[Toxoplasmosis in the Republic of Senegal. Sero-epidemiological survey].
The presence of Toxoplasmosis in Senegal was investigated by the detection of IgG antibodies. 415 samples were obtained from healthy subjects from different regions of the country. In subjects of over 30, a greater number were found positive for IgG antibodies if they lived in a humid climate (25% in Northern Senegal, 57.7% in eastern Senegal). In Dakar 33.3% of the pregnant women studied had antibodies. This study confirms the presence of Toxoplasmosis in Senegal.


Bayesian area-age-period-cohort model with carcinogenesis age effects in estimating cancer mortality.
Area-age-period-cohort (AAPC) model has been widely used in studying the spatial and temporal pattern of disease incidence and mortality rates. However, lack of biological plausibility and ease of interpretability on temporal components especially for age effects are generally the weakness of AAPC models. We develop a Bayesian AAPC model where carcinogenesis age effect is incorporated to explain age effects from the underlying disease process. An autoregressive prior structure and an arbitrary linear constraint are used to solve the nonidentifiability issues. Two multistage carcinogenesis models are employed to derive the hazard functions to substitute the age effects in the AAPC models. The Iowa county-wide lung cancer mortality data are used for the model fitting and Deviance Information Criteria (DIC) is used for model comparison. Our study shows that conventional AAPC model (DIC=19,231.30), AAPC model with Armitage-Doll age effect (DIC=19,233.00) and with two-stage clonal expansion (TSCE) age effect (DIC=19,234.70) achieved the similar DIC values which indicated consistent model fitting among three models. The spatial pattern shows that the high spatial effects are clustered in the south of Iowa and also in largely populated areas. The lung cancer mortality rate is continuously declining by birth cohorts while increasing by the calendar period until 2000-2004. The age effects show an increasing pattern over time which can be easily explained by Armitage-Doll carcinogenesis model since we assume a log-linear relationship between age and hazard function. Our finding suggests that the proposed Bayesian AAPC model can be used to replace the conventional AAPC model without affecting model performance while providing a more biological sound approach from the underlining disease process.


Infliximab Rescue in Acute Severe Ulcerative Colitis Complicated by Clostridium Difficile Infection: A Case Series.
Relapses in inflammatory bowel disease (IBD) complicated by Clostridium difficile infection (CDI) are associated with significant morbidity and mortality. CDI can exacerbate the course of IBD and may result in prolonged hospitalizations, admissions to intensive care, surgical interventions, or even death. Early detection and aggressive treatment with systemic corticosteroids or biologics such as infliximab are often needed in severe presentations. Five cases of relapsed ulcerative colitis complicated by fulminant CDI were retrospectively reviewed. Biological therapy with infliximab was initiated upon multidisciplinary team assessment as the cases were resistant to standard IBD therapy. All five patients improved clinically and avoided early surgical intervention. Some required prolonged therapy with infliximab to achieve remission. Early recognition of CDI and aggressive therapy with biologics may be required to avoid complications in the IBD patients experiencing a relapse. Infliximab therapy should be considered early on, especially where the disease is resistant to standard therapy.


Heterotrimeric G protein beta1gamma2 subunits change orientation upon complex formation with G protein-coupled receptor kinase 2 (GRK2) on a model membrane.
Few experimental techniques can assess the orientation of peripheral membrane proteins in their native environment. Sum Frequency Generation (SFG) vibrational spectroscopy was applied to study the formation of the complex between G protein-coupled receptor (GPCR) kinase 2 (GRK2) and heterotrimeric G protein β(1)γ(2) subunits (Gβγ) at a lipid bilayer, without any exogenous labels. The most likely membrane orientation of the GRK2-Gβγ complex differs from that predicted from the known protein crystal structure, and positions the predicted receptor docking site of GRK2 such that it would more optimally interact with GPCRs. Gβγ also appears to change its orientation after binding to GRK2. The developed methodology is widely applicable for the study of other membrane proteins in situ.


Immunoglobulin heavy chain allotypes in a sample of Sicilian patients with celiac disease.
The authors have studied the immunoglobulin heavy chain allotypes in 14 Sicilian patients with celiac disease (CD) and in 75 healthy controls. No association has been found between CD and Gm or Km phenotypes. When the role of Gm phenotypes in immune response against gliadin was analyzed, fb-positive CD patients on gluten-free diet for 1 year showed an increased antigliadin IgG response. Comparing the values of fb-positive subjects with those of negative ones, a significant difference was observed. These data, demonstrating that the presence or absence of a phenotype is able to define the breadth of immune response against alpha-gliadin antigen, are indicative of the role played by Ig allotypes in CD.


Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.
Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β0 thalassaemia (S-β0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β0 thal patients, respectively, and 50% of SS/S-β0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.


Bilaterally dislocated hips treated with the Pavlik harness are not at a higher risk for failure.
The purpose of this study is to evaluate the efficacy of the Pavlik harness treatment in patients with bilaterally dislocated hips, and to compare them with cases with unilaterally dislocated hips. Twenty-nine patients (58 hips) were identified who presented with bilateral dislocated hips with no earlier treatment and received dynamic ultrasound examination. The comparison group consisted of 38 patients (38 hips) with unilateral hip dislocation treated with the same protocol. Successful treatment was defined as relocation/reduction of the hips within 3 weeks of Pavlik harness application. Seventeen of 29 patients (59%) in the bilateral group (7 bilateral, 10 unilateral) and 22 of 38 patients (58%) in the unilateral group failed the harness treatment. There was no difference in the duration of harness wear for successful patients regardless of presentation. Patients presenting with bilaterally dislocated hips treated with the Pavlik harness are at no greater risk for failure than patients presenting with unilateral hip dislocation. Level 3.


Variation in Weed Seed Fate Fed to Different Holstein Cattle Groups.
Weed seeds may maintain their viability when passing through the digestive tract of cattle and can be therefore dispersed by animal movement or the application of manure. Whether different cattle types of the same species can cause differential weed seed fate is largely unknown to us particularly under non-grazed systems similar to Holstein-Friesian dairy farming. We investigated the effect on the seed survival of four weed species in the digestive tracts of four groups of Holstein cattle: lactating cows, feedlot male calves, dry cows and growing heifers. The weed species used were Cuscuta campestris, Polygonum aviculare, Rumex crispus and Sorghum halepense. Cattle excretion was sampled for recovery and viability of seeds at four 24 hourly intervals after seed intake. The highest seed recovery occurred two days after seed intake in all cattle groups. Averaged over weed species, dry and lactating cows had the lowest and highest seed recovery of 36.4% and 74.4% respectively. No significant differences were observed in seed recovery of the four weed species when their seeds were fed to dry cows. Based on a power model fitted to seed viability data, the estimated time to 50% viability loss after seed intake, over all cattle groups ranged from 65 h (R. crispus) to 76 h (P. aviculare). Recovered seeds from the dung of feedlot male calves showed the highest mortality among cattle groups. Significant correlation was found between seed viability and ruminal pH (r = 0.86; P<0.05). This study shows that management programs aiming to minimize weed infestation caused by livestock should account for the variation amongst cattle groups in seed persistence. Our findings can be used as a guideline for evaluating the potential risk of the spread of weeds via the application of cattle manure.


Systematic review and meta-analysis of factors associated with re-positive viral RNA after recovery from COVID-19.
Previous studies reported the positive viral RNA among coronavirus disease-2019 (COVID-19) recovered patients. This study aimed to summarize the current evidence of factors associated with the risk of disease recurrence. PubMed and Embase were searched until September 2020 to identify studies assessing characteristics of recurrence and nonrecurrence subjects after discharge. Random-effect meta-analysis was used to pool estimates of odds ratio (OR) or weighted mean difference (WMD) and their 95% confidence intervals (CIs) across studies. Meta-analysis data were available for age, sex, hospital duration, disease severity, seven comorbidities, five symptoms, five indexes of blood routine, nine indexes of blood biochemistry, four treatment therapies, two antibodies, and history of high-risk contact. Among them, hospital duration of recurrence cases was significantly shorter than nonrecurrence subjects (WMD, -1.55 days; 95% CI, -2.66 to -0.45). Fatigue, positive Immunoglobulin M (IgM), and positive IgG were associated with an increased risk of recurrence cases, with ORs and 95% CIs of 4.06 (1.14-14.4), 2.95 (1.15-7.61), and 3.45 (1.58-7.54), respectively. In contrast, the odds of recurrence cases were observed to significantly lower in subjects with elevated lactate dehydrogenase and C-reactive protein, low lymphocyte count, steroid and arbidol use, with ORs (95% CIs) of 1.08 (0.27-4.37), 0.49 (0.27-0.97), 0.64 (0.42-0.97), 0.48 (0.25-0.96), and 0.48 (0.25-0.92), respectively. This study provided up-to-date evidence of several clinical and epidemiological characteristics in the association with COVID-19 recurrence cases. Further in-depth analyses for the causal effect of factors on re-positive viral RNA are needed for the management of discharged patients with COVID-19.


Synthesis and antioxidant activities of novel 5-chlorocurcumin, complemented by semiempirical calculations.
The novel curcumin derivative (1E,4Z,6E)-5-chloro-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (5-chlorocurcumin) was prepared from natural curcumin. The newly synthesised compound was characterised by spectral studies (IR, 1H NMR, and 13C NMR). The free radical scavenging activity of 5-chlorocurcumin has been determined by measuring interaction with the stable free radical DPPH, and 5-chlorocurcumin has shown encouraging antioxidant activities. Theory calculations of the synthesised 5-chlorocurcumin were performed using molecular structures with optimised geometries. Molecular orbital calculations provided a detailed description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms.


SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3.
Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.


Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome.
Corticotropin-releasing hormone (CRH)-stimulated petrosal sinus sampling is currently the gold standard method for the differential diagnosis between pituitary and ectopic ACTH-dependent Cushing's syndrome. Our objective was to determine sensitivity and specificity of desmopressin test during petrosal sinus sampling. Forty-three patients had petrosal sinus sampling because of the lack of visible adenoma on magnetic resonance imaging (MRI) and/or because of discordant cortisol response to high-dose dexamethasone suppression test. ACTH sampling was performed in an antecubital vein, right and left petrosal sinuses, then at each location 5 and 10 min after injection of desmopressin. Diagnosis was based on the ACTH ratio between petrosal sinus and humeral vein ACTH after desmopressin test. Diagnosis was confirmed after surgery. A receiver operating characteristics curve was used to determine optimal sensitivity and specificity. Thirty-six patients had Cushing's disease (CD) and seven had ectopic ACTH secretion. A ratio > 2 after desmopressin was found in 35 of the 36 cases of CD (sensitivity: 95%). A ratio < or = 2 was found in the seven patients with ectopic ACTH secretion (specificity: 100%). Sinus sampling was ineffective in determining the left or right localization of the adenoma (sensitivity = 50%). No major adverse effects were observed during or after the procedure. Desmopressin test during petrosal sinus sampling is a safe and effective diagnostic procedure in ACTH-dependent Cushing's syndrome. It thus represents a valuable alternative to CRH.


Differentiation status of cultured murine keratinocytes modulates induction of genes responsive to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Primary murine keratinocytes were cultured in a chemically defined, serum-free medium which facilitated manipulation of their differentiation status. Exposure of basal cell and differentiating cultures to >/= 0.1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) preferentially elevated 7-ethoxyresorufin O-deethylase specific activities in differentiating cultures (28-fold versus 4-fold increases after 36 h of exposure). Semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) analyses demonstrated the presence of constitutive mRNA transcripts corresponding to four known TCDD-inducible genes (e.g., Cyp1a1, Cyp1b1, Ahd4, and Nmo1) in both differentiating and proliferating cultures of murine keratinocytes. All four genes were induced in differentiating cultures following exposure to TCDD. No induction occurred in comparably treated basal cell cultures. Indirect immunofluorescence analyses demonstrated the presence of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins in both basal and differentiating keratinocytes. Both proteins appeared to be associated with the nucleus and their nuclear association was independent of prior exposure to TCDD. These studies suggest that AHR activation in murine skin is regulated as a function of the keratinocyte differentiation program.


Enhanced Performance of Two-Photon Excited Amplified Spontaneous Emission by Cd-Alloyed CsPbBr3 Nanocrystals.
It has been demonstrated that the alloyed perovskite nanocrystals (NCs) with a small amount of Cd element may passivate the inherent halide vacancies in perovskite NCs and improve their stability. However, the study of the optical properties of such alloyed perovskite NCs still remains essentially untouched, which will seriously hinder relevant applications. Herein, using different amounts of CdBr2 as an alloyed metal precursor, a series of CsPbxCd1-xBr3 NCs (x = 1, 0.93, and 0.88) were synthesized. Compared with bare CsPbBr3 NCs, the Cd-alloyed NCs exhibited a near-unity photoluminescence quantum yield (99%), efficiently improved stability, and enhanced electron-phonon coupling strength. As the Cd-alloyed amount was increased, their hot-carrier cooling time became faster and the exciton-biexciton interaction decreased, causing a decreased threshold of two-photon excited amplified spontaneous emission (ASE) from 1.58 to 1.23 mJ cm-2. In addition, the Cd-alloying method can also improve the photostability of ASE, resulting in the initial ASE intensity remaining at 90% even after 7.5 × 105 pulse shots. This work implies that the Cd-alloyed CsPbBr3 NCs will be promising for application in a laser gain medium.


Immunohistochemical localization of proteoglycans in human periodontium.
Proteoglycans (PGs) are extracellular and cell surface-associated macromolecules that regulate cell adhesion, cell growth, matrix formation, and bind growth factors. In this work we studied the distribution of core proteins of four PGs (decorin, biglycan, a large molecular weight PG, and CD44) in human gingiva and periodontal ligament by immunohistochemical staining of frozen tissue sections with specific antibodies. Decorin, a major PG of this tissue, was localized on collagen fiber bundles in the gingival and periodontal connective tissues. Staining for decorin was most intense at the subepithelial region. Biglycan was a minor PG component of the human periodontium, showing some accumulation in connective tissue under the oral epithelium. At the immunohistochemical level, biglycan appeared to form fine filament-like structures on extracellular matrix fibers. Localization of large molecular weight PG differed from that of decorin and biglycan. It was concentrated in deep connective tissue areas of the gingiva and in the periodontal ligament, and was only weakly present at the subepithelial region. CD44 was mainly concentrated in cell-cell contact areas of basal and spinous layers of oral epithelium. In the connective tissue of gingiva and periodontal ligament, CD44 was localized on fibroblast cell surfaces. Connective tissue area under the junctional epithelium contained relatively small amounts of PGs. The results indicate that different parts of human periodontium contain a typical variety of PGs, suggesting a specific function for each PG species in the location at which they accumulate.


Perceptions of fever among adults in a family practice setting.
Febrile illnesses are common clinical problems for the family physician. A questionnaire study was conducted of 100 adult patients in a family practice clinic to gain understanding of their knowledge about fever and its management. Many misconceptions were documented among adult patients about their own fevers and those of children for whom they cared. Misconceptions included the conviction that fever is more dangerous in children than in adults and a distorted concern about bodily damage from fever. Patients demonstrated a poor understanding of normal body temperature, minimum and maximum febrile temperatures, and minimum temperatures warranting antipyresis. Though many owned thermometers, they indicated improper usage and demonstrated inaccurate temperature-reading technique. Questionnaire responses indicated that health care providers had done poorly in educating patients about fever, its consequences, and its proper treatment.


Effect of specialist retrieval teams on outcomes in children admitted to paediatric intensive care units in England and Wales: a retrospective cohort study.
Intensive care services for children have undergone substantial centralisation in the UK. Along with the establishment of regional paediatric intensive care units (PICUs), specialist retrieval teams were set up to transport critically ill children from other hospitals. We studied the outcome of children transferred from local hospitals to PICUs. We analysed data that were gathered for a cohort of children (<or=16 years) admitted consecutively to 29 PICUs in England and Wales during 4 years (Jan 1, 2005, to Dec 31, 2008). We compared unplanned admissions from wards within the same hospital as the PICU and from other hospitals; interhospital transfers by non-specialist and specialist retrieval teams; and patients transferred to their nearest PICU and those who were not. Primary outcome measures were mortality rate in PICU and length of stay in PICU. We analysed data by use of logistic regression analysis. There were 57 997 admissions to PICUs during the study. Nearly half of unplanned admissions (17 649 [53%] of 33 492) were from other hospitals. Although children admitted from other hospitals were younger (median 10 months [IQR 1-55] vs 18 months [3-85]), sicker at admission (median predicted risk of mortality 6% [4-10] vs 4% [2-7]), stayed longer in PICUs (75 h [33-153] vs 43 h [18-116]), and had higher crude mortality rates (1384 [8%] of 17 649 vs 996 [6%] of 15 843; odds ratio 1.27, 95% CI 1.16-1.38), the risk-adjusted mortality rate in PICUs was lower than among children admitted from within the same hospital (0.65, 0.53-0.80). In a multivariable analysis, use of a specialist retrieval team for transfer was associated with improved survival (0.58, 0.39-0.87). These findings support the policy of combining centralisation of intensive care services for children with transfer by specialist retrieval teams. National Clinical Audit and Patient Outcomes Programme through Healthcare Quality Improvement Partnership, Health Commission Wales Specialised Services, National Health Service (NHS) Lothian and National Service Division NHS Scotland, the Royal Belfast Hospital for Sick Children, and the Pan Thames PICU Commissioning Consortium.


A simple method for estimating the optimum number of prostate biopsy cores needed to maintain high cancer detection rates while minimizing unnecessary biopsy sampling.
The objective was to provide urologists with a simple basis for optimizing the number of prostate biopsy cores that should be taken. The records of 1024 patients who had undergone transrectal ultrasound-guided biopsies were reviewed. The prostate volume was divided by the number of biopsies to obtain the volume/biopsy ratio (VBR). Univariate and multivariate analyses were performed to determine the best predictors for positive biopsies. The analysis included 939 patients who had prostatic-specific antigen <20 ng/mL. The significant independent variables for positive biopsies were age, prostatic-specific antigen, and prostate volume and VBR (p < 0.001). VBR had the strongest correlation coefficient out of all significant variables. Stepwise analysis showed a consistent increase in cancer detection rates as VBR was decreased. The detection rates for VBRs of 2, 3, and 4 were 59%, 53%, and 50%, respectively. The detection rates dropped sharply to 42% and 30% for VBRs of 5 and 6, respectively. Cancers diagnosed with low VBRs were similar to those diagnosed with high VBRs in regard to Gleason scores and percentages of cancer in the prostatectomy specimens. Using VBR of 4 maintains high cancer detection rates without taking an excessive number of biopsy specimens. This is a simple and easy-to-remember method.


