Surgical techniques for medial clavicular tumors: A report of 3 cases.
Clavicular tumors are rare, consisting of <1 % of all skeletal tumors. In this series, we described our experience of treating medial clavicular tumors. We treated three patients with medial clavicle tumors at a national tertiary referral hospital in Jakarta, Indonesia. The patients were treated with wide excision following bony reconstruction from fibular bone and one patient was treated by marginal excision. Each patient was treated by surgery and one patient underwent reconstruction using non-vascularized fibular graft and composite using bone cement. All patients resulted in restoration of symmetry of the lower neck and upper chest and no post-surgical complication. Based on these cases above and the extension of tumor, we recommend medial clavicle tumor resection classification divided into three type to decide which type of surgical procedure that should be performed. In our report, all patients resulted in restoration of symmetry of the lower neck and upper chest and no post-surgical complication. Clavicle resection in management of medial third clavicle tumor is technically demanding. We proposed three types of clavicular resection based on tumor extension. The surgical technique of medial end clavicle in this patient resulted in tumor free margin of medial clavicular, medial scapula, and lateral scapular incision. Reconstruction surgery following clavicle resection can be done in order to restore symmetry of the lower neck and upper chest, protect nearby neurovascular bundle, and rarely associated with significant shoulder function loss.


Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis.
The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.


Anaerobic transport in Escherichia coli membrane vesicles.
Anaerobic lactose and/or amino acid transport by membrane vesicles prepared from Escherichia coli ML 308-225 can be coupled to at least four electron transfer systems: alpha-glycerol-P-dehydrogenase:nitrate reductase, formate dehydrogenase:nitrate reductase, alpha-glycerol-P dehydrogenase:fumarate reductase, and formate dehydrogenase:fumarate reductase. Vesicles contain one or more of these electron transfer systems depending on the growth conditions of the parent cells. alpha-Glycerol-P dehydrogenase and fumarate reductase are present only in vesicles prepared from cells grown in the presence of glycerol or fumarate, respectively. Formate dehydrogenase and nitrate reductase activities, on the other hand, are present in vesicles from cells grown on a variety of media. alpha-Glycerol-P and formate are able to drive aerobic transport in vesicles prepared from anaerobically grown cells, indicating coupling between aerobic and anaerobic electron transfer systems.


Beneficial Effects of Nonsurgical Treatment for Symptomatic Thumb Carpometacarpal Instability in Clinical Practice: A Cohort Study.
To describe outcomes of nonsurgical treatment for symptomatic thumb carpometacarpal joint (CMC-1) instability. Secondary, to evaluate the conversion rate to surgical treatment. Prospective cohort study. A total of 20 outpatient clinics for hand surgery and hand therapy in the Netherlands. A consecutive sample of patients with symptomatic CMC-1 instability (N=431). Nonsurgical treatment including exercise therapy and an orthosis. Pain (visual analog scale [VAS], 0-100) and hand function (Michigan Hand Outcomes Questionnaire [MHQ], 0-100) at baseline, 6 weeks, and 3 months. Conversion to surgery was recorded for all patients with a median follow-up of 2.8 years (range, 0.8-6.7y). VAS scores for pain during the last week, at rest, and during physical load improved with a mean difference at 3 months of 17 (97.5% CI, 9-25), 13 (97.5% CI, 9-18), and 19 (97.5% CI, 12-27), respectively (P<.001). No difference was present at 3 months for MHQ total score, but the subscales activities of daily living, work, pain, and satisfaction improved by 7 (97.5% CI, 1-14), 10 (97.5% CI, 4-16), 5 (97.5% CI, 2-9), and 12 (97.5% CI, 2-22) points, respectively (P<.001-.007). After median follow-up of 2.8 years, only 59 participants (14%) were surgically treated. Both in the subgroups that did and did not convert to surgery, VAS pain scores decreased at 3 months compared with baseline (P<.001-.010), whereas MHQ total score did not improve in both subgroups. However, VAS and MHQ scores remained worse for patients who eventually converted to surgery (P<.001). In this large sample of patients with symptomatic CMC-1 instability, nonsurgical treatment demonstrated clinically relevant improvements in pain and aspects of hand function. Furthermore, after 2.8 years, only 14% of all patients were surgically treated, indicating that nonsurgical treatment is a successful treatment of choice.


Baseline MRI inflammation is not a determinant of 5-year bone mineral density loss in patients with early spondyloarthritis.
The aim of this study was to assess the effect of baseline inflammation on Magnetic Resonance Imaging (MRI) on the change in Bone Mineral Density (BMD) over 5 years in patients with early spondyloarthritis (SpA). From the patients of the DESIR cohort (an early axial SpA cohort), patients with BMD data at both baseline and 5 years, and baseline spine and sacroiliac joints MRI were included. Inflammation was assessed with the SpondyloArthritis Research Consortium of Canada (SPARCC) spine score. Significant BMD loss was defined by a change of >0.03g/cm2. No patients had received TNF blockers before inclusion in the cohort. Univariate and multivariable prognostic analyses were performed. An inverse propensity score weighting method was used to handle confounders. One hundred and eighty-three patients were included (mean age 33.9±8.7 years, 58.5% men). A significant bone loss was reported in 51% (n=92) of patients at either lumbar spine or hip. Fourteen (7%) patients had low BMD (Z-score <-2) at the end of the follow-up vs. 28 (15%) at baseline. In multivariable analysis, age was a protective factor of 5 year-BMD loss at any site (OR=0.96, 95% CI [0.93-0.99]). Baseline MRI inflammation has no significant effect on BMD change at any site (OR=0.84, 95% CI [0.46-1.53]). Half of patients with early SpA have a significant bone loss at either lumbar spine or hip over 5 years. Baseline MRI inflammation is not a determinant of this bone loss.


Suitable device for thoracoscopic talc poudrage in malignant pleural effusion.
Chemical pleurodesis is widely used in symptomatic patients with malignant pleural effusion to relieve symptoms, prevent fluid recurrence, and improve quality of life. Talc has been repeatedly found to be the most effective sclerosant agent, and thoracoscopic talc poudrage has been found to be the most effective pleurodesis technique. A homogeneous talc distribution on the visceral and parietal pleura helps to achieve complete pleural symphysis. We have recently adopted a new suitable sterile device that delivers talc under low and constant pressure, facilitating uniform coating of the whole pleural surface and avoiding inappropriate deposition of talc clumps.


