloma patients.
To examine the co-expression of CD19, CD45, CD38, CD56, and CD138 molecules in plasma cells of bone marrow (BM) aspirates and their relation with BM infiltration, and treatment in patients with multiple myeloma by flow cytometry. Forty BM aspirate samples were assessed from 40 patients at diagnosis and on follow-up at the Medical Oncology Department, Cukurova University, Balcali Hospital, Turkey, between 2002 and 2004. The mean age was 56.83 +/- 9.1 and male:female ratio was 2.6. All patients received at least 4 courses of VAD(vincristine, adriamycin, dexamethasone) regimens and 20 of them were also treated with high dose melphalan and peripheral autologous stem cell transplantation. The median follow-up period was 19.1 +/- 22.7 months. Using light microscopy the BM smears stained with hematoxylin and eosin from patients on follow up were classified into one of 3 categories, complete remission (CR) (<5%), partial remission (PR) (>5% and <30%), and extensive infiltration (EI) (>30%). According to infiltration ratio 23 were evaluated CR, 2 were PR and 15 were EI. The mean value of CD19 was 6.01 +/- 9.5%, CD56 = 9.9 +/- 6.8%, CD138 = 8.6 +/- 5.6%, CD45 = 84.2 +/- 22.3% and CD38 = 59.5 +/- 25.4%. The flow cytometric analyses revealed that only the mean value of CD38 and CD45 expression were significantly high. We correlated infiltration ratio with each parametric and found statistically significant relations. We also correlated independent variables with each other and found a relation between CD38 and CD19 (p=0.005). We also defined the groups whether treated with peripheral autologous transplantation or not and compared the independent variables between them, in which CD138 was statistically significant (p=0.02). We suggest BM plasma cells expressed mainly by CD38 and CD45 may have a role in generation of BM plasma cells and that CD138 expression may be considered in follow-up for minimal residual disease after autologous transplantation in myeloma patients.


Cell type-specific responses to wingless, hedgehog and decapentaplegic are essential for patterning early eye-antenna disc in Drosophila.
The Drosophila eye-antenna imaginal disc (ead) is a flattened sac of two-layered epithelia, from which most head structures are derived. Secreted morphogens like Wingless (Wg), Hedgehog (Hh), and Decapentaplegic (Dpp) are important for early patterning of ead, but the underlying mechanisms are still largely unknown. To understand how these morphogens function in the ead of early larval stages, we used wg-LacZ and dpp-Gal4 markers for the examination of wild-type and mutant eads. We found that the ead immediately after hatching was crescent-shaped with the Bolwig's nerve at the ventral edge, suggesting that it consists of dorsal domain. In a subsequent step, transcriptional induction of dpp in the cells along the Bolwig's nerve was followed by rapid growth of the ventral domain. Both Wg and Hh were required for the formation of the ventral domain. Wg was crucial for the growth of the entire ead, but Hh was essential for cell division only in the dorsal domain. In the ventral domain, Hh regulated dpp transcription. Based on these data, we propose that signaling among distinct groups of cells expressing Wg, Dpp, or Hh in the ead of the first-instar larvae are critical for coordinated growth and patterning of ead.


The EspD protein of enterohemorrhagic Escherichia coli is required for the formation of bacterial surface appendages and is incorporated in the cytoplasmic membranes of target cells.
The formation of EspA-containing surface appendages in pathogenic Escherichia coli strains, both enteropathogenic E. coli (EPEC) and Shiga toxin-producing E. coli strains, is essential for critical events in the infective process, e.g., localized bacterial adherence to host cells with formation of microcolonies and induction of attaching and effacing lesions. It has been reported that EPEC mutants deficient in the production of EspD, which is encoded by the esp operon, are unable to accumulate actin underneath adherent bacteria but exhibit an attachment similar to that of the wild type. Here, we report the construction and characterization of an in-frame espD deletion mutant of the enterohemorrhagic E. coli (EHEC) strain EDL933. In contrast to what was observed in EPEC mutants, the EDL933 espD mutant not only lacked the capacity to accumulate actin but also exhibited an impaired attachment to HeLa cells. The synthesis of the EspD protein was also essential for the formation of EspA-containing filaments. Finally, localization studies demonstrated that the EspD protein is transferred to the cytoplasm and integrated into the cytoplasmic membranes of infected cells. These results help to elucidate the underlying molecular events in infections caused by EHEC.


Daytime variation in performance and tiredness/sleepiness ratings in patients with insomnia, narcolepsy, sleep apnea and normal controls.
Daytime tiredness or sleepiness and deficits in cognitive performance are common complaints in sleep disordered patients. Till now there are few studies comparing patients from different diagnostic groups of sleep disorders in the same experimental protocol. We studied the time course of cognitive functions and subjective alertness in a parallel group design with four groups of patients [narcolepsy, untreated or treated obstructive sleep apnea (OSA), or psychophysiological insomnia] and a control group of subjects without sleep complaints. Each group consisted of 10 subjects, matched for age and gender. After a night with polysomnography, subjects were studied for 10 h from 08:00 hours to 18:00 hours at 20 min intervals under standardized environmental conditions. Four psychological tests were applied, (1) a critical flicker fusion (CFF) test to measure optical fusion threshold (alertness); (2) a paper-and-pencil visual line tracking test (selective attention); (3) a visual analog scale (VAS) for tiredness/sleepiness; and (4) the Tiredness Symptoms Scale (TSS), a 14 items check list. Each test session lasted for 8 min, followed by a 12 min pause. The level and time course of cognitive performance and self-rating data were analysed with hierarchical linear mixed effects models. Cognitive tests showed decrements in alertness and selective attention in untreated patients with insomnia, narcolepsy, and sleep apnea. Narcoleptic patients and untreated OSA had a lower CFF threshold than controls, and for narcoleptic patients the time course differed from that of all other groups. In the visual tracking test the performance of all groups of patients was worse compared with normal controls. Self-rated tiredness/sleepiness was significantly more pronounced in the three groups of untreated patients than in control subjects.


Socio-economic determinants of mortality in Taiwan: combining individual and aggregate data.
There is a very large literature that examines the relationship between health and income. Two main hypotheses have been investigated: the income inequality hypothesis and the absolute income hypothesis. Most of previous studies that used mortality data have been criticized for estimating an aggregate model that does not account for non-linear links between health and income at the individual level. In this paper we follow a novel approach to avoid this bias, combining aggregate mortality data with individual-level data on socio-economic characteristics. We test the income inequality and absolute income hypotheses using county-level mortality data from Life Statistic of Department of Health and individual-level data from Taiwan census Family Income and Expenditure Survey (FIES) for 1976-2004. We find the evidence to support the absolute income hypothesis but not income inequality hypothesis in the case of the general population. We also find strong evidence that education does have significant effects on individuals' health and the estimates are not sensitive to income equivalent scales.


The role of upfront autologous stem cell transplantation in high-risk younger patients with primary central nervous system lymphoma.
Upfront autologous stem cell transplantation (ASCT) has shown favourable outcome in patients with primary central nervous system lymphoma (PCNSL), but the role of risk-adapted upfront ASCT consolidation has not been evaluated in PCNSL. As PCNSL patients with the International Extranodal Lymphoma Study Group (IELSG) prognostic score ≥2 or those who did not achieve complete response after two courses of induction chemotherapy (non-CR1) have shown inferior outcomes, we retrospectively analysed the role of upfront ASCT in 66 high-risk (IELSG ≥2 and/or non-CR1) younger (age <65 years) immunocompetent PCNSL patients who achieved at least partial response after initial high-dose methotrexate-based chemotherapy. Nineteen patients who received upfront ASCT exhibited significantly better overall survival (OS, P = 0·021) and progression-free survival (PFS, P = 0·005) compared to 47 patients who did not. In univariate and multivariate analyses, upfront ASCT was associated with better OS (P = 0·037 and P = 0·025, respectively) and PFS (P = 0·009 and P = 0·007, respectively). In a propensity score-matched cohort (n = 36), patients who received upfront ASCT also showed better outcome (P = 0·037 for OS, P = 0·001 for PFS). Our results suggest that upfront ASCT consolidation might be especially beneficial for high-risk PCNSL patients.


Ca(2+)-activated Cl(-) current in sheep lymphatic smooth muscle.
Freshly dispersed sheep mesenteric lymphatic smooth muscle cells were studied at 37 degrees C using the perforated patch-clamp technique with Cs(+)- and K(+)-filled pipettes. Depolarizing steps evoked currents that consisted of L-type Ca(2+) [I(Ca(L))] current and a slowly developing current. The slow current reversed at 1 +/- 1.5 mV with symmetrical Cl(-) concentrations compared with 23.2 +/- 1.2 mV (n = 5) and -34.3 +/- 3.5 mV (n = 4) when external Cl(-) was substituted with either glutamate (86 mM) or I(-) (125 mM). Nifedipine (1 microM) blocked and BAY K 8644 enhanced I(Ca(L)), the slow-developing sustained current, and the tail current. The Cl(-) channel blocker anthracene-9-carboxylic acid (9-AC) reduced only the slowly developing inward and tail currents. Application of caffeine (10 mM) to voltage-clamped cells evoked currents that reversed close to the Cl(-) equilibrium potential and were sensitive to 9-AC. Small spontaneous transient depolarizations and larger action potentials were observed in current clamp, and these were blocked by 9-AC. Evoked action potentials were triphasic and had a prominent plateau phase that was selectively blocked by 9-AC. Similarly, fluid output was reduced by 9-AC in doubly cannulated segments of spontaneously pumping sheep lymphatics, suggesting that the Ca(2+)-activated Cl(-) current plays an important role in the electrical activity underlying spontaneous activity in this tissue.