Z-guggulsterone induces PD-L1 upregulation partly mediated by FXR, Akt and Erk1/2 signaling pathways in non-small cell lung cancer.
Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule, that is overexpressed in non-small cell lung cancer (NSCLC) and has been associated with the response to anti-PD-1/PD-L1 immunotherapy. Z-guggulsterone (Z-GS), an active compound extracted from the gumresin of the Commiphora mukul tree, has been shown to have anti-tumor effects in NSCLC in our previous study. However, whether Z-GS could affect PD-L1 expression levels in tumor cells remains unknown. In this study, we verified the inhibitory effects of Z-GS on NSCLC cell viability and cell cycle progression in vitro, and mouse Lewis lung carcinoma (LLC) tumor growth in vivo. Notably, Z-GS treatment increased PD-L1 surface and mRNA expression levels, and gene transcription in NSCLC cells, in a dose- and time-dependent manner. Mechanistic experiments showed that the upregulation of PD-L1 was mediated, partly by farnesoid X receptor inhibition, and partly by the activation of the Akt and Erk1/2 signaling pathways in Z-GS-treated NSCLC cells. In vivo, Z-GS treatment dose-dependently increased PD-L1 expression levels in mouse LLC tumor models. Overall, our findings demonstrated a promoting role for Z-GS in PD-L1 expression in NSCLC and provided mechanistic insights, that may be used for further investigation into synergistic combined therapies.


The effect of environmental context on recall and category clustering scores following relational and individual item processing: a test of the outshining hypothesis.
This study investigated the effects of the reinstatement of environmental context on recall of a list of words after subjects had performed either relational processing or individual item processing on them at encoding (cf Einstein & Hunt, 1980). In the first experiment, subjects showed significantly less semantic category clustering when environmental cues were available to them at recall. This effect occurred regardless of encoding task, and suggests that subjects in the same context condition were using environmental cues to help them recall words from the list. Nevertheless, there was no effect of contextual reinstatement on the number of words recalled in either encoding condition. In Experiment 2, a list of words with a much less obvious categorical structure was used, which eliminated category clustering following individual item processing. Despite this, no beneficial effect of contextual reinstatement was seen on the number of words recalled by subjects who performed either the individual item or the relational processing task. In the relational processing group, contextual reinstatement once again significantly reduced the category clustering scores. The results of both experiments indicate that there are effects of contextual reinstatement on memory that are not necessarily apparent when overall level of recall is the dependent variable.


Condyloma acuminatum presenting as a dorsal tongue lesion in a patient with AIDS.
Oral lesions have been recognized as a prominent feature of HIV infection and AIDS since the beginning of the epidemic. This report describes the case of a man with advanced AIDS and a nonpainful but enlarging dorsal tongue soft tissue growth of 6 months' duration. Incisional biopsy showed a red, papillary lesion with koilocytosis consistent with condyloma acuminatum. In situ hybridization and molecular techniques were used to identify human papillomavirus (HPV)-31 sequences in warty tissue. Eighteen months later, the lesion recurred and was reexcised without complication. This case is reported to illustrate that venereal transmission may not be as important in warts of the oral cavity as in HIV-associated anogenital warts, because warts of the oral cavity are rarely associated with HPV types 6, 11, 16, and 18. Instead, they may be present as a result of activation of latent HPV infection or perhaps autoinfection from skin and facial lesions. The carcinogenic potential of oral warts in HIV disease is undefined, as is the role of antiretroviral therapy in controlling HPV-associated oral lesions.


Detection and classification of the breast abnormalities in digital mammograms via regional Convolutional Neural Network.
Automatic detection and classification of the masses in mammograms are still a big challenge and play a crucial role to assist radiologists for accurate diagnosis. In this paper, we propose a novel computer-aided diagnose (CAD) system based on one of the regional deep learning techniques: a ROI-based Convolutional Neural Network (CNN) which is called You Only Look Once (YOLO). Our proposed YOLO-based CAD system contains four main stages: mammograms preprocessing, feature extraction utilizing multi convolutional deep layers, mass detection with confidence model, and finally mass classification using fully connected neural network (FC-NN). A set of training mammograms with the information of ROI masses and their types are used to train YOLO. The trained YOLO-based CAD system detects the masses and classifies their types into benign or malignant. Our results show that the proposed YOLO-based CAD system detects the mass location with an overall accuracy of 96.33%. The system also distinguishes between benign and malignant lesions with an overall accuracy of 85.52%. Our proposed system seems to be feasible as a CAD system capable of detection and classification at the same time. It also overcomes some challenging breast cancer cases such as the mass existing in the pectoral muscles or dense regions.


Homotypic Cell Membrane-Cloaked Biomimetic Nanocarrier for the Targeted Chemotherapy of Hepatocellular Carcinoma.
Goals: Hepatocellular carcinoma (HCC) has been reported to be the third most common malignant tumor and has the highest rate of mortality. To increase the chemotherapy efficacy of HCC, a drug delivery system featured with desirable active targeting ability, delivery efficiency and immune evasion is in high demand. Methods: We have developed a drug nanocarrier by utilizing a homotypic cancer cell membrane for targeted chemotherapy of HCC. Structurally, the homotypic HepG2 cell membrane was used as the cloak, and a poly (lactic-co-glycolic acid) (PLGA) nanoparticle as the core, resulting in the nanocarrier HepM-PLGA. Results: The HepM-PLGA nanoparticles exhibit excellent targeting ability toward HepG2 cells. Doxorubicin (Dox) carried by HepM-PLGA possesses high delivery efficiency and a remarkable in vitro therapeutic effect. In in vivo experiments, HepM-PLGA delivers Dox directly to the tumor lesion of nude mice, and tumor volume decreases by approximately 90% after treatment. Conclusion: We have developed a drug nanocarrier by utilizing a homotypic cancer cell membrane for targeted chemotherapy of HCC with excellent active targeting ability. This biomimetic platform not only effectively treats HCC but also provides a sound strategy for the treatment of other cancers via changes in the corresponding homotypic cancer cell membrane.


IFN-adjuvanted DNA vaccine against infectious salmon anemia virus: Antibody kinetics and longevity of IFN expression.
Plasmids expressing interferon (IFN) have recently been shown to function as adjuvants in Atlantic salmon when co-injected with a DNA vaccine encoding hemagglutinin-esterase (HE) from infectious salmon anemia virus (ISAV). In this work we have compared the antibody kinetics and the systemic Mx/ISG15 response of fish vaccinated with HE-plasmid using either IFNa plasmid (pIFNa) or pIFNc as adjuvants over a longer time period, i.e. 22 weeks post vaccination (pv). The results showed that the antibody response against ISAV with pIFNa as adjuvant arose earlier (7 weeks pv) than with pIFNc as adjuvant (10 weeks pv), peaked at week 10 and declined at week 22. The antibody response with pIFNc as adjuvant peaked at 16 weeks and kept at this level 22 weeks pv. Fish injected with pIFNc alone expressed high levels of Mx and ISG15 in liver throughout the 22 week period. In contrast, fish injected with pIFNc together with HE-plasmid expressed high levels of Mx and ISG15 in liver for the first 10 weeks, but at week 16 this response was absent in two of three fish at week 16 and was absent in all tested fish at week 22 pv. This suggests that cells expressing HE and IFNc are intact at week 10 pv, but are eliminated by adaptive immune responses after week 10 due to recognition of HE. The longevity of the Mx/ISG15 response in pIFNc treated fish is likely due to the fact that IFNc is a self-antigen of salmon and is not attacked by the adaptive immune system.


Comparison of late night and early morning removal of short-term urethral catheters.
Indwelling urethral catheters (IUCs) are inserted in approximately 15-25% of all hospitalised patients mainly to assist clinicians to accurately monitor urine output during acute illness or following surgery, to treat urinary retention and for investigative purposes. However, this procedure is associated with significant morbidity. Although research has focused on the type and maintenance of urinary catheters and techniques for insertion, limited attention has been given to the procedures for their removal, in particular whether the time of day the IUC is removed influences patient outcomes. There is no consensus among clinicians about the optimal time for removal of IUCs, rather practices tend to be based on personal preference and tradition rather than on evidence from research. The objective of this review was to determine whether the timing of the removal of IUCs influences patient outcomes. The primary outcomes of interest included duration to and volume of first void; length of hospitalisation; number of patients developing urinary retention and number requiring recatheterisation. Secondary outcome measures included patient satisfaction and the percentage of IUCs removed according to the scheduled time for removal. A literature search was performed using the following databases Medline (1966-2000), CINAHL (1982-2002), Nursing Collection (1995-2002), EMBASE (1980-current) and the Cochrane Controlled Trials Register (Issue 2, 2002 of Cochrane Library). In addition, the reference lists of relevant trials and conference proceedings were also scrutinised. No language restrictions were applied. Company representatives, experts and investigators were contacted to elicit further information. All published and unpublished randomised and quasi-randomised controlled trials that compared the effects of the timing of removal of short-term IUC on patient outcomes were considered for inclusion in the review. Trials were included if they reported objective measures of time to and volume of the first void, length of hospital stay (number of hours from removal of the IUC to discharge), the number of patients who developed urinary retention following the removal of the IUC and the incidence of recatheterisation. Trials that included subjective measures of patient satisfaction were also considered for inclusion in the review. Eligibility of the trials for inclusion in the review, details of eligible trials and the methodological quality of the trials was assessed independently by two reviewers. All information was verified by a third reviewer. Odds ratios for dichotomous data and weighted mean differences for continuous data were calculated with 95% confidence intervals. Where synthesis was inappropriate a narrative overview was undertaken. Trials were grouped according to the types of operation. Eight randomised controlled trials comparing the effectiveness of early morning versus late night removal of IUCs were eligible for this review. Four trials (three following urological surgery and procedures and one involving patients following gynaecological surgery) demonstrated a statistically significant increase in the volume of the first void in patients whose IUCs were removed late at night compared to those removed in the morning. In the two trials on patients following transurethral resection of the prostate (TURP) there was no statistically significant difference in the volume of the first void.One trial that involved patients having gynaecological surgery reported that the time to first void was shorter when the IUC was removed at midnight (median 3 h 20 min) compared to early morning (median 5 h) (P = 0.012). Three trials undertaken on patients following urological surgery and procedures reported the time to first void was longer in patients whose IUCs were removed at midnight compared to those removed in the morning with all three trials demonstrating a statistically significant difference. The time to first void was shorter following TURP when IUCs were removed in the morning, although these results were not statistically significant. Patients who had their IUC removed at midnight were discharged from hospital significantly earlier (P < 0.00001) than those who had their IUC removed in the morning, which would result in potential cost savings for the hospitals. Based on the limited available evidence, this review suggests a benefit in terms of patient outcomes and reduction in the length of hospitalisation following midnight removal of the IUCs. Further trials should be undertaken in wider settings and on specific groups of patients to enhance generalisability. The trials should also examine the efficacy of midnight or early morning IUC removal compared to removal at any time of the day.