Belowground microbiota analysis indicates that Fusarium spp. exacerbate grapevine trunk disease.
Grapevine trunk diseases (GTDs) are disease complexes that are major threats to viticulture in most grapevine growing regions. The microbiomes colonizing plant belowground components form complex associations with plants, play important roles in promoting plant productivity and health in natural environments, and may be related to GTD development. To investigate associations between belowground fungal communities and GTD symptomatic or asymptomatic grapevines, fungal communities associated with three soil-plant compartments (bulk soils, rhizospheres, and roots) were characterized by ITS high-throughput amplicon sequencing across two years. The fungal community diversity and composition differs according to the soil-plant compartment type (PERMANOVA, p < 0.001, 12.04% of variation explained) and sampling year (PERMANOVA, p < 0.001, 8.83%), whereas GTD symptomatology exhibited a weaker, but still significant association (PERMANOVA, p < 0.001, 1.29%). The effects of the latter were particularly prominent in root and rhizosphere community comparisons. Many GTD-associated pathogens were detected, but their relative abundances were not correlated (or were negatively correlated) to symptomatology. Fusarium spp., were enriched in symptomatic roots and rhizospheres compared to asymptomatic counterparts, suggesting that their abundances were positively correlated with symptomatic vines. Inoculation tests revealed that Fusarium isolates, similar to Dactylonectria macrodidyma, a pathogen associated with black foot disease, caused dark brown necrotic spots on stems in addition to root rot, which blackened lateral roots. Disease indices were higher with co-inoculation than single inoculation with a Fusarium isolate or D. macrodidyma, suggesting that Fusarium spp. can exacerbate disease severity when inoculated with other known GTD-associated pathogens. The belowground fungal microbiota of grapevines varied from soil-plant compartments, the years and whether showed GTD symptoms. The GTDs symptoms were related to the enrichment of Fusarium spp. rather than the relative abundances of GTD pathogens. These results demonstrate the effects of fungal microbiota of roots and rhizospheres on GTDs, while providing new insights into opportunistic pathogenesis of GTDs and potential control practices.


Biochemical and quantitative analysis of Tamm Horsfall protein in rats.
The involvement of Tamm Horsfall protein (THP) in nephrolithiasis is currently under investigation in several laboratories. Although rat is a commonly used species as an in vivo model for such studies, there is only limited information available about the biochemical properties and excretion profile of THP in normal rats. In order to characterize rat THP, we purified and analyzed normal male rat THP, and compared it with normal human male urinary THP by gel electrophoresis. Both THPs migrated at approximately 90 KDa, and stained similarly for protein (Coomassie blue) as well as carbohydrates (periodic acid Schiff reagent). Compositional analysis revealed that rat THP was largely similar to human THP in amino acid and carbohydrate contents but showed differences in the individual sugar components from other mammals. There was considerable variation in the day-to-day urinary excretion of THP in normal rats, with values ranging from 552.96 micrograms to 2865.60 micrograms and a mean value of 1679.54 micrograms per 24 h. It was concluded from this study that rat THP did not contain any unusual biochemical components and was primarily similar to human THP in composition and mean urinary concentration.


Isolation and characterization of structural components of Aloe vera L. leaf pulp.
The clear pulp, also known as inner gel, of Aloe vera L. leaf is widely used in various medical, cosmetic and nutraceutical applications. Many beneficial effects of this plant have been attributed to the polysaccharides present in the pulp. However, discrepancies exist regarding the composition of pulp polysaccharide species and an understanding of pulp structure in relation to its chemical composition has been lacking. Thus, we examined pulp structure, isolated structural components and determined their carbohydrate compositions along with analyzing a partially purified pulp-based product (Acemannan hydrogel) used to make Carrisyn hydrogel wound dressing. Light and electron microscopy showed that the pulp consisted of large clear mesophyll cells with a diameter as large as 1000 microm. These cells were composed of cell walls and cell membranes along with a very limited number of degenerated cellular organelles. No intact cellular organelles were found in mesophyll cells. Following disruption of pulp by homogenization, three components were isolated by sequential centrifugation. They were thin clear sheets, microparticles and a viscous liquid gel, which corresponded to cell wall, degenerated cellular organelles and liquid content of mesophyll cells based on morphological and chemical analysis. These three components accounted for 16.2% (+/-3.8), 0.70% (+/-0) and 83.1% of the pulp on a dry weight basis. The carbohydrate composition of each component was distinct; liquid gel contained mannan, microparticles contained galactose-rich polysaccharide(s) and cell walls contained an unusually high level of galacturonic acid (34%, w/w; Gal A). The same three components were also found in Acemannan Hydrogel with mannan as the predominant component. Thus, different pulp structural components are associated with different polysaccharides and thus may potentially be different functionally. These findings may help lay a basis for further studies and development of better controlled processing methods and applications for this well-accepted medicinal plant.


Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach.
The extent to which accuracy of electric charges plays a role in protein-ligand docking is investigated through development of a docking algorithm, which incorporates quantum mechanical/molecular mechanical (QM/MM) calculations. In this algorithm, fixed charges of ligands obtained from force field parameterization are replaced by QM/MM calculations in the protein environment, treating only the ligands as the quantum region. The algorithm is tested on a set of 40 cocrystallized structures taken from the Protein Data Bank (PDB) and provides strong evidence that use of nonfixed charges is important. An algorithm, dubbed "Survival of the Fittest" (SOF) algorithm, is implemented to incorporate QM/MM charge calculations without any prior knowledge of native structures of the complexes. Using an iterative protocol, this algorithm is able in many cases to converge to a nativelike structure in systems where redocking of the ligand using a standard fixed charge force field exhibits nontrivial errors. The results demonstrate that polarization effects can play a significant role in determining the structures of protein-ligand complexes, and provide a promising start towards the development of more accurate docking methods for lead optimization applications.


Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: A South Korean nationwide cohort study.
The association between non-alcoholic fatty liver disease (NAFLD) and cholangiocarcinoma has been previously reported only in case-control studies. Therefore, we conducted this nationwide cohort study to evaluate the longitudinal association between NAFLD and the risk of biliary tract cancer (BTC), including cholangiocarcinoma and gallbladder cancer. We included 8,120,674 adults who underwent national health screening in 2009 based on the Korean National Health Insurance Service data. NAFLD was determined using the fatty liver index: ≥60, NAFLD; 30-59, intermediate score; <30, no NAFLD. The exclusion criteria were baseline clinical liver disease, heavy alcohol consumption and cancer. Participants were followed up until December 2017 for the development of BTC. Cox proportional hazards regression models were performed. During the median follow-up period of 7.2 years, 13,043 patients were with newly diagnosed BTC. NAFLD was associated with an increased risk of BTC (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.20-1.37) compared with no NAFLD. The aHRs for the association of cholangiocarcinoma and gallbladder cancer with NAFLD were 1.33 (95% CI, 1.23-1.43) and 1.14 (95% CI, 1.003-1.29), respectively. Overall, the aHR for BTC tended to increase with the increasing fatty liver index (P for trend < 0.001). Concomitant NAFLD and diabetes were associated with an increased risk of BTC by 47% (aHR, 1.47; 95% CI, 1.35-1.60). In this nationwide cohort study, NAFLD was associated with an increased risk of cholangiocarcinoma and gallbladder cancer. This finding suggests that NAFLD is a potentially modifiable risk factor for BTC.


