Realistic fear of cervical cancer risk in Japan depending on birth year.
In Japan, the possible adverse events upon HPV vaccination was widely reported in the media. MHLW announced the suspension of aggressively encouraging HPV vaccination in 2013, and inoculation rate has sharply declined. The aim of the present study was estimation of future cervical cancer risk. The latest data on vaccination rate at each age in Sakai City were first investigated. The rate of experiencing sexual intercourse at the age of 12, 13, 14, 15, 16, 17 and throughout lifetime is assumed to be 0%, 1%, 2%, 5%, 15%, 25%, and 85% respectively. The cervical cancer risk was regarded to be proportional to the relative risk of HPV infection over the lifetime. The risk in those born in 1993 whom HPV vaccination was not available yet for was defined to be 1.0000. The cumulative vaccination rates were 65.8% in those born in 1994, 72.7% in 1995, 72.8% in 1996, 75.7% in 1997, 75.0% in 1998, 66.8% in 1999, 4.1% in 2000, 1.5% in 2001, 0.1% in 2002, and 0.1% in 2003. The relative cervical cancer risk in those born in 1994-1999 was reduced to 0.56-0.70, however, the rate in those born in 2000-2003 was 0.98-1.0, almost the same risk as before introduction of the vaccine. The cumulative initial vaccination rates were different by the year of birth. It is confirmed that the risk of future cervical cancer differs in accordance with the year of birth. For these females, cervical cancer screening should be recommended more strongly.


Survival and quality of life in incident systemic sclerosis-related pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (SSc). We sought to determine survival, predictors of mortality, and health-related quality of life (HRQoL) related to PAH in a large SSc cohort with PAH. We studied consecutive SSc patients with newly diagnosed (incident) World Health Organization (WHO) Group 1 PAH enrolled in a prospective cohort between 2009 and 2015. Survival methods were used to determine age and sex-adjusted standardised mortality ratio (SMR) and years of life lost (YLL), and to identify predictors of mortality. HRQoL was measured using the Short form 36 (SF-36) instrument. Among 132 SSc-PAH patients (112 female (85%); mean age 62 ± 11 years), 60 (45.5%) died, with a median (±IQR) survival time from PAH diagnosis of 4.0 (2.2-6.2) years. Median (±IQR) follow up from study enrolment was 3.8 (1.6-5.8) years. The SMR for patients with SSc-PAH was 5.8 (95% CI 4.3-7.8), with YLL of 15.2 years (95% CI 12.3-18.1). Combination PAH therapy had a survival advantage (p < 0.001) compared with monotherapy, as did anticoagulation compared with no anticoagulation (p < 0.003). Furthermore, combination PAH therapy together with anticoagulation had a survival benefit compared with monotherapy with or without anticoagulation and combination therapy without anticoagulation (hazard ratio 0.28, 95% CI 0.1-0.7). Older age at PAH diagnosis (p = 0.03), mild co-existent interstitial lung disease (ILD) (p = 0.01), worse WHO functional class (p = 0.03) and higher mean pulmonary arterial pressure at PAH diagnosis (p = 0.001), and digital ulcers (p = 0.01) were independent predictors of mortality. Despite the significant benefits conferred by advanced PAH therapies suggested in this study, the median survival in SSc PAH remains short at only 4 years.


Nanomechanical properties of mineralised collagen microfibrils based on finite elements method: biomechanical role of cross-links.
Hierarchical structures in bio-composites such as bone tissue have many scales or levels and synergic interactions between the different levels. They also have a highly complex architecture in order to fulfil their biological and mechanical functions. In this study, a new three-dimensional (3D) model based on the finite elements (FEs) method was used to model the relationship between the hierarchical structure and the properties of the constituents at the sub-structure scale (mineralised collagen microfibrils) and to investigate their apparent nanomechanical properties. The results of the proposed FE simulations show that the elastic properties of microfibrils depend on different factors such as the number of cross-links, the mechanical properties and the volume fraction of phases. The results obtained under compression loading at a small deformation < 2% show that the microfibrils have a Young's modulus (Ef) ranging from 0.4 to 1.16 GPa and a Poisson's ratio ranging from 0.26 to 0.3. These results are in excellent agreement with experimental data (X-ray, AFM and MEMS) and molecular simulations.


[Serum NSE (neuron-specific enolase) levels in small cell lung cancer, with special reference to the measurement of serial serum NSE levels].
Serum neuron-specific enolase (NSE) was measured in 105 patients with lung cancer without prior therapy. Increasing serum levels of NSE were observed in 84% of cases of small cell lung cancer (SCLC). 11% of adenocarcinomas, 18.5% of squamous cell carcinomas and 37.5% of large cell carcinomas. Serum NSE levels changed in parallel with the effect of initial treatment. Although two of 5 patients with SCLC, in whom serial NSE levels were measured after treatment, showed elevation of serum NSE levels before clinical relapse, elevated serum NSE levels were not observed in 3 patients at clinical relapse. These data seem to suggest that measurement of serial NSE is useful for predicting relapse prior to clinical recognition. However, it still remains an important point to carry out clinical general surveillance for relapse.


Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.
The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance. We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment. A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either). AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.


Copolythiophene-derived colorimetric and fluorometric sensor for lysophosphatidic acid based on multipoint interactions.
3-Phenylthiophene-based water-soluble copolythiophenes (CPT9) were designed for colorimetric and fluorometric detection of lysophosphatidic acid (LPA) based on electrostatic interaction, hydrophobic interaction, and hydrogen bonding. Other negatively charged species gave nearly no interference, and the detection limit reached to 0.6 μM, which is below the requisite detection limits for LPA in human plasma samples. The appealing performance of CPT9 was demonstrated to originate from the multipoint interaction-induced conformational change of conjugated backbone and weakened electron transfer effect. To our best knowledge, this is the first polythiophene based optical sensor which displays emission peak red-shift followed with fluorescence enhancement.


Dirac Nodal Lines and Tilted Semi-Dirac Cones Coexisting in a Striped Boron Sheet.
The enchanting Dirac fermions in graphene stimulated us to seek other 2D Dirac materials, and boron monolayers may be a good candidate. So far, a number of monolayer boron sheets have been theoretically predicted, and three have been experimentally prepared. However, none of intrinsic sheets possess Dirac electrons near the Fermi level. Herein, by means of density functional theory computations, we identified a new boron monolayer, namely, hr-sB, with two types of Dirac fermions coexisting in the sheet: One type is related to Dirac nodal lines traversing Brillouin zone (BZ) with velocities approaching 106 m/s, and the other is related to tilted semi-Dirac cones with strong anisotropy. This newly predicted boron monolayer consists of hexagon and rhombus stripes. With an exceptional stability comparable to the experimentally achieved boron sheets, it is rather optimistic to grow hr-sB on some suitable substrates such as the Ag (111) surface.


Glomerular basement membrane: lamina rara, lamina densa.
Electron immunohistochemical and histochemical studies of glomerular and tubular basement membranes were undertaken to elucidate the relationship between lamina rara and lamina densa. Our results indicate that the lamina rara is not a fixation artifact and it has common antigenic determinants with lamina densa (type IV collagen antigens). Therefore, lamina rara has to be considered an integral component of basement membranes, and biochemical preparations containing only lamina densa should not be considered representative of the whole basement membrane.


Alteration of angiogenesis in Helicobacter heilmannii-induced mucosa-associated lymphoid tissue lymphoma: interaction with c-Met and hepatocyte growth factor.
The hepatocyte growth factor (HGF)/c-Met pathway has attracted attention in the formation of malignant tumors, as HGF secreted from the microcirculatory components as well as residing macrophages has been suggested to act on the c-Met receptors of cancer cells to decrease apoptosis and increase proliferation, invasion, and metastasis. The present study was undertaken to elucidate the interaction of the gastric, hepatic, and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma induced by Helicobacter heilmannii infection with c-Met and HGF. C57BL/6 female mice, infected with H. heilmannii for 3 months were used. The localization of the HGF, c-Met, and HGF activator immunoreactivities was observed by the indirect immunohistochemical methods. In addition, the effect of c-Met antibody and c-Met inhibitor, PHA-665752, was also investigated. c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of the antibody against c-Met or the c-Met inhibitor to the infected mice induced the significant suppression of hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size, while the active caspase 3 positive cells markedly decreased in the gastric, hepatic, and pulmonary MALT lymphoma after the treatment with the c-Met antibody or the c-Met antagonist. HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the MALT lymphoma after H. heilmannii infection.


Postural change of IOP in normal persons and in patients with primary wide open-angle glaucoma and low-tension glaucoma.
The values of intraocular pressure (IOP) measurements by an Alcon pneumatic tonometer and a Goldmann applanation tonometer were found to be close, with a correlation coefficient of 0.92. Measured by the pneumatonograph the IOP after 30 minutes in the supine position was highest in normal persons, in patients with primary wide open-angle glaucoma and low-tension glaucoma. The greatest difference in IOP between subjects sitting and supine was observed in patients with low-tension glaucoma.


Measurement of cerebral blood flow, cerebral blood volume, and cerebral capillary permeability in glioma-bearing rats.
Effective chemotherapy and radiation therapy of brain tumors require knowledge of the cerebral circulatory dynamics involved. In this study, regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), and regional cerebral capillary permeability (rCP) were measured in Wistar King Aptekman rats bearing experimental KEG-1 gliomas. These parameters were assessed by autoradiography with 14C-iodoantipyrine, 14C-deoxyglucose-labeled red blood cells, and 14C-aminoisobutyric acid, respectively. rCBF within the tumor was approximately one third that in the contralateral cortex and was consistently higher in the periphery than in the center of the tumor. In the periphery of the tumor, rCBV was approximately twice that in the contralateral cortex, but it was very low in the center of the tumor. Throughout the tumor, rCP was sharply increased relative to that measured in the contralateral cortex, and the increase was especially pronounced in the central portion. Thus, rCBF, rCBV, and rCP each appeared to vary within the tumor, implying that the combined use of lipid- and water-soluble chemotherapeutic agents is reasonable. Measurement of these parameters may also provide indices of radiation sensitivity.