Pharmacoresponsiveness of spontaneous recurrent seizures and the comorbid sleep disorder of epileptic Kcna1-null mice.
Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.


Retroperitoneal laparoscopic adrenalectomy.
Retroperitoneoscopic adrenalectomy is currently performed either by lateral flank approach or posterior lumbar approach. The retroperitoneal laparoscopic adrenalectomy avoids invading the intraperitoneal cavity and possible injury to the abdominal organs. The posterior lumbar approach allows direct access to the main adrenal vascular supply before the gland is manipulated. Retroperitoneal laparoscopic adrenalectomy by the posterior approach is technically feasible and most effective as regards the simplicity of vascular control. The lateral flank approach allows a more spacious working cavity, but a large tumor obscures the surgical plane to the adrenal vessels. The transection of the adrenal vein is performed at the end of the procedure. The operating time, perioperative morbidity and cost have been reduced with these retroperitoneal approaches. The retroperitoneal approach to the adrenal gland is technically simple and can be performed quickly, with a low postoperative morbidity and should be regarded as the routine approach for relatively small adrenal benign tumors that are less than 5 cm in diameter.


Influence of route of hepatic administration on drug availability.
The work investigates functional variability of hepatic arterial and portal venous streams in relation to drug availability. In an isolated rat liver system perfused in all experiments at a constant total flow of 10 ml X min-1, drug availability was found to be 18 and 3 times greater for lidocaine and meperidine, respectively, when infused through the hepatic artery compared to portal vein administration. When both hepatic artery and portal vein were perfused, drug availability increased log linearly for lidocaine, and linearly for meperidine with increasing hepatic artery flow contribution. Injection of 15-micron gamma-labeled microspheres into the hepatic artery and portal vein did not reveal arteriovenous or portovenous shunting channels greater than 15 micron in diameter. However, the ratios of the mean transit times of albumin and red blood cells were found to be significantly lower through the hepatic artery, indicating a possible reduction in perisinusoidal albumin space. When both hepatic artery and portal vein were perfused, linear correlations were obtained for values of this ratio plotted against increasing hepatic artery flow contributions. Data from the red blood cell transit time studies, as well as data on lidocaine availability, suggest the presence of functionally separate capillary beds for the hepatic arterial and venous streams.


[Studies on tsutsugamushi disease in Gifu prefecture. 4. Survey results in Ena and Takayama City, and the summary of the studies in the prefecture].
Investigations of trombiculid mites and Rickettsia tsutsugamushi in wild rodents were made in Ena (Nov. 1988) and Takayama (May 1989) City. In the former area where no patient has been reported so far, Leptotrombidium pallidum (63.9%) was most predominant and no L. scutellare was found. A Karp-related rickettsia (11.1%) was isolated from wild rodents and 30% of them had antibody to R. tsutsugamushi (anti-Karp was prominent). The latter area where patients were reported in spring as well as in autumn, L. pallidum (22.4%) was one of the dominant species in spring. Karp-related strains were isolated from 37.5% of wild rodents. And the antibody possession rate was 50.0%. These data reconfirmed our hypothesis that the majority of patients in autumn were infected by L. scutellare and a part by L. pallidum. In spring in Takayama area, the vector was L. pallidum which possessed Karp-related strain(s).


Rhabdophis tigrinus (Yamakagashi) Bites in Japan Over the Last 50 Years: A Retrospective Survey.
Introduction:Rhabdophis snakes, which include 27 species, are rear-fanged venomous snakes that are widely distributed from India to East Asia and Russia. Severe envenomation by R. tigrinus (Yamakagashi snake) in Japan and R. subminiatus in Southeast Asia has been reported. The epidemiology of R. tigrinus bites, such as geographical features, the incidence, and changes in the number of bites over time have not been comprehensively examined. Hence, we intended to clarify the epidemiological features of R. tigrinus bites through a careful review of scientific data over the last 50 years in Japan. Methods: Patient records of R. tigrinus bites between 1971 and 2020 at the Japan Snake Institute were examined retrospectively. The following were ascertained: patient characteristics, clinical symptoms, laboratory data, treatment-related factors, and hospital mortality. These variables were compared in the antivenom and the without-antivenom groups. Results: Over the 50-year study period, 43 R. tigrinus bites, including five fatal cases, were encountered. Severe cases of R. tigrinus bites have been treated with antivenom since 1985; however, fatalities occurred in 2006 and 2020. R. tigrinus bite cases have been well-distributed in the western part of Japan since 2000. The mortality rate in the antivenom group was significantly lower in the patient group that was not administered the antivenom (0 vs. 23.8%, p = 0.048). Conclusion: This study clarified the epidemiology of R. tigrinus bites in Japan over a 50-year period. Almost all severe cases of R. tigrinus bites have been treated with the antivenom in the current situation, and fatalities occurred in cases not treated with the antivenom. It is important to diagnose R. tigrinus bites in the early phase of the clinical course. The antivenom, the definitive treatment for R. tigrinus bites, is an unapproved drug. Hence, approval needs to be obtained for the drug.


Maternal-fetal transmission of HIV-1 infection.
Studies to examine the mechanisms responsible for perinatal HIV transmission and clinical trials to reduce this transmission are ongoing. A more complete understanding of the timing and modalities of vertical transmission will permit more precise targeting of future clinical trials. Perinatal transmission of HIV infection is most likely due to multiple factors. The degree of viral replication, neutralizing antibody and other maternal immune factors, genetic factors, and an intact placental barrier are most likely important and may be interrelated. Multiple different combination therapies may be necessary to interrupt maternal-fetal HIV transmission. Pregnancy is a well-defined and limited time period, and offers a model for HIV transmission where clinical, virological, and immunological factors can be evaluated in relation to the occurrence of HIV infection in the infant. The analysis of perinatal trials may provide insight into factors involved in protection and have implications. As HIV infection rates in the heterosexual populations of US inner cities and in impoverished areas of the third world continue to rise rapidly, strategies are needed urgently to curb the AIDS epidemic in children. Targeting the HIV-infected pregnant woman for therapies is one of the few hopes we have of preventing infection in children at risk of HIV infection. Without such therapeutic strategies, many of these at-risk infants are destined to acquire a chronic viral infection with significant morbidity and mortality.


Maternal epistemological perspectives and variations in mental state talk.
This study examined how complexity of maternal epistemological beliefs predicted mothers' and children's talk about the mind. Twenty-eight mothers of 5- to 10-year-olds completed a measure of receptive vocabulary, and mothers and children participated in a storytelling task specifically designed to elicit talk about the mind. Their use of mental state terms to encode pragmatic functions and mothers' epistemologies were assessed and compared. Maternal mental state talk and amount of talk increased with epistemological complexity. With the number of utterances held constant, mothers with simple, dualistic perspectives of knowledge used mental states more often to direct interaction; mothers with more complex epistemologies used mental states more often to encourage child reflection. Mothers with the less complex perspective underperformed on the receptive vocabulary measure in comparison to others. Children's amount of talk and use of a variety of mental state terms also increased with maternal epistemological complexity. The amount of talk and mental state terms produced by mothers and children frequently persisted after the effects of maternal receptive vocabulary were removed. Maternal epistemologies predict several qualities of mothers' and children's mental state talk that may contribute to children's developing theory of mind.


Insertion and deletion processes in recent human history.
Although insertions and deletions (indels) account for a sizable portion of genetic changes within and among species, they have received little attention because they are difficult to type, are alignment dependent and their underlying mutational process is poorly understood. A fundamental question in this respect is whether insertions and deletions are governed by similar or different processes and, if so, what these differences are. We use published resequencing data from Seattle SNPs and NIEHS human polymorphism databases to construct a genomewide data set of short polymorphic insertions and deletions in the human genome (n = 6228). We contrast these patterns of polymorphism with insertions and deletions fixed in the same regions since the divergence of human and chimpanzee (n = 10,546). The macaque genome is used to resolve all indels into insertions and deletions. We find that the ratio of deletions to insertions is greater within humans than between human and chimpanzee. Deletions segregate at lower frequency in humans, providing evidence for deletions being under stronger purifying selection than insertions. The insertion and deletion rates correlate with several genomic features and we find evidence that both insertions and deletions are associated with point mutations. Finally, we find no evidence for a direct effect of the local recombination rate on the insertion and deletion rate. Our data strongly suggest that deletions are more deleterious than insertions but that insertions and deletions are otherwise generally governed by the same genomic factors.