[Fragmented red cells are the major cause of spuriously high platelet counts in patients with fragmented red cells when counts are obtained by automated blood cell counter].
Platelet counts measured by automated blood cell counter often show spuriously high values when measuring samples contain particles of equal size to platelets. The major cause of spuriously high platelet counts in samples with fragmented red cells (FRC) is thought to be the FRC themselves. We studied the correlation between FRC and spuriously high platelet counts in 40 patients demonstrating FRC on blood smears. FRC were measured by manual hemocytometry and by flow cytometry using a monoclonal antibody against glycophorin A (GPA method). There was a significant correlation between spuriously high platelet counts and FRC by manual hemocytometry (r=0.60, p<0.001) or FRC by the GPA method (r=0.45, p<0.005). These data suggest that FRC are the major cause of spuriously high platelet counts in samples with FRC.


Research Note: A baseline survey of thermotolerant Campylobacter in retail chicken in southern Brazil.
Chicken is a leading source of thermotolerant Campylobacter, which triggers human foodborne enteritis. This study evaluated thermotolerant Campylobacter contamination of retail chicken in southern Brazil, using qualitative and quantitative analyses. Selective enrichment in Bolton broth for 24 and 48 h after plating onto modified charcoal-cefoperazone-deoxycholate (mCCD) agar and Preston agar was assessed. The combined results of the detection and enumeration methods revealed a frequency of 70% occurrence of thermotolerant Campylobacter in chicken samples. Campylobacter was enumerated in 60% of the samples, whereas 46% of the samples were positive in the qualitative analysis. Quantitative analysis showed average counts of 3.10 ± 0.15 log10 CFU/sample. Higher numbers of Campylobacter-positive samples were found using 24-h enrichment before plating onto Preston agar (46%) than onto mCCD agar (2%). The majority of isolated strains were identified as Campylobacter jejuni, and Campylobacter coli was also found but to a lesser extent. Subtyping revealed a clear distinction between strains isolated from different chicken sources. The enriched samples plated onto mCCD agar showed extensive spreading of nonproducing extended-spectrum β-lactamases Proteus mirabilis that hampered the identification of Campylobacter colonies. P. mirabilis strains showed resistance to cefoperazone, trimethoprim, and polymyxin B present in broth and plate media used and were inhibited by rifampicin present in Preston agar. The results underline the effect of the spread of contaminant strains on Campylobacter cultures, which might be prevented using a recently revised International Organization for Standardization method for qualitative analysis of chicken.


A genome-wide association study of plasma phosphorylated tau181.
Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10-25) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10-08), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10-07, nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS.


Dysregulation of FTX/miR-545 signaling pathway downregulates Tim-3 and is responsible for the abnormal activation of macrophage in cirrhosis.
Accumulating evidence has suggested the involvement of miR-545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR-545 and lncRNA FTX in hepatitis B virus (HBV)-related cirrhosis. The level of Tim-3, TLR-4, and endotoxin was detected in CD14+ , CD14 + CD16 + , and CD14 + CD16 - monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), IL-1β, and Nuclear factor kB (NF-kB). In-silico analysis, luciferase assay, real-time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR-545 and Tim-3. The levels of Tim-3, Tim-3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim-3 was also decreased in the CD14 + CD16 - monocytes isolated from patients with cirrhosis, whereas the level of Tim-3 in CD14 + CD16 + monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR-4 was highly expressed in CD14 + CD16 + monocytes isolated from patients with cirrhosis, whereas Tim-3 was negatively regulated by endotoxin and the correlation coefficient was -0.5287. After the LPS stimulation, although the level of TNF-a, IL-6, IL-1β, and NF-kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim-3, but a higher level of miR-545. Moreover, miR-545 directly bound to the 3'untranslated region (3'UTR) of Tim-3 and inhibited the luciferase activity of cells cotransfected with miR-545 mimics and wild-type 3'UTR of Tim-3. Furthermore, FTX downregulated the expression of miR-545, TNF-a, IL-6, IL-1β, and NF-kB, but upregulated the expression of Tim-3. The results of this study confirmed the effect of FTX, miR-545, and Tim-3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV-related cirrhosis.


Which N Descriptor Is More Predictive of Prognosis in Resected Non-small Cell Lung Cancer: The Number of Involved Nodal Stations or the Location-Based Pathological N Stage?
The eighth edition of nodal classification for non-small cell lung cancer (NSCLC) is defined only by the anatomical location of metastatic lymph nodes. We sought to evaluate the prognostic significance and discriminatory capability of the number of involved nodal stations (nS) in a large Chinese cohort. A total of 4,011 patients with NSCLC undergoing surgical resection between 2009 and 2013 were identified. The optimal cutoff values for nS classification were determined with X-tile software. Kaplan-Meier and multivariate Cox analysis were used to examine the prognostic performance of nS classification in comparison with location-based N classification. A decision curve analysis was performed to evaluate the standardized net benefit of nS classification in predicting prognosis. All the patients were classified into four prognostically different subgroups according to the number of involved nodal stations: (1) nS0 (none positive), (2) nS1 (one involved station), (3) nS2 (two involved stations), and (4) nS ≥ 3 (three or more involved stations). The prognoses among all the neighboring categories of nS classification were statistically significantly different in terms of disease-free survival and overall survival. The multivariate Cox analysis demonstrated that nS was an independent prognostic factor of disease-free survival and overall survival. Patients with N1 or N2 stage disease could be divided into three prognostically different subgroups according to nS classification. However, the prognosis was similar between the N1 and N2 subgroups when patients were staged in the same nS category. The decision curve analysis showed that nS classification tended to have a higher predictive capability than location-based N classification. The nS classification could be used to provide a more accurate prognosis for patients with resected NSCLC. The nS is worth taking into consideration when defining nodal category in the forthcoming ninth edition of the staging system.


[How does one manage patients with rheumatoid arthritis and positive serology to hepatitis B, hepatitis C, human immunodeficiency virus?].
Chronic viral infections in rheumatic patients are a diagnostic and therapeutic challenge. Some of the disease-modifying antirheumatic drugs (DMARD) commonly used in rheumatoid arthritis, such as methotrexate and leflunomide, are hepatotoxic. With biological therapy, which is now widely used in patients refractory to these and other DMARD, some cases of reactivation of hepatitis B, even fulminant cases, have been reported, especially when employing TNF antagonists and rituximab, so their use must be carefully assessed and usually accompanied by antiviral therapy. However, there have not been reports of reactivation of hepatitis C after immunosuppressive therapy. In patients with HIV infection, administration of immunosuppressive therapy carries a high risk of opportunistic infections, although the new highly active antiviral therapy allows the use of some drugs in selected cases.