Diagnostic Utility of Three-Dimensional Rotational Angiography in Congenital Cardiac Catheterization.
We evaluated the diagnostic utility of the three modalities of three-dimensional rotational angiography (3DRA): rotational angiography (RA), multiplanar reformat (MPR) and three-dimensional angiographic reconstruction (3D-R) in pediatric cardiac catheterization. The 3DRA studies were classified by anatomy of interest based on our injection protocol: pulmonary arteries (PA), aorta, cavopulmonary connection (CPC), and others. Retrospective review of 3DRA images by two reviewers for each modality was conducted with grading as inferior, similar, or superior in comparison with the diagnostic quality of fixed-plane angiography (FPA). The percentages of grades for each modality were averaged. Weighted kappa statistic was used to evaluate inter-rater reliability. In total, 114 3DRA studies were performed on 87 patients between August 2010 and March 2012. Median age was 2.7 years (1 day-48.4 years) and median weight 12.1 kg (3.6-106.5 kg). For RA: 79.4 % of the studies were of diagnostic quality and 52.2 % were superior; 3D-R: 82 % were of diagnostic quality and 65.8 % were superior; and MPR: 83.5 % were of diagnostic quality and 63 % were superior. Overall 3DRA technologies (RA, 3D-R, MPR) were of diagnostic quality or better in 111/114 (97.4 %) studies and 103/114 (90.4 %) were judged superior. Most common reasons for inferior grading were limited opacification and metallic artifact. In pediatric cardiac catheterization, 3DRA imaging was of diagnostic quality and frequently provided additional clinically relevant data when compared to FPA.


Oral Tori in Chronic Peritoneal Dialysis Patients.
The pathogenesis of oral tori has long been debated and is thought to be the product of both genetic and environmental factors, including occlusal forces. Another proposed mechanism for oral tori is the combination of biomechanical forces, particularly in the oral cavity, combined with cortical bone loss and trabecular expansion, as one might see in the early stages of primary hyperparathyroidism. This study investigated the epidemiology of torus palatinus (TP) and torus mandibularis (TM) in peritoneal dialysis patients, and analyzed the influences of hyperparathyroidism on the formation of oral tori. In total, 134 peritoneal dialysis patients were recruited between July 1 and December 31, 2015 for dental examinations for this study. Patients were categorized into two subgroups based on the presence or absence of oral tori. Demographic, hematological, biochemical, and dialysis-related data were obtained for analysis. The prevalence of oral tori in our sample group was high at 42.5% (57 of 134), and most patients with oral tori were female (61.4%). The most common location of tori was TP (80.7%), followed by TP and TM (14.0%), then TM (5.3%). All 54 TP cases were at the midline, and most were <2 cm (59.3%), flat (53.7%), and located in the premolar region (40.7%). Of the 11 TM cases, all were bilateral and symmetric, mostly <2 cm (81.9%), lobular (45.4%), and located at premolar region (63.6%). Interestingly, patients with oral tori had slightly lower serum levels of intact parathyroid hormones than those without oral tori, but the difference was not statistically significant (317.3±292.0 versus 430.1±492.6 pg/mL, P = 0.126). In addition, patients with oral tori did not differ from patients without tori in inflammatory variables such as serum high sensitivity C-reactive protein levels (6.6±8.2 versus 10.3±20.2 mg/L, P = 0.147) or nutritional variables such as serum albumin levels (3.79±0.38 versus 3.77±0.45 g/dL, P = 0.790). Furthermore, there were no differences between patients with and without oral tori in dialysis adequacy (weekly Kt/Vurea, 2.14±0.39 versus 2.11±0.33, P = 0.533; weekly creatinine clearance rate, 59.31±17.58 versus 58.57±13.20 L/1.73 m2, P = 0.781), or peritoneal membrane transporter characteristics (P = 0.098). Secondary hyperparathyroidism does not contribute to the formation of tori in peritoneal dialysis patients. Further studies are warranted.


Noise-induced symmetry breaking in a network of excitable ecological systems.
Noise-induced symmetry breaking has barely been unveiled on the ecological grounds, though its occurrence may elucidate mechanisms responsible for maintaining biodiversity and ecosystem stability. Here, for a network of excitable consumer-resource systems, we show that the interplay of network structure and noise intensity manifests a transition from homogeneous steady states to inhomogeneous steady states, resulting in noise-induced symmetry breaking. On further increasing the noise intensity, there exist asynchronous oscillations, leading to heterogeneity crucial for maintaining a system's adaptive capacity. The observed collective dynamics can be understood analytically in the framework of linear stability analysis of the corresponding deterministic system.


[Protective effects of liquid extract of Lishi No.5 formula against excitatory amino acid damage of neurons].
To investigate the effect of liquid extract of Lishi No.5 formula in protecting the neurons from excitatory amino acid injury. Cultured neonatal SD rat hippocampal neurons were treated with 300 micromol/L NMDA and 5 micromol/L glycine for 10 min, and the conditioned culture medium was replaced by normal culture medium. After cell culture for 18 h, MTT assay and Hoechst33258 staining were performed to examine the cell survival rate and cell apoptosis, respectively. Intracellular free calcium concentration was assayed by image analysis of the calcium signals with confocal microscope and Fluo-3/AM indicator. The survival rate of the cultured cell was significantly decreased in response to treatment with 300 micromol/L NMDA and 5 micromol/L glycine, but the effects were obviously reversed by treatment with 0.5 mg/ml liquid extract from Lishi No.5 formula. Intracellular free calcium concentration was significantly increased by 10 micromol/L NMDA, which was remarkably inhibited by the liquid extract. The effects of NMDA on intracellular free calcium was abolished by pretreatment of the cells with MK-801 for 10 min, whereas the liquid extract significantly lowered the antagonizing effect of MK-801. Lishi No.5 formula protects the neurons from toxicity by excitatory amino acids possibly by alleviating intracellular free calcium overload induced by these amino acids.


Cationization of lignocellulosic fibers with betaine in deep eutectic solvent: Facile route to charge stabilized cellulose and wood nanofibers.
In this study, a deep eutectic solvent (DES [based on triethylmethylammonium chloride (TEMA) and imidazole]) was used as a reaction medium for cationization of cellulose fibers with trimethylglycine (betaine) hydrochloride in the presence of p-Toluenesulfonyl (tosyl) chloride. Cellulose betaine ester with a cationic charge up to 1.95 mmol/g was obtained at mild reaction conditions (four hours at 80 °C). The reaction was further demonstrated in the fabrication of cationic cellulose nanofibers (CCNFs) by a mild mechanical disintegration of cationized cellulose. In addition to CCNFs, cationic wood nanofibers (CWNFs) were produced directly from groundwood pulp (GWP) with a high lignin content (27 w%). Individualized CCNFs and CWNFs had a fiber diameter of 4.7 ± 2.0 and 3.6 ± 1.3 nm, respectively, whereas some larger fiber aggregates (diameter below 200 nm) were also observed, especially in the case of CWNFs.


Practical determination of the rheological behavior of pasty biosolids.
In this paper, we demonstrate that the rheological behavior of pasty sewage sludges, regardless of origin, treatment or composition, follows a Herschel-Bulkley model. The yield stress and solid volume fraction are found to be the only two distinctive rheological characteristics of these materials. By scaling the shear rate and the shear stress with two parameters depending only on the yield stress and the solid fraction, the flow curves of 48 pasty sludges all fall along a unique dimensionless master curve. This result may be used in practice to determine, from simple, independent measurements, the rheological behavior of any pasty sludge: the yield stress can be measured with the help of the 'slump test' and the solid concentration determined from the organic and mineral matter contents. The results obtained with this technique are in very good agreement with those obtained by direct rheometry.


The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries.
The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival. p140Cap dampens ERBB2-positive tumour cell progression, impairing tumour onset and growth in the NeuT mouse model, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. One major mechanism is the ability of p140Cap to interfere with ERBB2-dependent activation of Rac GTPase-controlled circuitries. Our findings point to a specific role of p140Cap in curbing the aggressiveness of ERBB2-amplified breast cancers and suggest that, due to its ability to impinge on specific molecular pathways, p140Cap may represent a predictive biomarker of response to targeted anti-ERBB2 therapies.


[Dissemination of blaIMP-8 among Enterobacteriaceae isolates from a Buenos Aires Hospital].
From August 2008 to December 2011, six metallo-β-lactamase-producing isolates, four Enterobacter cloacae, one Klebsiella oxytoca and one Citrobacter freundii, were detected at Hospital Interzonal General de Agudos "Evita" in Lanús. All six isolates showed multiresistant profiles and the presence of the blaIMP-8 gene. Five isolates also expressed PER-2 extended spectrum β-lactamase. The blaIMP-8 gene was found as the first cassette in a class 1 integron. However, the 3´ conserved sequence could not be detected in three isolates. In all cases, blaIMP-8 was transferred by conjugation to azide-resistant Escherichia coli J53. PFGE analysis revealed that the four E. cloacae isolates were not genetically related. These are the first metallo-β-lactamases detected in this institution and our results suggest a possible intra- and inter-species horizontal dissemination of blaIMP-8.


Cricket ball trauma causing temporal space abscess: report of a case.
A 9-year-old boy reported with swelling on right side of the face after injury by a cricket ball while fielding. There was a history of hot fermentation after which the swelling increased in size leading to a temporal space abscess. The patient underwent incision and drainage with uneventful healing and was followed-up for a period of 7 years.


Perfusion enhanced polydimethylsiloxane based scaffold cell culturing system for multi-well drug screening platform.
Conventional two-dimensional cultures in monolayer and sandwich configuration have been used as a model for in vitro drug testing. However, these culture configurations do not present the actual in vivo liver cytoarchitecture for the hepatocytes cultures and thus they may compromise the cells liver-specific functions and their cuboidal morphology over longer term culture. In this study, we present a three-dimensional polydimethylsiloxane (PDMS) scaffold with interconnected spherical macropores for the culturing of rat liver cells (hepatocytes). The scaffolds were integrated into our perfusion enhanced bioreactor to improve the nutrients and gas supply for cell cultures. The liver-specific functions of the cell culture were assessed by their albumin and urea production, and the changes in the cell morphology were tracked by immunofluorescence staining over 9 days of culture period. N-Acetyl-Para-Amino-Phenol (acetaminophen) was used as drug model to investigate the response of cells to drug in our scaffold-bioreactor system. Our experimental results revealed that the perfusion enhanced PDMS-based scaffold system provides a more conducive microenvironment with better cell-to-cell contacts among the hepatocytes that maintains the culture specific enzymatic functions and their cuboidal morphology during the culturing period. The numerical simulation results further showed improved oxygen distribution within the culturing chamber with the scaffold providing an additional function of shielding the cell cultures from the potentially detrimental fluid induced shear stresses. In conclusion, this study could serve a crucial role as a platform for future preclinical hepatotoxicity testing.


