[Clinical report of 81 cases of multiple primary cancers in laryngeal carcinoma].
To explore the clinical characteristics and the survival status of the patients with laryngeal squamous cell carcinoma in the multiple primary cancers (MPC). Follow-up and clinical data were analyzed retrospectively in 81 laryngeal squamous cell cancer patients with MPC among 1101 patients with laryngeal carcinoma. Survival analysis and every influencing factor on survival rate were performed by Kaplan-Meier method. The occurrence rate of MPC in the patients with laryngeal squamous cell cancer was 7.4% (81/1101) in this report. Oral cavity carcinoma and nasopharyngeal carcinoma were the most common MPC in 29 cases (35.8%) in head and neck regions. MPC in head and neck regions were more often seen among patients who had treated with radiotherapy (chi2 = 5.7, P = 0.017). Lung carcinoma (25.9%, 21/81) and esophageal carcinoma (22.2%, 18/81) were the most common MPC in remote organs in 52 cases (64.2%). Thirty seven MPC cases (45.7%) were occurred in aerodigestive tract and 32 cases(39.5%) in respiratory tract in this series. Fourteen cases (17.3%) were synchronous MPC, the median time interval was 2 months. Other 67 cases (82.7%) were metachronous MPC, the median time interval was 28 months. The squamous cell carcinoma (66.7%) was the most common pathologic type among all MPC in 81 cases, which was more often seen among patients who had smoked and drunk (P = 0.007). The MPC of esophageal carcinoma and oropharyngeal carcinoma were more often seen among patients of supraglottic index cancer presentation (P = 0.04). The MPC of oral cavity cancers and nasopharyngeal carcinoma and lung carcinoma were more often seen among patients of glottic index cancer presentation (P = 0.006). The total three-and five-year survival rates were 45.2% and 29.7% respectively of all MPC patients, the five-year survival rate for patients (53 cases) who received actively different therapies for their MPC was 45.5%, obviously higher than that of untreated patients (28 cases) whose three-year survival rate was zero (P = 0.000). Lung carcinoma and esophageal carcinoma were the most common multiple primary cancers among MPC of the laryngeal cancer. MPC of the laryngeal cancer in head and neck regions were more often seen among patients who had treated with radiotherapy. The pathologic type of squamous carcinomas of MPC was more often seen among patients who had smoked and drunk. MPC affected the prognosis of patients in laryngeal cancer largely. Treating effectively and in time could help to improve the survival rate of patients with MPC in laryngeal squamous cell carcinomas.


Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity.
Leishmania braziliensis is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with L. braziliensis. We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Quantification of host and bacterial transcripts on human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcomes in L. braziliensis-infected mice colonized with S. aureus, given that its neutralization reduced pathology and inflammation. These results highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences.


Another 'Cushing ulcer'.
The authors describe the case of a 39-year-old man who presented to our hospital with easy fatigability and malaise. On physical examination, hypertension was noted without any cushingoid appearance. Laboratory testing revealed normochromic-normocytic anaemia with positive results of occult blood in the stool, hyperglycaemia and hypokalemia. Upper endoscopy revealed active gastric ulcer with Helicobacter pylori infection, likely causing gastrointestinal bleeding. Endocrine examinations showed that both serum adrenocorticotropic hormone and cortisol were elevated with loss of diurnal variation. A diagnosis of Cushing's disease secondary to pituitary adenoma was made as results of brain MRI and blood sampling from inferior petrosal sinus. In a patient with peptic ulcer disease, physician should be alert to the possible endocrine background.


Chronologic presentation of a severe case of progressive hemifacial atrophy (parry-romberg syndrome) with the loss of an eye.
Progressive hemifacial atrophy, also known as Parry-Romberg syndrome, is a slowly advancing degenerative disease that mostly affects the cutaneous, subcutaneous fatty tissue, muscle tissue, and bone structures on one side of the face. We describe the chronological progression of this very rare syndrome from early childhood until adulthood in a patient who developed severe atrophy and lost one eye. We also discuss the aetiology and pathophysiology of this syndrome.


Density functional theory augmented with an empirical dispersion term. Interaction energies and geometries of 80 noncovalent complexes compared with ab initio quantum mechanics calculations.
Standard density functional theory (DFT) is augmented with a damped empirical dispersion term. The damping function is optimized on a small, well balanced set of 22 van der Waals (vdW) complexes and verified on a validation set of 58 vdW complexes. Both sets contain biologically relevant molecules such as nucleic acid bases. Results are in remarkable agreement with reference high-level wave function data based on the CCSD(T) method. The geometries obtained by full gradient optimization are in very good agreement with the best available theoretical reference. In terms of the standard deviation and average errors, results including the empirical dispersion term are clearly superior to all pure density functionals investigated-B-LYP, B3-LYP, PBE, TPSS, TPSSh, and BH-LYP-and even surpass the MP2/cc-pVTZ method. The combination of empirical dispersion with the TPSS functional performs remarkably well. The most critical part of the empirical dispersion approach is the damping function. The damping parameters should be optimized for each density functional/basis set combination separately. To keep the method simple, we optimized mainly a single factor, s(R), scaling globally the vdW radii. For good results, a basis set of at least triple-zeta quality is required and diffuse functions are recommended, since the basis set superposition error seriously deteriorates the results. On average, the dispersion contribution to the interaction energy missing in the DFT functionals examined here is about 15 and 100% for the hydrogen-bonded and stacked complexes considered, respectively.


Transcription analysis of cochlear development in minipigs.
The critical stage for cochlear gene regulation in the embryo is E49-E56. These data provide a valuable resource to help elucidate gene regulation in cochlear development and will benefit ear-related studies, especially those that focus on gene and stem cell therapies in hearing loss. To investigate gene regulation in cochlear development and provide reference information for ear-related research. Total RNA extraction from the Bama miniature pig cochlea was performed at five time points that covered most of the cochlea development process (E42, E49, E56, E91, P13). Transcriptome sequencing was performed by Illumina HiSeq 2500. Transcriptome data were mapped to the genome using TopHat2. Gene expression was quantified using the Cuffquant and Cuffnorm modules. GO and KEGG pathway-enrichment analysis were in progress about the differentially expressed genes (DEGs) by Perl programs. Sequencing of 1778643560000 paired reads revealed 35.9 G of data, and 19,432 expression genes were detected. The ratio of these pairs to the Ensembl genome database was approximately 71% in all samples. The stages E49-E91 and, especially, E49-E56 included the most rapid changes in gene regulation and differentiation for the cochlea. The stem cell characteristics of neural stem cells decreased most rapidly during this period.


Phylogeography and post-glacial recolonization in wolverines (Gulo gulo) from across their circumpolar distribution.
Interglacial-glacial cycles of the Quaternary are widely recognized in shaping phylogeographic structure. Patterns from cold adapted species can be especially informative - in particular, uncovering additional glacial refugia, identifying likely recolonization patterns, and increasing our understanding of species' responses to climate change. We investigated phylogenetic structure of the wolverine, a wide-ranging cold adapted carnivore, using a 318 bp of the mitochondrial DNA control region for 983 wolverines (n=209 this study, n=774 from GenBank) from across their full Holarctic distribution. Bayesian phylogenetic tree reconstruction and the distribution of observed pairwise haplotype differences (mismatch distribution) provided evidence of a single rapid population expansion across the wolverine's Holarctic range. Even though molecular evidence corroborated a single refugium, significant subdivisions of population genetic structure (0.01< ΦST <0.99, P<0.05) were detected. Pairwise ΦST estimates separated Scandinavia from Russia and Mongolia, and identified five main divisions within North America - the Central Arctic, a western region, an eastern region consisting of Ontario and Quebec/Labrador, Manitoba, and California. These data are in contrast to the nearly panmictic structure observed in northwestern North America using nuclear microsatellites, but largely support the nuclear DNA separation of contemporary Manitoba and Ontario wolverines from northern populations. Historic samples (c. 1900) from the functionally extirpated eastern population of Quebec/Labrador displayed genetic similarities to contemporary Ontario wolverines. To understand these divergence patterns, four hypotheses were tested using Approximate Bayesian Computation (ABC). The most supported hypothesis was a single Beringia incursion during the last glacial maximum that established the northwestern population, followed by a west-to-east colonization during the Holocene. This pattern is suggestive of colonization occurring in accordance with glacial retreat, and supports expansion from a single refugium. These data are significant relative to current discussions on the conservation status of this species across its range.


Serial optical coherence tomography images of trapped balloon catheter after bailout stenting.
The increased use of endovascular interventions has resulted in a growing number of complications pertaining to unretrievable devices. We report a case of balloon dislodgement in a coronary artery during percutaneous coronary intervention (PCI) with bailout stenting using bare metal stent (BMS). We could not retrieve the remnant despite several attempts and techniques. Thereafter, we deployed BMS to bail out thrombus to recover the coronary flow. Emergency surgery was not considered because of high perioperative mortality (EuroSCORE II 55.91%). We did careful follow-up with frequency domain optical coherence tomography images, which revealed thick neointima hyperplasia that completely covered the BMS over the balloon. On the other hand, relevant amounts of thrombus remained on the proximal shaft. In cases where remnants are difficult to retrieve using a percutaneous transcatheter technique and the patients are high-risk for surgery, sealing whole remnants with a BMS is a feasible treatment option.