How to define the right ambient temperature range for storage and distribution of pharmaceutical raw materials.
To ensure the quality of raw materials for pharmaceutical products, the right storage and distribution temperature conditions should be applied. Labeled temperature conditions of 539 raw materials at non-cold chain conditions (thus excluding 2-8 °C or < 0 °C conditions) were reviewed that revealed a set of 26 different temperature requirements. From a manufacturer perspective, it is hard or undoable to manage that number of temperature conditions, especially because regulatory guidance towards raw material temperature conditions is lacking. Therefore, the question raised whether it would be possible to define subsets of temperature conditions in order to simplify the storage and distribution management of raw materials. The data set was further analyzed and it resulted in a new storage and distribution model of three temperature conditions for raw materials: 15-25 °C, 2-30 °C and unrestricted (no minimum and maximum temperature limit). The model can be applied to all non-cold chain raw materials by suppliers and manufacturers in order to harmonize temperature conditions and to manage temperature excursions easier during operations.


Preventive care utilization among the uninsured by race/ethnicity and income.
Health insurance status affects access to preventive services. Effective use of preventive services is a key factor in the reduction of important health concerns and has the potential to enable adults to live longer, healthier lives. To analyze the use of U.S. Preventive Services Task Force (USPSTF)-recommended preventive services among uninsured adults, with a focus on variation across race, ethnicity, and household income. Using pooled 2004-2011 Medical Expenditure Panel Survey data, this study conducted multivariate logistic regressions to estimate variation in receipt of eight USPSTF-recommended preventive services by race/ethnicity among adults aged 18 years and older uninsured in the previous year. Stratified analyses by household income were applied. Data were analyzed in 2013. Uninsured adults received preventive services far below Healthy People 2020 targets. Among the uninsured, African Americans had higher odds of receiving Pap tests, mammograms, routine physical checkups, and blood pressure checks according to guidelines than whites. Moreover, compared to whites, Hispanics had higher odds of receiving Pap tests, mammograms, influenza vaccinations, and routine physical checkups and lower odds of receiving blood pressure screening and advice to quit smoking. When results were stratified by household income, racial/ethnic differences persisted except for the highest income levels (≥400% Federal Poverty Level), where they were largely non-significant. Generally, uninsured African American and Hispanic populations fare better than uninsured whites in preventive service utilization. Future research should examine reasons behind these racial/ethnic differences to inform policy interventions aiming to increase preventive service utilization among the uninsured.


Recovery of auditory evoked response attentional gain modulation following the first psychotic episode indexes improvements in symptom severity.
Attentional control of auditory N100/M100 gain is reduced in individuals with first-episode psychosis (FEP). Persistent problems with executive modulation of auditory sensory activity may impact multiple aspects of psychosis. As a follow-up to our prior work reporting deficits in attentional M100 gain modulation in auditory cortex, we examined changes in M100 gain modulation longitudinally, and further examined relationships between auditory M100 and symptoms of psychosis. We compared auditory M100 in auditory sensory cortex between 21 FEP and 29 matched healthy participants and between timepoints separated by 220 ± 100 days. Magnetoencephalography data were recorded while participants alternately attended or ignored tones in an auditory oddball task. M100 was measured as the average of 80-140 ms post-stimulus in source-localized evoked responses within bilateral auditory cortex. Symptoms were assessed using the PANSS and PSYRATS. M100 amplitudes, attentional modulation of M100 amplitudes, and symptom severity all improved in FEP over time. Further, improvement in M100 modulation correlated with improvements in negative symptoms (PANSS) as well as physical, cognitive, and emotional components of hallucinations (PSYRATS). Conversely, improvements in the overall size of the M100, rather than the difference between active and passive M100 amplitudes, were related to worsening of positive symptoms (PANSS) and physical components of hallucinations. Results indicate a link between symptoms (particularly auditory hallucinations) and auditory cortex neurophysiology in FEP, where auditory attention and auditory sensation have opposed relationships to symptom change. These findings may inform current models of psychosis etiology and could provide nonpharmaceutical avenues for early intervention.


Recycled crushed glass in road work applications.
A comprehensive suite of geotechnical laboratory tests was undertaken on samples of recycled crushed glass produced in Victoria, Australia. Three types of recycled glass sources were tested being coarse, medium and fine sized glass. Laboratory testing results indicated that medium and fine sized recycled glass sources exhibit geotechnical behavior similar to natural aggregates. Coarse recycled glass was however found to be unsuitable for geotechnical engineering applications. Shear strength tests indicate that the fine and medium glass encompass shear strength parameters similar to that of natural sand and gravel mixtures comprising of angular particles. Environmental assessment tests indicated that the material meets the requirements of environmental protection authorities for fill material. The results were used to discuss potential usages of recycled glass as a construction material in geotechnical engineering applications particularly road works.


Dual action of metabotropic glutamate receptor agonists on neuronal excitability and synaptic transmission in spinal ventral horn neurons in vitro.
A dual action of selective metabotropic glutamate receptor agonists on neuronal excitability and dorsal root-evoked excitatory (DR-EPSPs) and inhibitory (DR-IPSPs) neurotransmission is described for immature rat ventral horn neurons in vitro. Trans-1-Aminocyclopentane-1,3 -dicarboxylate (trans-ACPD), its stereoisomer (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG-1) produced a concentration-related and alpha-methyl-4 -carboxyphenylglycine (MCPG)-sensitive depolarisation. An (1S,3R)-ACPD- or L-CCG-1-induced increase in intrinsic neuronal excitability was apparently independent of the depolarisation and was observed as (a) a fall in the threshold current required to elicit regenerative excitation and (b) an increased number of spikes to a fixed amplitude step depolarisation. The spike after-hyperpolarisation (AHP) duration and amplitude were reduced, suggesting an mGluR agonist action on potassium channels. Synaptic responses were depressed by the mGluR agonists. (1S,3R)-ACPD or L-CCG-1 reduced the mean +/- S.E.M. peak amplitude of a subthreshold EPSP elicited by low-intensity stimuli likely to recruit only low-threshold sensory afferents. The peak amplitude of longer-latency EPSPs elicited by higher-intensity stimuli likely to recruit high-threshold afferents in addition was attenuated. (1S,3R)-ACPD- or L-CCG-1 reduced the peak amplitude of an IPSP evoked by dorsal root stimulation. These effects on synaptic transmission were likely to be due to the combined activation of postsynaptic and presynaptic metabotropic glutamate receptors. The implications of these data for the physiological role of spinal mGluRs is discussed.


Quantification of normal range of inflammatory changes in morphologically normal pediatric muscle.
The aim of this study was to define normal ranges of histological features in pediatric muscle in comparison with muscle demonstrating inflammatory changes. Sixteen pediatric muscle biopsy samples, considered normal by standard histology, were analyzed for the presence of inflammatory cells, and the expression of neonatal myosin and major histocompatibility complex (MHC) Class 1. Normal findings were defined for each feature. These data will facilitate quantitative analysis of inflammatory changes in pediatric muscle biopsy.