Potential of in-situ sensors with ion-selective electrodes for aeration control at wastewater treatment plants.
A pilot-scale activated sludge wastewater treatment plant (WWTP) operated with nitrification and pre-denitrification was monitored with a set of on-line sensors for over 3 years. Wet-chemistry ex-situ analyzers, UV and UV-Visible in-situ sensors and in-situ sensors based on ion-selective electrodes (ISE) were used. New ISE sensors for ammonium, nitrate and nitrite, adapted to water and wastewater matrices, have been released in recent years, With adequate quality control they proved to be highly accurate and reliable in WWTP influents and activated sludge (AS) reactors even at the end of the biological treatment zone, working at low ammonium concentrations (1-2 mgN/l). The ammonium measurement was used to test several feed-forward and feed-back aeration control strategies. The first aim was to keep inorganic nitrogen compounds, i.e. ammonium, nitrate and particularly nitrite, as low as possible in the effluent, and within Swiss national standards (<2.0 mgNH(4)-N/l, <0.3 mgNO(2)-N/l, 24 h average). All the strategies were successful at keeping ammonium low and subsequently at gaining denitrification capacity to significantly reduce the total nitrogen discharge. Some control strategies however generated temporary peaks of ammonium or even accumulation of nitrite.


Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease.
Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.


Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies.
The presence of cirrhosis increases the mortality of patients with peptic ulcer bleeding (PUB). Both acute variceal bleeding (AVB) and PUB are associated with substantial mortality in cirrhosis. This multicenter cohort study was performed to assess whether the mortality of patients with cirrhosis with PUB is different from that of those with AVB. Patients with cirrhosis and acute gastrointestinal bleeding were consecutively included and treated with somatostatin and proton pump inhibitor infusion from admission and with antibiotic prophylaxis. Emergency endoscopy with endoscopic therapy was performed within the first 6 hours. 646 patients with AVB and 144 with PUB were included. There were baseline differences between groups, such as use of gastroerosive drugs or β-blockers. Child-Pugh and Model for End-Stage Liver Disease MELD scores were similar. Further bleeding was more frequent in the AVB group than those in the PUB group (18% vs. 10%; odds ratio [OR] = 0.50; 95% confidence interval [CI] = 0.29-0.88). However, mortality risk at 45 days was similar in both groups (19% in the AVB group vs. 17% in the PUB group; OR = 0.85; 95% CI = 0.55-1.33; P = 0.48). Different parameters, such as Child-Pugh score, acute kidney injury, acute on chronic liver failure, or presence of shock or bacterial infection, but not the cause of bleeding, were related to the risk of death. Only 2% of the PUB group versus 3% of the AVB group died with uncontrolled bleeding (P = 0.39), whereas the majority of patients in either group died from liver failure or attributed to other comorbidities. Using current first-line therapy, patients with cirrhosis and acute peptic ulcer bleeding have a similar survival than those with variceal bleeding. The risk of further bleeding is higher in patients with variceal hemorrhage. However, few patients in both groups died from uncontrolled bleeding, rather the cause of death was usually related to liver failure or comorbidities. (Hepatology 2018;67:1458-1471).


Prostatic carcinoma. Diagnostic pathology and prognosis.
The pathologic evaluation of prostatic specimens goes well beyond simple diagnosis. A number of features can be evaluated which have prognostic significance. In addition, evaluation of radical prostatectomy specimens is leading to better radiologic correlation, which may lead to improvements in imaging protocols.


Kinematic Comparison on Lower Limb Kicking Action of Fetuses in Different Gestational Weeks: A Pilot Study.
The fetal movements during different gestational weeks are essential for normal musculoskeletal development. The kinematic characteristics of fetuses with small differences in gestational weeks may be different and important. Ultrasonographic videos of fetal kicking action and plantarflexion action were collected from three healthy pregnant women (24, 27, and 30 gestational weeks) with normal fetal development. The kinematic characteristics, including angular range and angular velocity, were analyzed. These kinematic parameters were measured using simi motion. The final knee angle was found to decrease with progressive gestational weeks. Compared with 24 w, the knee joint angle at 27 w and 30 w was significantly reduced at the end of a kick-type movement (p < 0.01). Except for the mean angular velocity of the knee joint, there were no significant differences in the other conditions. The value at 30 w for mean angular velocity was significantly higher than that at 24 w (p = 0.02). In the ankle joint, no significant differences were observed between different conditions. Therefore, we can conclude that there was no significant difference in the kinematic characteristics of the ankle joint for small gestational age gaps, but there was a significant difference in the knee joint. As the gestation weeks increase, the range of kicking motion tends to decrease. The reason may be that with the increase of gestational weeks, fetal lower limb musculoskeletal development is gradually enhanced; the slower growth rate indicates that development reaches a peak level in weeks 24 to 30.


Family care as collaboration: effectiveness of a multicomponent support program for elderly couples with dementia. Randomized controlled intervention study.
To determine whether community care of people with dementia can be prolonged with a 2-year multicomponent intervention program and to analyze effects of the intervention on total usage and expenses of social and healthcare services. Randomized controlled trial. Community-dwelling couples with one spouse caring for the other spouse with dementia. Couples with dementia (N=125) were allocated at random to the intervention (n=63) or control group (n=62). Intervention couples were provided with a multicomponent intervention program with a family care coordinator, a geriatrician, support groups for caregivers, and individualized services. Time from enrollment to institutionalization of spouses with dementia and use of services and service expenditure of couples. At 1.6 years, a larger proportion in the control group than in the intervention group was in long-term institutional care (25.8% vs 11.1%, P=.03). At 2 years, the difference was no longer statistically significant. The 2-year adjusted hazard ratio for the intervention group was 0.53 (95% confidence interval (CI)=0.23-1.19, P=.12). Intervention led to reduction in use of community services and expenditures. The difference for the benefit of intervention group was -7,985 Euro (95% CI=-16,081 to -1,499, P=.03). When the intervention costs were included, the differences between the groups were not significant. Although the intervention did not result in a significant difference in the need for institutional care after 2 years, individualizing services in collaboration with families may lead to reduction in use of and expenditures on municipal services.


A Ni-P@NiCo LDH core-shell nanorod-decorated nickel foam with enhanced areal specific capacitance for high-performance supercapacitors.
Recently, transition metal-based nanomaterials have played a key role in the applications of supercapacitors. In this study, nickel phosphide (Ni-P) was simply combined with NiCo LDH via facile phosphorization of Ni foam and subsequent electrodeposition to form core-shell nanorod arrays on the Ni foam; the Ni-P@NiCo LDH was then directly used for a pseudocapacitive electrode. Owing to the splendid synergistic effect between Ni-P and NiCo LDH nanosheets as well as the hierarchical structure of 1D nanorods, 2D nanosheets, and 3D Ni foam, the hybrid electrode exhibited significantly enhanced electrochemical performances. The Ni-P@NiCo LDH electrode showed a high specific capacitance of 12.9 F cm-2 at 5 mA cm-2 (3470.5 F g-1 at a current density of 1.3 A g-1) that remained as high as 6.4 F cm-2 at a high current density of 100 mA cm-2 (1700 F g-1 at 27 A g-1) and excellent cycling stability (96% capacity retention after 10 000 cycles at 40 mA cm-2). Furthermore, the asymmetric supercapacitors (ASCs) were assembled using Ni-P@NiCo LDH as a positive electrode and activated carbon (AC) as a negative electrode. The obtained ASCs delivered remarkable energy density and power density as well as good cycling performance. The enhanced electrochemical activities open a new avenue for the development of supercapacitors.