Anti-inflammatory effect of gold nanoparticles supported on metal oxides.
Gold (Au) can be deposited as nanoparticles (NPs) smaller than 10 nm in diameter on a variety of metal oxide (MOx) NPs. Au/MOx have high catalytic performance and selective oxidation capacity which could have implications in terms of biological activity, and more specifically in modulation of the inflammatory reaction. Therefore, the aim of this study was to examine the effect of Au/TiO2, Au/ZrO2 and Au/CeO2 on viability, phagocytic capacity and inflammatory profile (TNF-α and IL-1β secretion) of murine macrophages. The most important result of this study is an anti-inflammatory effect of Au/MOx depending on the MOx nature with particle internalization and no alteration of cell viability and phagocytosis. The effect was dependent on the MOx NPs chemical nature (Au/TiO2 > Au/ZrO2 > Au/CeO2 if we consider the number of cytokines whose concentration was reduced by the NPs), and on the inflammatory mediator considered. The effect of Au/TiO2 NPs was not related to Au NPs size (at least in the case of Au/TiO2 NPs in the range of 3-8 nm). To the best of our knowledge, this is the first demonstration of an anti-inflammatory effect of Au/MOx.


Overview of the 2015 American Thyroid Association guidelines for managing thyroid nodules and differentiated thyroid cancer.
The last few years have witnessed numerous publications addressing the management of thyroid nodules and differentiated thyroid cancers. The purpose of this review is to provide a simplified summary of the newly released guidelines by the American Thyroid Association. A systematic approach has been recommended to evaluate a thyroid nodule through clinical assessment, measurement of serum Thyroid Stimulating Hormone, neck ultrasonography and Fine Needle Aspiration where appropriate. This is followed by cytology analysis using the Bethesda scoring system to detect malignancy. Once diagnosed, thyroid cancers need to be staged and risk stratification needs to be applied to develop further treatment plans. Lastly, several recommendations have been presented to assure proper follow-up and support for thyroid cancer patients regardless of the treatment received.


Aptamer-Functionalized Liposomes as a Potential Treatment for Basal Cell Carcinoma.
More than one out of every three new cancers is a skin cancer, and the large majority are basal cell carcinomas (BCC). Targeted therapy targets the cancer's specific genes, proteins, or tissue environment that contributes to cancer growth and survival and blocks the growth as well as the spread of cancer cells while limiting damage to healthy cells. Therefore, in the present study AS1411 aptamer-functionalized liposomes for the treatment of BCC were obtained and characterized. Aptamer conjugation increased liposome size, suggesting that the presence of an additional hydrophilic molecule on the liposomal surface increased the hydrodynamic diameter. As expected, the negatively charged DNA aptamer reduced the surface potential of the liposomes. Vertical Franz diffusion cells with artificial membranes were used to evaluate the in vitro release of 5-fluorouracil (5-FU). The aptamer moieties increase the stability of the liposomes and act as a supplementary steric barrier leading to a lower cumulative amount of the released 5-FU. The in vitro cell viability, targeting capability and apoptotic effects of liposomes on the human dermal fibroblasts and on the basal cell carcinoma TE 354.T cell lines were also evaluated. The results indicate that the functionalized liposomes are more efficient as nanocarriers than the non-functionalized ones.


Scenario-based participatory design of a collaborative clinical trial protocol authoring system.
We present our experience of using prototype scenarios to actively involve users in the design of a collaborative clinical trial protocol authoring system. This method enables us to do usability testing and elicit prompt user feedback at the early phase of de-sign. We conclude that it is an effective approach to the design of complex medical information systems.


Paediatric motor phenotypes in early-onset ataxia, developmental coordination disorder, and central hypotonia.
To investigate the accuracy of phenotypic early-onset ataxia (EOA) recognition among developmental conditions, including developmental coordination disorder (DCD) and hypotonia of central nervous system origin, and the effect of scientifically validated EOA features on changing phenotypic consensus. We included 32 children (4-17y) diagnosed with EOA (n=11), DCD (n=10), and central hypotonia (n=11). Three paediatric neurologists independently assessed videotaped motor behaviour phenotypically and quantitatively (using the Scale for Assessment and Rating of Ataxia [SARA]). We determined: (1) phenotypic interobserver agreement and phenotypic homogeneity (percentage of phenotypes with full consensus by all three observers according to the underlying diagnosis); (2) SARA (sub)score profiles; and (3) the effect of three scientifically validated EOA features on phenotypic consensus. Phenotypic homogeneity occurred in 8 out of 11, 2 out of 10, and 1 out of 11 patients with EOA, DCD, and central hypotonia respectively. Homogeneous phenotypic discrimination of EOA from DCD and central hypotonia occurred in 16 out of 21 and 22 out of 22 patients respectively. Inhomogeneously discriminated EOA and DCD phenotypes (5 out of 21) revealed overlapping SARA scores with different SARA subscore profiles. After phenotypic reassessment with scientifically validated EOA features, phenotypic homogeneity changed from 16 to 18 patients. In contrast to complete distinction between EOA and central hypotonia, the paediatric motor phenotype did not reliably distinguish between EOA and DCD. Reassessment with scientifically validated EOA features could contribute to a higher phenotypic consensus. Early-onset ataxia (EOA) and central hypotonia motor phenotypes were reliably distinguished. EOA and developmental coordination disorder (DCD) motor phenotypes were not reliably distinguished. The EOA and DCD phenotypes have different profiles of the Scale for Assessment and Rating of Ataxia.


Severe keratomycosis secondary to Scedosporium apiospermum.
To report an unusual case of severe keratomycosis caused by Scedosporium apiospermum without any known previous ocular injury, that resulted in a corneal perforation, which was treated with an emergency penetrating tectonic keratoplasty and later with phacoemulsification and astigmatic keratotomy to restore good visual function. A 45-year-old woman with a history of multiple sclerosis presented with a severe and refractory corneal abscess in her right eye without any known prior injury. Corneal scrapings were obtained and stained for microscopic evaluation. The samples were sent for aerobic and anaerobic bacterial and fungal cultures. Microbiologic examination of the corneal scraping showed Scedosporium apiospermum micelle. The fungal culture was sensitive to miconazole, itraconazole and voriconazole. Partial clinical improvement was achieved with hourly topical natamycin, amphotericin B, and systemic itraconazole application, although in vitro sensitivity tests showed resistance to the topical antifungal agents used. A corneal paracentral perforation occurred despite aggressive treatment. An emergency eccentric penetrating keratoplasty was performed with satisfactory results. Subsequent phacoemulsification and astigmatic keratotomy restored a good visual function. A fungal etiology should be suspected in a progressive and refractory corneal abscess. This report highlights the utility of microbiologic investigation to perform an early and accurate diagnosis. Aggressive medical treatment and even therapeutic penetrating keratoplasty to remove infected tissue could result in the maintenance of useful visual function. In view of the poor prognosis of this specific fungus, a closer observation and early keratoplasty might be required to preserve the ocular globe.


Flow cytometric DNA analysis of 20 bronchopulmonary neuroendocrine tumours.
Deoxyribonucleic acid (DNA) content of bronchopulmonary neuroendocrine tumours was measured by flow cytometry in order to investigate correlations between ploidy, S-phase fraction (SPF) and two histological classifications (World Health Organization (WHO), Warren and Gould), and clinical staging. A paraffin-embedded technique was used on 20 surgical specimens. Cases comprised (according to the classification of Warren and Gould) 7 carcinoids, 3 well-differentiated neuroendocrine carcinomas (WDNC), 6 intermediate neuroendocrine carcinomas (INC), and 4 small cell neuroendocrine carcinomas (SCNC). DNA aneuploidy was demonstrated in 3 out of 7 of the carcinoids, 3 out of 9 of the WDNCs and INCs, and 2 out of 4 of the SCNCs. A variable SPF was found in each group, except for the SCNCs which showed a constantly high SPF. In our small series, no correlation was noted between high SPF or aneuploidy and metastases. In conclusion, we observed no diagnostic value of malignancy for DNA aneuploidy. The SCNC group appeared to be an homogeneous group according to the SPF compared to the small cell carcinoma (SCC) group of the WHO classification. This and the prognostic incidence of high SPF need to be further studied.


The reactive adventitia: fibroblast oxidase in vascular function.
The vascular adventitia is activated in a variety of cardiovascular disease states and has recently been shown to be a barrier to nitric oxide bioactivity. Vascular fibroblasts produce substantial amounts of NAD(P)H oxidase-derived reactive oxygen species (ROS) that appear to be involved in fibroblast proliferation, connective tissue deposition, and perhaps vascular tone. However, the physiological and pathophysiological roles of the adventitia have not been extensively studied, possibly because of its location in large blood vessels remote from the vascular endothelium. In recent years, substantial information has been gathered on pathways leading to oxidase activation in smooth muscle cells and fibroblasts and the downstream signaling pathways leading to hypertrophy and proliferation. A clearer understanding of the molecular mechanisms involved will likely lead to therapeutic strategies aimed at preventing vascular dysfunction in diseases such as atherosclerosis, in which these pathways are activated.