Basophilic invasion in the neurohypophysis is increased in patients with Alzheimer's disease.
The prevalence of basophilic invasion (BI) and degenerative changes in the neurohypophysis of humans with neurodegenerative disease is not established. We evaluated 122 pituitary glands reviewed at autopsy including 45 with Alzheimer's disease (AD) Braak and Braak stage V or VI, 18 with Lewy body disease (LBD), and 59 age-matched controls for BI. In addition, pituitary glands from 51 patients including 25 patients with AD and 18 aged-matched controls were studied with a periodic acid Schiff (PAS) stain and immunohistochemistry with a polyclonal antibody to nestin. Samples were graded as negative (0) or positive (1). BI was seen in 35 of 45 patients with AD (0.78 ± 0.06 mean and SE: 78%) and was significantly higher than 30 of 59 controls (0.51 ± 0.07; 51%) (p = 0.0236). BI was seen in 7 of 18 patients with LBD (0.39 ± 0.12; 39%) compared to controls (p = 0.387). BI was also significantly higher in AD compared to LBD (p = 0.0001). Nestin immunoreactivity was detected in the neurohypophysis of all patients. Definite nestin was not found in BI but was seen in Herring body-like structures, in pituicytes and axons. Phospho-τ-immunoreactive Herring bodies were seen in 65% with AD but phospho-τ-immunoreactive neurofibrillary tangles were not found. BI is increased in AD compared to controls or LBD but not associated with nestin immunoreactivity. The significance and role of BI as a marker for AD warrants additional study.


Current progress in genomics and targeted therapies for neurofibromatosis type 2.
Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22. About half of patients inherit a germline mutation from a parent, and nearly 60% of de novo NF2 patients are estimated to have somatic mosaicism. The development of technical methods to detect NF2 gene mutation, including targeted deep sequencing from multiple tissues, improved the diagnostic rate of mosaic NF2. With improved understanding of genetics and pathogenesis, the diagnostic criteria for NF2 were updated to assist in identifying and diagnosing NF2 at an earlier stage. The understanding of cell signaling pathways interacting with merlin has led to the development of molecular-targeted therapies. Currently, several translational studies are searching for possible therapeutic agents targeting VEGF or VEGF receptors. Bevacizumab, an anti-VEGF monoclonal antibody, is widely used in many clinical trials aiming for hearing improvement or tumor volume control. Currently, a randomized, double-masked trial to assess bevacizumab is underway. In this randomized control trial, 12 other Japanese institutions joined the principal investigators in the clinical trial originating at Fukushima Medical University. In this review, we will be discussing the latest research developments regarding NF2 pathophysiology, including molecular biology, diagnosis, and novel therapeutics.


Development of a safe neutralization assay for SARS-CoV and characterization of S-glycoprotein.
The etiological agent of severe acute respiratory syndrome (SARS) has been identified as a novel coronavirus SARS-CoV. Similar to other coronaviruses, spike (S)-glycoprotein of the virus interacts with a cellular receptor and mediates membrane fusion to allow viral entry into susceptible target cells. Accordingly, S-protein plays an important role in virus infection cycle and is the primary target of neutralizing antibodies. To begin to understand its biochemical and immunological properties, we expressed both full-length and ectodomain of the protein in various primate cells. Our results show that the protein has an electrophoretic mobility of about 160-170 kDa. The protein is glycosylated with high mannose and/or hybrid oligosaccharides, which account for approximately 30 kDa of the apparent protein mass. The detection of S-protein by immunoassays was difficult using human convalescent sera, suggesting that the protein may not elicit strong humoral immune response in virus-infected patients. We were able to pseudotype murine leukemia virus particles with S-protein and produce SARS pseudoviruses. Pseudoviruses infected Vero E6 cells in a pH-independent manner and the infection could be specifically inhibited by convalescent sera. Consistent with low levels of antibodies against S-protein, neutralizing activity was weak with 50% neutralization titers ranging between 1:15 to 1:25. To facilitate quantifying pseudovirus-infected cells, which are stained blue with X-Gal, we devised an automated procedure using an ELISPOT analyzer. The high-throughput capacity of this procedure and the safety of using SARS pseudoviruses should make possible large-scale analyses of neutralizing antibody responses against SARS-CoV.


Does the therapy manual or the therapist matter most in treatment of obsessive-compulsive disorder? A randomized controlled trial of exposure with response or ritual prevention in 118 patients.
The importance of the therapist's education and experience for the successful behavior treatment of obsessive-compulsive disorder (OCD) has not been investigated. Data on the relative effectiveness of self-controlled versus therapist-controlled in vivo exposure with response or ritual prevention (ERP) have yielded conflicting results. The present study compared the effectiveness of 4 different modes of delivery of ERP in a referred sample of OCD patients. Of the 146 eligible OCD outpatients, 118 patients enrolled in this randomized controlled trial and were randomly assigned to (1) therapist-controlled ERP performed by experienced behavior therapists; (2) therapist-controlled ERP performed by master's students of clinical psychology; (3) self-controlled ERP performed by experienced behavior therapists; and (4) self-controlled ERP performed by master's students of clinical psychology. This trial was performed from January 1999 to January 2005. Our analyses revealed no significant differences in clinical outcome between any of the different modes of delivery of ERP at posttreatment. The different ERP modes of delivery were associated with significant pretreatment to posttreatment improvement on all measurements, with large effect sizes on the primary outcome measure, the Yale-Brown Obsessive Compulsive Scale. Our results indicate that clinically inexperienced master's students with no postgraduate training can be as capable as experienced and certified behavior therapists in treating OCD patients, as long as therapists adhere to a standardized treatment manual and adequate training and supervision is provided. In contrast to other studies, we did not find a supposed benefit of therapist-controlled ERP versus self-controlled ERP in patients with OCD. www.trialregister.nl Identifier: NTR1444.


Clinical value of bone marrow cultures in childhood pure red cell aplasia.
We assessed the value of marrow cultures for defining the pathophysiology, diagnosis, and therapeutic response to immunosuppressive therapy in childhood pure red cell aplasia (PRCA). Patients were evaluated either at diagnosis (n = 23) or at the time of treatment failure (n = 2). Twelve patients had transient erythroblastopenia of childhood (TEC), 4 had Diamont-Blackfan anemia (DBA), and 9 had acquired sustained PRCA (A-Su-PRCA). Bone marrow mononuclear cells were cultured with combination of human recombinant (rhu) erythropoietin (EPO), granulocyte monocyte colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), Interleukin 3 (IL-3), either with or without stem cell factor (SCF), and burst forming unit of erythroid (BFU-E) growth was assessed. The combination of growth factors without SCF failed to induce any erythropoiesis (BFU-E < 10/10(5) mononuclear cells) in 10 patients (2 with TEC, 2 with DBA, and 6 with A-Su-PRCA), although the growth of erythroid colonies was substantially lower in the remaining patients than in controls (45.5 +/- 15.4 versus 91.7 +/- 12.7, p < 0.05). Addition of SCF restored erythropoiesis in all but 6 patients (5 with A-Su-PRCA and 1 with DBA). Five of 6 nonresponders did not respond to any immunomodulating therapy; of the 5, 3 had or developed some evidence of myelodysplasia. Our data indicate that in vitro colony studies might prove to be a useful diagnostic tool, because erythropoiesis' poor response to growth factors, including SCF, may suggest the diagnosis of myelodysplasia. Moreover, it may have predictive value; in cases of PRCA, regardless of etiology, poor growth of erythropoietic colonies may predict refractoriness to immunomodulating therapy.


Ion leaching of a glass-ionomer glass: an empirical model and effects on setting characteristics and strength.
The release of ions from a glass-ionomer glass, which in the polyacid matrix effects the cross-linking and setting of a cement, can be modelled and initiated by acid-treatment in a dilute acid. This study examined the effect of time of acetic acid leaching on the working time, setting time, and strength of a model GIC. A reactive fluoride glass was immersed in hot acetic acid for 0 (control), 5, 15, 35, 65, 95 and 125 min, filtered and dried. The glass was mixed with an experimental GI liquid in a capsule system and the mixed pastes assessed for working and initial setting time. Compressive strength testing was undertaken according to ISO9917:2003. Immersion time had a significant effect on both working and setting time of the resultant pastes only up to 65 min of immersion, and corresponded with a thin-film ion diffusion model. Compressive strength did not vary significantly with immersion time. The glass-ionomer setting reaction can be conveniently retarded by immersion of the powder in acetic acid, without affecting strength. A reactivity model was developed, whereby the effects of various changes to the leaching process may be usefully examined.