Significance of Blood Eosinophil Count in Patients with Chronic Rhinosinusitis with Nasal Polyposis.
Chronic Rhino Sinusitis (CRS) is one of the most prevalent chronic illnesses across the globe, affecting persons of all ages. It is an inflammatory process that involves the paranasal sinuses with symptoms lasting longer than 12 weeks. To establish the significance of blood eosinophil (count) levels in CRS with nasal polyps and to compare blood eosinophil count with eosinophil count in the histopathology specimens of the polyps. This was a retrospective study done to review the medical records of 63 patients who underwent endoscopic sinus surgery for CRS with Nasal polyps. The patients were divided into two groups, 1 and 2 based on the number of patients suffering from non eosinophilic rhino sinusitis (Group 1) and those from eosinophlic rhino sinusitis (Group 2). The clinical examination findings, nasal endoscopy observations and MDCT-Paranasal sinuses were notified. Also, the mean Eosinophil Count (EC), Absolute Eosinophil Count (AEC), and Histopathology Eosinophil Count (HPE) was compared between two groups. This was aided by CT Scan Lund Mackay Scores (LMS). Among the patients from Group 1, the male to female ratio was found to be 1.14:1 with 53.3% males and in Group 2 the same were noted as 1.75:1 and 63.6% respectively and found a male preponderance. With regard to symptomatology, significantly higher number of patients in the Group 2 suffered from nasal block (97% vs. 46.7%; p<0.001), nasal obstruction (90.9% vs. 46.7%; p<0.001), nasal discharge (81.8% vs. 56.7%; p=0.030), hyposmia (97% vs. 30%; p<0.001) and asthma (69.7% vs. 3.3%; p<0.001). However, facial pain (66.7% vs. 81.8%; p=0.168) and para nasal sinus tenderness (53.3% vs. 54.6%; p=0.923) were comparable in Groups 1 and 2. Mean EC, AEC and HPE were significantly high in Group 2 compared to Group 1. The study demonstrated that there was a significant correlation between tissue and blood eosinophil counts with increased severity of symptoms in patients with Eosinophilic CRS with nasal polyps in the Indian population.


Melanopsin activates divergent phototransduction pathways in intrinsically photosensitive retinal ganglion cell subtypes.
Melanopsin signaling within intrinsically photosensitive retinal ganglion cell (ipRGC) subtypes impacts a broad range of behaviors from circadian photoentrainment to conscious visual perception. Yet, how melanopsin phototransduction within M1-M6 ipRGC subtypes impacts cellular signaling to drive diverse behaviors is still largely unresolved. The identity of the phototransduction channels in each subtype is key to understanding this central question but has remained controversial. In this study, we resolve two opposing models of M4 phototransduction, demonstrating that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dispensable for this process and providing support for a pathway involving melanopsin-dependent potassium channel closure and canonical transient receptor potential (TRPC) channel opening. Surprisingly, we find that HCN channels are likewise dispensable for M2 phototransduction, contradicting the current model. We instead show that M2 phototransduction requires TRPC channels in conjunction with T-type voltage-gated calcium channels, identifying a novel melanopsin phototransduction target. Collectively, this work resolves key discrepancies in our understanding of ipRGC phototransduction pathways in multiple subtypes and adds to mounting evidence that ipRGC subtypes employ diverse phototransduction cascades to fine-tune cellular responses for downstream behaviors.


Impact of intravenous thrombolysis on functional outcome in patients with mild ischemic stroke without large vessel occlusion or rapidly improving symptoms.
Optimal treatment strategy in patients with mild ischemic stroke remains uncertain. While functional dependency or death has been reported in up to one-third of non-thrombolyzed mild ischemic stroke patients, intravenous thrombolysis is currently not recommended in this patient group. Emerging evidence suggests two risk factors-rapid early improvement and large vessel occlusion-as main associates of unfavorable outcome in mild ischemic stroke patients not undergoing intravenous thrombolysis. To analyze natural course as well as safety and three-month outcome of intravenous thrombolysis in mild ischemic stroke without rapid early improvement or large vessel occlusion. Mild ischemic stroke was defined by a National Institute of Health Stroke Scale score ≤6. We used the modified Rankin Scale (mRS) to compare three-month functional outcome in 370 consecutive mild ischemic stroke patients without early rapid improvement and without large vessel occlusion, who either underwent intravenous thrombolysis (n = 108) or received best medical treatment (n = 262). Favorable outcome (mRS ≤ 1) was common in both groups (intravenous thrombolysis: 91%; no intravenous thrombolysis: 90%). Although intravenous thrombolysis use was independently associated with a higher risk of asymptomatic hemorrhagic transformation (OR = 4.62, p = 0.002), intravenous thrombolysis appeared as an independent predictor of mRS = 0 at three months (OR = 3.33, p < 0.0001). Mild ischemic stroke patients without rapidly improving symptoms and without large vessel occlusion have a high chance of favorable three-month outcome, irrespective of treatment type. Patients receiving intravenous thrombolysis, however, more often achieved complete remission of symptoms, which particularly in mild ischemic stroke may constitute a meaningful endpoint.


Long-term Effects of Early Exposure to Stress, Pain, Opioids and Anaesthetics on Pain Sensitivity and Neurocognition.
Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also - and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies.


Neural and muscular mechanisms of electrically induced fatigue in patients with spinal cord injury.
Intervention study. The present study aimed at examining whether spinal and/or peripheral alterations are in the origin of neuromuscular fatigue development induced by intermittent neuromuscular electrical stimulation (NMES) in subjects with complete spinal cord injury (SCI). Neurological Rehabilitation Center CMN Propara, Montpellier, France. Thirteen volunteers with complete SCI participated in the study. The right triceps surae muscle was fatigued using a 30-Hz NMES protocol (2 s ON-2 s OFF) composed of three series of five trains. Spinal excitability (assessed by the H-reflex), muscle excitability (assessed by the M-wave), muscle contractile properties (assessed by mechanical response parameters) and torque evoked by NMES were tested before and after each five-train series. NMES-evoked torque significantly decreased throughout the protocol (P<0.001). This decrease was accompanied by a significant increase in M-wave amplitude (P<0.001), whereas H-reflex and the Hmax/Mmax ratio were not significantly modified. The amplitude of the mechanical response was significantly decreased at the end of the protocol (P<0.05). The results indicate significant fatigue development, which was attributed to impaired cross-bridge force-generating capacity, without modification of spinal excitability nor muscle excitability.


Federalizing medical campaigns against alcoholism and drug abuse.
The formation of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Special Action Office for Drug Abuse Prevention (SAODAP) in the early 1970s dramatically expanded scientific and medical efforts to control alcoholism and drug abuse in the United States. Drawing on a variety of primary, secondary, and archival sources, this article describes the creation and early years of these agencies. I show that while the agencies appeared at roughly the same time, their creation involved separate sets of issues and actors. In addition, I show that SAODAP received more money and resources, even though advocates for alcoholics mobilized a stronger lobbying campaign. Two factors explain this discrepancy in money and resources: (1) alcoholism was framed as a public health problem, whereas drug abuse was drawn into broader debates about crime and social decline; and (2) alcohol programs relied on congressional support, whereas drug programs found champions at high levels of the Nixon administration. These political and cultural factors help explain why current programs for illegal drugs receive more federal support, despite alcohol's greater public health burden.


The prediction of adaptive evolution: empirical application of the secondary theorem of selection and comparison to the breeder's equation.
Adaptive evolution occurs when fitness covaries with genetic merit for a trait (or traits). The breeder's equation (BE), in both its univariate and multivariate forms, allows us to predict this process by combining estimates of selection on phenotype with estimates of genetic (co)variation. However, predictions are only valid if all factors causal for trait-fitness covariance are measured. Although this requirement will rarely (if ever) be met in practice, it can be avoided by applying Robertson's secondary theorem of selection (STS). The STS predicts evolution by directly estimating the genetic basis of trait-fitness covariation without any explicit model of selection. Here we apply the BE and STS to four morphological traits measured in Soay sheep (Ovis aries) from St. Kilda. Despite apparently positive selection on heritable size traits, sheep are not getting larger. However, although the BE predicts increasing size, the STS does not, which is a discrepancy that suggests unmeasured factors are upwardly biasing our estimates of selection on phenotype. We suggest this is likely to be a general issue, and that wider application of the STS could offer at least a partial resolution to the common discrepancy between naive expectations and observed trait dynamics in natural populations.


Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma.
Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient's clinical outcome. Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.


[Gastrostomy and nutrition. Nursing care].
The article refers to the nursing treatment required when using a gastrostomy to administer enteral nutrition, mainly for children. Emphasis is placed on the attention to parents, since they are the ones who will apply this treatment. The author analyses the cures for a stoma, external support mechanisms and possible complications that may arise along with solutions for them.


Functional Analysis of Chicken IRF7 in Response to dsRNA Analog Poly(I:C) by Integrating Overexpression and Knockdown.
In order to develop novel strategies to protect against increasingly virulent bird-linked pathogens, a better understanding of the avian antiviral response mechanism is essential. Type I interferons (IFNs) are recognized as the first line of defense in a host's antiviral response; and it has been suggested that IRF7, a member of the IFN regulatory factor (IRF) family, plays an important role in modulating the immune response to avian influenza virus infection in chickens. The objective of this study was to identify candidate genes and pathways associated with IRF7 regulation at the transcriptome level as a first step towards elucidating the underlying cellular mechanisms of IRF7 modulation in the chicken antiviral response. IRF7 overexpression and knockdown DF-1 cell lines were established and stimulated by various pathogen-associated molecular patterns. Significant IRF7 and type I IFN expression changes were observed in both the IRF7 overexpression cell line and the IRF7 knockdown cell line upon exposure to the double stranded RNA (dsRNA) analog poly(I:C). Using RNA-seq based transcriptome analysis, we identified potential novel genes that IRF7 may help regulate as part of the host immune response to dsRNA; potential biomarkers and therapeutic targets revealed as a result of this study warrant further investigation. Based on our results, we suggest that IRF7 may have conserved functional activity in the avian antiviral response, and plays a crucial role in type I IFN regulation.