How to face a patient with benzodiazepine dependence in primary health care? Strategies for withdrawal.
Benzodiazepines are widely used in primary health care, and their prolonged use is an important problem given the medical consequences particularly in older adults, such as dependence, cognitive impairment, and risk of falls, among others. Primary care doctors generally have few tools to help with managing withdrawal from benzodiazepines. We conducted a review of the best available evidence on practical strategies to avoid dependence at the time of the initial prescription, and to help the patient with prolonged and probably dependent use. We found ten relevant systematic reviews showing evidence in favor of the use of multifaceted prescription strategies, gradual dose reduction, standardized letters, standardized counseling, pharmacotherapy and cognitive behavioral psychotherapy. For benzodiazepine withdrawal, a simple strategy that can be effective and long-lasting is to inform patients of the need to reduce consumption, giving them in writing the withdrawal guideline, indicating the possible effects of withdrawal and its solution. Given the available evidence, an integrated and step-by-step model is proposed for the management of the benzodiazepine user, from prescription to withdrawal.


Traditional and ultrasound physical examinations: a hybrid approach to improve clinical care.
Point-of-care ultrasonography, which is performed at the bedside by physicians who are not specialists in imaging, has become possible thanks to recent technological advances that have allowed for a device with greater portability while maintaining image quality. The increasing use of point-of-care ultrasonography in different specialties has made it possible to expand physical examinations, make timely decisions about the patients and allows the performance of safer medical procedures. In this review, three cases from our experience are presented that highlight the use of point-of-care ultrasonography by clinicians. Bedside ultrasonography is a convenient modality used in a clinical setting to aid in early diagnosis of several common conditions. It is suggested that a hybrid approach of physical examination and point-of-care ultrasonography in the everyday clinical practice is an inevitable change of paradigm that is improving quality of care in a variety of clinical settings.


The new pharmacology of somatostatin and its multiple receptors.
A large number of somatostatin analogs taken from several major families of peptides has been examined for binding to three newly discovered somatostatin receptors (SSTR1, 2 and 3) transfected and expressed in various cell membrane preparations. Extremely potent octapeptide analogs related to and including octreotide (SMS 201-995) were found to bind with high affinity to SSTR2 receptors, which appear to be primarily of a pituitary type, and indeed affinities correlated extremely well with inhibitory potencies for inhibition of GH release from rat pituitary cells. Several new octapeptides were discovered with affinities and in vitro potencies greater than previously reported analogs. Whereas all of the octapeptides had much lower affinity for SSTR1 and SSTR3 receptors, which appear to be primarily present in the CNS, high affinity and highly specific ligands for the latter were found within a series of linear somatostatin analogs. No analogs were found which had high affinity for SSTR1 receptors. These studies confirm the feasibility of designing ligands which are specific for the various somatostatin receptors. These should provide useful tools for delineating the physiological roles of these receptors, specifically labeling certain receptors, and developing therapeutically interesting compounds targeted towards specific physiological events.


The role of Runx2 in facilitating autophagy in metastatic breast cancer cells.
Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress, and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker. The electron and confocal microscopic analyses were utilized to identify alterations in autophagic vesicles. The Runx2 knockdown cells accumulate LC3B-II protein and autophagic vesicles due to reduced turnover. Interestingly, Runx2 promotes autophagy by enhancing trafficking of LC3B vesicles. Our mechanistic studies revealed that Runx2 promotes autophagy by increasing acetylation of α-tubulin sub-units of microtubules. Inhibiting autophagy decreased cell adhesion and survival of Runx2 knockdown cells. Furthermore, analysis of LC3B protein in clinical breast cancer specimens and tumor xenografts revealed significant association between high Runx2 and low LC3B protein levels. Our studies reveal a novel regulatory mechanism of autophagy via Runx2 and provide molecular insights into the role of autophagy in metastatic cancer cells.


Association of N-ethylmaleimide sensitive fusion (NSF) protein and soluble NSF attachment proteins-alpha and -gamma with glucose transporter-4-containing vesicles in primary rat adipocytes.
To investigate the role of N-ethylmaleimide sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAP)-containing fusion complexes in glucose transporter-4 (GLUT4) membrane trafficking, the subcellular distributions of NSF, alpha-SNAP, and gamma-SNAP in primary rat adipocytes were determined. A large fraction of the NSF and SNAPs were associated with intracellular membranes, distributed between the low-density microsomes (LDM) and high-density microsomes. Very little of the NSF and SNAPs were associated with the plasma membrane fraction. This distribution did not change after insulin stimulation. Approximately 75% of the NSF and SNAPs in the LDM fraction were coimmunoprecipitated with 85% of the GLUT4 and 60% of the vesicle associated membrane proteins (VAMPs; synaptobrevins) VAMP-2 and cellubrevin in anti-GLUT4 immunoadsorptions. In contrast to NSF and the SNAPs, the beta-coatomer protein (beta-COP) found in the LDM fraction was excluded from GLUT4 vesicles. When LDM fractions were solubilized with Thesit (octaethylene glycol dodecyl ether) or Triton X-100, approximately 40% of the alpha-SNAP was colocalized with NSF on glycerol gradients in large (approximately 20S), ATP-sensitive complexes. VAMP-2 and cellubrevin are concentrated in the LDM fractions and in GLUT4 vesicles; both were excluded from these complexes. These data suggest that the steady state association of NSF and the SNAPs with GLUT4 vesicles and cell membranes is independent of the formation of fusion complexes.


Truncated Dyrk1A aggravates neuronal apoptosis by inhibiting ASF-mediated Bcl-x exon 2b inclusion.
Aggravated neuronal loss, caused mainly by neuronal apoptosis, is observed in the brain of patients with Alzheimer's disease (AD) and animal models of AD. A truncated form of Dual-specific and tyrosine phosphorylation-regulated protein kinase 1A (Dyrk1A) plays a vital role in AD pathogenesis. Downregulation of anti-apoptotic Bcl-xL is tightly correlated with neuronal loss in AD. However, the molecular regulation of neuronal apoptosis and Bcl-x expression by Dyrk1A in AD remains largely elusive. Here, we aimed to explore the role and molecular mechanism of Dyrk1A in apoptosis. Cell Counting Kit-8 (CCK8), flow cytometry, and TdT-mediated dUTP Nick-End Labeling (TUNEL) were used to check apoptosis. The cells, transfected with Dyrk1A or/and ASF with Bcl-x minigene, were used to assay Bcl-x expression by RT-PCR and Western blots. Co-immunoprecipitation, autoradiography, and immunofluorescence were conducted to check the interaction of ASF and Dyrk1A. Gene set enrichment analysis (GSEA) of apoptosis-related genes was performed in mice overexpressing Dyrk1A (TgDyrk1A) and AD model 5xFAD mice. Dyrk1A promoted Bcl-xS expression and apoptosis. Splicing factor ASF promoted Bcl-x exon 2b inclusion, leading to increased Bcl-xL expression. Dyrk1A suppressed ASF-mediated Bcl-x exon 2b inclusion via phosphorylation. The C-terminus deletion of Dyrk1A facilitated its binding and kinase activity to ASF. Moreover, Dyrk1a1-483 further suppressed the ASF-mediated Bcl-x exon 2b inclusion and aggravated apoptosis. The truncated Dyrk1A, increased Bcl-xS, and enrichment of apoptosis-related genes was observed in the brain of 5xFAD mice. We speculate that increased Dyrk1A and truncated Dyrk1A may aggravate neuronal apoptosis by decreasing the ratio of Bcl-xL/Bcl-xS via phosphorylating ASF in AD.


Complications of central lines in neonates admitted to a level III Neonatal Intensive Care Unit.
To investigate the incidence and risk factors for central line related complications in neonates. A retrospective cohort study of infants who underwent central line (CL) placement, from 1 July 2014 to 31 June 2016, was conducted in Neonatal Intensive Care Unit of Centro Hospitalar de São João. Infants hospitalized more than 2 d and CLs placed for more than 24 h were included. Patients' demographic characteristics, hospital data, and information on CLs were collected. Indwelling complications were compared between infant groups and types of CL inserted. A total of 400 CLs were inserted in 240 infants with a CL utilization ratio of 0.64. Overall CL complication rate was 29.6 per 1000 catheter days. Of all complications, central line-associated bloodstream infection had the highest incidence (12.4 per 1000 catheter days). Infiltration was the most reported mechanical complication. Non-umbilical catheters showed a significantly higher incidence of complications than umbilical ones. Low gestational age, low birth weight, prolonged catheter stay, long duration of total parenteral nutrition, and peripherally inserted central catheter placement were associated with a higher risk of indwelling complication. The implementation of measures to prevent catheter-related complications must be a priority in care of vulnerable neonates.


Clinical profile and genetic correlation of patients with spinocerebellar ataxia: A study from a tertiary care centre in Eastern India.
Progressive cerebellar ataxia inherited by autosomal dominant transmission is known as Spino Cerebellar Ataxia (SCA). To look for various clinical profile and molecular genetics of patients with SCAs and their phenotype-genotype correlation of patients with SCAs. This was a cross-sectional study conducted at Bangur Institute of Neurosciences, Kolkata from June 2010 to April 2013. We selected patients from the neurogenetic clinic of our institute and performed genetic test for SCA 1, 2, 3, 6 and 12. The diagnosis was based on suggestive clinical features and positive genetic study, done by polymerase chain reaction. 83 patients were tested for trineucleotide repeats and turned out 45 positive for the mentioned SCAs. We found 13(28.9%) SCA-1, 18(40%) SCA-2, 7(15.6%) SCA-3, 6(13.3) SCA-6 and 1(2.2%) SCA-12 patients. Half of the remaining 38 patients had positive family history. The mean age of onset were 38.46 years in SCA-1, 29.55 years in SCA-2, 38.43 years in SCA-3, 47.33 years in SCA-6. Slow saccades were observed in 7(53.8%) SCA-1, 17(94.4%) SCA-2, 4(57.1%) SCA-3, 3(50%) SCA-6 patients. Hyporeflexia was noticed in 5(27.8%) SCA-2 patients. Pyramidal tract involvement was found in 8(61.5%) SCA-1, 4(22.2%) SCA-2, 4(57.1%) SCA-3 and 1(16.7%) SCA-6 patients. Our study showed SCA-2 is the most common variety of SCA and genotypic-phenotypic correlation was observed in SCA-1,2,6 and 12 patients.