High neonatal triiodothyronine levels reduce the period of Sertoli cell proliferation and accelerate tubular lumen formation in the rat testis, and increase serum inhibin levels.
T3 was injected daily in newborn rats from birth to 16 days of age. Control rats received daily injections of vehicle during the same period. The proliferative activity of the Sertoli cells was studied by means of bromodeoxyuridine incorporation, and tubular lumen formation and nuclear size were taken as markers of Sertoli cell differentiation. T3 treatment strongly reduced the proliferative activity of Sertoli cells from day 7 on, and on day 12, proliferation of Sertoli cells had ceased, while in control rats proliferating Sertoli cells were observed up to day 16. As a result of the reduced Sertoli cell proliferation, the final Sertoli cell number per testis at 23 days of age was reduced by 50% from 38 +/- 1 x 10(6) in control rats to 19 +/- 1 x 10(6) in T3-treated rats. Lumen formation in seminiferous tubules of T3-treated rats began at 12 days of age, while in controls lumen formation was first observed at 16 days. The area of the Sertoli cell nuclei was somewhat larger in T3-treated rats on day 16, but not at any other age examined. Body and testis weights in adult rats at 100 days of age were reduced by 46% and 48% of control values, respectively. The high neonatal T3 levels reduced serum levels of TSH on days 7 and 9, but not at any other age examined. FSH levels were reduced in T3-injected rats on days 5 and 7 and increased on day 23, after cessation of treatment. Immunoreactive inhibin-alpha levels were increased on days 5-9 and reduced on days 16 and 23. These findings indicate that T3 stimulates the production of immunoreactive inhibin by Sertoli cells, but also of bioactive inhibin, as indicated by the reduced FSH levels. It is concluded that the levels of thyroid hormones early in life are important for the terminal differentiation of Sertoli cells and, therefore, for determining adult testis size. The data indicate that this might be a direct effect of T3 on Sertoli cells.


Molten Alkali Halide Flux Growth of an Extensive Family of Noncentrosymmetric Rare Earth Sulfides: Structure and Magnetic and Optical (SHG) Properties.
Twenty new alkali rare earth thiosilicates and thiogermanates with the general formula ALnTS4 (A = alkali metal, Ln = lanthanide, and T = Si, Ge) were grown as X-ray diffraction-quality single crystals from molten alkali chloride fluxes. These include KNdSiS4, KPrSiS4, RbLnSiS4 (Ln = Ce, Pr, Nd, Gd, Tb, Dy, and Ho), RbLaGeS4, CsLnSiS4 (Ln = La, Pr, and Nd), and CsLnGeS4 (La, Ce, Pr, Nd, Eu, Gd, and Tb). Herein, we discuss the use of a molten chloride flux growth approach for the preparation of the title compounds and their structure determination via single-crystal X-ray diffraction. In addition, we comment on the magnetic properties of RbNdSiS4, CsNdSiS4, CsNdGeS4, and CsGdGeS4, which were found to be paramagnetic for T = 2-300 K and exhibited negative Weiss temperatures with no obvious antiferromagnetic transition down to 2 K. The optical properties of CsLaGeS4 and CsNdTS4(T = Si, Ge) were measured by UV-vis spectroscopy. Second harmonic generation measurements performed on CsLaGeS4 confirmed the crystallization of the compound in the noncentrosymmetric orthorhombic space group, P212121; CsLaGeS4 was found to be SHG-active with nearly half the intensity of α-SiO2 upon irradiation with a Nd:YAG 1064 nm laser, and a semiconductor exhibiting a band gap of 3.60 eV based on UV-vis diffuse reflectance measurements.


Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label.
The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice. The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents. A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001). The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection.


Polypoidal Choroidal Vasculopathy with Feeder Vessels: Characteristics, Fellow Eye Findings, and Long-term Treatment Outcomes.
To evaluate the long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with feeder vessels and to investigate fellow-eye findings. This retrospective observational study included 14 eyes with treatment-naïve PCV accompanied by feeder vessels that were treated with anti-VEGF monotherapy. The best-corrected visual acuity (BCVA) at baseline was compared with that at the last follow-up. The fellow-eye indocyanine green angiography findings were also analyzed. The mean follow-up period was 28.1 ± 19.2 months (range, 12 to 60 months). During the follow-up period, 5.9 ± 2.5 anti-VEGF injections were administered. The logarithm of the minimal angle of resolution (logMAR) BCVAs at the time of diagnosis, at 3 months, and at the last follow-up were 0.81 ± 0.49, 0.55 ± 0.44, and 0.71 ± 0.54, respectively. Although the BCVA at the last follow-up was not different from the baseline value (p=0.809), an improvement of ≥0.2 logMAR BCVA was observed in seven eyes (50.0%). In 11 eyes that underwent bilateral indocyanine green angiography at diagnosis, PCV, branching vascular networks, and late geographic hyperfluorescence were noted in two (18.2%), five (45.4%), and three (27.3%) fellow eyes, respectively. During the follow-up period, the development of polypoidal lesions in the fellow eye was observed in three patients. In this study, long-term improvement in BCVA was noted in 50% of the included patients who received anti-VEGF monotherapy. A relatively high incidence of pathological findings in the fellow eye and bilateral involvement suggest the need for bilateral examinations.


[Posology of analgesics in patients with kidney failure].
Doses and dosing interval of analgesic drugs in renal failure are not always available in the data sheet compendium. The aim of the article is to analyse literature references and to present main pharmacokinetics modifications for each analgesic drug in renal failure. Pharmacokinetics parameters, doses and dosing intervals depending on creatinine concentrations are presented for each drug in a table.


Influence of heparin molecular size on the induction of C- terminal unfolding in β2-microglobulin.
Dialysis-related amyloidosis (DRA) is characterized by accumulation of amyloid β2- microglobulin (β2m) in the interstitial matrix. Matrix substances such as heparin have reportedly been strongly implicated in the pathogenesis of dialysis-related amyloidosis. In clinical setting of hemodialysis, two types of heparin, i.e., high and low molecular heparin (H.M.H. and L.M.H.) have been routinely used. Still commonly used is H.M.H., followed by L.M.H. preparations with distinct advantages. Here, we studied that the interaction of native and two amyloidogenic β2m variants: ΔN6β2m and D76N β2m with H.M.H. and L.M.H. We also investigated whether heparin could induce β2m to have an amyloidogenic conformation. Biolayer interferometry revealed that ΔN6β2m had a strong reaction and D76N β2m had a moderate reaction with H.M.H.. Furthermore,H.M.H. induced the C-terminal unfolding in a native β2m. By contrast, L.M.H. showed no reaction even with ΔN6β2m. This study showed firstly a direct binding of β2m with H.M.H.. H.M.H. would provoked a C-terminal unfolding of β2m, which indicated production of an amyloidogenic intermediate, i.e., β2m92-99. In addition, our findings also suggest that L.M.H. may provide beneficial effects against the development of the DRA.


Interleukin-17A plays a key role in pulmonary fibrosis following Propionibacterium acnes-induced sarcoidosis-like inflammation.
Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis.


Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects.
A study was undertaken to define the computed tomographic (CT) appearance of the lungs in subjects with uncomplicated asthma and to compare the prevalence of bronchial dilatation at CT in asthmatic and healthy subjects. Clinical features, pulmonary physiologic findings, chest radiographs, and high-resolution CT scans of 48 asthmatic subjects were reviewed. Forty-one (85%) of the 48 asthmatic subjects were undergoing bronchodilator therapy, 28 (58%) were undergoing steroid therapy, and 21 (44%) were cigarette smokers. Twenty-seven healthy control subjects underwent limited high-resolution CT. At selected CT levels, any bronchus with an internal diameter greater than that of the accompanying pulmonary artery was considered dilated. In the asthmatic subjects, 153 (36%) of 429 bronchi evaluated met criteria for bronchial dilatation compared with 37 (26%) of 142 bronchi in the control group (P < .05). Because bronchial dilatation demonstrated at CT did not correlate with clinical data, the authors conclude a bronchus larger in diameter than the adjacent vessel is not sufficient evidence to diagnose cylindric bronchiectasis.


Wipe sampling for nicotine as a marker of thirdhand tobacco smoke contamination on surfaces in homes, cars, and hotels.
Secondhand smoke contains a mixture of pollutants that can persist in air, dust, and on surfaces for months or longer. This persistent residue is known as thirdhand smoke (THS). Here, we detail a simple method of wipe sampling for nicotine as a marker of accumulated THS on surfaces. We analyzed findings from 5 real-world studies to investigate the performance of wipe sampling for nicotine on surfaces in homes, cars, and hotels in relation to smoking behavior and smoking restrictions. The intraclass correlation coefficient for side-by-side samples was 0.91 (95% CI: 0.87-0.94). Wipe sampling for nicotine reliably distinguished between private homes, private cars, rental cars, and hotels with and without smoking bans and was significantly positively correlated with other measures of tobacco smoke contamination such as air and dust nicotine. The sensitivity and specificity of possible threshold values (0.1, 1, and 10 μg/m(2)) were evaluated for distinguishing between nonsmoking and smoking environments. Sensitivity was highest at a threshold of 0.1 μg/m(2), with 74%-100% of smoker environments showing nicotine levels above threshold. Specificity was highest at a threshold of 10 μg/m(2), with 81%-100% of nonsmoker environments showing nicotine levels below threshold. The optimal threshold will depend on the desired balance of sensitivity and specificity and on the types of smoking and nonsmoking environments. Surface wipe sampling for nicotine is a reliable, valid, and relatively simple collection method to quantify THS contamination on surfaces across a wide range of field settings and to distinguish between nonsmoking and smoking environments.