C-C coupling reactivity of an alkylgold(III) fluoride complex with arylboronic acids.
Previously, alkylgold(III) fluorides have been proposed as catalytic intermediates that undergo C-C coupling with reagents such as arylboronic acids in Au(I)/Au(III) cross-coupling reactions. Here is reported the first experimental evidence for this elementary mechanistic step. Complexes of the type (NHC)AuMe (NHC = N-heterocyclic carbene) were oxidized with XeF(2) to yield cis-(NHC)AuMeF(2) products, which were found to be in equilibrium with their fluoride-dissociated, dimeric [(NHC)AuMe(μ-F)](2)[F](2) forms. In one case, a monomeric cis-(NHC)AuMeF(2) complex was favored exclusively in solution, and it was found to react with a variety of ArB(OH)(2) reagents to yield Ar-CH(3) products.


A method for evaluating antianginal drugs in experimental animals: assessment of myocardial ischemia by myocardial pH.
This paper describes a method by which antianginal drugs can be evaluated in the dog heart in situ. Myocardial pH was measured continuously by a micro glass pH electrode inserted in the left ventricular endocardial layers of the dog anesthetized with pentobarbital. Occlusion of the left anterior descending coronary artery (LAD) decreased myocardial pH, and release of the LAD restored the pH. The myocardial acidosis induced by ischemia was metabolic in nature and accompanied by a decrease in the levels of adenosine triphosphate and creatine phosphate and an increase in the levels of lactate in the myocardium. Drugs were injected intravenously 30 min after incomplete (partial) occlusion ot the LAD, lasting until 60 min after drug injection. Propranolol, atenolol, and sotalol markedly attenuated the myocardial pH that had been decreased by LAD occlusion. Nitroglycerin, diltiazem, and nicorandil also attenuated the pH, but these drugs were less active in attenuating myocardial acidosis. Dipyridamole, nifedipine, and beta-2 adrenoceptor antagonists were least active in this regard. It is concluded that myocardial pH can be used as an indicator of myocardial regional ischemia and utilized for evaluation of antianginal drugs.


[Beneficial effects of direct call to Emergency Medical Services on time delays and management of patients with acute myocardial infarction. The RICO (obseRvatoire des Infarctus de Côte-d'Or) data].
The influence of direct calls to specialized Emergency Medical Services in case of suspected myocardial infarction has not been extensively studied. The RICO registry is an exhaustive registry implemented in all six institutions participating in primary care of patients with acute myocardial infarction in one French administrative department (Côte-d'Or). From January 2001 to October 2001, 322 patients were admitted for acute myocardial infarction, among whom only 57 (18%) had directly called emergency medical services after the onset of symptoms. The baseline characteristics of patients who had directly called the emergency services were not different from those of the patients who had not. However, the time from symptom onset to first medical intervention (48 versus 105 minutes, p = 0.02) and from first medical intervention to hospital admission (60 versus 103 minutes, p = 0.02) were markedly shorter in patients who had directly called the emergency medical services. This resulted in a significant increase in the use of reperfusion therapy (70% versus 38%, p = 0.003), including a higher proportion of primary angioplasty (33% versus 20%, p = 0.04). This study documents the beneficial effect of a direct call to the Emergency Medical Services by the patients themselves. Too few patients, however use this opportunity and actions should be taken for informing the lay public of the benefits of this medical service.


[A case of Guillain-Barré syndrome treated with plasma exchange and intravenous high-dose immune globulin].
We describe a 69-year-old female with Guillain-Barré syndrome (GBS) whose paresthesia and weakness improved after plasma exchange (PE) and intravenous high-dose immune globulin (i.v.I.G.). She felt a paresthesia in her right arm, and 7 days later she noticed right arm weakness followed by gait disturbance within 2 days. She received a series of 6 PEs, but paresthesia and weakness did not improve. Following the last PE trial of this series, she was treated by i.v.I.G. (0.4 g/kg) for 5 days. After i.v.I.G., paresthesia and weakness improved in a few days. After 2nd series of 6 PEs, she was able to walk. In this clinical course, the treatment of i.v.I.G. after PE seemed to be effective. This case raises the possibility that i.v.I.G. might be the treatment in GBS patients with insufficient effect of PE.


[An autopsy case of a bicycle accident with ring fracture at the base of the skull].
We report the autopsy case of a 41-year old passenger who suffered a significant head injury with a typical ring fracture at the base of the skull as a result of a violent fall from a bicycle. Several reports about ring fractures of the base of the skull revealed that they were due to crashing a car at high speed, a collision and/or a fall while riding a motorcycle and a fall in piloting a gyrocopter and so on resulting in severe injury to another part of the body. In this case, the ring fracture occurred when his spine was pushed up by high impact of the parieto-occipital region against the ground.


Na"Fuzzy space": does it exist, and is it important in ischemic injury?
Work is reviewed which provides evidence for the presence of a subsarcolemmal microdomain, in which the [Na(+)] is influenced by Na(+) influx via the Na(+) channel and the activity of the Na pump. The sarcolemma adjacent to this microdomain, which has been referred to as "Na(+) fuzzy space," appears to include Na-Ca exchangers, and thus alterations of [Na(+)] in this space may influence Ca(2+) influx and efflux, and thus Ca(2+) loading, more directly than do alterations of bulk cytoplasmic [Na(+)]. The degree of Ca(2+) loading is an important determinant of contractility in heart muscle, and therefore alterations in fuzzy space [Na(+)] may be important in mediating the positive inotropic effects of Na pump inhibitors, such as digitalis, and the negative inotropic effects of Na(+) channel blockers such as disopyramide. During ischemia, myocyte Ca(2+) overload can contribute to ATP depletion by activation of Ca(2+)-dependent ATPases and by induction of the mitochondrial permeability transition, and thus is an important contributor to myocyte dysfunction and injury. Hypoxia associated with ischemia can induce Na(+) influx via a persistent opening of the Na(+) channel. It is likely that this Na(+) influx elevates [Na(+)] in the fuzzy space, and thus increases Ca(2+) influx via Na-Ca exchange, and increases Ca(2+) loading. Inhibition of the persistent Na(+) current with a resulting decrease in Ca(2+) loading by drugs such as tetrodotoxin (TTX) and ranolazine may be a mechanism by which these agents produce a cardio-protective effect during ischemia.


Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices.
Brief exposure to excitotoxic agonists can result in substantial loss of the microtubule-associated protein MAP2 from neuronal dendrites, and accumulation in somata. A possible mechanism underling MAP2 loss is the activation of the calcium-dependent protease calpain by excessive dendritic Ca2+-loading. The present study examined mechanisms of MAP2 redistribution and loss of synaptic efficacy in the CA1 region of acutely prepared hippocampal slices. Brief NMDA exposure resulted in persistent and profound inhibition of postsynaptic potentials, and loss of MAP2 from dendritic compartments. When Ca2+ was removed during NMDA exposure, synaptic potentials recovered significantly during NMDA washout, and MAP2 loss was reduced. Calpain inhibition with MDL 28,170 (20 microM) did not prevent the loss of synaptic potentials, nor did it attenuate the initial aggregation of MAP2 into irregular dendritic swellings. However MDL 28,170 did reduce subsequent MAP2 loss from abnormal dendritic aggregates. Pre-exposure of slices to taxol (100 nM) effectively prevented microtubule depolymerization following NMDA exposure, as well as MAP2 disorganization and loss from apical dendrites. Slices treated with taxol also exhibited substantial recovery of synaptic potentials after transient NMDA stimulus. These results demonstrate a close correspondence between the maintained localization of MAP2 in apical dendrites and the recovery of postsynaptic potentials following transient NMDA exposure. In addition, it appears that rather than underlying the initial disruption of microtubule structure via MAP2 proteolysis, calpain activity instead may contribute to the degradation of irregularly aggregated MAP2 observed following microtubule depolymerization.


Grains in Selectively Grown MoS2 Thin Films.
Transition metal dichalcogenides (TMDCs) have recently been studied using various synthesis methods, such as chemical vapor deposition for large-scale production. Despite the realization of large-scale production with high material quality, a range of approaches have been made to solve the patterning issue of TMDCs focusing on the application of integrated devices; however, patterning is still under study to accurately represent nanoscale-sized patterns, as well as the desired positions and shapes. Here, an insulating substrate is treated selectively with O2 plasma, and MoS2 growth is induced in the superhydrophilic area. Selectively well-grown MoS2 patterns are confirmed by atomic force microscopy and Raman and photoluminescence spectroscopy. In addition, the grain size, according to the growth size, and grain boundary are analyzed by annual dark field transmission electron microscopy (TEM) and spherical aberration-corrected scanning TEM to confirm the selective growth. An analysis of the device performance and the optical properties reveals an enhancement with increasing grain size. This method presents the path of the growth technique for patterning, as well as the direction that can be applied to devices and integrated circuits.