A role for compromise: synaptic inhibition and electrical coupling interact to control phasing in the leech heartbeat CpG.
How can flexible phasing be generated by a central pattern generator (CPG)? To address this question, we have extended an existing model of the leech heartbeat CPG's timing network to construct a model of the CPG core and explore how appropriate phasing is set up by parameter variation. Within the CPG, the phasing among premotor interneurons switches regularly between two well defined states - synchronous and peristaltic. To reproduce experimentally observed phasing, we varied the strength of inhibitory synaptic and excitatory electrical input from the timing network to follower premotor interneurons. Neither inhibitory nor electrical input alone was sufficient to produce proper phasing on both sides, but instead a balance was required. Our model suggests that the different phasing of the two sides arises because the inhibitory synapses and electrical coupling oppose one another on one side (peristaltic) and reinforce one another on the other (synchronous). Our search of parameter space defined by the strength of inhibitory synaptic and excitatory electrical input strength led to a CPG model that well approximates the experimentally observed phase relations. The strength values derived from this analysis constitute model predictions that we tested by measurements made in the living system. Further, variation of the intrinsic properties of follower interneurons showed that they too systematically influence phasing. We conclude that a combination of inhibitory synaptic and excitatory electrical input interacting with neuronal intrinsic properties can flexibly generate a variety of phase relations so that almost any phasing is possible.


Omentin-1 levels in patients with premature coronary artery disease, metabolic syndrome and healthy controls. Short communication.
Omentin-1 is an adipokine which could have a protective role against the manifestation of atherosclerosis. Only limited data are available on omentin-1 serum values in patients with premature clinical manifestations of atherosclerosis. We tested omentin-1 in human serum by ELISA method in 61 individuals with a premature manifestation of coronary artery disease (CAD), 40 patients with metabolic syndrome and 40 healthy control subjects. Omentin-1 serum levels were significantly lower in patients with CAD (103.1±62.7 mg/L) compared to metabolic syndrome (668.2±339.6 mg/L) and healthy subjects (623.0±373.5 mg/L) (P < 0.01). In CAD patients, omentin-1 serum levels did not differ between patients sampled in the acute phase of myocardial infarction (n = 28; 110.3±82.4 mg/L) and in the chronic phase several months or years after myocardial infarction (n = 33; 97.0±39.3 mg/L) (P = 0.41). We found a weak positive correlation between omentin-1 and body mass index (r = 0.21, P = 0.014). No significant correlation was found between peak cardiac troponin T and omentin-1 (correlation coefficient r = 0.118, P = 0.406). Serum omentin-1 seems to be a useful biomarker of coronary artery disease across the whole age spectrum.


Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate.
The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.


Rapid polymerase chain reaction assay to detect herpes simplex virus in the genital tract of women in labor.
To develop a rapid quantitative real-time polymerase chain reaction (PCR) to detect herpes simplex virus (HSV) in the genital secretions of women that may be used in labor. Samples of genital secretions from women in labor, swabs of active genital lesions, and swabs of buffer solution were analyzed using a newly developed rapid HSV PCR assay to detect HSV glycoprotein B gene and quantitate virion copy number. A previously validated TaqMan PCR to detect HSV glycoprotein B gene was performed as the comparator gold standard. Positivity determination that optimized sensitivity and specificity was determined with receiver operating characteristic curves. The median time to result for rapid HSV PCR was 2 hours (range 1.5-3.5 hours). A positivity determination rule that required both wells of the rapid test to detect 150 copies or greater of HSV per milliliter maximized specificity (96.7%) without appreciable loss of sensitivity (99.6%). Among positive samples, the correlation between the rapid test and TaqMan for the quantity of HSV isolated was excellent (R=0.96, P<.001). The rapid test had a positive predictive value of 96.7% and a negative predictive value of 99.6% in a population with HSV shedding prevalence of 10.8%, based on the prevalence of genital HSV previously found among HSV-2 seropositive women in labor. Rapid HSV PCR provides results with excellent sensitivity and specificity within a timeframe that could inform clinical decision making for identifying neonates at risk of neonatal HSV infection. II.


Sentinel Lymph Node-Targeted Therapy by Oncolytic Sendai Virus Suppresses Micrometastasis of Head and Neck Squamous Cell Carcinoma in an Orthotopic Nude Mouse Model.
In clinical N0 (cN0) cases with head and neck squamous cell carcinoma (HNSCC), a treatment selection is still controversial: elective neck dissection or watchful waiting. We focused on sentinel lymph node (SLN)-targeted therapy using the urokinase-type plasminogen activator (uPA)-dependent oncolytic Sendai virus "BioKnife." The objectives of this study were to investigate BioKnife migration into SLNs and elucidate its antitumor effect on lymph node metastases (LNM). We established an orthotopic nude mouse model of HNSCC, with LNM being frequently induced. We inoculated HSC-3-M3, human highly metastatic tongue squamous cell carcinoma cells, in the tongue of the nude mice, and after 2 weeks, we injected BioKnife into the primary tumor. We tracked BioKnife migration into the SLNs by immunostaining, RT-PCR, and an in vivo imaging system. We also examined its antitumor effects and mechanisms through serial section analysis of lymph nodes. GFP reporter expression was clearly visible in the lymph nodes of virus groups, which corresponded to SLNs. Relative GFP mRNA was significantly increased in both the tongues and lymph nodes in the virus groups compared with that in the control group (P < 0.05). Serial section analysis showed that BioKnife infected cancer cells and exhibited significant antitumor effect against LNM compared with the control groups (P < 0.05). We detected apoptosis in LNM infected by BioKnife. BioKnife migrated into SLNs after its injection into the primary tumor and effectively suppressed LNM, suggesting that SLN-targeted therapy using BioKnife has great potential to provide a novel and promising alternative to elective neck dissection in cN0 patients with HNSCC.


[Expression and Clinical Significance of DNMT in Patients with Chronic Myeloid Leukemia].
To investigate the expression and clinical significance of DNA methyltransferases (DNMT) mRNA in patients with chronic myeloid leukemia (CML). The expression levels of DNMT mRNA in mononucllear cells (MNC) of bone marrow or in peripheral blood of 93 CML patients in 3 different phases and 10 normal controls (NC) were detected by SYBR Green flurescent quatitative PCR. The relative expression levels of DNMT1 mRNA in NC, chronic phase CML (CML-CP), accelerated phase (CML-AP) and blastic phase (CML-BP) were 1.45 ± 0.22, 1.83 ± 0.63, 2.95 ± 0.87 and 3.24 ± 1.39 resectively. The expression of DNMT1 mRNA showed no statistically significant difference between CML-CP and NC (P = 0.28). The expression of DNMT1 mRNA in advanced stages (including CML-AP and CML-BP) of CML obviously increased in comparison with CML-CP and NC (P < 0.05). The expression of DNMT1 mRNA in CML-AP was not significantly different from that in CML-BP (P = 0.336). The relative expression levels of DNMT3a mRNA in NC, CML-CP, CML-AP and CML-BP groups were 1.29 ± 0.34, 1.34 ± 0.46, 2.33 ± 1.05 and 3.18 ± 1.23 resectively. And the expression levels of DNMT3a mRNA were not statistically significantly different between CML-CP and NC (P = 0.844). The results showed that the expression of DNMT3a mRNA in the advanced phase of CML significantly increased in comparison with that in CML-CP and NC (P < 0.05). Meanwhile, the expression of DNMT3a mRNA in CML-AP was not different from that in CML-BP (P = 0.304). The relative expression levels of DNMT3b mRNA in NC, CML-CP, CML-AP and CML-BP groups were 1.37 ± 0.31, 16.41 ± 22.50, 9.36 ± 5.50 and 12.17 ± 13.44 resectively. It was also found that the level of DNMT3b mRNA in CML significantly increased in comparison with NC (P < 0.05), and that the between the 3 different phase of CML was not statistically significantly different (P >0.05). The expression of DNMT mRNA increases in advanced CML as compared with normal controls and CML-CP, and the increased levels of DNMT mRNA probably correlate with disease progression in CML.


Saururaceae. V. Composition of essential oil from foliage of Houttuynia cordata and chemo systematics of Saururaceae.
The chemical composition of the essential oil from the aerial parts of Houttuynia cordata was examined by ir, glc and gc-ms, as a part of the study of the Saururaceae whose members have rich folkloric medicinal history. The analysis indicate that the essential oil from H. cordata is very rich (81.4 percent v/v) in lipid compounds. A comparision of the composition of the essential oils from three members of the Saururaceae, namely Anemopsis californica, Saururus cernuus and H. cordata from a chemosystematic point of view shows that each species investigated hitherto has its own characteristic type essential oil. While from the morphological and anatomical point of view, Saururus seems to represent the least specialized genus, the presently available chemical evidence does not clearly assign such a status to Saururus.