Approaches used by parents to keep their children safe at home: a qualitative study to explore the perspectives of parents with children aged under five years.
Childhood unintentional injury represents an important global health problem. Many unintentional injuries experienced by children aged under 5 years occur within the home and are preventable. The aim of this study was to explore the approaches used by parents of children under five in order to help prevent unintentional injuries in the home and the factors which influence their use. Understanding how parents approach risk-management in the home has important implications for injury practitioners. A multi-centre qualitative study using semi-structured interviews. A thematic approach was used to analyse the data. Sixty five parents of children aged under 5 years, from four study areas were interviewed: Bristol, Newcastle, Norwich and Nottingham. Three main injury prevention strategies used by parents were: a) Environmental such as removal of hazards, and use of safety equipment; b) parental supervision; and c) teaching, for example, teaching children about safety and use of rules and routine. Strategies were often used in combination due to their individual limitations. Parental assessment of injury risk, use of strategy and perceived effectiveness were fluid processes dependent on a child's character, developmental age and the prior experiences of both parent and child. Some parents were more proactive in their approach to home safety while others only reacted if their child demonstrated an interest in a particular object or activity perceived as being an injury risk. Parents' injury prevention practices encompass a range of strategies that are fluid in line with the child's age and stage of development; however, parents report that they still find it challenging to decide which strategy to use and when.


Awareness and Knowledge of Glaucoma and their Associated Factors among People Visiting a Tertiary Level Hospital in Central Nepal.
Background Glaucoma is one of the major causes of irreversible blindness globally. Almost 60 million people globally are affected by glaucoma making it the second leading cause of blindness worldwide. Diagnosis of glaucoma early on is vital for timely management and prevention of blindness. However, it is challenging to diagnose it early because it is asymptomatic in the initial stage, and there is also the dearth of appropriate screening tools. Awareness, knowledge, and beliefs are believed to influence the treatment-seeking behavior of people as well as their uptake of services. Objective To assess the awareness and knowledge about glaucoma among general patients and patient attendants visiting Dhulikhel Hospital. Method We conducted a cross sectional quantitative study among general patients visiting Dhulikhel Hospital. We collected data using face-to-face interviews with semistructured questionnaires. We analyzed data in R version 4.0.3 (2020-10-10). We presented numerical variables as mean and standard deviation whereas categorical variables as frequency and percentage. We determined factors associated with awareness and knowledge of glaucoma using logistic regression analysis and estimated adjusted odds ratio (AOR) with 95% confidence interval. Result Of 379 participants, a total of 214 (56.5%) participants had heard about glaucoma. Out of the participants who heard about glaucoma, the mean knowledge score was 48.3±21.7 and 53.3% had good knowledge on glaucoma. The odds of having heard about glaucoma were two percent lower (AOR=0.98; 95%CI: 0.97-0.99; p-value 0.036) in the older participants compared to one year younger participant, 1.98 (95%CI:1.01-3.86; p-value 0.046) times higher among literates and 2.79 (95%CI: 1.76- 4.41; p-value < 0.001) times among participants with previous ocular examination. The odds of having good knowledge was 1.94 (95%CI: 1.10-3.42; p value 0.021) times among participants with previous ocular examinations. Conclusion The knowledge and awareness regarding glaucoma in a hospital-visiting population in central Nepal was low. Half of the participants were unaware of the disease glaucoma and half of the participants who heard of the glaucoma had poor knowledge on glaucoma.


The validity of self-reported vs. measured body weight and height and the effect of self-perception.
The objective was to assess the validity of self-reported body weight and height and the possible influence of self-perception of body mass index (BMI) status on the actual BMI during the adolescent period. This cross sectional study was conducted on 3918 high school students. Accurate BMI perception occurred when the student's self-perception of their BMI status did not differ from their actual BMI based on measured height and weight. Agreement between the measured and self-reported body height and weight and BMI values was determined using the Bland-Altman metod. To determine the effects of "a good level of agreement", hierarchical logistic regression models were used. Among male students who reported their BMI in the normal region, 2.8% were measured as overweight while 0.6% of them were measured as obese. For females in the same group, these percentages were 1.3% and 0.4% respectively. Among male students who perceived their BMI in the normal region, 8.5% were measured as overweight while 0.4% of them were measured as obese. For females these percentages were 25.6% and 1.8% respectively. According to logistic regression analysis, residence and accurate BMI perception were significantly associated with "good agreement" (p ≤ 0.001). The results of this study demonstrated that in determining obesity and overweight statuses, non-accurate weight perception is a potential risk for students.


[Hemodynamics after reconstruction of the outflow tract in tetralogy of Fallot. Infundibulectomy, patchreconstruction or valve rearing conduit (author's transl)].
The peak systolic pressure ratio PRV/PLV of the right and left ventricle after correction of the outflow tract (OFT) in Tetralogy of Fallot (TF) yields reliable dates about the efficiency of the outflowtract correction and the probability of survival. In 110 patients (2 to 57 years) the ratio after correction PRV/PLV was measured and compared with different methods of reconstruction of the OFT. Infundibulectomy (54) pericard-patch insertion across the pulmonary valve ring (43) and a valve bearing Hancock-Conduit (13) were used. To calculate the statistical differences the U-test according to Wilcoxon, Whitney, Mann was applied on the 95% level. Moreover the pulmonary insufficiency (PI) was evaluated in 60 patients within 15 to 60 days, after correction with a videodensitometric method. There is no PI after use of a valve bearing Hancock-Conduit. In severe TF a valve bearing Hancock-Conduit is hemodynamically superior to a pericard-patchreconstruction of OFT to relief right ventricular hypertension, particularly if hypoplasia of pulmonary vessels and pulmonary vascular disease after shunt-operation is present.


The prognosis of breech delivered singleton low birth weight infants.
An estimate of the probability of long term neurological sequelae in breech delivered low birth weight infants is an important factor in deciding on the method of delivery in breech presentation. From the hospital records we have identified those infants who during the years 1973 and 1974 were live born of low birth weight (under 2500 g) and who were delivered by the breech. Of 51 infants, 36 survived the neonatal period. Two have died, one of multiple congenital abnormalities and one of accidental, two left the country during their second of life at which time they were known to be developing normally. Two remained untraced. The remaining 30 are all living locally, they are all neurologically normal and are attending ordinary schools. In the absence of intensive methods of neonatal care the risk to the breech delivered low birth weight baby is of neonatal death rather than of long term neurological sequelae.


Validation of a 3D perfused cell culture platform as a tool for humanised preclinical drug testing in breast cancer using established cell lines and patient-derived tissues.
3D cell culture models of cancer are currently being developed to recapitulate in vivo physiological conditions and to assess therapeutic responses. However, most models failed to incorporate the biochemical and biophysical stimuli from fluid flow. In this study, a three-dimensional scaffold, SeedEZ was applied within the PerfusionPal perfused culture system to investigate how perfusion, and blood-like oxygen delivery influenced breast cancer cell growth and their responses to a commonly used breast cancer drug tamoxifen. Our results showed that breast cancer cells could be maintained over 3 weeks in PerfusionPal with increased cell viability compared to static 3D culture in fully humanised conditions. This platform also supported examining the effect of tamoxifen on breast cancer cell lines and in primary patient-derived breast cancer samples. Future work is warranted to further the adaption for fully humanised assessment of drug effectiveness in a patient personalized approach with the aim to reduce the burden of animal use in cancer research and increase the degree of human pre-clinical data translation to clinic.


Outcome of an HIV education program for primary care providers: Screening and late diagnosis rates.
Late HIV diagnosis remains one of the challenges in combating the epidemic. Primary care providers play an important role in screening for HIV infection. Our study aims to evaluate the relationship between knowledge and barriers to HIV testing and screening outcomes. The impact of an education program for primary care providers, towards improving HIV testing and late diagnosis rates, is also assessed. A self-administered questionnaire that was developed within the framework of the European project OptTEST was used to examine HIV knowledge and barriers to HIV testing scores before and after being involved in an HIV education program. A quasi-experimental design with pre- and post-intervention measures was performed to investigate its impact. We performed multivariable logistic regression analysis to assess the relationship between variables for the HIV testing offer. A total of 20 primary care centers and 454 primary care staff were included. Baseline OptTEST results showed that more knowledgeable staff offered an HIV test more frequently (OR 1.07; CI 95% 1.01-1.13; p = 0.027) and had lower barrier scores (OR 0.89; CI 95% 0.77-0.95; p = 0.005). Nurses had lower scores in knowledge-related items (OR 0.28; CI 95% 0.17-0.46; p<0.001), but higher scores in barrier-related items than physicians (OR 3.28; CI 95% 2.01-5.46; p<0.001). Specific centers with more knowledgeable staff members had a significant association with a greater level of new HIV diagnosis rates (OR 1.61; CI 95% 1.04-2.49; p = 0.032). After the intervention, we found that 12 out of 14 individual questions showed improved scores. In the 6 months after the training program, we similarly found a higher HIV testing rate (OR 1.19; CI 1.02-1.42; p = 0.036). This study highlights the association between knowledge and barriers to HIV testing, including HIV testing rates. It shows that it is possible to modify knowledge and reduce perceived barriers through educational programs, subsequently improving HIV screening outcomes.