Methodology challenges in studying human gut microbiota - effects of collection, storage, DNA extraction and next generation sequencing technologies.
The information on microbiota composition in the human gastrointestinal tract predominantly originates from the analyses of human faeces by application of next generation sequencing (NGS). However, the detected composition of the faecal bacterial community can be affected by various factors including experimental design and procedures. This study evaluated the performance of different protocols for collection and storage of faecal samples (native and OMNIgene.GUT system) and bacterial DNA extraction (MP Biomedicals, QIAGEN and MO BIO kits), using two NGS platforms for 16S rRNA gene sequencing (Ilumina MiSeq and Ion Torrent PGM). OMNIgene.GUT proved as a reliable and convenient system for collection and storage of faecal samples although favouring Sutterella genus. MP provided superior DNA yield and quality, MO BIO depleted Gram positive organisms while using QIAGEN with OMNIgene.GUT resulted in greatest variability compared to other two kits. MiSeq and IT platforms in their supplier recommended setups provided comparable reproducibility of donor faecal microbiota. The differences included higher diversity observed with MiSeq and increased capacity of MiSeq to detect Akkermansia muciniphila, [Odoribacteraceae], Erysipelotrichaceae and Ruminococcaceae (primarily Faecalibacterium prausnitzii). The results of our study could assist the investigators using NGS technologies to make informed decisions on appropriate tools for their experimental pipelines.


Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury.
We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)-10. Wistar rats were subjected to 3h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03mg/kg)±IL-10 neutralizing antibody (0.1mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. C21 provides direct neuroprotection as well as indirect protection through IL-10.


Anesthetic Considerations of Hereditary Neuropathy With Liability to Pressure Palsies in an Obstetric Patient: A Case Report.
Hereditary neuropathy with liability to pressure palsies is an autosomal dominant condition occurring in up to 16 per 100,000 people and predisposes to neural compressive injury. Given the rarity of this condition, no guidelines currently exist for the anesthetic management of hereditary neuropathy with liability to pressure palsies. We describe the management of analgesia during labor in a woman diagnosed with hereditary neuropathy with liability to pressure palsies and a history of nerve palsy after obstetric anesthesia. Our report highlights the necessity of clinician awareness of hereditary neuropathy with liability to pressure palsies and the anesthetic precautions used to successfully avoid neural injury in this case.


Suicide notes in alcoholism.
Alcoholism is associated with a vast number of suicides. The most systematic study of suicide among alcoholics is the work of Eli Robins and George Murphy. The suicide notes in these studies have remained unanalyzed to date. The present analysis suggested that these suicide notes of alcoholics did not differ from those of nonalcoholics; core themes in their deaths are unbearable psychological pain, cognitive constriction, indirect expressions, rejection-aggression, and identification-aggression. Although caution is in order in accepting the null hypothesis, we can at least suggest that further study is needed.


Turning tumors into vaccines: co-opting the innate immune system.
Immunotherapy of cancer must be effective in the pre-established disease; i.e., in the therapeutic rather than prophylactic setting. Here, we review novel immunotherapeutic approaches for targeting established cancers. In addition to novel checkpoint-blocking antibodies, recent insight into innate immune sensors may further improve cancer immunotherapy protocols and help to overcome the limitations of conventional therapeutic immunization strategies. Specifically, the local induction of IL-12 and IFNα turns the immunosuppressive tumor microenvironment into an immunosupportive tissue, which is attained, for example, by local Toll-like receptor or RIG-I-like receptor triggering. Notably, the latter are endogenously expressed in all tumor cells and have the advantage of turning tumors into tumor vaccines by inducing apoptosis and improving antigen presentation. Thus, immunostimulatory agents embody strong promise as a part of combinatorial cancer immunotherapies.


The use of clinical criteria alone in the management of the clinically negative neck among patients with squamous cell carcinoma of the oral cavity and oropharynx.
Management of the clinically negative neck among patients with oral and oropharyngeal squamous cell carcinoma at the Royal Prince Alfred Hospital, Sydney, Australia has been based on the site and stage of the primary cancer, the likely incidence of microscopic nodal involvement, the treatment modality used for the primary cancer, and whether the neck will be entered during resection or reconstruction. This report analyzes the results of treatment when patients are allocated to either treatment or observation of the neck based on these clinical factors. This is a prospectively documented series of 162 consecutively treated patients with squamous cell carcinoma of the oral cavity and oropharynx and clinically negative necks, treated by 1 surgeon (C.J.O.). There were 128 oral cavity and 34 oropharyngeal cancers clinically staged at T1 for 62 patients, T2 for 61, T3 for 16, and T4 for 23 patients. Management of the neck consisted of elective neck dissection (END) in 96 patients (12 bilateral), elective radiotherapy in 8, and observation in 58. Neck treatment correlated with the T stage in a statistically significant way. Forty-six patients underwent postoperative radiotherapy, which was directed to the neck in 22 patients because of pathological findings following neck dissection. Free-flap reconstruction was used in 90 patients. Metastatic squamous cell carcinoma was identified in 32 of 108 neck dissections (30%). There was 1 positive node in 15 necks, 2 positive nodes in 11 necks, and 3 or more positive nodes in 6 necks. Extracapsular spread was present in 8 of 32 positive END specimens (25%). Regional control rates in the neck at 3 years were 94% for END, 100% for elective radiotherapy, and 98% for patients initially observed and then treated by therapeutic neck dissection. Death with uncontrolled disease in the neck occurred in 4 of 96 patients (4%) after END and 1 of 58 patients (2%) after neck observation. Overall disease-specific survival was 83%, comprising an 86% rate for patients with pathologically negative necks and 68% if pathologically positive. Disease-specific survival was 86% at 3 years for patients having END, 67% following radiotherapy, and 94% for the observation group. Elective neck dissection was performed in most patients, and occult metastatic disease was found in nearly 30% of neck dissections. Observation was most frequently used for patients with early stage disease, and subsequent development of neck metastases was uncommon (9%) in this group. Selective treatment of the clinically negative neck based on the primary tumor site and stage led to a high rate of regional disease control in this series.


STOP Signs: A Population-based Interrupted Time Series Analysis of Antibiotic Duration for Complicated Intraabdominal Infection Before and After the Publication of a Landmark RCT.
To determine if the STOP-IT randomized controlled trial changed antibiotic prescribing in patients with Complicated Intraabdominal Infection (CIAI). CIAI is common and causes significant morbidity. In May 2015, the STOP-IT randomized controlled trial showed equivalent outcomes between four-day and clinically determined antibiotic duration. This was a population-based retrospective cohort study using interrupted time series methods. The STOP-IT publication date was the exposure. Median duration of inpatient antibiotic prescription was the outcome. All adult patients admitted to four hospitals in Calgary, Canada between July 2012 and December 2018 with CIAI who survived at least four days following source control were included. Analysis was stratified by infectious source as appendix or biliary tract (group A) versus other (group B). Among 4384 included patients, clinical and demographic attributes were similar before vs after publication. In Group A, median inpatient antibiotic duration was 3 days and unchanged from the beginning to the end of the study period [adjusted median difference -0.00 days, 95% confidence interval (CI) -0.37 - 0.37 days]. In Group B, antibiotic duration was shorter at the end of the study period (7.87 vs 6.73 days; -1.14 days, CI-2.37 - 0.09 days), however there was no change in trend following publication (-0.03 days, CI -0.16 - 0.09). For appendiceal or biliary sources of CIAI, antibiotic duration was commensurate with the experimental arm of STOP-IT. For other sources, antibiotic duration was long and did not change in response to trial publication. Additional implementation science is needed to improve antibiotic stewardship.


Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes.
Cyclin-dependent kinase (Cdk)-5 is activated by both cyclin I and the noncyclin activator p35 in terminally differentiated cells such as kidney podocytes and neurons. Cyclin I and p35 are restricted to podocytes in the kidney, and each limit podocyte apoptosis by activating Cdk5. To determine whether both activators are necessary, or whether they serve backup roles, a double cyclin I-p35 null mouse was generated. Experimental glomerular disease characterized by podocyte apoptosis was then induced by administering an anti-podocyte antibody. The results showed that under nonstressed conditions double mutants had normal kidney structure and function and were indistinguishable from wild-type, cyclin I(-/-), or p35(-/-) mice. In contrast, when stressed with disease, podocyte apoptosis increased fourfold compared with diseased cyclin I(-/-) or p35(-/-) mice. This resulted in a more pronounced decrease in podocyte number, proteinuria, and glomerulosclerosis. Under normal states and nephritic states, levels for the prosurvival protein Bcl-2 were lower in double cyclin I(-/-) p35(-/-) mice than the other mice. Similarly, levels of Bcl-xL, another prosurvival member, were lower in normal and nephritic double cyclin I(-/-) p35(-/-) mice but similar to single-cyclin I(-/-) mice. Moreover, levels of ERK1/2 and MEK1/2 activation were lower in nephritic double cyclin I(-/-) p35(-/-) mice but similar to single-cyclin I(-/-) mice. The results demonstrate that the activators of Cdk5, p35, and cyclin I are not required for normal kidney function. However, they play pivotal coordinated roles in maintaining podocyte survival during stress states in disease.


Millefeuille-Inspired Thermal Interface Materials based on Double Self-Assembly Technique for Efficient Microelectronic Cooling and Electromagnetic Interference Shielding.
Owing to the increasing power density of miniaturized and high-frequency electronic devices, flexible thermal interface materials (TIMs) with the electromagnetic interference (EMI) shielding property are in urgent demand to maintain the system performance and reliability. Recently, carbon-based TIMs receive considerable attention due to the ultrahigh intrinsic thermal conductivity (TC). However, the large-scale production of such TIMs is restricted by some technical difficulties, such as production-induced defects of graphite sheets, poor microstructure architecture within the matrix, and nonnegligible interfacial thermal resistance result from the strong phono scattering. In this work, inspired by the structure and production process of millefeuille cakes, a unique double self-assembly strategy for fabricating ultrahigh thermal conductive TIMs with superior EMI shielding performance is demonstrated. The percolating and oriented multilayered microstructure enables the TIM to exhibit an ultrahigh in-plane TC of 233.67 W m-1 K-1 together with an outstanding EMI shielding effectiveness of 79.0 dB (at 12.4 GHz). In the TIM evaluation system, a nearly 45 °C decrease is obtained by this TIM when compared to the commercial material. The obtained TIM achieves the desired balance between thermal conduction and EMI shielding performance, indicating broad prospects in the fields of military applications and next-generation thermal management systems.


Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats.
Aged rats are impaired on a spatial memory task for at least 24-48 h after isoflurane-nitrous oxide anesthesia. In this study, we tested how long the impairment lasts and investigated the role of nitrous oxide. Eighteen-month-old rats were randomized to anesthesia for 2 h with 1.2% isoflurane with or without 70% nitrous oxide or a control group (30% oxygen). Two weeks later, rats were tested daily for 14 days on a 12-arm radial maze. The number of correct choices to first error, total errors, and time to complete the maze were recorded. Rats anesthetized with 1.2% isoflurane with 70% nitrous oxide made fewer correct choices before first error (P < or = 0.05). Trends toward similar results were noted for error rate and time to complete the maze, but these did not achieve statistical significance. Post hoc analysis comparing all anesthetized rats to controls demonstrated that anesthetized rats made fewer correct choices to first error (P < or = 0.05) and took longer to complete the maze (P <or = 0.05). There were no differences in total number of errors (P < or = 0.06). Thus, spatial memory is impaired for 2 wk after general anesthesia in aged rats independent of whether nitrous oxide is used.


Family history of illness in the seriously suicidal adolescent: a life-cycle approach.
Highly suicidal, depressed adolescents were compared to nonsuicidal depressed adolescents with regard to family history of illness. Chronic psychiatric illness of a parent, particularly depression occurring during the childhood of patients, was found to be more frequent among families of highly suicidal adolescents. Implications of this finding are considered.


[Bag3 gene expression in chronic lymphocytic leukemia and its association with patients' prognosis].
The aim of this study was to investigate bag3 gene expression in chronic lymphocytic leukemia (CLL)patients and its association with clinical prognosis. A total of 46 blood samples from untreated CLL patients were collected, SYBR Green-based real-time PCR was used to detect the bag3 mRNA expression, and its association with prognostic index was analyzed by statistical software. The results showed that the median values of bag3 level detected by real-time PCR in 46 CLL patients and normal controls were 0.021 (0.0007 - 1.124) and 0.0025 (0.0005 - 0.014) respectively, the former was significantly higher than the latter. The bag3 level in drug-resistant group was obviously higher as compared with the drug-responsive group. No association was found between bag3 expression and patient clinical baseline information (gender and age) as well as established prognostic factors (lymphocyte count, disease stage, IgVH mutation status, cytogenetics analysis and CD38, ZAP 70 expression). It is concluded that the bag3 expression in CLL patients is markedly higher than that in normal controls, while the high bag3 level in CML patients is probably related with drug resistance, but is not related with clinically established prognostic factors.


Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis.
In a double blind noncrossover study, dietary supplementation with fish oil (18 g/day), was compared with an olive oil supplement over a 12-week period in patients with rheumatoid arthritis receiving established conventional therapies. An improvement in tender joint score and grip strength was seen at 12 weeks in the fish oil treated group but not in the olive oil treated group. The more subjective measures of mean duration of morning stiffness and analogue pain score improved to a similar extent in both groups, although statistical significance was only achieved in paired analyses in the olive oil treated group. Production of leukotriene B4 by isolated neutrophils stimulated in vitro was reduced by 30% in the fish oil treated group and unchanged in the olive oil treated group.


Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis.
Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients. We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (< or =800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly). The average 25(OH)D level was 71 +/- 39 nmol/L (Mean +/- SD), and 167(84%) patients had insufficient levels (< or =100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (> or =100 nmol/L) were only achieved in less than 40% of patients. We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.


Paediatric endoscopy performed by adult-service gastroenterologists.
Children often travel from district hospitals to teaching centres for endoscopic procedures by paediatric gastroenterologists. A 10-year district hospital experience of 'adult-service' gastroenterologists endoscoping children is reported with the aim of quantifying the workload, indications, sedation/anaesthesia practices, findings and safety of paediatric endoscopy performed by adult-service gastroenterologists. Data on endoscopic procedures in patients younger than 16 years of age between 1997 and 2006 were obtained from hospital case-notes and computerized endoscopy/histology databases and were analysed. A total of 174 procedures (118 gastroscopies, 41 colonoscopies and 15 flexible sigmoidoscopies) were performed in 162 children. The median (interquartile range) age was 11.5 (5-14) years. Sixty-nine percent of patients were referred by paediatricians and 31% by general practitioners /other adult specialties. Children referred as outpatients waited a total of 50 (23.5-95) days from referral to procedure. Inpatient children waited 3 (1-4) days for their procedure. General anaesthesia was used in 89% (63 of 71) endoscopic procedures in children aged below 11 years and 100% of 47 procedures in children aged below 6 years. In contrast, 96% (99 of 103) procedures in children aged 11 years or older were done in the endoscopy unit with intravenous or no sedation. Organic disease was identified from 90 (52%) procedures. The most common diagnoses were coeliac disease (41), inflammatory bowel disease (26), gastro-oesophageal reflux (six) and foreign body removal (seven). No endoscopic complications occurred. General gastroenterologists supported by paediatricians can provide endoscopic services for children safely and promptly in their local hospital. This is appropriate for the management of common gastrointestinal problems affecting children.


Fourier transform infrared microspectroscopy and multivariate methods for radiobiological dosimetry.
The scientific literature contains an ever-growing number of reports of applications of vibrational spectroscopy as a multivariate non-invasive tool for analysis of biological effects at the molecular level. Recently, Fourier transform infrared microspectroscopy (FTIRM) has been demonstrated to be sensitive to molecular events occurring in cells and tissue after exposure to ionizing radiation. In this work the application of FTIRM in the examination of dose-dependent molecular effects occurring in skin cells after exposure to ionizing radiation with the use of partial least-squares regression (PLSR) and generalized regression neural networks (GRNN) was studied. The methodology is shown to be sensitive to molecular events occurring with radiation dose and time after exposure. The variation in molecular species with dose and time after irradiation is shown to be non-linear by virtue of the higher modeling efficiency yielded from the non-linear algorithms. Dose prediction efficiencies of approximately +/-10 mGy were achieved at 96 h after irradiation, highlighting the potential applications of the methodology in radiobiological dosimetry.


Moonstone: a novel natural language processing system for inferring social risk from clinical narratives.
Social risk factors are important dimensions of health and are linked to access to care, quality of life, health outcomes and life expectancy. However, in the Electronic Health Record, data related to many social risk factors are primarily recorded in free-text clinical notes, rather than as more readily computable structured data, and hence cannot currently be easily incorporated into automated assessments of health. In this paper, we present Moonstone, a new, highly configurable rule-based clinical natural language processing system designed to automatically extract information that requires inferencing from clinical notes. Our initial use case for the tool is focused on the automatic extraction of social risk factor information - in this case, housing situation, living alone, and social support - from clinical notes. Nursing notes, social work notes, emergency room physician notes, primary care notes, hospital admission notes, and discharge summaries, all derived from the Veterans Health Administration, were used for algorithm development and evaluation. An evaluation of Moonstone demonstrated that the system is highly accurate in extracting and classifying the three variables of interest (housing situation, living alone, and social support). The system achieved positive predictive value (i.e. precision) scores ranging from 0.66 (homeless/marginally housed) to 0.98 (lives at home/not homeless), accuracy scores ranging from 0.63 (lives in facility) to 0.95 (lives alone), and sensitivity (i.e. recall) scores ranging from 0.75 (lives in facility) to 0.97 (lives alone). The Moonstone system is - to the best of our knowledge - the first freely available, open source natural language processing system designed to extract social risk factors from clinical text with good (lives in facility) to excellent (lives alone) performance. Although developed with the social risk factor identification task in mind, Moonstone provides a powerful tool to address a range of clinical natural language processing tasks, especially those tasks that require nuanced linguistic processing in conjunction with inference capabilities.


Phenotyping analysis of p53 knockout mice produced by gene editing and comparison with conventional p53 knockout mice.
Knockout (KO) mice developed by homologous recombination (HR) have become useful tools to elucidate gene function. However, HR has low KO efficiency and is time-consuming, labor-intensive, and expensive. 'Gene editing' has received much attention for efficient genetic manipulation. As generation of KO mice is simplified, KO mice produced by HR can be feasibly reproduced using gene editing. However, phenotyping analysis and comparison between KO mice produced by these two techniques is necessary. We generated p53 KO mice through gene editing and compared their phenotype with the already reported HR-mediated p53 KO mice. Tumors occurred in 36 (73%) of 49 homozygous KO mice and the mean age of occurrence was 23 weeks, with lymphoma (64%) and sarcoma (23%) being the most common. Tumors were also developed in 12 heterozygous mice and the mean age of occurrence was 40 weeks, with sarcoma (54%) and lymphoma (46%) in high proportion. Homozygotes had a mean life span of 157 ± 52 days and developmental abnormalities were found in females compared to in males (P < 0.05, P < 0.001). We analyzed the basic phenotype of p53 KO mice and observed no significant difference from the conventional HR-mediated p53 KO mice.