[Cracovian program for secondary prevention of ischemic heart disease. Secondary prevention of ischemic heart disease after discharge in 1997-98 and 1999-2000].
Although most actions undertaken within the scope of the secondary prevention of ischaemic heart disease should be initiated during hospitalization, obtaining maximal effects (quantified by cardiovascular risk reduction) depends largely on continuation and appropriate adjustment of these measures in the post-discharge period. The aim of this paper is to assess the implementation of guidelines on secondary prevention of ischaemic heart disease in the period after discharge from the hospital in the years 1999/2000 as compared with 1997/98. In the first phase 515 subjects hospitalized in cardiac departments of university and general hospitals in Cracow were included. Out of them, 427 patients attended the control visit 6-18 months after index hospitalization. Based on a standardized questionnaire a structured medical history was obtained including the presence of risk factors and medication. At the same time body height and mass and blood pressure were measured and blood samples were obtained for lipid profile and fasting glucose level. Elevated cholesterol levels (> or = 5.2 mmol/l) were observed in 65.8% of patients in 1998/99 and 66.3% in 1999/2000, high blood pressure (> or = 140/90 mmHg) in 46.2% and 50.4%, obesity (BMI > or = 30 kg/m2) in 24.6% and 27.2%, fasting hyperglycemia (> or = 6.0 mmol/l) in 17.7% and 27.4% (p < 0.05) and smoking in 16.3% and 15.9%, respectively. An increase was observed in the rate of antiplatelet (76.1% in 1998/99 vs 86.7% in 1999/2000, p < 0.001) and lipid lowering drug use (34.0% vs 41.9%, p < 0.05). The rate of beta-blockers and ACE inhibitors use did not change significantly. In the years 1999/2000 the control of main risk factors of ischaemic heart disease did not improve when compared with 1997/98. There was only an increase in the percentage of patients on antiplatelet and lipid lowering drugs. These results indicate that the dissemination of the guidelines for secondary prevention of ischaemic heart disease among physicians and patients remains one of the top priorities of cardiology in Poland.


Neuro-fuzzy chip to handle complex tasks with analog performance.
This paper presents a mixed-signal neuro-fuzzy controller chip which, in terms of power consumption, input-output delay, and precision, performs as a fully analog implementation. However, it has much larger complexity than its purely analog counterparts. This combination of performance and complexity is achieved through the use of a mixed-signal architecture consisting of a programmable analog core of reduced complexity, and a strategy, and the associated mixed-signal circuitry, to cover the whole input space through the dynamic programming of this core. Since errors and delays are proportional to the reduced number of fuzzy rules included in the analog core, they are much smaller than in the case where the whole rule set is implemented by analog circuitry. Also, the area and the power consumption of the new architecture are smaller than those of its purely analog counterparts simply because most rules are implemented through programming. The paper presents a set of building blocks associated to this architecture, and gives results for an exemplary prototype. This prototype, called multiplexing fuzzy controller (MFCON), has been realized in a CMOS 0.7 /spl mu/m standard technology. It has two inputs, implements 64 rules, and features 500 ns of input to output delay with 16-mW of power consumption. Results from the chip in a control application with a dc motor are also provided.


PENELOPE/PRIMO-calculated photon and electron spectra from clinical accelerators.
The availability of photon and electron spectra in digital form from current accelerators and Monte Carlo (MC) systems is scarce, and one of the packages widely used refers to linacs with a reduced clinical use nowadays. Such spectra are mainly intended for the MC calculation of detector-related quantities in conventional broad beams, where the use of detailed phase-space files (PSFs) is less critical than for MC-based treatment planning applications, but unlike PSFs, spectra can easily be transferred to other computer systems and users. A set of spectra for a range of Varian linacs has been calculated using the PENELOPE/PRIMO MC system. They have been extracted from PSFs tallied for field sizes of 10 cm × 10 cm and 15 cm × 15 cm for photon and electron beams, respectively. The influence of the spectral bin width and of the beam central axis region used to extract the spectra have been analyzed. Spectra have been compared to those by other authors showing good agreement with those obtained using the, now superseded, EGS4/BEAM MC code, but significant differences with the most widely used photon data set. Other spectra, particularly for electron beams, have not been published previously for the machines simulated in this work. The influence of the bin width on the spectrum mean energy for 6 and 10 MV beams has been found to be negligible. The size of the region used to extract the spectra yields differences of up to 40% for the mean energies in 10 MV beams, but the maximum difference for TPR 20,10 values derived from depth-dose distributions does not exceed 2% relative to those obtained using the PSFs. This corresponds to kQ differences below 0.2% for a typical Farmer-type chamber, considered to be negligible for reference dosimetry. Different configurations for using electron spectra have been compared for 6 MeV beams, concluding that the geometry used for tallying the PSFs used to extract the spectra must be accounted for in subsequent calculations using the spectra as a source. An up-to-date set of consistent spectra for Varian accelerators suitable for the calculation of detector-related quantities in conventional broad beams has been developed and made available in digital form.


Virtual learning solutions in COVID-19 era: University Italian Ophthalmology department perspective.
Few months after the COVID-19 pandemic burst, many aspects of the human life, including education, dramatically changed. Because of the lockdown measures taken to limit the virus spread in Italy, in-person teaching and learning have been interrupted in all health care disciplines and readapted in virtual formulae. As academic ophthalmology departments, we had to maintain the educational needs of medical and orthoptic students, internships, surgical training of residents, as well as to cover the scientific update of health care personnel (HCPs), and the continuation of research and academic activities. To assure these needs we ideated an educational strategy and a team, which was then translated on a multichannel virtual platform created with Microsoft Teams. In this platform there were 21 channels organized in a public view mode, open to all Team members, or in private view mode to separate non-permanent HCPs, internships, residents, and students' tasks, from permanent HCPs tasks. Virtual channels were dedicated to provide theoretical lessons, clinical cases, surgical video, internal meetings and webinar, to offer news from scientific societies, requests of appointments from biomedical companies, links with ophthalmological websites, to move forward research projects, to participate at institutional academic duties, and to obtain feedbacks from users. Residents continued their training on surgery using a surgical simulator, after consulting an agenda uploaded into the dedicated virtual channel. These positive initial results should represent a boost to rapidly proceed with the development of even more versatile virtual learning solutions, given that the forecasts for the duration of the COVID-19 pandemic are not encouraging.


Influence of N-Glycosylation on Virus-Host Interactions in Halorubrum lacusprofundi.
N-glycosylation is a post-translational modification of proteins that occurs across all three domains of life. In Archaea, N-glycosylation is crucial for cell stability and motility, but importantly also has significant implications for virus-host interactions. While some archaeal viruses present glycosylated proteins or interact with glycosylated host proteins, the direct influence of N-glycosylation on archaeal virus-host interactions remains to be elucidated. In this study, we generated an N-glycosylation-deficient mutant of Halorubrum lacusprofundi, a halophilic archaeon commonly used to study cold adaptation, and examined the impact of compromised N-glycosylation on the infection dynamics of two very diverse viruses. While compromised N-glycosylation had no influence on the life cycle of the head-tailed virus HRTV-DL1, we observed a significant effect on membrane-containing virus HFPV-1. Both intracellular genome numbers and extracellular virus particle numbers of HFPV-1 were increased in the mutant strain, which we attribute to instability of the surface-layer which builds the protein envelope of the cell. When testing the impact of compromised N-glycosylation on the life cycle of plasmid vesicles, specialized membrane vesicles that transfer a plasmid between host cells, we determined that plasmid vesicle stability is strongly dependent on the host glycosylation machinery. Our study thus provides important insight into the role of N-glycosylation in virus-host interactions in Archaea, while pointing to how this influence strongly differs amongst various viruses and virus-like elements.


Impact of the 2017 Child and Adult Care Food Program Meal Pattern Requirement Change on Menu Quality in Tribal Early Care Environments: The Food Resource Equity and Sustainability for Health Study.
Native American (NA) children have a high prevalence of obesity contributing to lifespan health disparities. Dietary intake is important to promote healthy weight gain, growth, and development. In 2017, the USDA enforced changes to the Child and Adult Care Food Program (CACFP). The CACFP provides reimbursement to qualifying Early Care and Education (ECE) programs that serve foods that uphold the program's nutrition requirements. This study had the following 2 objectives: 1) Describe a novel index to evaluate ECE menus based on revised CACFP requirements (accounting for food substitutions) and best practices for 3- to-5-y-old children, and 2) analyze CACFP requirement and best practice compliance and nutrient changes in 9 NA ECE programs before and after enforcement of the revised CACFP requirements. This longitudinal study is within a larger community-based participatory research study. Menus and meals served were evaluated for 1 wk at each of 9 programs before and after enforcement of the revised meal patterns. Nutrient analysis, CACFP requirement and best practice compliance, and substitution quality were evaluated. Differences were determined using a paired t-test or Wilcoxon matched test. This trial was registered at clinicaltrials.gov as NCT03251950. Total grams of fiber consumed increased (5.0 ± 1.2 compared with 5.9 ± 0.8 g, P = 0.04) and total grams of sugar consumed decreased (53.8 ± 12.6 compared with 48.4 ± 7.9 g, P = 0.024), although room for further improvement exists. Although total grams of fat remained unchanged, grams of saturated fat significantly increased (7.8 ± 1.4 compared with 10.5 ± 3.4, P = 0.041). Other nutrients remained unchanged. Overall CACFP requirement and best practice compliance scores improved, although this finding was not statistically significant. No significant changes in food quality associated with substitutions occurred. This study provides early evidence to support the beneficial impact of the revised CACFP requirements. Understanding barriers to compliance within rural NA communities would be an important next step in enhancing the health of vulnerable children.


Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial.
It is common practice in many centers to offer antithrombotic medications to women with unexplained recurrent miscarriage, in the presence or absence of inherited thrombophilia. Although no benefit of aspirin vs placebo has been clearly demonstrated, a double-blind placebo-controlled trial on the effect of low-molecular-weight heparin is lacking. We enrolled 258 pregnant women with a history of unexplained recurrent miscarriage (≥2 consecutive miscarriages before 15 weeks' gestation) and a negative thrombophilia workup. They were randomly assigned to receive one daily subcutaneous injection of enoxaparin 40 mg or placebo until 35 weeks' gestation. We included 256 women (mean age 32 years, ≥3 miscarriages: 72%; mean gestational age 39 days of amenorrhea) in the intention-to-treat analysis; 66.6% of 138 who received enoxaparin had a live birth vs 72.9% of 118 who received placebo. The absolute difference was -6% (95% CI, -17.1 to 5.1), excluding a 10% increase in the rate of live-birth on enoxaparin (P = .34). In this first randomized, double-blind, placebo-controlled trial, enoxaparin (40 mg once daily) did not improve the chance of a live birth in nonthrombophilic women with unexplained recurrent miscarriage. This trial is registered at www.ClinicalTrials.gov as #NCT00740545 and the French National Health and Drug Safety Agency (EudraCT #2006-003350-18).


Microneedle Coating Methods: A Review with a Perspective.
A coated microneedle array comprises sharp micrometer-sized needle shafts attached to a base substrate and coated with a drug on their surfaces. Coated microneedles are under investigation for drug delivery into the skin and other tissues, and a broad assortment of active materials, including small molecules, peptides, proteins, deoxyribonucleic acids, and viruses, have been coated onto microneedles. To coat the microneedles, different methods have been developed. Some coating methods achieve selective coating of just the microneedle shafts, whereas other methods coat not only microneedle shafts but also the array base substrate. Selective coating of just the microneedle shafts is more desirable since it provides control over drug dosage, prevents drug waste, and offers high delivery efficiency. Different excipients are added to the coating liquid to modulate its viscosity and surface tension in order to achieve uniform coatings on microneedles. Coated microneedles have been used in a broad range of biomedical applications. To highlight these different applications, a table summarizing the different active materials and the amounts coated on microneedles is provided. We also discuss factors that should be considered when deciding suitability of coated microneedles for new-drug delivery applications. In recent years, many coated microneedles have been investigated in human clinical trials, and there is now a strong effort to bring the first coated microneedle-based product to market.


Impact of critical bed status on emergency department patient flow and overcrowding.
To compare measurements of emergency department (ED) patient flow during periods of acute ED overcrowding and times of normal patient volume (NPV). Retrospective ED chart review comparing ED flow for patients treated in a tertiary care teaching hospital during periods of ED overcrowding, defined as critical bed status (CBS), and NPV. All periods of CBS during July 2001 were identified. CBS time intervals were matched with NPV times by month, day of the week, time of day, and number of care providers. All patients registered during these matched time intervals were reviewed. Times were collected for each of the following activities: check-in, bed placement, physician assessment, first intervention, and disposition. Corresponding intervals were calculated in minutes. Triage category was used as a marker of illness severity (1 = most severe, 5 = least severe). Descriptive statistics were performed. One hundred eighteen patient charts were reviewed: 61 CBS and 57 NPV. There was no statistical difference in illness severity between the two groups. In the cumulative analysis, patients waited significantly longer for an ED bed (30.4 min, p = 0.01) but did not experience significant delays in other intervals. Triage category analysis revealed no significant difference in triage 2 patients. Intermediate-severity patients (triage 3) waited longer in every interval and significantly longer for physician assessment (30.8 min longer, p < 0.05). Low-severity patients (triage 4) waited longer for an ED bed (40 min, p = 0.02) but did not experience other significant delays. During times of acute overcrowding, the most significant delay occurs awaiting placement in the ED bed.


Speak Up! Prosocial Intervention Verbalizations Predict Successful Bystander Intervention for a Laboratory Analogue of Sexual Aggression.
This study evaluated a mechanism by which men's self-efficacy to intervene increases their likelihood of preventing a laboratory analogue of sexual aggression (SA) via specific verbalizations and whether alcohol inhibits this mechanism. A sample of 78 male peer dyads were randomly assigned to consume an alcoholic or nonalcoholic beverage and complete a laboratory paradigm to assess bystander intervention to prevent SA toward a female who had ostensibly consumed an alcoholic or nonalcoholic beverage. Participants' verbalizations during the task were subjected to quantitative analysis. Regardless of alcohol use, bystander self-efficacy increased the likelihood of successful bystander intervention via participants' use of more prosocial verbalizations. Findings highlight prosocial verbalizations within the male peer context that may effectively prevent SA.


Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition: Revised 2021 standards of practice and standards of professional performance for registered dietitian nutritionists (competent, proficient, and expert) in nutrition support.
Nutrition support is a therapy that crosses all ages, diseases, and conditions as health care practitioners strive to meet the nutrition requirements of individuals who are unable to meet nutrition and/or hydration needs with oral intake alone. Registered dietitian nutritionists (RDNs), as integral members of the nutrition support team provide needed information, such as identification of malnutrition risk, macro- and micronutrient requirements, and type of nutrition support therapy (eg, enteral or parenteral), including the route (eg, nasogastric vs nasojejunal or tunneled catheter vs port). The Dietitians in Nutrition Support Dietetic Practice Group, American Society for Parenteral and Enteral Nutrition, along with the Academy of Nutrition and Dietetics Quality Management Committee, have updated the Standards of Practice (SOP) and Standards of Professional Performance (SOPP) for RDNs working in nutrition support. The SOP and SOPP for RDNs in Nutrition Support provide indicators that describe the following 3 levels of practice: competent, proficient, and expert. The SOP uses the Nutrition Care Process and clinical workflow elements for delivering patient/client care. The SOPP describes the 6 domains that focus on professional performance. Specific indicators outlined in the SOP and SOPP depict how these standards apply to practice. The SOP and SOPP are complementary resources for RDNs and are intended to be used as a self-evaluation tool for assuring competent practice in nutrition support and for determining potential education and training needs for advancement to a higher practice level in a variety of settings.


[Analysis of glycosphingolipids from human myeloid leukemias].
Neutral glycosphingolipids of human myeloid leukemia cells in different differentiation stages from nine patients were analyzed by high performance liquid chromatography. All cells contained ceramide monohexoside, lactosylceramide and neutral glycosphingolipids of the lacto-series. However, some of the leukemic cells contained neutral glycosphingolipids of the globo-series. Especially myelomonocytic cells (French-American-British or FAB classification M4) and poorly differentiated cells (FAB M0 and M1) were found to contain globo glycosphingolipids. On myeloblast cells, (FAB M2), globo glycosphingolipids were missing or present only in very low amounts. It seemed, therefore, that on myeloid leukemic cells the glycosphingolipid composition may be dependent on their differentiation stage.


Algorithmic self-assembly of DNA Sierpinski triangles.
Algorithms and information, fundamental to technological and biological organization, are also an essential aspect of many elementary physical phenomena, such as molecular self-assembly. Here we report the molecular realization, using two-dimensional self-assembly of DNA tiles, of a cellular automaton whose update rule computes the binary function XOR and thus fabricates a fractal pattern--a Sierpinski triangle--as it grows. To achieve this, abstract tiles were translated into DNA tiles based on double-crossover motifs. Serving as input for the computation, long single-stranded DNA molecules were used to nucleate growth of tiles into algorithmic crystals. For both of two independent molecular realizations, atomic force microscopy revealed recognizable Sierpinski triangles containing 100-200 correct tiles. Error rates during assembly appear to range from 1% to 10%. Although imperfect, the growth of Sierpinski triangles demonstrates all the necessary mechanisms for the molecular implementation of arbitrary cellular automata. This shows that engineered DNA self-assembly can be treated as a Turing-universal biomolecular system, capable of implementing any desired algorithm for computation or construction tasks.


Association of deep-vein thrombosis (DVT) with missed doses of prophylactic antithrombotic medications in ICU patients: a case-control study.
Medications for prevention of venous thromboembolism (VTE) are routinely prescribed in critically ill patients. To identify any association between missed doses of VTE prophylaxis medications and acute, in-hospital deep-vein thrombosis (DVT). Case-control study in hospitalized adult patients at high risk for developing VTE, defined as an ICU length of stay (LOS) of at least 24 hours. Cases were defined as patients with acute DVT during hospitalization, and controls were patients with no documented DVT. Multivariate logistic regression was used to assess the odds of acute DVT in patients with any missed dose of prophylactic antithrombotic medication. Of 920 patients, 59 (6.4%) experienced an acute, in-hospital DVT. Overall, 64% of patients missed at least 1 dose of VTE prophylaxis medication, and 33% missed more than 3 doses. In the univariate analysis, there was no significant association between any missed dose of prophylaxis medication and acute DVT (odds ratio [OR] = 0.96; CI = 0.56-1.7). Multivariate logistic regression modeling confirmed no association between missed doses of pharmacological VTE medications and acute DVT (OR = 0.69 [0.39-1.2]; P = 0.21). Prolonged hospital LOS was associated with increased odds of acute DVT (LOS = 4-6 days; OR = 0.75 [0.21-2.6]; LOS = 7-13 days; OR = 2.3 [0.9-5.9]; and LOS = ≥14 days; OR = 6.4 [2.6-15.9]). We found no evidence of a relationship between any missed dose of prophylactic antithrombotic medication and development of acute DVT. The odds of acute DVT increased in patients with prolonged hospital LOS.