Probiotic bacteria affect the composition of salivary pellicle and streptococcal adhesion in vitro.
The use of probiotic bacteria is increasing worldwide and at least some of them can transiently colonize the oral cavity. Several studies have shown that probiotic bacteria, which are often thought of in relation only to intestinal health, can also affect the oral ecology, but the mechanisms for this are largely unknown. The aim of this study was to investigate in vitro if the probiotic bacteria used in commercial products affect the protein composition of the salivary pellicle and the adherence of other oral bacteria. Salivary pellicle on hydroxyapatite and the adhesion of two oral streptococci, Streptococcus mutans and Streptococcus gordonii, were used as a model. Probiotic bacteria that bound to saliva-coated hydroxyapatite reduced the adhesion of S. mutans but the inhibitory effect on the adherence of S. gordonii was weaker. Salivary pellicle protein composition was modified by all the strains tested. The modifications in the pellicle affected the adherence of S. mutans but not of S. gordonii. Two of the proteins missing from the pellicles made of saliva-treated with the probiotic bacteria were identified as salivary agglutinin gp340 and salivary peroxidase. All bacterial strains bound salivary agglutinin gp340. The ability of the probiotic bacteria to degrade peroxidase was demonstrated with purified bovine lactoperoxidase and two of the probiotic strains. This in vitro study showed that probiotic strains used in commercial products may affect the oral ecology by specifically preventing the adherence of other bacteria and by modifying the protein composition of the salivary pellicle.


Reliability of the EchoMRI Infants System for Water and Fat Measurements in Newborns.
The precision and accuracy of a quantitative magnetic resonance (EchoMRI Infants) system in newborns were determined. Canola oil and drinking water phantoms (increments of 10 g to 1.9 kg) were scanned four times. Instrument reproducibility was assessed from three scans (within 10 minutes) in 42 healthy term newborns (12-70 hours post birth). Instrument precision was determined from the coefficient of variation (CV) of repeated scans for total water, lean mass, and fat measures for newborns and the mean difference between weight and measurement for phantoms. In newborns, the system accuracy for total body water (TBW) was tested against deuterium dilution (D2 O). In phantoms, the repeatability and accuracy of fat and water measurements increased as the weight of oil and water increased. TBW was overestimated in amounts >200 g. In newborns weighing 3.14 kg, fat, lean mass, and TBW were 0.52 kg (16.48%), 2.28 kg, and 2.40 kg, respectively. EchoMRI's reproducibility (CV) was 3.27%, 1.83%, and 1.34% for total body fat, lean mass, and TBW, respectively. EchoMRI-TBW values did not differ from D2 O; mean difference, -1.95 ± 6.76%, P = 0.387; mean bias (limits of agreement), 0.046 kg (-0.30 to 0.39 kg). The EchoMRI Infants system's precision and accuracy for total body fat and lean mass are better than established techniques and equivalent to D2 O for TBW in phantoms and newborns.


Is parental competitive ability in winter negatively affected by previous springs' family size?
Reproductive behavior cannot be understood without taking the local level of competition into account. Experimental work in great tits (Parus major) showed that (1) a survival cost of reproduction was paid in environments with high levels of competition during the winter period and (2) experimentally manipulated family size negatively affected the ability of parents to compete for preferred breeding boxes in the next spring. The fact that survival was affected in winter suggests that the competitive ability of parents in winter may also be affected by previous reproductive effort. In this study, we aim to investigate whether (1) such carryover effects of family size on the ability of parents to compete for resources in the winter period occurred and (2) this could explain the occurrence of a survival cost of reproduction under increased competition. During two study years, we manipulated the size of in total 168 great tit broods. Next, in winter, we induced competition among the parents by drastically reducing the availability of roosting boxes in their local environment for one week. Contrary to our expectation, we found no negative effect of family size manipulation on the probability of parents to obtain a roosting box. In line with previous work, we did find that a survival cost of reproduction was paid only in plots in which competition for roosting boxes was shortly increased. Our findings thus add to the scarce experimental evidence that survival cost of reproduction are paid under higher levels of local competition but this could not be linked to a reduced competitive ability of parents in winter.


Sublingual delivery of vaccines for the induction of mucosal immunity.
The mucosal surfaces are constantly exposed to incoming pathogens which can cause infections that result in severe morbidity and/or mortality. Studies have reported that mucosal immunity is important for providing protection against these pathogens and that mucosal vaccination is effective in preventing local infections. For many years, the sublingual mucosa has been targeted to deliver immunotherapy to treat allergic hypersensitivities. However, the potential of vaccine delivery via sublingual mucosal has received little attention until recently. Recent studies exploring such potential have documented the safety and effectiveness of sublingual immunization, demonstrating the ability of sublingual immunization to induce both systemic and mucosal immune responses against a variety of antigens, including soluble proteins, inter particulate antigens, and live-attenuated viruses. This review will summarize the recent findings that address the promising potential of sublingual immunization in proving protection against various mucosal pathogens.


Grain boundary pinning and glassy dynamics in stripe phases.
We study numerically and analytically the coarsening of stripe phases in two spatial dimensions, and show that transient configurations do not achieve long ranged orientational order but rather evolve into glassy configurations with very slow dynamics. In the absence of thermal fluctuations, defects such as grain boundaries become pinned in an effective periodic potential that is induced by the underlying periodicity of the stripe pattern itself. Pinning arises without quenched disorder from the nonadiabatic coupling between the slowly varying envelope of the order parameter around a defect, and its fast variation over the stripe wavelength. The characteristic size of ordered domains asymptotes to a finite value R(g) approximately lambda(0)epsilon(-1/2)exp(absolute value of a/square root of epsilon), where epsilon<<1 is the dimensionless distance away from threshold, lambda(0) the stripe wavelength, and a a constant of order unity. Random fluctuations allow defect motion to resume until a new characteristic scale is reached, function of the intensity of the fluctuations. We finally discuss the relationship between defect pinning and the coarsening laws obtained in the intermediate time regime.


Interhospital Transfer of Neurosurgical Patients: Implications of Timing on Hospital Course and Clinical Outcomes.
Interhospital transfer of neurosurgical patients is common; however, little is known about the impact of transfer parameters on clinical outcomes. Lower survival rates have been reported for patients admitted at night and on weekends in other specialties. Whether time or day of admission affects neurosurgical patient outcomes, specifically those transferred from other facilities, is unknown. To examine the impact of the timing of interhospital transfer on the hospital course and clinical outcomes of neurosurgical patients. All consecutive admissions of patients transferred to our adult neurosurgical service were retrospectively analyzed for a 1-year study period using data from a central transfer database and the electronic health record. Patients arrived more often at night (70.8%) despite an even distribution of transfer requests. The lack of transfer imaging did not affect length of stay, intervention times, or patient outcomes. Daytime arrivals had shorter total transfer time, but longer intenstive care unit and overall length of stay (8.7 and 11.6 days, respectively), worse modified Rankin Scale scores, lower rates of functional independence, and almost twice the mortality rate. Weekend admissions had significantly worse modified Rankin Scale scores and lower rates of functional independence. The timing of transfer arrivals, both by hour or day of the week, is correlated with the time to intervention, hospital course, and overall patient outcomes. Patients admitted during the weekend suffered worse functional outcomes and a trend towards increased mortality. While transfer logistics clearly impact patient outcomes, further work is needed to understand these complex relationships.


Molecular and MALDI-TOF identification of ticks and tick-associated bacteria in Mali.
Ticks are considered the second vector of human and animal diseases after mosquitoes. Therefore, identification of ticks and associated pathogens is an important step in the management of these vectors. In recent years, Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been reported as a promising method for the identification of arthropods including ticks. The objective of this study was to improve the conditions for the preparation of tick samples for their identification by MALDI-TOF MS from field-collected ethanol-stored Malian samples and to evaluate the capacity of this technology to distinguish infected and uninfected ticks. A total of 1,333 ticks were collected from mammals in three distinct sites from Mali. Morphological identification allowed classification of ticks into 6 species including Amblyomma variegatum, Hyalomma truncatum, Hyalomma marginatum rufipes, Rhipicephalus (Boophilus) microplus, Rhipicephalus evertsi evertsi and Rhipicephalus sanguineus sl. Among those, 471 ticks were randomly selected for molecular and proteomic analyses. Tick legs submitted to MALDI-TOF MS revealed a concordant morpho/molecular identification of 99.6%. The inclusion in our MALDI-TOF MS arthropod database of MS reference spectra from ethanol-preserved tick leg specimens was required to obtain reliable identification. When tested by molecular tools, 76.6%, 37.6%, 20.8% and 1.1% of the specimens tested were positive for Rickettsia spp., Coxiella burnetii, Anaplasmataceae and Borrelia spp., respectively. These results support the fact that MALDI-TOF is a reliable tool for the identification of ticks conserved in alcohol and enhances knowledge about the diversity of tick species and pathogens transmitted by ticks circulating in Mali.


Reduction of O2 to superoxide anion (O2.-) in water by heteropolytungstate cluster-anions.
Fundamental information concerning the mechanism of electron transfer from reduced heteropolytungstates (POM(red)) to O2, and the effect of donor-ion charge on reduction of O2 to superoxide anion (O2.-), is obtained using an isostructural series of 1e--reduced donors: alpha-X(n+)W12O40(9-n)-, X(n+) = Al3+, Si4+, P5+. For all three, a single rate expression is observed: -d[POM(red)]/dt = 2k12[POM(red)][O2], where k12 is for the rate-limiting electron transfer from POM(red) to O2. At pH 2 (175 mM ionic strength), k12 increases from 1.4 +/- 0.2 to 8.5 +/- 1 to 24 +/- 2 M-1s-1 as Xn+ is varied from P5+ (3red) to Si4+ (2red) to Al3+ (1red). Variable-pH data (for 1red) and solvent-kinetic isotope (KIE = kH/kD) data (all three ions) indicate that protonated superoxide (HO2.) is formed in two steps--electron transfer, followed by proton transfer (ET-PT mechanism--rather than via simultaneous proton-coupled electron transfer (PCET). Support for an outersphere mechanism is provided by agreement between experimental k12 values and those calculated using the Marcus cross relation. Further evidence is provided by the small variation in k12 observed when Xn+ is changed from P5+ to Si4+ to Al3+, and the driving force for formation of O2.- (aq), which increases as cluster-anion charge becomes more negative, increases by nearly +0.4 V (a decrease of >9 kcal mol-1 in DeltaG degrees ). The weak dependence of k12 on POM reduction potentials reflects the outersphere ET-PT mechanism: as the anions become more negatively charged, the "successor-complex" ion pairs are subject to larger anion-anion repulsions, in the order [(3(ox)3-)(O2.-)]4- < [(2(ox)4-)(O2.-)]5- < [(1(ox)5-)(O2.-)]6-. This reveals an inherent limitation to the use of heteropolytungstate charge and reduction potential to control rates of electron transfer to O2 under turnover conditions in catalysis.