HPr prevents FruR-mediated facilitation of RNA polymerase binding to the fru promoter in Vibrio cholerae.
Phosphorylation state-dependent interactions of the phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) components with transcription factors play a key role in carbon catabolite repression (CCR) by glucose in bacteria. Glucose inhibits the PTS-dependent transport of fructose and is preferred over fructose in Vibrio cholerae, but the mechanism is unknown. We have recently shown that, contrary to Escherichia coli, the fructose-dependent transcriptional regulator FruR acts as an activator of the fru operon in V. cholerae and binding of the FruR-fructose 1-phosphate (F1P) complex to an operator facilitates RNA polymerase (RNAP) binding to the fru promoter. Here we show that, in the presence of glucose, dephosphorylated HPr, a general PTS component, binds to FruR. Whereas HPr does not affect DNA-binding affinity of FruR, regardless of the presence of F1P, it prevents the FruR-F1P complex from facilitating the binding of RNAP to the fru promoter. Structural and biochemical analyses of the FruR-HPr complex identify key residues responsible for the V. cholerae-specific FruR-HPr interaction not observed in E. coli. Finally, we reveal how the dephosphorylated HPr interacts with FruR in V. cholerae, whereas the phosphorylated HPr binds to CcpA, which is a global regulator of CCR in Bacillus subtilis and shows structural similarity to FruR.


The isolation and some properties of dipeptidyl peptidases II and III from porcine spleen.
1. Dipeptidyl peptidases (DPP) II and III from porcine spleen have been purified to homogeneity as assessed by disc gel electrophoresis, HPLC and chromatofocusing. 2. The enzyme are both inhibited by diisopropylfluorophosphate suggesting that the active site contains an essential serine residue, but they are also inhibited by a variety of other reagents. 3. The pI of DPP II is 4.8, that of DPP III, 4.0. 4. The former enzyme has a molecular weight of 97,000, the latter 66,000 and both are glycoproteins. 5. The enzymes are compared with those from other sources.


Polypoid invasive carcinoma of the gallbladder-Another challenging polypoid neoplasm.
Invasive gallbladder carcinoma generally presents as nodular-sclerosing growth. Recently, "polypoid invasive carcinoma (PICA)" showing grossly visible polypoid neoplasm and histologically invasive carcinoma with no adenomatous components was proposed as a neoplastic polyp of the gallbladder. We herein report five cases of PICA collected from 49 cases of invasive gallbladder carcinoma in comparison with another polypoid preinvasive neoplasm of gallbladder, intracholecystic papillary neoplasm (ICPN). Polypoid invasive carcinomas were composed of four males and one female with an average age of 74 years. Polypoid lesions were sessile (height ranging from 6 to 10 mm and the largest diameter ranging from 12 to 40 mm), and histologically, polypoid neoplasms presented papillary configuration containing tubular and cribriform components with thin inflammatory, fibrotic stroma. Polypoid carcinoma invaded directly and continuously into the gallbladder wall with destruction of the muscle layer. These patterns of PICA were different from ICPN, showing papillary patterns containing tubular components with fine fibrovascular stalks and with occasional focal stromal invasion but with preserved muscle layer. Post-operative outcome was not favorable in PICA but was favorable in ICPN. Polypoid invasive carcinoma shared several pathological features with ICPN, such as intraluminal polypoid pattern with papillary configurations, but PICAs were invasive adenocarcinoma with destruction of muscle layer while ICPNs were preinvasive neoplasm with occasional focal stromal invasion, thus both should be differentiated from each other.


Heterotypic Multicellular Spheroids as Experimental and Preclinical Models of Sprouting Angiogenesis.
Sprouting angiogenesis is the common response of live tissues to physiological and pathological angiogenic stimuli. Its accurate evaluation is of utmost importance for basic research and practical medicine and pharmacology and requires adequate experimental models. A variety of assays for angiogenesis were developed, none of them perfect. In vitro approaches are generally less physiologically relevant due to the omission of essential components regulating the process. However, only in vitro models can be entirely non-xenogeneic. The limitations of the in vitro angiogenesis assays can be partially overcome using 3D models mimicking tissue O2 and nutrient gradients, the influence of the extracellular matrix (ECM), and enabling cell-cell interactions. Here we present a review of the existing models of sprouting angiogenesis that are based on the use of endothelial cells (ECs) co-cultured with perivascular or other stromal cells. This approach provides an excellent in vitro platform for further decoding of the cellular and molecular mechanisms of sprouting angiogenesis under conditions close to the in vivo conditions, as well as for preclinical drug testing and preclinical research in tissue engineering and regenerative medicine.


The multiload IUD--a U.S. researcher's evaluation of a European device.
This evaluative review focused on the performance and safety of the Dutch-made Multiload copper IUD, primarily the Multiload-375 (MLCu-375) model which has a longer life expectancy (5 or more years) than the Multiload-250 (MLCu-250) model, usually cited for a life expectancy for three years. This copper-medicated IUD differs from the copper-T IUDs in shape and insertion technique. The review shows that (a) the MLCu-375 IUD seems to be slightly less effective in preventing pregnancies than TCu-380A IUD. Its efficacy is comparable to that of the Nova-T by two to three years of use; (b) the MLCu-250 IUD is similarly effective to TCu-200 but may be slightly less effective than TCu-220C; (c) no consistent differences were detectable in expulsion rates or in removal rates for bleeding/pain between the Multiload IUDs and comparative Copper-T IUDs; (d) the Multiload IUDs may perform better in nulliparous women than the T-shaped devices; (e) no or a very low incidence of uterine perforation is associated with insertions of the Multiload IUD; (f) ectopic pregnancy risks are similarly low in Multiload IUD users as in Copper-T-380A users; and (g) pelvic inflammatory disease (PID) risks are similarly low in Multiload IUD users as in users of T-shaped copper IUDs.


Mid-infrared luminescence properties of Dy-doped silver halide crystals.
The absorption and the kinetics of the emission in the mid-infrared (mid-IR) were investigated in AgCl(x)Br(1-x) crystals doped with Dy(3+) ions. Strong emission bands were detected at 3, 4.4, and 5.5 μm and attributed to the (6)H(13/2)→(6)H(15/2), (6)H(11/2)→(6)H(13/2), and (6)F(11/2)+(6)H(9/2)→(6)H(11/2) transitions. Various optical parameters were calculated for the Dy(3+) doped crystals, using the Judd-Ofelt approximation and the rate equations. The measured results and the calculated parameters indicate that these doped crystals could be used for the development of mid-IR solid-state lasers or mid-IR fiber lasers.