Urocortins as biomarkers in cardiovascular disease.
The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.


Occurrence of Oxidative Stress and Premature Senescence in the Anterior Segment of Acute Primary Angle-Closure Eyes.
To explore whether oxidative stress and premature senescence occur in the anterior segment of acute primary angle-closure (APAC) eyes after increased intraocular pressure. The eye samples of 21 APAC patients, 22 age-related cataract patients, and 10 healthy donors were included. Aqueous humor (AqH), iris, and anterior lens capsule samples were collected. The levels of oxidative stress markers and senescence-associated secretory phenotype (SASP)-related cytokines in AqH were estimated using relevant reagent kits and multiplex bead immunoassay technique. The intensity of relevant markers in anterior segment tissues was examined by immunofluorescence- and senescence-associated β-galactosidase (SA-β-gal) staining. Oxidative stress marker levels elevated significantly in the AqH of APAC eyes. Reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine levels were positively correlated with preoperative peak intraocular pressure and age, whereas reduced glutathione/oxidized glutathione (GSH/GSSH) ratio was negatively correlated with both parameters. The levels of several SASP-related cytokines were markedly increased. ROS and malondialdehyde levels were positively correlated with the levels of some SASP-related cytokines, whereas superoxide dismutase level and GSH/GSSH ratio showed an opposite trend. The number of cells positive for oxidative mitochondrial DNA damage and apoptosis-related markers increased in the iris and anterior lens capsule of the APAC group. Senescence-associated markers (p16, p21, and p53) and SA-β-gal activity were increased in the iris of the APAC group. Oxidative stress and premature senescence occurred in the anterior segment of APAC patients, suggesting that they may be involved in the development of pathological changes in the anterior segment of APAC eyes.


Physiological and biochemical effects of iron deficiency on rat skeletal muscle.
Young rats were made iron deficient by feeding them a low-iron diet for 8 wk. Iron deficiency resulted in a 50% decrease in cytochrome c and cytochrome oxidase and a 26% decrease in mitochondrial glycerol-3-phosphate dehydrogenase activity in skeletal muscle. Respiratory capacity of muscle homogenates was reduced 55%. After 8 days of iron treatment, respiratory capacity, cytochrome c, cytochrome oxidase, and glycerol-3-phosphate dehydrogenase had returned 50% toward normal. Maximum O2 uptake of contracting hindlimb muscles averaged 8.5 mumol O2.min-1.g-1 in control, 4.3 mumol O2.min-1.g-1 in iron-deficient, and 6.2 mumol O2.min-1.g-1 in the 8-day-iron-repleted rats. Muscle fatigue during 10 min of stimulation was greater in the iron-deficient group. Lactate concentration in red muscle was higher in iron-deficient than in control rats after stimulation. The muscle fatigue and lactate responses returned 50% toward normal during 8 days of iron treatment. We conclude that iron deficiency results in a decrease in skeletal muscle capacity for aerobic metabolism and, by this mechanism, increases susceptibility to fatigue.


Physicochemical characterization of the ribosomal RNA species of the Mollusca. Molecular weight, integrity and secondary-structure features of the RNA of the large and small ribosomal subunits.
1. The rRNA species of the Cephalopoda Octopus vulgaris and Loligo vulgaris were found to have unexpectedly high sedimentation coefficients and molecular weights. In 0.1 M-NaCl the L-rRNA (RNA from large ribosomal subunit) has the same s20 value as the L-rRNA of the mammals (30.7S), whereas the S-rRNA (RNA from small ribosomal subunit) sediments at a faster rate (20.1S) than the S-rRNA of both the mammals and the fungi (Neurospora crassa) (17.5S). The molecular weights of the L-rRNA were determined by gel electrophoresis in formamide and found to be 1.66 X 10(6) (Octupus) and 1.89 X 10(6) (Loligo); the mol.wt. of the S-rRNA of both species is 0.96 X 10(6), i.e. much larger than that of the mammals (0.65 X 10(6)) and almost coincident with that of the '23S' RNA of the prokaryotes. 2. By contrast, the less evolved Gastropoda and Lamellibranchiata (Murex trunculus and Macrocallista chione) have S-rRNA and L-rRNA species with mol.wts. of 0.65 X 10(6) and approx. 1.40 X 10(6).3. All the mature L-rRNA molecules of the cephalopoda are composed of two unequal fragments held together by regions of hydrogen-bonding having a similar, low, thermal stability in the two species; the molecular weights of the two fragments composing the L-rRNA are estimated to be 0.96 X 10(6) and 0.88 X 10(6) (Loligo) and 0.96 X 10(6) and 0.65 X 10(6) (Octupus). THe S-rRNA of both species is a continuous chain with exactly the same molecular weight (0.96 X 10(6)) as the heavier of the two fragments of the L-rRNA. 4. The secondary-structure features of the L-rRNA and S-rRNA species of the Caphalopoda were investigated by thermal 'melting' analysis in 4.0 M-guanidinium chloride; 60-70% of the residues are estimated to form short, independently 'melting' bihelical segments not more than 10 base-pairs in length. 5. Bases are unevenly distributed between non-helical and bihelical portions of the rRNA molecules, G and C residues being preferentially concentrated in bihelical comains. 6. The secondary-structure regions of the L-rRNA species of Octopus and Loligo are heterogenous, including two discrete fractions of independently 'melting' species that give rise to biphasic 'melting' profiles: a fraction consisting of shorter (G + C)-poorer segments (60-68% G + C, not more than 5 base-pairs in length) and a fraction consisting of longer (G + C)-richer segments (80-88% G + C, 5-10 base-pairs in length). No evidence for heterogeneity has been detected in the S-rRNa.


Structure of water in microemulsions: electrical, birefringence, and nuclear magnetic resonance studies.
Microemulsions, which are optically transparent oil-water dispersions, were produced by mixing hexadecane, hexanol, potassium oleate, and water. As the amount of water is increased, the microemulsion exhibits a clear to turbid to clear transition. In contrast to the clear regions, the turbid region possesses birefringence. The development of birefringence is also accompanied by a sharp decrease in the electrical resistance. The high-resolution (220 megacycle) nuclear magnetic resonance data suggest that water exists in two distinct molecular environments in the birefringent region; the first environment is characterized by relatively less mobile water molecules than oil molecules, whereas in the second environment oil molecules are less mobile than water molecules. The electrical, birefringence, and nuclear magnetic resonance data are in agreement with the proposed mechanism of change in the structure of water from water spheres to water cylinders to water lamellae. The chemical shift of water protons suggests that the molecular environment of water in spheres is different from that of water in cylinders or that of water in lamellae.


The association of selected cancers with service in the US military in Vietnam. II. Soft-tissue and other sarcomas. The Selected Cancers Cooperative Study Group.
As part of a series of investigations into the health of Vietnam veterans, we conducted a population-based, case-control study of soft-tissue and other sarcomas between 1984 and 1988. All men born between 1929 and 1953 and diagnosed in an area covered by eight cancer registries were considered eligible. Controls were selected by random-digit dialing. Analyses of 342 men with pathologically confirmed sarcoma and 1776 controls showed that Vietnam veterans had a relative risk of 1.0 for sarcoma in comparison with men who did not serve in Vietnam (95% confidence interval, 0.6 to 1.6). Restriction of the analysis to the 254 men with soft-tissue sarcoma yielded a relative risk of 0.9 (95% confidence interval, 0.5 to 1.6). Several attributes of military service in Vietnam (eg, branch, duration of service, military region, and other characteristics that may have been associated with the use of Agent Orange) were examined, and none was associated with an increased risk for the development of sarcoma. Furthermore, no morphologic type of sarcoma was overrepresented among Vietnam veterans. Results were unchanged if Vietnam veterans were compared with (1) other veterans or (2) men who never served in the military. This study, which had 97% power to detect a relative risk of 2.0 for all sarcomas, provides no evidence that the risk for the development of soft-tissue or other sarcomas is increased among veterans 15 to 25 years following service in Vietnam.