Perception and Appreciation of Tactile Objects: The Role of Visual Experience and Texture Parameters.
This exploratory study was designed to examine the effects of visual experience and specific texture parameters on both discriminative and aesthetic aspects of tactile perception. To this end, the authors conducted two experiments using a novel behavioral (ranking) approach in blind and (blindfolded) sighted individuals. Groups of congenitally blind, late blind, and (blindfolded) sighted participants made relative stimulus preference, aesthetic appreciation, and smoothness or softness judgment of two-dimensional (2D) or three-dimensional (3D) tactile surfaces through active touch. In both experiments, the aesthetic judgment was assessed on three affective dimensions, Relaxation, Hedonics, and Arousal, hypothesized to underlie visual aesthetics in a prior study. Results demonstrated that none of these behavioral judgments significantly varied as a function of visual experience in either experiment. However, irrespective of visual experience, significant differences were identified in all these behavioral judgments across the physical levels of smoothness or softness. In general, 2D smoothness or 3D softness discrimination was proportional to the level of physical smoothness or softness. Second, the smoother or softer tactile stimuli were preferred over the rougher or harder tactile stimuli. Third, the 3D affective structure of visual aesthetics appeared to be amodal and applicable to tactile aesthetics. However, analysis of the aesthetic profile across the affective dimensions revealed some striking differences between the forms of appreciation of smoothness and softness, uncovering unanticipated substructures in the nascent field of tactile aesthetics. While the physically softer 3D stimuli received higher ranks on all three affective dimensions, the physically smoother 2D stimuli received higher ranks on the Relaxation and Hedonics but lower ranks on the Arousal dimension. Moreover, the Relaxation and Hedonics ranks accurately overlapped with one another across all the physical levels of softness/hardness, but not across the physical levels of smoothness/roughness. These findings suggest that physical texture parameters not only affect basic tactile discrimination but differentially mediate tactile preferences, and aesthetic appreciation. The theoretical and practical implications of these novel findings are discussed.


Transcriptional profiling identifies altered intracellular labile iron homeostasis as a contributing factor to the toxicity of adaphostin: decreased vascular endothelial growth factor secretion is independent of hypoxia-inducible factor-1 regulation.
Adaphostin was developed as an inhibitor of the p210(bcr-abl) tyrosine kinase, but as its activity is not limited to tumor cell lines containing this translocation, transcriptional profiling was used as a tool to elucidate additional mechanisms responsible for adaphostin cytotoxicity. Profiles of drug-induced transcriptional changes were measured in three hematopoietic cell lines following 1 and 10 micromol/L adaphostin for 2 to 6 hours and then confirmed with real-time reverse transcription-PCR (2-24 hours). These data indicated altered iron homeostasis, and this was confirmed experimentally. Alteration of vascular endothelial growth factor (VEGF) secretion through hypoxia-inducible factor-1 (HIF-1) regulation was also investigated. Drug-induced genes included heat shock proteins and ubiquitins, but an intriguing response was the induction of ferritins. Measurement of the labile iron pool showed release of chelatable iron immediately after treatment with adaphostin and was quenched with the addition of an iron chelator. Pretreatment of cells with desferrioxamine and N-acetyl-cysteine reduced but did not ablate the sensitivity of the cells to adaphostin, and desferrioxamine was able to modulate adaphostin-induced activation of p38 and inactivation of AKT. VEGF secretion was shown to be reduced in cell lines after the addition of adaphostin but was not dependent on HIF-1. Adaphostin-induced cytotoxicity is caused in part by a rapid release of free iron, leading to redox perturbations and cell death. Despite this, reduced VEGF secretion was found to be independent of regulation by the redox responsive transcription factor HIF-1. Thus, adaphostin remains an interesting agent with the ability to kill tumor cells directly and modulate angiogenesis.


Establishment of an Alphavirus-Specific Neutralization Assay to Distinguish Infections with Different Members of the Semliki Forest complex.
Alphaviruses are transmitted by arthropod vectors and can be found worldwide. Alphaviruses of the Semliki Forest complex such as chikungunya virus (CHIKV), Mayaro virus (MAYV) or Ross River virus (RRV) cause acute febrile illness and long-lasting arthralgia in humans, which cannot be clinically discriminated from a dengue virus or Zika virus infection. Alphaviruses utilize a diverse array of mosquito vectors for transmission and spread. For instance, adaptation of CHIKV to transmission by Aedes albopictus has increased its spread and resulted in large outbreaks in the Indian Ocean islands. For many alphaviruses commercial diagnostic tests are not available or show cross-reactivity among alphaviruses. Climate change and globalization will increase the spread of alphaviruses and monitoring of infections is necessary and requires virus-specific methods. We established an alphavirus neutralization assay in a 384-well format by using pseudotyped lentiviral vectors. MAYV-specific reactivity could be discriminated from CHIKV reactivity. Human plasma from blood donors infected with RRV could be clearly identified and did not cross-react with other alphaviruses. This safe and easy to use multiplex assay allows the discrimination of alphavirus-specific reactivity within a single assay and has potential for epidemiological surveillance. It might also be useful for the development of a pan-alphavirus vaccine.


Impact of functional mandibular advancement appliances on the temporomandibular joint - a systematic review.
Although many orthodontists have no doubts about the effectiveness of functional appliances for mandibular advancement, the impact on the temporomandibular joint (TMJ) is still in dispute. The objective of this systematic review is to examine the main effects on the TMJ of using functional appliances, both in healthy patients and in patients with a pre-existing disorder. A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Only systematic reviews, meta-analyses, randomized clinical trials (RCTs), case-control studies and cohort studies were included. A detailed language-independent electronic search was conducted in the Pubmed, Scopus, Cochrane Library and Embase databases. All studies published between 2000 and 2015 were included. A total of 401 articles were identified. Of these, 159 were duplicates and were excluded. On reading the title and abstract, 213 articles were excluded because they did not answer the research question, leaving a total of 29 articles. These articles were read and assessed. Following critical reading of the full text, eight articles were excluded: seven because they were considered of low quality and one because it published redundant data. As a result, 21 articles were included. After treatment with functional appliances, the condyle was found to be in a more advanced position, with remodelling of the condyle and adaptation of the morphology of the glenoid fossa. No significant adverse effects on the TMJ were observed in healthy patients and the appliances could improve joints that initially presented forward dislocation of the disk.


Supratentorial brain schwannomas: an uncommon location for a common tumour.
Intracranial schwannomas not related to cranial nerves are uncommon brain tumours. Such tumours account for less than 1% of all surgically treated schwannomas. Only 79 cases have been reported in the literature. We describe two cases treated in our centre. The patients are young women with seizures as a presenting symptom. Both underwent surgery with the presumptive diagnosis of benign brain tumour. Histopathological examination revealed the certain diagnosis of Schwannoma. Good outcome was achieved with total excision of the tumour. Based on the literature, demographic data, clinical aspects, imaging features and theories on the possible origin of this rare tumour are discussed. These tumours should be included in the differential diagnosis of supratentorial benign tumours in young adults. Total excision, whenever possible, is the treatment of choice.


Correction of Hirschsprung-Associated Mutations in Human Induced Pluripotent Stem Cells Via Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, Restores Neural Crest Cell Function.
Hirschsprung disease is caused by failure of enteric neural crest cells (ENCCs) to fully colonize the bowel, leading to bowel obstruction and megacolon. Heterozygous mutations in the coding region of the RET gene cause a severe form of Hirschsprung disease (total colonic aganglionosis). However, 80% of HSCR patients have short-segment Hirschsprung disease (S-HSCR), which has not been associated with genetic factors. We sought to identify mutations associated with S-HSCR, and used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system to determine how mutations affect ENCC function. We created induced pluripotent stem cell (iPSC) lines from 1 patient with total colonic aganglionosis (with the G731del mutation in RET) and from 2 patients with S-HSCR (without a RET mutation), as well as RET+/- and RET-/- iPSCs. IMR90-iPSC cells were used as the control cell line. Migration and differentiation capacities of iPSC-derived ENCCs were analyzed in differentiation and migration assays. We searched for mutation(s) associated with S-HSCR by combining genetic and transcriptome data from patient blood- and iPSC-derived ENCCs, respectively. Mutations in the iPSCs were corrected using the CRISPR/Cas9 system. ENCCs derived from all iPSC lines, but not control iPSCs, had defects in migration and neuronal lineage differentiation. RET mutations were associated with differentiation and migration defects of ENCCs in vitro. Genetic and transcriptome analyses associated a mutation in the vinculin gene (VCL M209L) with S-HSCR. CRISPR/Cas9 correction of the RET G731del and VCL M209L mutations in iPSCs restored the differentiation and migration capacities of ENCCs. We identified mutations in VCL associated with S-HSCR. Correction of this mutation in iPSC using CRISPR/Cas9 editing, as well as the RET G731del mutation that causes Hirschsprung disease with total colonic aganglionosis, restored ENCC function. Our study demonstrates how human iPSCs can be used to identify disease-associated mutations and determine how they affect cell functions and contribute to pathogenesis.