Who fired the gun? A casuistic contribution to the differentiation between self-inflicted and non-self-inflicted gunshot wounds.
A fatal gunshot wound to the thorax from a .357 Magnum revolver is reported. The entrance wound was located dorsally at the transition of the right shoulder and the upper arm, the exit wound below the left axilla and a re-entry at the medial aspect of the left upper arm. A friend of the victim, who was present when the gunshot was fired, stated that it was a self-inflicted accident. But the inclusion of both upper arms in the trajectory allowed a comparison between the posture of the upper arms at the moment the gunshot was fired and the posture of the upper arms necessary for a self-inflicted gunshot wound. This reconstruction, which is presented in detail, definitely excluded a self-inflicted wound. The friend then confessed that he had fired the gun accidentally.


MR image analysis of ex-vivo mouse model of heart ischemia.
Myocardial infarction is one of the major causes of death and disability. Various diagnostic modalities used to investigate cardiac ischaemia. Advances in Magnetic Resonance Imaging technology has opened up new horizons for investigating the cardiac function and quantifying any pathology that may be present. The present study was designed to quantify the cardiac area at risk and infarction reperfusion areas using the mismatch of iron oxide contrast and gadolinium (Gd) contrast imaging (MRIs) and to test if a combination of T1, T2, and iron oxide T2* contrasts will distinguish the infarction and AAR zones. A well-established mouse model was used to induced cardiac ischaemia and reperfusion. Six mice models' hearts were harvested and processed according to various protocols. MI was induced through ligation technique for five mice, and one was kept as normal control. MR imaging and Reperfusion were performed using a Three-dimensional gradient-echo fast low angle shot (3DFLASH) and three-dimensional multi-slice multi-echo sequence (3DMSME). Generation of T1 and T2 maps, image post-processing including segmentation and mismatch measurement and drawing of the area of interest. The edematous myocardium had significant high signal intensity in 3DMSME with variable echo time (14, 28, 42 ms). The combination of 3DFLASH and 3DMSME at an echo time of 42 ms was statistically significant, detecting the AAR more accurately. Both T1 and T2 sequences had the potential to determine the AAR zone. The infarct area has significantly high signal intensity compared to normal areas (p = 0.04 for the T1 map and p = 0.01 for the T2 map). The study demonstrated that Cardiac MRI was a valuable technology to investigate infarct areas and zones that are at risk.


A Survey of Healthcare Internet-of-Things (HIoT): A Clinical Perspective.
In combination with current sociological trends, the maturing development of IoT devices is projected to revolutionize healthcare. A network of body-worn sensors, each with a unique ID, can collect health data that is orders-of-magnitude richer than what is available today from sporadic observations in clinical/hospital environments. When databased, analyzed, and compared against information from other individuals using data analytics, HIoT data enables the personalization and modernization of care with radical improvements in outcomes and reductions in cost. In this paper, we survey existing and emerging technologies that can enable this vision for the future of healthcare, particularly in the clinical practice of healthcare. Three main technology areas underlie the development of this field: (a) sensing, where there is an increased drive for miniaturization and power efficiency; (b) communications, where the enabling factors are ubiquitous connectivity, standardized protocols, and the wide availability of cloud infrastructure, and (c) data analytics and inference, where the availability of large amounts of data and computational resources is revolutionizing algorithms for individualizing inference and actions in health management. Throughout the paper, we use a case study to concretely illustrate the impact of these trends. We conclude our paper with a discussion of the emerging directions, open issues, and challenges.


Factor VII deficiency: a rare genetic bleeding disorder in a 7-year-old child: a case report.
Factor VII deficiency is a rare inherited bleeding disorder that has similar clinical presentation to hemophilia. A 7-year-old male child of African origin experienced recurrent nasal bleeding since 3 years of age and recurrent swelling of the joints that was remarkable at the age of 5-6 years. He received multiple blood transfusions and has been managed as a patient with hemophilia until he presented to our facility. Reviewed evaluation of the patient revealed abnormal prothrombin and normal activated partial thromboplastin time, FVII analysis showed activity level of less than 1%, and the diagnosis of FVII deficiency was made. The patient was treated with fresh frozen plasma, vitamin K injection, and tranexamic tablets. Even though factor VII deficiency is an extremely rare bleeding disorder, it does occur in our setting. This case highlights the need for clinicians to consider this condition when faced with challenging patients presenting with bleeding disorders.


Shell layers of the black-lip pearl oyster Pinctada margaritifera: matching microstructure and composition.
The nacre-prism transition of the mollusc shell Pinctada margaritifera was studied using scanning electron microscopy, electron probe micro-analysis (EPMA) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). Mineralogical change is correlated with a change in organic matrix. Previous analyses had shown that sugars were involved in the transition layer (fibrous aragonite). The new Energy Dispersive Spectrometry (EDS) and TOF-SIMS maps show that the modifications at the layer boundary are complex, and that proteins and lipids are also involved. Detailed TOF-SIMS maps show that the thick organic envelopes surrounding the prisms, and between the prisms and the fibrous aragonitic layer, are not composed by regular layers, but are a patchwork of various molecules. The amino acid compositions of the nacreous and prismatic layer are compared thanks to the TOF-SIMS localized analyses.


Control of protein synthesis by hemin. Isolation and characterization of a supernatant factor from rabbit reticulocyte lysate.
The regulation of protein synthesis by hemin in rabbit reticulocyte lysates is mediated by a hemin-controlled translational repressor protein (HCR) that inhibits polypeptide chain initiation. The effect of this translational inhibitor can be reversed by a high molecular weight protein in the post-ribosomal supernatant fraction. This supernatant factor has been purified approx. 700-fold. It is as effective in reversing the inhibition of protein synthesis due to an early form of HCR (intermediate HCR) as it is in stimulating protein synthesis in the absence of hemin. It is progressively less effective at reversing the inhibition of protein synthesis due to a late from of HCR (irreversible HCR), double-stranded RNA, and oxidized glutathione. The supernatant factor is chromatographically different from the initiation factor IF-MP, isolated from reticulocyte ribosomes, that can also overcome the inhibitory effect of HCR. The supernatant factor does not require hemin for activity, and its action is somewhat suppressed by a level of hemin that is optimal for protein synthesis.


SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses.
Glutamate uptake into synaptic vesicles (SVs) depends on cation/H+ exchange activity, which converts the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane at the presynaptic terminals. Thus, the proper recruitment of cation/H+ exchanger to SVs is important in determining glutamate quantal size, yet little is known about its localization mechanism. Here, we found that secretory carrier membrane protein 5 (SCAMP5) interacted with the cation/H+ exchanger NHE6, and this interaction regulated NHE6 recruitment to glutamatergic presynaptic terminals. Protein-protein interaction analysis with truncated constructs revealed that the 2/3 loop domain of SCAMP5 is directly associated with the C-terminal region of NHE6. The use of optical imaging and electrophysiological recording showed that small hairpin RNA-mediated knockdown (KD) of SCAMP5 or perturbation of SCAMP5/NHE6 interaction markedly inhibited axonal trafficking and the presynaptic localization of NHE6, leading to hyperacidification of SVs and a reduction in the quantal size of glutamate release. Knockout of NHE6 occluded the effect of SCAMP5 KD without causing additional defects. Together, our results reveal that as a key regulator of axonal trafficking and synaptic localization of NHE6, SCAMP5 could adjust presynaptic strength by regulating quantal size at glutamatergic synapses. Since both proteins are autism candidate genes, the reduced quantal size by interrupting their interaction may underscore synaptic dysfunction observed in autism.