Validation of the PREDICT Prognostication Tool in US Patients With Breast Cancer.
PREDICT is an online prognostication tool derived from breast cancer registry information on approximately 6,000 women treated in the United Kingdom that estimates the postsurgical treatment benefit of surgery alone, chemotherapy, trastuzumab, endocrine therapy, and/or adjuvant bisphosphonates in early-stage breast cancer. Our aim was to validate the PREDICT algorithm in predicting 5- and 10-year overall survival (OS) probabilities using real-world outcomes among US patients with breast cancer. A retrospective study was performed including women diagnosed with unilateral breast cancer in 2004 through 2012. Women with primary unilateral invasive breast cancer were included. Patients with bilateral or metastatic breast cancer, no breast surgery, or missing critical clinical information were excluded. Prognostic scores from PREDICT were calculated and external validity was approached by assessing statistical discrimination through area under time-dependent receiver-operator curves (AUC) and comparing the predicted survival to the observed OS in relevant subgroups. We included 708,652 women, with a median age of 58 years. Most patients were White (85.4%), non-Hispanic (88.4%), and diagnosed with estrogen receptor-positive breast cancer (79.6%). Approximately 50% of patients received adjuvant chemotherapy, 67% received adjuvant endocrine therapy, 60% underwent a partial mastectomy, and 59% had 1 to 5 axillary sentinel nodes removed. Median follow-up time was 97.7 months. The population's 5- and 10-year OS were 89.7% and 78.7%, respectively. Estimated 5- and 10-year median survival with PREDICT were 88.3% and 73.8%, and an AUC of 0.77 and 0.76, respectively. PREDICT performed most poorly in patients with high Charlson-Deyo comorbidity scores (2-3), where PREDICT overestimated OS. Sensitivity analysis by year of diagnosis and HER2 status showed similar results. In this prognostic study utilizing the National Cancer Database, the PREDICT tool accurately predicted 5- and 10-year OS in a contemporary and diverse population of US patients with nonmetastatic breast cancer.


Pituitary and gonadal response to LH releasing hormone administration in the female and male cheetah.
Luteinizing hormone releasing hormone (LHRH, 50 micrograms) or saline was administered (i.m.) to adult female and male cheetahs under anaesthesia to evaluate pituitary and gonadal response. Serum LH levels did not fluctuate over a 120-min sampling period in saline-treated animals. Serum LH concentrations were raised (P less than 0.05) in both female and male cheetahs after LHRH injection, the temporal response being similar to previously reported results in unanaesthetized, domestic carnivores. The magnitude of the LHRH-induced LH response was sex-dependent. Over a 120-min post-injection period both saline control and LHRH-induced LH levels were about twofold greater in males than females. Although LHRH had no acute influence on ovarian oestradiol-17 beta production in the female, serum testosterone levels were raised (P less than 0.05) in male cheetahs by 60 min after treatment. This study (1) provides introductory endocrine information on the cheetah, an endangered species, and (2) indicates that exogenous LHRH is effective in acutely altering pituitary (female) and pituitary/gonadal (male) function in an anaesthetized, non-domestic felid.


Intradural spinal metastases in patients with posterior fossa brain metastases from various primary cancers.
Intradural spinal metastases (ISM) are rare and primarily found associated with certain types of brain tumors like medulloblastoma. Their association with metastases to the brain has been recently described and seems to occur more frequently in posterior fossa lesions. We reviewed patients treated at Massachusetts General Hospital for posterior fossa brain metastases from various primary cancers, and evaluated the risk of concomitant or subsequent ISM. Of 104 patients, 10 developed ISM, with a 1-year actuarial risk of 25%. The risk was not significantly related to age, sex, histology, site of primary tumor or previous therapy. The study suggests that in patients with posterior fossa metastasis, particular attention should be paid to seeding via cerebrospinal fluid and drop metastases to the spinal cord.


A Phosphanyl-Phosphagallene that Functions as a Frustrated Lewis Pair.
Phosphagallenes (1 a/1 b) featuring double bonds between phosphorus and gallium were synthesized by reaction of (phosphanyl)phosphaketenes with the gallium carbenoid Ga(Nacnac) (Nacnac=HC[C(Me)N(2,6-i-Pr2 C6 H3 )]2 ). The stability of these species is dependent on the saturation of the phosphanyl moiety. 1 a, which bears an unsaturated phosphanyl ring, rearranges in solution to yield a spirocyclic compound (2) which contains a P=P bond. The saturated variant 1 b is stable even at elevated temperatures. 1 b behaves as a frustrated Lewis pair capable of activation of H2 and forms a 1:1 adduct with CO2 .


Effect of cobalt sorption on metal fractionation in anaerobic granular sludge.
A sequential extraction procedure was applied to two anaerobic methanogenic sludges (Eerbeek and Nedalco) to examine the speciation of micro- and macronutrients in the sludges after cobalt sorption by exposing the sludge to a 1 mM Co solution for 4 d at pH 7 and 30 degrees C. The effect of different physicochemical conditions on cobalt sorption was studied as well: effect of pH (6-8), effect of competition by a second trace element (Ni or Fe), modification of the granular matrix by glutaraldehyde or heat treatment, and EDTA (ethylenediaminetetraacetic acid) addition. Sorbed Co was found to distribute between the carbonates, organic matter + sulfides, and residual fractions. Cobalt adsorption resulted in an antagonistic interaction with other metals present in the granular matrix, evidenced by the solubilization of other trace elements (e.g., Ni, Cu, and Zn) as well as macronutrients (especially Ca and Fe). Modification of the sludge matrix by glutaraldehyde or heat treatment, or exposure to EDTA, led to serious modifications of the Co sorption capacity and strong interactions with multivalent cations (i.e., Ca(2+) and Fe(2+)).


Effects of dobutamine, dopamine, phenylephrine and noradrenaline on systemic haemodynamics and intestinal perfusion in isoflurane anaesthetised horses.
In the horse, effects of cardiovascular-active drugs on local perfusion of the gastrointestinal tract are poorly understood. To determine the effect of drugs commonly used to support blood pressure, on local intestinal blood flow and tissue oxygenation under isoflurane anaesthesia. In vivo randomised crossover experiment. Ten horses were anaesthetised with isoflurane. After 90 min of equilibration three doses (μg/kg bwt/min) of dobutamine (DOB 0.5/1/3), dopamine (DA 1/2/5), noradrenaline (NA 0.1/0.2/0.5) and phenylephrine (PHE 0.5/1/3) were infused for 15 min, in a randomised order, with a 45 min washout-period. Blood flow and tissue oxygenation (sO2 ) of jejunum, colon and stomach were measured using white light remission spectrophotometry and laser doppler flowmetry; heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO) were measured and systemic vascular resistance (SVR) calculated. Compared to baseline high dose dobutamine significantly increased CO, HR, MAP (P<0.001) and blood flow to the jejunum (+47 ± 26%, P = 0.001) and colon (+29 ± 15%, P<0.001) (mean ± s.d.). Dopamine (DA5) increased CO but decreased colonic blood flow (-39 ± 21% from baseline, P<0.001), as well as SVR and MAP compared to baseline (P<0.001). Noradrenaline had no significant influence on intestinal perfusion, but increased MAP and SVR from baseline (P<0.001). Phenylephrine (PHE3) caused a significant decrease in blood flow and sO2 , most profoundly at the colon compared to baseline (flow -44 ± 21%; sO2 -16 ± 3%, P<0.001), while MAP and SVR increased and CO and HR decreased (P<0.001). The measurement technique only allows for flow measurements in arbitrary units, which can limit comparability to other techniques. At the investigated doses dobutamine improved systemic and peripheral haemodynamics, while dopamine decreased MAP and peripheral perfusion. Noradrenaline increased MAP and SVR while peripheral blood flow was maintained, phenylephrine increased MAP, but reduced both local and systemic perfusion.


Breast cancer in Asian Americans in California, 1988-2013: increasing incidence trends and recent data on breast cancer subtypes.
In contrast to other US racial/ethnic groups, Asian Americans (AA) have experienced steadily increasing breast cancer rates in recent decades. To better understand potential contributors to this increase, we examined incidence trends by age and stage among women from seven AA ethnic groups in California from 1988 to 2013, and incidence patterns by subtype and age at diagnosis for the years 2009 through 2013. Joinpoint regression was applied to California Cancer Registry data to calculate annual percentage change (APC) for incidence trends. Incidence rate ratios were used to compare rates for AA ethnic groups relative to non-Hispanic whites (NHW). All AA groups except Japanese experienced incidence increases, with the largest among Koreans in 1988-2006 (APC 4.7, 95% CI 3.8, 5.7) and Southeast Asians in 1988-2013 (APC 2.5, 95% CI 0.8, 4.2). Among women younger than age 50, large increases occurred for Vietnamese and other Southeast Asians; among women over age 50, increasing trends occurred in all AA ethnic groups. Rates increased for distant-stage disease among Filipinas (2.2% per year, 95% CI 0.4, 3.9). Compared to NHW, Filipinas and older Vietnamese had higher incidence rates of some HER2+ subtypes. Breast cancer incidence rates have risen rapidly among California AA, with the greatest increases in Koreans and Southeast Asians. Culturally tailored efforts to increase awareness of and attention to breast cancer risk factors are needed. Given the relatively higher rates of HER2-overexpressing subtypes in some AA ethnicities, research including these groups and their potentially unique exposures may help elucidate disease etiology.


Photostable Solid Dispersion of Nifedipine by Porous Calcium Silicate.
Nifedipine (NIF) is a typical light-sensitive drug requiring protection from light during manufacture, storage, and handling of its dosage forms. The purpose of this study was to evaluate the utility of porous calcium silicate (PCS) for maintaining the photostability of NIF in a solid dispersion formulation. Adsorption solid dispersion (ASD) prepared using NIF and PCS as an amorphous formulation was more stable to light irradiation than a physical mixture of NIF and microcrystalline cellulose (a control physical mixture) as a crystalline formulation. In addition, PCS in physical mixtures with NIF adequately protected NIF from photodegradation, suggesting that this protective effect could be because of some screening effect by the porous structure of PCS blocking the passage of light reaching NIF in pores of PCS. These findings suggest that PCS is useful for improving the solubility and photostability of NIF in solid dispersion formulation.