Clonal evolution in paired endometrial intraepithelial neoplasia/atypical hyperplasia and endometrioid adenocarcinoma.
Endometrial intraepithelial neoplasia (EIN) and atypical endometrial hyperplasia (AH) are histomorphologically defined precursors to endometrioid adenocarcinoma, which are unified as EIN/AH by the World Health Organization. EIN/AH harbors a constellation of molecular alterations similar to those found in endometrioid adenocarcinoma. However, the process of clonal evolution from EIN/AH to carcinoma is poorly characterized. To investigate, we performed next-generation sequencing, copy number alteration (CNA) analysis, and immunohistochemistry for mismatch repair protein expression on EIN/AH and endometrioid adenocarcinoma samples from 6 hysterectomy cases with spatially distinct EIN/AH and carcinoma. In evaluating all samples, EIN/AH and carcinoma did not differ in mutational burden, CNA burden, or specific genes mutated (all P>.1). All paired EIN/AH and carcinoma samples shared at least one identical somatic mutation, frequently in PI(3)K pathway members. Large CNAs (>10 genes in length) were identified in 83% of cases; paired EIN/AH and carcinoma samples shared at least one identical CNA in these cases. Mismatch repair protein expression matched in all paired EIN/AH and carcinoma samples. All paired EIN/AH and carcinoma samples had identical The Cancer Genome Atlas subtype, with 3 classified as "copy number low endometrioid" and 3 classified as "microsatellite instability hypermutated." Although paired EIN/AH and carcinoma samples were clonal, private mutations (ie, present in only one sample) were identified in EIN/AH and carcinoma in all cases, frequently in established cancer-driving genes. These findings indicate that EIN/AH gives rise to endometrioid adenocarcinoma by a complex process of subclone evolution, not a linear accumulation of molecular events.


Glycyrrhizin injection therapy prevents hepatocellular carcinogenesis in patients with interferon-resistant active chronic hepatitis C.
There is no useful and effective treatment for patients with non-sustained response to interferon, from the viewpoint of cancer prevention. Our aim was to elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon-resistant hepatitis C Methods: We retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase values of twice or more of the upper limit of normal, 244 patients received i.v. glycyrrhizin injection and 102 patients did not, after judgment of interferon resistance. Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the fifth year, and 21.5% and 35.5% at the 10th year, respectively (P = 0.021). Proportional hazard analysis using time-dependent covariates disclosed that fibrotic stage, gender and glycyrrhizin treatmentwere significantly associated with future carcinogenesis. A long-term glycyrrhizin injection therapy decreased the hepatocarcinogenesis rate (hazard ratio, 0.49; 95% confidence interval, 0.27-0.86, P = 0.014) after adjusting the background features with significant covariates. Cancer preventive activity was also found in a subgroup of older patients of 60 years or more. Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with interferon-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of the upper limit of normal after interferon.


European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.
Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.


Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.
Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit. APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12-15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12-15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12-15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013). In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.


Quantum cascade lasers with integrated plasmonic antenna-array collimators.
We demonstrated in simulations and experiments that by defining a properly designed two-dimensional metallic aperture-grating structure on the facet of quantum cascade lasers, a small beam divergence angle can be achieved in directions both perpendicular and parallel to the laser waveguide layers (denoted as theta perpendicular and theta parallel, respectively). Beam divergence angles as small as theta perpendicular=2.7 degrees and theta parallel=3.7 degrees have been demonstrated. This is a reduction by a factor of approximately 30 and approximately 10, respectively, compared to those of the original lasers emitting at a wavelength of 8.06 microm. The devices preserve good room temperature performance with output power as high as approximately 55% of that of the original unpatterned lasers. We studied in detail the trade-off between beam divergence and power throughput for the fabricated devices. We demonstrated plasmonic collimation for buried heterostructure lasers and ridge lasers; devices with different waveguide structures but with the same plasmonic collimator design showed similar performance. We also studied a device patterned with a "spider's web" pattern, which gives us insight into the distribution of surface plasmons on the laser facet.


Reduced Glutamine Synthetase Activity Alters the Fecundity of Female Bactrocera dorsalis (Hendel).
Glutamine synthetase (GS) is a key enzyme in glutamine synthesis and is associated with multiple physiological processes in insects, such as embryonic development, heat shock response, and fecundity regulation. However, little is known about the influence of GS on female fecundity in the oriental fruit fly, Bactrocera dorsalis. Based on the cloning of BdGSs, mitochondrial BdGSm and cytoplasmic BdGSc, we determined their expressions in the tissues of adult B. dorsalis. BdGSm was highly expressed in the fat body, while BdGSc was highly expressed in the head and midgut. Gene silencing by RNA interference against two BdGSs isoforms suppressed target gene expression at the transcriptional level, leading to a reduced ovarian size and lower egg production. The specific inhibitor L-methionine S-sulfoximine suppressed enzyme activity, but only the gene expression of BdGSm was suppressed. A similar phenotype of delayed ovarian development occurred in the inhibitor bioassay. Significantly lower expression of vitellogenin and vitellogenin receptor was observed when GS enzyme activity was suppressed. These data illustrate the effects of two GS genes on adult fecundity by regulating vitellogenin synthesis in different ways.


TagDock: an efficient rigid body docking algorithm for oligomeric protein complex model construction and experiment planning.
We report here new computational tools and strategies to efficiently generate three-dimensional models for oligomeric biomolecular complexes in cases where there is limited experimental restraint data to guide the docking calculations. Our computational tools are designed to rapidly and exhaustively enumerate all geometrically possible docking poses for an oligomeric complex, rather than generate detailed, atomic-resolution models. Experimental data, such as interatomic distance measurements, are then used to select and refine docking poses that are consistent with the experimental restraints. Our computational toolkit is designed for use with sparse data sets to generate intermediate-resolution docking models, and utilizes distance difference matrix analysis to identify further restraint measurements that will provide maximum additional structural refinement. Thus, these tools can be used to help plan optimal residue positions for probe incorporation in labor-intensive biophysical experiments such as chemical cross-linking, electron paramagnetic resonance, or Förster resonance energy transfer spectroscopy studies. We present benchmark results for docking the collection of all 176 heterodimer protein complexes from the ZDOCK database, as well as a protein homodimer with recently collected experimental distance restraints, to illustrate the toolkit's capabilities and performance, and to demonstrate how distance difference matrix analysis can automatically identify and prioritize additional restraint measurements that allow us to rapidly optimize docking poses.


Exceptional points enhance sum sideband generation in a mechanical PT-symmetric system.
Systems exhibiting parity-time (PT) symmetry are, in general, non-Hermitian systems, in which exceptional points (EPs) emerge when the system transits from the PT-symmetric phase to the broken-PT-symmetric phase. Based on the abnormal exponential amplification effect in EPs, it is often used to generate, control and transmit light in non-Hermitian systems. In this paper, we theoretically analyze the generation of the frequency components at the sum sideband by considering the nonlinear terms of the optomechanical dynamics in a double-probe-field-driven mechanical PT-symmetric system. Using experimentally achievable parameters, we demonstrate that the efficiency of sum sideband generation (SSG) can be significantly enhanced in EPs, even that the efficiency of SSG can be raised by three orders of magnitude compared to the general optomechanical system by adjusting the appropriate system parameters. These results are beneficial to explore the transmission and conversion of light in chip-scale optical communications.


Using a model to assess the role of the spatiotemporal pattern of inhibitory input and intrasegmental electrical coupling in the intersegmental and side-to-side coordination of motor neurons by the leech heartbeat central pattern generator.
Previously we presented a quantitative description of the spatiotemporal pattern of inhibitory synaptic input from the heartbeat central pattern generator (CPG) to segmental motor neurons that drive heartbeat in the medicinal leech and the resultant coordination of CPG interneurons and motor neurons. To begin elucidating the mechanisms of coordination, we explore intersegmental and side-to-side coordination in an ensemble model of all heart motor neurons and their known synaptic inputs and electrical coupling. Model motor neuron intrinsic properties were kept simple, enabling us to determine the extent to which input and electrical coupling acting together can account for observed coordination in the living system in the absence of a substantive contribution from the motor neurons themselves. The living system produces an asymmetric motor pattern: motor neurons on one side fire nearly in synchrony (synchronous), whereas on the other they fire in a rear-to-front progression (peristaltic). The model reproduces the general trends of intersegmental and side-to-side phase relations among motor neurons, but the match with the living system is not quantitatively accurate. Thus realistic (experimentally determined) inputs do not produce similarly realistic output in our model, suggesting that motor neuron intrinsic properties may contribute to their coordination. By varying parameters that determine electrical coupling, conduction delays, intraburst synaptic plasticity, and motor neuron excitability, we show that the most important determinant of intersegmental and side-to-side phase relations in the model was the spatiotemporal pattern of synaptic inputs, although phasing was influenced significantly by electrical coupling.