VALUE-BASED ORAL HEALTH CARE: IMPLEMENTATION LESSONS FROM FOUR CASE STUDIES.
Value-Based Healthcare has gained considerable attention in medicine but relatively little in oral health care so far. Implementation of Value-Based Oral Health Care (VBOHC) is complicated by a multitude of system-level and contextual factors, especially the siloed innovation culture in dentistry which has been evolving separately from the broader medical system. Previous literature has described 4 key limitations to adaptation of value-based health care, that is creating multidisciplinary units, measuring patient-centered outcomes, attributing and communicating costs, and bundling payments. This paper presents 4 case studies on oral health care which provide relevant learnings about addressing challenges when seeking to implement VBOHC: (i) The Nurse Practitioner-Dental (NPD) Model outlines an approach for creating a multi-disciplinary center in monitoring chronic diseases improving healthcare outcomes; (ii) Treatment of Early Childhood Caries displays the utility of quality measures in value measurement and placing patients at the center of their care; (iii) ClearChoice Dental Implant Centers outlines how cost attribution leads to better management and creation of value centers; and (iv) Proposed Payment Model Changes in Oral Maxillofacial Surgery outlines a method to cover all episodic care of this otherwise expensive disease. Despite the challenges of implementing VBOHC, this paper provides insights into its feasibility and actionability.


Posterior tibial tendon dysfunction.
Posterior tibial tendon dysfunction, a common entity, frequently is unrecognized and inappropriately managed. Acutely, pain and swelling are present over the medial ankle and longitudinal arch. Long-standing inflammation can lead to tendon rupture, resulting in a progressive planovalgus or "flat foot" deformity. Plain radiographs illustrate the changes in bony anatomy associated with chronic posterior tibial deficiency, while magnetic resonance imaging scans can identify the three stages of posterior tibial tendon pathology. Most cases are amenable to conservative therapy, including rest and administration of nonsteroidal antiflammatory agents. Often a short period of immobilization in a cast or the use of an orthosis is beneficial. In cases with persistent tenosynovitis, complete tendon rupture, or progressive deformity, surgical intervention is indicated.


Preservation of neuronal ultrastructure in hippocampal slices using rapid microwave-enhanced fixation.
The goal of this study was to obtain fixation as rapidly as possible and to achieve preservation of neuronal ultrastructure to a depth in hippocampal slices where electrophysiological responses are optimal. This study demonstrates that perfusion quality preservation of in vitro hippocampal slices can be achieved within seconds after removal from the incubation chamber by using microwave (MW)-enhanced immersion in mixed aldehydes. The optimal method was determined to be MW irradiation of the slice for 8-11 s, to a tissue temperature of 35-50 degrees C, during immersion in fixative containing 6% glutaraldehyde and 2% paraformaldehyde. Electron microscopy of these slices revealed ultrastructural preservation that was comparable to hippocampi from animals perfused with mixed aldehyde fixative containing 2.5% glutaraldehyde and 2% paraformaldehyde. Excellent ultrastructural preservation extended to 100-175 microns from the hippocampal slice surface after MW-enhanced fixation and therefore was much deeper than the 8-20 microns that can be obtained by rapid freezing. Hippocampal slices are routinely maintained in vitro for electrophysiological or pharmacological studies. This method of MW-enhanced fixation preserves tissue within seconds after removal from incubation, and should provide good preservation of the hippocampal anatomy that might be associated with in vitro physiology.


p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies.
A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particularly, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very different outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldeströn macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these different subtypes of monoclonal gammopathies. The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenström Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three different assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite). Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenström Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.


Associations of Strength and Spatiotemporal Gait Variables With Knee Loading During Gait After Anterior Cruciate Ligament Reconstruction.
Altered knee moments are common during gait in patients after anterior cruciate ligament reconstruction (ACLR). Modifiable factors that influence knee moments and are feasible to record in clinical settings such as strength and spatiotemporal values (eg, step length, step width) have not been identified in persons after ACLR. To identify strength and spatiotemporal gait values that can predict knee moments in persons after ACLR. Cross-sectional study. Laboratory. Twenty-three individuals with ACLR (14.4 ± 17.2 months post-ACLR). Peak knee-flexion and -adduction moments were measured while the participants walked at self-selected speeds. Peak isokinetic knee-extensor strength (60°/s) was recorded on a dynamometer, and spatiotemporal gait values were recorded using a pressure walkway. Pearson coefficients were calculated to examine the association of peak knee moments with strength and gait values. Variables correlated with peak knee-flexion and -adduction moments were entered into a stepwise regression model. Knee-extensor strength and step width were the strongest predictors of knee-flexion moment, accounting for 44% of the variance, whereas stance-phase time and step width were the strongest predictors of knee-adduction moment, explaining 62% of the variance. The identified spatiotemporal variables could be clinically feasible targets for biofeedback to improve gait after ACLR.


Testosterone is correlated with courtship but not aggression in the tropical buff-banded rail, Gallirallus philippensis.
Past studies into the roles of testosterone in birds have focused on species that occur in temperate regions. In such species, plasma testosterone levels are high during the establishment of territories in the spring and are associated with increased aggression. In contrast to most temperate species, tropical birds frequently defend territories year-round, during which time territoriality often occurs in a nonsexual context. The few studies that have been carried out on tropical birds show lower levels of circulating testosterone than occur in their temperate counterparts. In some year-round territorial tropical species, testosterone and aggression are dissociated, while in other species testosterone still plays a role in regulating aggression. This study examined the relationship between aggression and plasma testosterone levels in a year-round territorial, subtropical population of the buff-banded rail with characteristics typical of tropical species. Peak testosterone levels were substantially lower than those found in temperate species. Males displayed a seasonal peak in plasma testosterone level when their partners were most likely to be fertile. At other times, testosterone levels were mostly undetectable, despite year-round territoriality. We found that T levels increased with courtship behavior but showed no relationship with aggression, supporting the hypothesis that dissociation between testosterone and territoriality may be widespread among tropical avian taxa.