Attenuation of itraconazole fungicidal activity following preexposure of Aspergillus fumigatus to fluconazole.
Fluconazole (FLC), a triazole with limited activity against Aspergillus species, is frequently used as prophylaxis in leukemia patients and bone marrow transplant recipients. Prior FLC use has been associated with an increasing incidence of invasive aspergillosis in these patients. We hypothesized that prior exposure of Aspergillus fumigatus to FLC could result in altered in vitro susceptibility of this fungus to other, more active triazoles. Thus, we performed serial passages of conidia of 10 clinical isolates of A. fumigatus (all itraconazole [ITC] susceptible) on FLC-containing yeast agar glucose plates. The MICs and minimal fungicidal concentrations (MFCs) of amphotericin B, FLC, ITC, and voriconazole (VRC) for A. fumigatus conidia were measured following four passages on FLC-containing medium according to the National Committee for Clinical Laboratory Standards microdilution method. Serial passages on FLC-containing plates resulted in a fourfold increase in the MFCs (but not the MICs) of ITC for nine isolates. The attenuated ITC fungicidal activity against A. fumigatus following FLC preexposure was medium independent and was also observed against FLC-preexposed A. fumigatus hyphae with the viability staining FUN-1 dye. Moreover, FLC preexposure of A. fumigatus conidia resulted in an analogous increase in the MFCs (but not the MICs) of VRC. Our findings suggest that preexposure of A. fumigatus to FLC attenuates the in vitro fungicidal activity of subsequent ITC use against it. This phenotypic adaptation is not captured by a routine MIC determination but requires MFC measurement. The in vivo significance of this in vitro phenomenon requires further investigation.


Morphological and functional evaluation of leg-muscle reinnervation after coupler coaptation of the divided rat sciatic nerve.
Mechanical couplers are successfully used for microvascular venous anastomoses. The advantages include a simple and fast technique and a high patency rate. Couplers offer a secluded coaptation site, and might also be of use in peripheral nerve repair. The present study was designed to investigate coupler coaptation of the rat sciatic nerve, evaluating the number and locations of motor and sensory neurons projecting to the selected muscles as well as stimulation-induced muscle contraction force. Adult rats underwent either suture or coupler repair after left sciatic nerve transection. In all rats, the experimental side was compared to the healthy right side. Evaluation after 20 weeks included retrograde labeling of motoneurons and dorsal root ganglion neurons projecting to the tibial anterior muscle and to the tibial posterior muscle, histology, muscle contraction force (tibial anterior muscle and gastrocnemius muscle), and a pinch reflex test. The results show that the suture and the coupler groups did not differ significantly regarding the examined parameters, except for discrete signs of nerve compression at the coaptation site after coupler repair due to fibrous tissue ingrowth. However, this did not impair axonal regeneration. Importantly, axonal outgrowth from the repair site to the surrounding tissue was not observed after coupler coaptation, but it was observed after suture repair. These results suggest that couplers may be of value for repair of nerves in adjacency to avoid axonal crisscrossing between nerves during regeneration.


The efficacy and safety of a proposed herbal moisturising cream for dry skin and itch relief: a randomised, double-blind, placebo-controlled trial--study protocol.
Moisturisers prevent and treat dry skin. They can also protect sensitive skin, improve skin tone and texture, and mask imperfections. Herbal medicines or their extracts have been available as topical formulations and cosmetics. Arctium lappa L. (Asteraceae) has been used to treat inflammatory disorders and various skin problems. It could be a candidate herbal medicine for treating dry skin condition.This study aims to establish the efficacy and safety of a proposed herbal moisturising cream containing Arctium lappa L. seed extract, which has been approved by the Korean Ministry of Food and Drug Safety for use in cosmetics. This study is a randomised, double-blind, placebo-controlled study with two parallel groups (proposed herbal moisturising cream vs. placebo cream). We will recruit 66 healthy male and female participants, aged 20 to 65 years, who have been diagnosed with dry skin conditions. Participants will be randomly allocated to receive either the proposed herbal moisturising cream or a placebo cream for four weeks. Each participant will be examined for signs and symptoms before and after using the cream. Skin hydration, sebum (oily secretion) levels and transepidermal water loss (TEWL; constitutive loss of water from the skin surface) will be assessed. Participants will also be asked to fill out a health-related quality of life questionnaire. Safety will be assessed using blood tests, urine analysis, a pregnancy test, and the assessment of vital signs. This trial will utilise high-quality methodologies in accordance with both consolidated standards for reporting trials guidelines and the guidelines for clinical trials of cosmetics products that are aimed at expressions and advertisement approval in Korea. It will evaluate the clinical efficacy and safety of a proposed herbal moisturising cream containing Arctium lappa L. seed extract to treat dry skin conditions and provide itch relief. Moreover, we will also employ health-related quality of life questionnaires to assess changes in the quality of life. The results of this study will be used to present the evidence needed to request advertising/display allowances, in compliance with the recently amended Cosmetics Act for advertisement in Korea. Current Controlled Trials ISRCTN46216631.


Abnormal modulation of reward versus punishment learning by a dopamine D2-receptor antagonist in pathological gamblers.
Pathological gambling has been associated with dopamine transmission abnormalities, in particular dopamine D2-receptor deficiency, and reversal learning deficits. Moreover, pervasive theoretical accounts suggest a key role for dopamine in reversal learning. However, there is no empirical evidence for a direct link between dopamine, reversal learning and pathological gambling. The aim of the present study is to triangulate dopamine, reversal learning, and pathological gambling. Here, we assess the hypothesis that pathological gambling is accompanied by dopamine-related problems with learning from reward and punishment by investigating effects of the dopamine D2-receptor antagonist sulpiride (400 mg) on reward- and punishment-based reversal learning in 18 pathological gamblers and 22 healthy controls, using a placebo-controlled, double-blind, counter-balanced design. In line with previous studies, blockade of D2 receptors with sulpiride impaired reward versus punishment reversal learning in controls. By contrast, sulpiride did not have any outcome-specific effects in gamblers. These data demonstrate that pathological gambling is associated with a dopamine-related anomaly in reversal learning from reward and punishment.


Loss of water transport capacity due to xylem cavitation in roots of two CAM succulents.
Loss of axial hydraulic conductance as a result of xylem cavitation was examined for roots of the Crassulacean acid metabolism (CAM) succulents Agave deserti and Opuntia ficus-indica. Vulnerability to cavitation was not correlated with either root size or vessel diameter. Agave deserti had a mean cavitation pressure of -0.93 ± 0.08 MPa by both an air-injection and a centrifugal method compared to -0.70 ± 0.02 MPa by the centrifugal method for O. ficus-indica, reflecting the greater tolerance of the former species to low water potentials in its native habitat. Substantial xylem cavitation would occur at a soil water potential of -0.25 MPa, resulting in a predicted 22% loss of conductance for A. deserti and 32% for O. ficus-indica. For an extended drought of 3 mo, further cavitation could cause a 69% loss of conductance for A. deserti and 62% for O. ficus-indica. A model of axial hydraulic flow based upon the cavitation response of these species predicted that water uptake rates are far below the maximum possible, owing to the high root water potentials of these desert succulents. Despite various shoot adaptations to aridity, roots of A. deserti and O. ficus-indica are highly vulnerable to cavitation, which partially limits water uptake in a wet soil but helps reduce water loss to a drying soil.


Film formation from monodisperse acrylic lattices 1. Influence of concentration and layer thickness on particle ordering.
The influence of concentration and layer thickness on particle ordering in polymer latex films, both open and closed, has been studied by means of rheology, microscopy and turbidimetry. Monodisperse acrylic lattices were synthesized by semicontinuous emulsion polymerization. The lattices exhibited a distinct thixotropy above a certain concentration, which is attributed to crystallization. Microscopy revealed a three-layer structure and a dependence of crystal size and crystal packing on layer thickness and layer concentration. Turbidimetry (i.e., analysis of light transmission and interference) was used to study the progress of ordering in open and closed systems. In closed films crystallization proceeds faster at higher concentrations and in thinner films. Above a sufficiently high concentration no crystallization was observed. Furthermore, an induction time was found below certain concentrations. The drying of open latex films at temperatures below the minimum film formation temperature (MFFT) was shown to proceed through five distinct stages. The drying of open films at temperatures below the MFFT was studied by analysis of the turbidity of rewetted films. A more compact structure was found in thinner films. The structure in lattices is discussed as a result of long-range and short-range ordering.


Bile constituents in blood and lymph during biliary obstruction. I. The dynamics of absorption and transport of ions and colloid molecules.
Na125I and 131I-labeled albumin was infused in dogs into the common bile duct at pressures of 20 to 25 and 40 mmHg. At 40 mmHg, the amounts of the iodide ion and labeled albumin in circulating plasma were, after correction for the secondary loss from the circulation, nearly identical. At 20-25 mmHg more iodid than labeled albumin was found in the circulation. In thoracic duct lymph the same fraction of the infused amount of albumin was recovered at both pressures. Lymphatic concentrations of albumin were in both types of experiments substantially higher than plasma concentrations. It is concluded, that at increased pressure fluid leaks first from the small biliary ducts into the Mall's spaces. In consequence of water absorption and the diffusion of ions and small molecules into the blood capillaries the concentrations of protein or protein bound molecules in this part of the hepatic interstitial fluid increases. This is reflected in their high concentration in the lymph. If bile pressure rises further, fluid leaks also into the Disse's spaces. This leads to a bulk flow of solvent and solutes into the sinusoids and to the near disappearance of the differences in the venous transport of ions and colloids.