Detection of a new type of mouse eosinophil colony by Luxol-fast-blue staining.
Staining with Luxol-fast-blue was shown to be a satisfactory method for identifying mouse eosinophils. IN agar cultures of mouse marrow stimulated by pokeweed mitogen-stimulated spleen conditioned medium (SCM), 2-10 compact Luxol-fast-blue positive eosinophil colonies varied according to the batch of human plasma used in the culture medium. Similar colony-forming cells were detected in the spleen and peripheral blood but not in the thymus or lymph nodes. Some Luxol-fast-blue positive eosinophil colonies were stimulated to develop by crude mouse lung conditioned medium and by high concentrations of GM-CSF purified from this source. The cells forming Luxol-fast-blue positive eosinophil colonies sedimented more rapidly (5.5-6.5 mm/h) than the cells forming dispersed-eosinophil colonies 94.5 mm/h). Transfer studies using intact colonies or redispersed colony cells failed to demonstrate an interrelationship between the two types of eosinophil colonies and the cells forming Luxol-fast-blue positive eosinophil colonies appear to be a distinct subset of eosinophil percursors.


Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.
Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.


Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity.
Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment. The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency. Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design. The study was conducted at general clinical research centers and with collaborating endocrinologists. Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than -2 for age and sex, and evidence of resistance to GH. rhIGF-I was administered sc in doses between 60 and 120 microg/kg twice daily. Height velocity, skeletal maturation, and adverse events were measured. Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%). Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.


Gastrointestinal dysplasia.
The term dysplasia (intraepithelial neoplasia) is used to refer to neoplastic but non-invasive epithelium. Dysplasia in the gastrointestinal tract is considered a carcinoma precursor and a marker of high cancer risk for the site at which it is found. It is diagnosed by pathologists using a set of cytological and architectural features. There are many pitfalls in the diagnosis of gastrointestinal dysplasia. One reason for difficulty in dysplasia diagnosis is the significant heterogeneity in the appearances of each grade of dysplasia. In addition, the features that characterise dysplasia are only subtly different from those of regenerating epithelium, particularly at the low end of the spectrum, making this distinction difficult. For these reasons, and because of significant implications of this diagnosis for patient care, the interpretations of biopsies taken for dysplasia surveillance are considered challenging by most pathologists. In this article, we review definition, classification, and histological features and grading of gastrointestinal dysplasia with focus on Barrett's oesophagus (BE) related dysplasia, gastric epithelial dysplasia (GED) and dysplasia arising in the background of inflammatory bowel disease (IBD). We also discuss observer variability and the role of adjunctive markers in dysplasia diagnosis, and limitation with regard to surveillance of patients with BE and IBD due to sampling error.


Improving temporal resolution in fMRI using a 3D spiral acquisition and low rank plus sparse (L+S) reconstruction.
Rapid whole-brain dynamic Magnetic Resonance Imaging (MRI) is of particular interest in Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI). Faster acquisitions with higher temporal sampling of the BOLD time-course provide several advantages including increased sensitivity in detecting functional activation, the possibility of filtering out physiological noise for improving temporal SNR, and freezing out head motion. Generally, faster acquisitions require undersampling of the data which results in aliasing artifacts in the object domain. A recently developed low-rank (L) plus sparse (S) matrix decomposition model (L+S) is one of the methods that has been introduced to reconstruct images from undersampled dynamic MRI data. The L+S approach assumes that the dynamic MRI data, represented as a space-time matrix M, is a linear superposition of L and S components, where L represents highly spatially and temporally correlated elements, such as the image background, while S captures dynamic information that is sparse in an appropriate transform domain. This suggests that L+S might be suited for undersampled task or slow event-related fMRI acquisitions because the periodic nature of the BOLD signal is sparse in the temporal Fourier transform domain and slowly varying low-rank brain background signals, such as physiological noise and drift, will be predominantly low-rank. In this work, as a proof of concept, we exploit the L+S method for accelerating block-design fMRI using a 3D stack of spirals (SoS) acquisition where undersampling is performed in the kz-t domain. We examined the feasibility of the L+S method to accurately separate temporally correlated brain background information in the L component while capturing periodic BOLD signals in the S component. We present results acquired in control human volunteers at 3T for both retrospective and prospectively acquired fMRI data for a visual activation block-design task. We show that a SoS fMRI acquisition with an acceleration of four and L+S reconstruction can achieve a brain coverage of 40 slices at 2mm isotropic resolution and 64 x 64 matrix size every 500ms.


DNA-dependent ATPase activity associated with phage P22 gene 12 protein.
The product of bacteriophage P22 gene 12 is known from genetic experiments to be essential for phage DNA replication. The P22 12 protein has been purified to near homogeneity from Escherichia coli lysogenic for lambda-P22 hybrid phage containing the replication genes of P22. The protein has a subunit molecular weight of 46,000. The purified protein contains ATPase activity that is stimulated by single-stranded DNA. The ATPase is poorly stimulated by double-stranded DNA. All four ribonucleoside triphosphates are hydrolyzed; none of the deoxynucleoside triphosphates are hydrolyzed. In addition, the P22 12 protein binds to single-stranded DNA in the presence of ATP. Studies of oligonucleotide synthesis by P22 12 protein in conjunction with E. coli dnaG primase are presented in the succeeding paper (Wickner, S. (1984) J. Biol. Chem. 259, 14044-14047).


Methylation-sensitive high-resolution melting-curve analysis of the SNRPN gene as a diagnostic screen for Prader-Willi and Angelman syndromes.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. Lack of paternal contribution results in PWS either by paternal deletion (approximately 70%) or maternal uniparental disomy (UPD) (approximately 25%). Most cases of AS result from the lack of a maternal contribution from this same region, by maternal deletion (70%) or paternal UPD (approximately 5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus differentiates the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Methylation-sensitive high-resolution melting-curve analysis (MS-HRM) using the DNA binding dye EvaGreen was used to analyze methylation differences at the SNRPN locus in anonymized DNA samples from individuals with PWS (n = 39) or AS (n = 31) and from healthy control individuals (n = 95). Results from the MS-HRM assay were compared to those obtained by use of a methylation-specific PCR (MSP) protocol that is used commonly in diagnostic practice. With the MS-HRM assay 97.6% of samples were unambiguously assigned to the 3 diagnostic categories (AS, PWS, normal) by use of automated calling with an 80% confidence percentage threshold, and the failure rate was 0.6%. One PWS sample showed a discordant result for the MS-HRM assay compared to MSP data. MS-HRM is a simple, rapid, and robust method for screening methylation differences at the SNRPN locus and could be used as a diagnostic screen for PWS and AS.


Preparation and characterization of chitosan/graphene oxide nanocomposite coatings on Mg-2 wt% Zn scaffold by pulse electrodeposition process.
Mg and its alloys are biodegradable and mechanically strong materials, which can be used for an orthopedic implant and device applications, but corrosion rate of these alloys is high. In this research, the nanocomposite coatings of chitosan (CS)/graphene oxide (GO) were fabricated to improve the corrosion resistance of the Mg-2 wt% Zn scaffold. The contents of the GO nanosheets and the pulse electrodeposition process parameters, including peak current density (CD) and duty cycle (DC), will also be investigated. The Mg-2 wt% Zn as a substrate of the scaffold was prepared using a powder metallurgy process. The influence of the porosity was studied on the microstructure fabricated scaffolds. The coating microstructures and morphologies were investigated by Raman spectroscopy, x-ray diffraction, thermogravimetric analysis, and SEM. The atomic force microscopy was performed to study the thickness of the nanocomposite coatings. The zeta potential measurement was conducted for the dispersion of the GO nanosheets in the CS matrix. The obtained results showed that the optimum conditions to fabricate a uniform CS/GO coating on the scaffolds were 2 wt% GO, CD = 20 mA cm-2, and DC = 0.5. The pH, time and temperature for the fabrication of the coatings were conducted at 5, 20 min, and 37 °C, respectively. Additionally, the potentiodynamic polarization measurement in simulated body fluid indicated that the CS/GO coatings could provide effective protection of the scaffolds against corrosion. Additionally, the optimum sample obtained from the aspect of the corrosion behavior demonstrated adequate biocompatibility with proper adhesion of mouse fibroblast cells (L929) on the CS-2 wt% GO coating.


Small intestine inflammation in Roquin-mutant and Roquin-deficient mice.
Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquin(san/san) mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquin(san/san) mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquin(gt/gt) mice) had small intestinal inflammation that mimicked that of Roquin(san/san) mice. MLN cells in Roquin(san/san) mice consisted of activated proliferating T cells, and had increased numbers of CD44(hi) CD62L(lo) KLRG1(+) short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquin(san/san) mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquin(san/san) mice consisted of a high proportion of Gr-1(+) T cells that included IL-17A(+) cells and CD8(+) IFN-γ(+) cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquin(san/san) mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.