Clinical and biological effects of recombinant interferon-beta administered intravenously daily in phase I trial.
Interferon-beta serine (IFN-beta ser) was administered intravenously (i.v.) daily for 14 days at doses of 3, 10, 30 X 10(6) units to 19 patients. In this Phase I trial, IFN-beta ser was tolerated without limiting fever or subjective toxicities. At 30 X 10(6) units, 3 patients developed hematologic toxicity and dose escalation was thus terminated. No patient developed detectable binding or neutralizing antibody to IFN-beta. A significant (p less than 0.006) increase in serum beta 2-microglobulin and a significant (less than 0.005) increase in 2',5'-oligoadenylate synthetase (2-5A) in peripheral mononuclear cells were identified. Increase in these proteins did not correlate with dose or with the disappearance of serum IFN over the first 5 h after injection. Two patients, one with renal carcinoma and one with melanoma, had objective responses. This trial further confirms safety and biological potency of this synthetic mutant of IFN-beta.


OLA1 gene sequencing in patients with BRCA1/2 mutation-negative suspected hereditary breast and ovarian cancer.
Of individuals with suspected hereditary breast and ovarian cancer (HBOC), approximately 30-70 % do not harbor mutations in either BRCA1 or BRCA2 gene, which suggests that these individuals have other genetic or epigenetic alterations that could lead to the onset of this hereditary disease. We have recently identified OLA1 as a novel BRCA1/BARD1-interacting protein. In the present study, we aimed to elucidate whether any genetic mutations in OLA1 are detected among patients with suspected HBOC without BRCA1 or BRCA2 mutations. Among 53 patients with suspected HBOC enrolled at Hoshi General Hospital, 23 patients without any BRCA1 or BRCA2 mutations were analyzed for OLA1 mutations. Genomic DNA was extracted from the peripheral blood samples. PCR and Sanger sequencing were performed to elucidate whether there were any mutations in any of the ten exons and flanking introns of the OLA1 gene. No germline sequence variation was detected in the OLA1 gene among the 23 patients enrolled in this study. No germline mutations were found in the OLA1 gene among the cohort of patients with suspected HBOC without BRCA1 or BRCA2 mutations. Further studies are needed to clarify whether other mutations/epigenetic alterations are involved in the pathogenesis of BRCA1 or BRCA2 mutation-negative inherited disease with breast or ovarian cancer.


Artificial intelligence in radiology: decision support systems.
Computer-based systems that incorporate artificial intelligence techniques can help physicians make decisions about their patients' care. In radiology, systems have been developed to help physicians choose appropriate radiologic procedures and to formulate accurate diagnoses. These decision support systems use techniques such as rule-based reasoning, artificial neural networks, hypertext, Bayesian networks, and case-based reasoning. This article reviews these artificial intelligence techniques, describes their application in radiology, and discusses the role that decision support systems may play in radiology's future.


TomoAlign: A novel approach to correcting sample motion and 3D CTF in CryoET.
TomoAlign is a software package that integrates tools to mitigate two important resolution limiting factors in cryoET, namely the beam-induced sample motion and the contrast transfer function (CTF) of the microscope. The package is especially focused on cryoET of thick specimens where fiducial markers are required for accurate tilt-series alignment and sample motion estimation. TomoAlign models the beam-induced sample motion undergone during the tilt-series acquisition. The motion models are used to produce motion-corrected subtilt-series centered on the particles of interest. In addition, the defocus of each particle at each tilt image is determined and can be corrected, resulting in motion-corrected and CTF-corrected subtilt-series from which the subtomograms can be computed. Alternatively, the CTF information can be passed on so that CTF correction can be carried out entirely within external packages like Relion. TomoAlign serves as a versatile tool that can streamline the cryoET workflow from initial alignment of tilt-series to final subtomogram averaging during in situ structure determination.


Analysis of Driver Evasive Maneuvering Prior to Intersection Crashes Using Event Data Recorders.
Intersection crashes account for over 4,500 fatalities in the United States each year. Intersection Advanced Driver Assistance Systems (I-ADAS) are emerging vehicle-based active safety systems that have the potential to help drivers safely navigate across intersections and prevent intersection crashes and injuries. The performance of an I-ADAS is expected to be highly dependent upon driver evasive maneuvering prior to an intersection crash. Little has been published, however, on the detailed evasive kinematics followed by drivers prior to real-world intersection crashes. The objective of this study was to characterize the frequency, timing, and kinematics of driver evasive maneuvers prior to intersection crashes. Event data recorders (EDRs) downloaded from vehicles involved in intersection crashes were investigated as part of NASS-CDS years 2001 to 2013. A total of 135 EDRs with precrash vehicle speed and braking application were downloaded to investigate evasive braking. A smaller subset of 59 EDRs that collected vehicle yaw rate was additionally analyzed to investigate evasive steering. Each vehicle was assigned to one of 3 precrash movement classifiers (traveling through the intersection, completely stopped, or rolling stop) based on the vehicle's calculated acceleration and observed velocity profile. To ensure that any significant steering input observed was an attempted evasive maneuver, the analysis excluded vehicles at intersections that were turning, driving on a curved road, or performing a lane change. Braking application at the last EDR-recorded time point was assumed to indicate evasive braking. A vehicle yaw rate greater than 4° per second was assumed to indicate an evasive steering maneuver. Drivers executed crash avoidance maneuvers in four-fifths of intersection crashes. A more detailed analysis of evasive braking frequency by precrash maneuver revealed that drivers performing complete or rolling stops (61.3%) braked less often than drivers traveling through the intersection without yielding (79.0%). After accounting for uncertainty in the timing of braking and steering data, the median evasive braking time was found to be between 0.5 to 1.5 s prior to impact, and the median initial evasive steering time was found to occur between 0.5 and 0.9 s prior to impact. The median average evasive braking deceleration for all cases was found to be 0.58 g. The median of the maximum evasive vehicle yaw rates was found to be 8.2° per second. Evasive steering direction was found to be most frequently in the direction of travel of the approaching vehicle. The majority of drivers involved in intersection crashes were alert enough to perform an evasive action. Most drivers used a combination of steering and braking to avoid a crash. The average driver attempted to steer and brake at approximately the same time prior to the crash.


Relationships between umbilical cord arterial blood pH levels at delivery and Bayley Psychomotor Development Index scores in early childhood.
To correlate data on umbilical cord arterial blood pH (pHa) levels obtained at delivery with subsequent Bayley Psychomotor Development (PDI) scores determined on the same cohort of children at age 18 months. At delivery, we obtained umbilical cord bloods for pHa levels along with other biological parameters. Following the birth cohort prospectively, at age 18 months we did a comprehensive, blinded neurodevelopmental examination to determine a PDI score for each child. Over the broad range of umbilical cord arterial blood pH levels from 7.03 to 7.52, no statistically significant correlation (Pearson correlation coefficient, -0.016, P=0.88) was found between pHa at delivery and PDI scores at age 18 months. To study our finding in greater detail, we formed a subset of the data consisting only of lower pHa levels at delivery (defined as <or=7.20) and subsequent PDI scores. In this data subset, we again found that no significant relationship existed (Pearson correlation coefficient, +0.003, P=0.99). Our findings are consistent with the evolving hypothesis that adverse neurological outcomes in children often have etiologies other than intrapartum fetal acidemia.


Circadian Blood Pressure Rhythm Is Changed by Improvement in Hypoalbuminemia and Massive Proteinuria in Patients with Minimal Change Nephrotic Syndrome.
Proteinuria and nighttime blood pressure (BP) elevation are notable risk markers of chronic kidney disease and correlate closely with each other. However, daily urinary protein excretion (UPE) always fluctuates. In patients with minimal change nephrotic syndrome (MCNS), serum albumin concentrations (SAC) decrease but fluctuate less than UPE. We evaluated whether SAC is a reliable marker for proteinuria, and compared the relations among circadian BP changes, SAC, and UPE. In patients with MCNS (12 men and 11 women, 43 ± 18 years), blood and spot urine samples were collected on three consecutive days before treatment, and 24-hour BP was also measured on the three days. Then, an intervention study was conducted in the patients to examine circadian BP changes induced by treatment. Sleeping/waking BP ratio was analyzed as an indicator of circadian BP rhythm. In the three-day measurements before treatment, mean coefficient of variation, an index of dispersion of data, for SAC was 7.4 ± 7.4%, which was markedly lower (p < 0.01) than 35.7 ± 15.4% for UPE. SAC correlated inversely with sleeping/waking systolic and diastolic BP ratios on all three days, whereas UPE did not correlate significantly with sleeping/waking diastolic BP ratio on day 3. Sleeping/waking systolic and diastolic BP ratios were 96 ± 5 and 95 ± 6%, and were higher (p < 0.05) than in healthy subjects (89 ± 8 and 88 ± 10%). Treatment improved hyperproteinuria and hypoalbuminemia, and was accompanied by decreases (p < 0.05) in sleeping and waking systolic/diastolic BP ratio to 91 ± 8 and 89 ± 9%. These findings suggest that reduced SAC in patients with proteinuria is associated with disrupted circadian BP rhythm.