[Roles of follicular helper T cells and follicular regulatory T cells in pathogenesis of Henoch-Schönlein purpura in children].
To study the roles of follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells in the pathogenesis of Henoch-Schönlein purpura (HSP) in children. Peripheral blood samples were collected from 40 HSP children and 25 healthy controls. The percentages of Tfh and Tfr cells were measured by flow cytometry; the mRNA expression levels of Bcl-6, c-MAF, Blimp-1, and PD-1 in peripheral blood were measured by real-time polymerase chain reaction. Compared with the controls, the children with HSP had significantly increased percentage of Tfh cells and Tfh/Tfr ratio but a significantly reduced percentage of Tfr cells in the peripheral blood (P<0.05). Compared with the controls, the children with HSP had significantly increased mRNA expression of Bcl-6 and c-MAF but significantly reduced mRNA expression of Blimp-1 in CD4+ T cells (P<0.05), and had significantly increased mRNA expression of PD-1 but significantly reduced mRNA expression of Blimp-1 in CD4+CD25+ regulatory T cells (P<0.05). Abnormal percentages of Tfh and Tfr cells may be involved in the pathogenesis of HSP in children, and over-expression of Bcl-6, c-MAF, and PD-1 mRNA and inhibited expression of Blimp-1 mRNA may be considered as important reasons for abnormal percentages of Tfh and Tfr cells.


Influence of the base sequence on the conformational behaviour of DNA polynucleotides in solution.
NMR studies were carried out on samples of the non-self-complementary tetramers d(C-A-C-A), d(T-G-T-G), d(G-A-G-A) and d(T-C-T-C) and of 1:1 mixtures of the complementary tetramers d(C-A-C-A) X d(T-G-T-G) and d(G-A-G-A) X d(T-C-T-C) at two DNA concentrations and of the self-complementary octamers d(C-A-C-A-T-G-T-G) and d(G-A-G-A-T-C-T-C). Assignments, based upon one-dimensional NOE and homonuclear-decoupling and two-dimensional correlated and NOE spectroscopies are given of the resonances of most of the base and sugar protons. Chemical shift vs temperature profiles, constructed for all samples, yielded insight into the temperature- and concentration-dependent conformational behaviour of the compounds and were used to obtain thermodynamic parameters pertaining to the stacked-single-strand----random-coil and duplex----random-coil equilibria. Vicinal proton-proton couplings were analyzed in terms of the conformation of the deoxyribose rings in the single-stranded tetramers and duplexed octamers. The NOE patterns, chemical shift profiles, imino-proton resonances and coupling data revealed that the compounds adopt B-DNA-like structures. The ratio duplexed/stacked-single-strand/random coil depends upon external conditions as well as upon base sequence. The thermodynamic data indicate that: in terms of single-helical stacking, the R-R steps (Tm 321-328 K) appear more stable than the Y-R or R-Y steps (Tm 308-316 K) and the Y-Y steps score least (Tm 290-300 K), and the duplexes consisting of alternating, d(Y-R)n, strands are more stable, in terms of delta H degrees, compared to the d(R-R)n X d(Y-Y)n duplexes. The analyses of the couplings demonstrated that the sugars of the single-stranded tetramers and duplexed octamers occur as a blend of N- and S-type conformers, with a preference for the S-type (C2'-endo) sugar conformation: upon duplex formation, no significant shift in the N-type/S-type ratio was observed. The fraction S-type sugar conformation of a given residue, %S, in the stacked-single strands was found to depend upon the nature of its own base and that of the adjacent residues: sugars in an R-R stretch display high values of %S (90-100), whereas those in Y-Y stretches show relatively low values (approximately equal to 65).(ABSTRACT TRUNCATED AT 400 WORDS)


Tracking health disparities through natural-language processing.
Health disparities and solutions are heterogeneous within and among racial and ethnic groups, yet existing administrative databases lack the granularity to reflect important sociocultural distinctions. We measured the efficacy of a natural-language-processing algorithm to identify a specific immigrant group. The algorithm demonstrated accuracy and precision in identifying Somali patients from the electronic medical records at a single institution. This technology holds promise to identify and track immigrants and refugees in the United States in local health care settings.


Macrophage migration inhibitory factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken.
Macrophage migration inhibitory factor (MIF) is a soluble factor produced by sensitized T lymphocytes that inhibits the random migration of macrophages. Homologues of MIF from invertebrates have been identified, making it an interesting molecule from a functional perspective. In the present study, the localization of a parasite MIF protein as well as its effect on the host was characterized. Western blot analysis shows that Eimeria MIF (EMIF) is found during all parasite developmental stages tested. Transmission electron microscopy shows that MIF is distributed throughout cytosol and nucleus of Eimeria acervulina merozoites. Immunohistochemical analysis suggests that EMIF may be released into the surrounding tissues as early as 24 h after infection, while later during oocyst formation, MIF expression is localized to areas immediately surrounding the oocysts, as well as in wall-forming bodies. The chemotaxis assay revealed an inhibitory function of EMIF on chicken monocyte migration. Quantitative real-time PCR was performed to examine the effect of EMIF on host immune system by measuring the transcripts of inflammatory mediators. An ex vivo stimulation study showed that E. acervulina MIF (EaMIF) enhanced expression of pro-inflammatory cytokines and chemokines in the presence of lipopolysaccharide (LPS). Furthermore, sequential treatment of adherent peripheral blood mononuclear cells with EaMIF, chicken MIF, and LPS in 2-h intervals led to the highest levels of interleukin (IL)-1B, chemokine CCLi3, IL-18, and interferon-gamma mRNA expression. This study shows that parasite MIF is widely expressed and may have potential effects on the immune system of the host.


Sialic acid as a tumor marker.
The term sialic acid is used to describe derivatives of neuraminic acid, where the amino group of neuraminic acid is substituted by either an acetyl or glycolyl group. The unique structural features of the molecule, which includes a negative charge owing to a carboxyl group, enables it to play a role in cellular functions, such as transport of positively charged compounds, cell-to-cell repulsion, influencing conformation of glycoproteins on cell membranes, and even masking antigenic determinants on receptor molecules. Focus on sialic acid as a tumor marker should be examined from the perspective of aberrant glycosylation in cancer cell membranes owing to activation of new glycosyl transferases that are characteristic of tumor cells, and the role played by sialic acid in tumor cell metastasis including increased capacity to adhere to vascular endothelium, and decreased capacity of cancer cells to be destroyed by host defence mechanisms. The high sensitivity of sialic acid as a tumor marker has been reported in a variety of cancerous conditions. Its specificity, however, is relatively low since there is also an increase in sialic acid-rich glycoproteins in inflammatory diseases. Sialic acid measurements, however, have value in monitoring cancer patients during treatment. A variety of methods are available for the measurement of both total and lipid associated sialic acids in serum or plasma. The newer high performance liquid chromatographic procedures can detect picogram levels of sialic acid and are relatively free of interferences seen with classical procedures.


In vivo 31P nuclear magnetic resonance findings on heterotopically allografted hearts in rats treated with a novel immunosuppressant, FK506.
Administration of FK506 for 15 days at daily doses of 3.2 mg/kg p.o., 10 mg/kg p.o., 0.32 mg/kg i.m., or 1 mg/kg i.m. to heart-allografted rats resulted in a significant prolongation of graft survival time. The best graft acceptance was obtained in the 1 mg/kg i.m. group: all six grafts survived longer than 50 days, and two of them, indefinitely. The 31P nuclear magnetic resonance (NMR) technique was utilized to investigate in vivo the energy metabolism of grafts. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP were useful parameters for monitoring cardiac insufficiency after transplantation. The mean ratios of Pi/PCr and PCr/ATP in syngeneic grafts were 0.38 +/- 0.11 and 1.88 +/- 0.42, respectively. In the control allografts, a rapid increase in the Pi/PCr ratio and a decrease in the PCr/ATP ratio were found from day 5. During the period of FK506 administration, increased Pi/PCr and decreased PCr/ATP ratios were also observed in all groups. The changes in these ratios were related with FK506 dosage. The results suggest that FK506 has a side-effect on graft metabolism. The metabolism tended to improve upon cessation of the drug in all grafts, but it worsened again in 3-3 1/2 weeks in the rats treated with 3.2 mg/kg p.o., 10 mg/kg p.o., or 0.32 mg/kg i.m. This seemed to be due to graft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical management where medicine meets management. The American way.
Close relationships between business managers and clinicians, and purchaser and provider, are valuable in chronic-disease management. Organisations used high-quality clinical information and performance management. Chronic-disease management based on risk-management, proactive case managers and patient education is effective.


Fine needle cytology of complex thyroid nodules.
To evaluate whether a preliminary aspiration (ASP) of the cystic component and/or using spinal needles in complex thyroid nodules (CTN) could improve the adequacy of cytological sampling. Between January 2004 and December 2006, 386 consecutive patients with CTN were enrolled in this prospective investigation. Ultrasound (US) fine needle aspiration cytology (FNAC) of the solid component of the nodule (one nodule per patient) was performed using two different 25 gauge needles, with (Yale Spinal, YS) or without (Neolus, NS) a stylet, in alternate sequence on consecutive patients. In addition, a subgroup of patients presenting larger cystic component (approximately 50%) was submitted to total aspiration of the cystic component (ASP+) or not submitted (ASP-) before US-FNAC, in alternate sequence within each needle type group. All the samplings were performed by a single endocrinologist. Adequate specimens were observed in 163 (84.5%) and 183 (94.8%) nodules investigated by NS and YS respectively. Sampling with the stylet needle was associated with an overall significant reduction of non-diagnostic specimens (15.5% vs 5.2% by NS and YS respectively, P < 0.001). The favourable result obtained with YS was independent from preliminary aspiration of the cystic component (ASP+: 14.8% vs 5.7% by NS and YS; ASP-: 16.2% vs 4.8%, not significant). A logistic regression analysis, taking into account nodule size and presence of intranodal vascularity at eco-colour evaluation of the solid component, confirmed that needle type was the only significant predictor of successful sampling (odds ratio 3.6 (95% confidence interval 1.7-7.6), P < 0.001). Our data show that adopting stylet needles to perform FNAC in CTN may significantly improve the percentage of adequate sampling. On the other hand, preliminary aspiration of CTN with large cystic component does not add any advantage.


Measuring Intercellular Interface Area in Plant Tissues Using Quantitative 3D Image Analysis.
The cells which make up plant tissues remain fixed together through shared cell walls. Cell-to-cell communication principally takes place through these shared interfaces through a combination of plasmodesmata, transporters, and the apoplastic space. To better understand the capacity for intercellular communication in plant tissues, this chapter outlines a method which can be used to quantify the surface area of shared intercellular interfaces using whole mount imaging and quantitative 3D image analysis. This method allows the potential for intercellular communication as prescribed by cellular architecture to be measured at single cell resolution.


New developments in resin restorative systems.
Efforts have been made during the last several years to develop polymer formulations that could replace ceramic materials for the restoration of occlusal surfaces. In most cases, resins have exhibited insufficient wear resistance, whereas the ceramic materials have had a history of excessively abrading whatever opposes them occlusally. Based on recent clinical information, it appears that major successes have been achieved in reaching the goal. The author discusses these advances and proposes a possible replacement for amalgam, based on new technology.


Broadened forward-masked tuning curves from intense masking tones: delay-time and probe-level manipulations.
Forward-masked psychophysical tuning curves were obtained from normal-hearing listeners under two conditions: lengthened delay time between masker and probe, and increased probe level. Both conditions required higher-level masking tones and both conditions resulted in broader tuning curves. Comparisons were made of tuning curves obtained with different probe-level and delay-time combinations that were chosen to require equivalent masker levels at the probe frequency. Nearly identical tuning-curve shapes were obtained when masker level at the probe frequency was the same. The results are predicted by a two-process model, consisting of a nonlinear filter followed by an exponential decay. Tuning-curve shapes in forward masking appear to be largely dependent upon the masker level (filter output level) at which one attempts to measure them.


Ultrastructural alterations of the air-blood barrier in sarcoidosis and hypersensitivity pneumonitis and their relation to lung histopathology.
To evaluate the incidence of air-blood barrier lesions in the course of chronic interstitial lung diseases, we studied by electron microscopy open lung biopsy specimens from patients with sarcoidosis or chronic hypersensitivity pneumonitis, and compared the distribution of ultrastructural air-blood barrier lesions (including swelling or destruction of epithelial and endothelial cells, type II cell hyperplasia, and basement membrane disruption) with the type of histopathologic abnormalities present (including inflammation, inflammation and fibrosis, or fibrosis alone). Ultrastructural lesions of the air-blood barrier were frequently observed in sarcoidosis as well as hypersensitivity pneumonitis. Their nature and distribution were highly dependent on the histologic pattern of lung tissue in which they were present: epithelial and/or endothelial injury was more frequently observed in inflammatory areas (90 to 100% of all lung specimens displaying inflammation alone), whereas type II cell hyperplasia was mainly identified in fibrotic tissues (83 to 100% of all lung specimens displaying fibrosis alone). Strikingly, in lung tissue considered as normal by light microscopy, air-blood barrier was frequently found to be damaged (50 to 62% of apparently normal lung specimens), suggesting that alveolar lesions may constitute an early phenomenon in the course of pulmonary inflammatory processes. The air-blood barrier alterations observed in this study may provide an anatomic basis for the modifications of alveolar permeability described in pulmonary sarcoidosis and hypersensitivity pneumonitis.


Rift Valley fever on the east coast of Madagascar.
In March 1990, a Rift Valley fever virus (RVFV) outbreak was suspected in the district of Fenerive on the east coast of Madagascar after an abnormally high incidence of abortions and disease in livestock. Sera from humans and cattle were tested for RVFV antibodies by immunofluorescence assay (IFA) and ELISA-IgM capture. Sera and mosquitoes collected in the same area were tested for virus isolation by tissue culture and suckling mouse intracerebral inoculation, and for antigen detection by an ELISA antigen capture assay. Among cattle from the area, RVFV antibody prevalence was 58.6% by IFA and 29.6% by ELISA-IgM. In contrast, human populations in the same area had a lower RVFV antibody prevalence, with 8.01% IFA and 5.4% IgM-positive sera. No RVFV antigen was detected and virus isolation was unsuccessful from the sera and mosquito pools tested. Different hypotheses concerning the emergence and diffusion of RVFV in this area and the occurrence of the outbreak are discussed.


Targeting the Tumor Microenvironment in Renal Cell Cancer Biology and Therapy.
Renal cell cancer (RCC) is a highly vascularized and immunogenic tumor type. The inhibition of vessel formation by anti-angiogenic therapies, as well as the stimulation of the immune system by immunotherapy has revolutionized the therapeutic landscape of RCC in recent years. Nevertheless, both therapies are associated with therapy resistance due to a highly dynamic, adaptive and heterogeneous tumor microenvironment (TME). The aim of this short review article is to provide an overview of the components of the RCC TME as well as to discuss their contribution to disease progression. In addition, we report on preclinical and clinical findings and how the different TME components can be modulated to impede treatment progression as well as to overcome therapy resistance to anti-angiogenic or immunomodulating therapy concepts. Furthermore, we discuss the predictive and prognostic role of the TME in RCC therapy. We also report on the concept of combinational targeting of anti-angiogenic therapies and immune checkpoint inhibitor therapy, also including the latest results of clinical studies discussed at recent oncological meetings. Finally, promising new therapeutic targets within the TME are mentioned.


Effects of rarefaction in microflows between coaxial cylinders.
Microscale gas flows between two rotating coaxial circular cylinders of infinite length with different temperatures are investigated. Navier-Stokes-Fourier (NSF) and regularized 13-moment (R13) equations in their linear form are used to independently analyze velocity and temperature fields in shear-driven rotary flows, i.e., cylindrical Couette flows. Knudsen boundary layers, which present non-Newtonian stress and non-Fourier heat flow, are predicted as the dominant rarefaction effects in the linear theory. We show that the R13 system yields more accurate results for this boundary value problem by predicting the Knudsen boundary layers, which are not accessible for NSF equations. Furthermore, a set of second-order boundary conditions for velocity slip and temperature jump are derived for the NSF system. It is shown that the proposed boundary conditions effectively improve the classical hydrodynamics. The accuracy of NSF and R13 equations is discussed based on their comparison with available direct simulation Monte Carlo data.


A case of granulosa cell tumor of the ovary detected from metastatic foci.
The authors report a case of granulosa cell tumor of the ovary that followed a rare clinical course, where the primary focus did not appear as a mass, and disseminated foci grew in the abdominal cavity. In 2008, a 70-year-old patient, gravida 6 and para 3, was diagnosed with a perihepatic mass, peritoneal dissemination, and an abdominal wall mass as confirmed by computed tomography (CT) scanning. There was no mass lesion in the pelvis. The pathological diagnosis based on the resected mass in the abdominal wall was malignant mesothelioma. During follow-up, abdominal bloating developed from April 2009. CT scans indicated growth of the intraperitoneal lesions. Therefore, the patient received two cycles of combination therapy with cisplatin and pemetrexed. The treatment was discontinued due to lack of efficacy. The intraperitoneal lesions grew but the clinical course was slow and inconsistent with that of malignant mesothelioma. Central pathological review was requested in April 2011, and a granulosa cell tumor was diagnosed. The patient was referred to the department for detailed examination and treatment. The patient underwent incision of the intraperitoneal tumors, simple total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. The final pathological diagnosis was normal-size adult-type granulosa cell tumor originating from the left ovary. It was a case of granulosa cell tumor without ovarian enlargement where growth of the metastatic foci was the major observation. As complete surgical resection was achieved and no additional therapy was given, the subject was followed on an outpatient basis and no recurrence was identified.