Bimodal Stimulation in Prelingually Deaf Children: Lessons from a Cross-sectional Survey.
(1) To survey the use of bimodal stimulation by prelingually deaf children receiving unilateral cochlear implantation and (2) to investigate demographic and audiologic factors explaining the use of bimodal stimulation. Cross-sectional survey. Tertiary care institution. The study included 44 unilaterally implanted prelingually deaf children from a single institution, with a minimum follow-up of 1 year. During routine follow-up visits, an examiner interviewed parents on their children's use of bimodal stimulation. At the same time, residual hearing and hearing aid gain in the contralateral ear were assessed. Approximately half of patients (52%) used bimodal stimulation. On average, bimodal users showed better mean unaided and aided thresholds than nonbimodal users (P < .001). A mean 250- to 500-Hz unaided threshold ≤90 dB HL in the contralateral, nonimplanted ear was associated with a higher probability of bimodal use (P = .008). Parental satisfaction with the contralateral hearing aid was inversely correlated with mean 125- to 500-Hz and 1000- to 4000-Hz unaided thresholds (P < .001) and mean 250- to 500-Hz and 1000- to 4000-Hz aided thresholds (P < .001). A mean 250- to 500-Hz unaided threshold ≤90 dB HL is associated with a higher probability of bimodal use by prelingually deaf children. Better residual hearing is associated with a higher degree of parental satisfaction with the contralateral hearing aid. This information could be useful to counsel parents of prelingually deaf children, when deciding between bimodal stimulation and simultaneous bilateral cochlear implantation.


Esculetin ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats.
Esculetin (ESC) is a coumarin that is present in several plants such as Fraxinus rhynchophylla and Artemisia capillaris. Our previous study found that FR ethanol extract (FR(EtOH)) significantly ameliorated rats' liver function. This study was intended to investigate the protective mechanism of ESC in hepatic apoptosis in rats induced by carbon tetrachloride. Rat hepatic apoptosis was induced by oral administration of CCl(4). All rats were administered orally with CCl(4) (20%, 0.5 mL/rat) twice a week for 8 weeks. Rats in the ESC groups were treated daily with ESC, and silymarin group were treated daily with silymarin. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the activities of the anti-oxidative enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase in the liver were measured. In addition, expression of liver apoptosis proteins and anti-apoptotic proteins were detected. ESC (100, 500 mg/kg) significantly reduced the elevated activities of serum ALT and AST caused by CCl(4) and significantly increased the activities of catalase, GPx and SOD. Furthermore, ESC (100, 500 mg/kg) significantly decreased the levels of the proapoptotic proteins (t-Bid, Bak and Bad) and significantly increased the levels of the anti-apoptotic proteins (Bcl-2 and Bcl-xL). ESC inhibited the release of cytochrome c from mitochondria. In addition, the levels of activated caspase-9 and activated caspase-3 were significantly decreased in rats treated with ESC than those in rats treated with CCl(4) alone. ESC significantly reduced CCl(4)-induced hepatic apoptosis in rats.


Aerobic Photobiocatalysis Enabled by Combining Core-Shell Nanophotoreactors and Native Enzymes.
Biocatalysis has become a powerful tool in synthetic chemistry, where enzymes are used to produce highly selective products under mild conditions. Using photocatalytically regenerated cofactors in synergistic combination with enzymes in a cascade fashion offers an efficient synthetic route to produce specific compounds. However, the combination of enzymes and photocatalysts has been limited due to the rapid degradation of the biomaterials by photogenerated reactive oxygen species, which denature and deactivate the enzymatic material. Here, we design core-shell structured porous nano-photoreactors for highly stable and recyclable photobiocatalysis under aerobic conditions. The enzymatic cofactor NAD+ from NADH can be efficiently regenerated by the photoactive organosilica core, while photogenerated active oxygen species are trapped and deactivated through the non-photoactive shell, protecting the enzymatic material. The versatility of these photocatalytic core-shell nanoreactors was demonstrated in tandem with two different enzymatic systems, glycerol dehydrogenase and glucose 1-dehydrogenase, where long-term enzyme stability was observed for the core-shell photocatalytic system.


Glucagon and insulin for the treatment of hepatic failure in dimethylnitrosamine-intoxicated rats.
When rats received dimethylnitrosamine every 24 h until death, plus hormone treatment after the first 24 h, the survival was enhanced between 100 and 140 h compared with the control rats, with attenuated derangements of prothrombin time and serum albumin levels at 120 h. In rats given a single dose of dimethylnitrosamine, hepatic DNA synthesis peaked at 48 h. The synthesis was increased after hormone treatment when started immediately, but not when delayed for 24 h. Hormone treatment for 3 days starting 24 h after a single dose of dimethylnitrosamine produced a rapid normalization of decreased hepatic protein content on day 9, although hepatic DNA content was not affected. These results suggest that this treatment is effective for hepatic failure, and the promotion of restoration of liver function is a contributing factor to its effect, in addition to the stimulation of hepatocyte proliferation.


Malignant mesothelioma of the tunica vaginalis testis.
Eighteen patients with malignant mesothelioma of the tunica vaginalis testis have been previously reported. These and the six patients reported here are reviewed for natural history and response to treatment. This tumor should be considered in men of any age with scrotal masses that include a hydrocele. Staging procedures should include computerized tomography scanning of the chest and abdomen. Inguinal orchiectomy appears to be the optimal primary surgical approach. Intraabdominal disease found at diagnostic laparotomy may be effectively treated by surgery and/or abdominal radiotherapy. Clinical features such as a long asymptomatic interval from initial presentation to clinical recurrence were observed and are also worthy of emphasis. Thus, serial follow-up is advised. Upon recurrence, treatment remains unsatisfactory but some responsiveness to chemotherapy has been noted. Doxorubicin-containing regimens were administered to five patients with measurable pulmonary nodules resulting in two partial regressions by standard criteria.


Anti-NMDAR encephalitis complicating pregnancy.
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first reported in 2005 in four patients with ovarian teratomas; there have been many further cases reported since the antigen for the NMDAR antibody was confirmed in 2007. Patients characteristically have a well-defined set of features, characterised by psychiatric disturbance, seizures and cognitive disturbance, followed by movement disorders, disorders of consciousness and dysautonomia. To date, 14 cases of NMDAR encephalitis have been described in the context of pregnancy. We report a case of NMDAR encephalitis in a 34-year-old woman at 8 weeks' gestation. She had a turbulent clinical course and was initially admitted to a psychiatric unit. She was successfully treated with first-line immunomodulatory therapies and surgical resection of an ovarian teratoma. Following discharge she delivered a healthy baby and made a complete clinical recovery.


[Alveolar ridge preservation after tooth extraction using allograft (Maxgraft®) and full arch fixed prosthetic rehabilitation on implants].
A 69-year-old woman consulted the Oral surgery and implantology unit of the Geneva University Hospitals with the chief complaint of chewing difficulties, aesthetic discomfort and dry mouth. The wish of the patient was to receive a reliable fixed solution in the long term. The patient had chronic nonspecific sialadenitis accompanied by xerostomia. She wore a total prosthesis stabilized on two inter-foraminal implants and had multiple cavities of the remaining maxillary teeth. The goals of treatment were to improve masticatory function with fixed prosthetic rehabilitation on upper and lower implants. With a post-extraction alveolar ridge preservation technique, the placement of Straumann® maxillary implants could be performed with a basic sequence without bone augmentation which reduced morbidity, treatment time and costs compared to reconstruction of the edentulous and atrophied mandible. The patient was very satisfied at the follow-up at 3 and 6 months as well as at 1 and 2 years, and the restorations were stable. In summary, the post-extraction preservation of the alveolar ridges is a predictable therapeutic option that can be considered in a context of multiple extraction in order to limit the complexity of the implant treatment.


Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice.
Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. Recently, a role for free radicals has been proposed in the mortality associated with Gram-negative bacterial sepsis. To determine if pretreatment with free radical scavengers can prevent endotoxin-induced mortality, mice rendered sensitive to endotoxin with actinomycin D were treated with either superoxide dismutase (SOD), N-acetylcysteine (NAC) or saline and were then challenged with a dose of endotoxin calculated to cause a mortality of greater than 80%. Mortality was assessed at 12-h intervals after challenge. Increased survival was seen in the SOD-treated group compared to the control group (p less than or equal to .05). In contrast, survival in mice treated with NAC, another potential scavenger, was not significantly different from the control group. These results support the hypothesis that superoxide and hydroxyl radicals contribute to mortality in Gram-negative bacterial sepsis.


Etiology of Hypopituitarism in Adult Patients: The Experience of a Single Center Database in the Serbian Population.
There are only a few published studies related to the population-based etiology of hypopituitarism. New risks for developing hypopituitarism have been recognized in the last 10 years. Aim. To present data regarding the etiology of hypopituitarism collected in a tertiary center over the last decade. This is a cross-sectional database study. Patients and Methods. We included 512 patients (pts) with hypopituitarism, with a mean age of 45.9 ± 1.7 yrs (range: 18-82; male: 57.9%). Results. Nonfunctional pituitary adenomas were presented in 205 pts (40.5%), congenital causes in 74 pts (14.6%), while acromegaly and prolactinomas were presented in 37 (7.2%) and 36 (7.0%) patients, respectively. Craniopharyngiomas were detected in 30 pts (5.9%), and head trauma due to trauma brain injury-TBI and subarachnoid hemorrhage-SAH in 27 pts (5.4%). Survivors of hemorrhagic fever with renal syndrome (HFRS) and those with previous cranial irradiation were presented in the same frequency (18 pts, 3.5% each). Conclusion. The most common causes of hypopituitarism in our database are pituitary adenomas. Increased awareness of the other causes of pituitary dysfunction, such as congenital, head trauma, extrapituitary cranial irradiation, and infections, is the reason for a higher frequency of these etiologies of hypopituitarism in the presented database.


[Small for gestational age - Somatic, neurological and cognitive development until adulthood].
The somatic, neurological and cognitive development of children born small for gestational age (SGA) until adulthood was assessed in recent studies. Studies that assessed mortality, morbidity, somatic, neurological and cognitive development of SGA children were compared. In the studies very low birth weight SGA children were compared to very low birth weight appropriate for age children (AGA, birth weight below 1500 g or 1250 g). Full-term SGA children were compared to full-term appropriate for age children. Growth of SGA children remained under the 10th percentile, if catch up growth did not occur until the end of the second year. Cerebral palsy appeared more often in VLBW-AGA than in VLBW-SGA children. Cognitive development problems appeared in VLBW-SGA and FT-SGA children more often than in VLBW-AGA and FT-AGA children. These cognitive development problems were observed mainly as poor school performance. When reaching adulthood, the differences in cognitive function seem to be less significant. Low socioeconomic status and persistence of microcephaly were associated with problems in neurological and cognitive development. Growth and cognitive development problems appeared more often in SGA children. More longterm studies are necessary to show, if these cognitive development problems remain significant until adulthood.