Effects of Conditioned Medium from Bone Marrow Cells on Human Umbilical Cord Perivascular Cells.
Mesenchymal cells derived from human umbilical cord tissue are attracting increasing attention as a source for cell therapy. However, for applying the same in tissue engineering, it has been shown that the differentiation capacity of mesenchymal stromal cells (MSCs) is influenced by the tissue from which the cells are harvested. Thus, to explore the possibility of increasing the osteogenic capacity of MSCs derived from the perivascular tissue of the human umbilical cord (human umbilical cord perivascular cells, HUCPVCs), we cultured these cells using conditioned medium (CM) derived from cultures of human bone marrow-derived mesenchymal stromal cells (hBMMSCs). However, hBM-CM contains a wide variety of growth factors, the amounts and ratios of which are considered to vary with the cell culture stage. Thus, we aimed to evaluate the effects of hBM-CM derived from different stages of hBMMSC culture on the osteogenic capacity of HUCPVCs. The stages of hBMMSC culture were defined as follows: Stage 1 (mitogenic stage) represented the period from the start of hBMMSC culture to 70% cell confluence; Stage 2 (confluent stage) represented the period from 70% confluence to the initiation of calcified nodule formation; and Stage 3 (calcification stage) represented the period following the initiation of calcified nodule formation. An analysis of growth factors contained in the CM obtained at each stage by enzyme-linked immunosorbent assay showed that insulin-like growth factor 1 (IGF-1) was significantly elevated at Stage 2, whereas vascular endothelial growth factor (VEGF) was significantly elevated at Stage 3. HUCPVCs were cultured using the CM from each of the stages for 1, 2, or 3 weeks. RUNX2 expression was the most upregulated at week 1 and then downregulated in all the groups. The expression of collagen 1 was significantly elevated in Stage 2 HUCs at week 3. Alkaline phosphatase (ALP) activity, ALP, and alizarin staining were higher in Stage 2 HUCs and Stage 3 HUCs. The calcium content was the highest in Stage 2 HUCs. The calcium content of HUCPVC obtained by the method used in this study was six times higher than that reported in the previous study. Collectively, our results show that the CM obtained at Stage 2 was most effective in driving the osteogenic differentiation of HUCPVCs. Impact Statement Mesenchymal stromal cells (MSCs) derived from the perivascular tissue of umbilical cords are promising candidates for regenerative medicine. Because these are able to be differentiated into bone cells, cartilage cells, and adipocytes. The number of MSCs in perivascular tissue (HUCPVCs) is ∼1/300 but the number of HUCPVCs that differentiates into osteogenic cells is quite low. In order to promote osteogenic differentiation of HUCPVCs, we cultured HUCPVCs using conditioned medium collected from human bone marrow-derived mesenchymal stromal cells. Our study suggests that the use of conditioned medium can be effective on inducing osteogenic differentiation of HUCPVCs.


Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors.
The concurrent influence of multiple neurotransmitter systems in mediating cocaine-induced convulsions is predicted by the results of previous receptor binding studies. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alters the occurrence of cocaine-induced convulsions. The 5-HT reuptake inhibitor fluoxetine enhanced the occurrence and severity of convulsions produced by 100 mg/kg (-) cocaine, while the 5-HT2 receptor antagonists cinanserin, ketanserin and pirenperone antagonized cocaine-induced convulsions in a dose-dependent manner. Further, the M1 receptor antagonist pirenzepine antagonized cocaine-induced convulsions, but atropine did not. In addition, both the (+) and (-) stereoisomers of the sigma ligand SKF 10047 significantly attenuated cocaine-induced convulsions. (+)SKF 10047 was more potent than (-)SKF 10047 in this effect, suggesting a stereoselective effect at sigma receptor sites. In constrast, DA and NE neurotransmission do not appear to modulate the proconvulsant effects of cocaine in a specific, dose-dependent manner. Thus, of the CNS binding sites with which cocaine is known to interact, the results are consistent with the conclusion that 5-HT transporters and 5-HT2 receptor sites appear to be direct and primary sites related to cocaine-induced convulsions, while M1 and sigma binding sites appear to play important but secondary and modulatory roles in this response.


Validation of an 8-item Recovery Assessment Scale (RAS-8) for people with schizophrenia in China.
The 24-item Recovery Assessment Scale (RAS) is the most widely-used and well-validated tool for measuring recovery for people with mental illness. The current study aims to assess the reliability and validity of an 8-item short form of RAS (RAS-8) among a Chinese sample of people living with schizophrenia. A sample of 400 people living with schizophrenia were recruited for scale validation. Internal consistency was tested by calculating Cronbach's α. Test-retest reliability was calculated using the intraclass correlation coefficient (ICC) for the total score and weighted kappa for each item. Factor structure was tested with confirmatory factor analysis, and concurrent validity was examined by investigating the correlation of the RAS-8 with patient symptoms, disability, depression, anxiety, patient functioning, quality of life and general health. The RAS-8 full scale and subscales showed good internal consistency with Cronbach's alpha ranging from 0.87 to 0.92. ICC of 0.99 and weighted kappa ranged from 0.62 to 0.88, which generally indicates good test-retest reliability. The findings supported an a priori two-factor structure, χ2/df = 2.93, CFI = 0.98, TLI = 0.98, RMSEA = 0.07, SRMR = 0.035. Concurrent validity of the RAS-8 was further supported by its significant negative correlations with patient symptoms (r = -0.24, p < 0.01), disability (r = -0.30, p < 0.01), depression (r = -0.16, p < 0.05), and anxiety (r = -0.14, p < 0.05), and its significant positive relationships with patient functioning (r = 0.26, p < 0.01), quality of life (r = 0.39, p < 0.01) and general health (r = 0.34, p < 0.01). This study confirmed the reliability and validity of an 8-item short-form RAS for people living with schizophrenia in Chinese communities. The validation of the RAS-8 allows for its use as an alternative for the full RAS as a rapid assessment tool in clinical and research settings. The findings are discussed for their implications for application and validation with other populations and in other countries.


Fatty-acid composition of Mycoplasma lipids: biomembrane with only 1 fatty acid.
Mycoplasma strain Y grew well when elaidate was the only fatty acid added to the medium, and this acid then comprised over 97 percent of the lipid fatty acids. It also grew well when elaidate was supplied together with any one of a series of straight-chain saturated fatty acids, and the lipids then contained both in approximately equimolar proportions. The ratio of cholesterol to phospholipid remained constant.


Gray matter pathology in (chronic) MS: modern views on an early observation.
Involvement of the gray matter (GM) in the pathology of multiple sclerosis (MS) was already recognized in the early days of MS research, but the detection of (cortical) GM lesions under the microscope and with magnetic resonance imaging (MRI) techniques was initially suboptimal and could only recently be enhanced. The visualization of GM lesions in vivo opens new doors for studies focusing on clinical, especially cognitive, effects of GM pathology, as well as for monitoring of neuroprotective treatment. However, so far little is known about what causes GM pathology. In this review, several pathogenetic mechanisms will be discussed, affecting the MS brain both from the 'outside-in' and from the 'inside-out'. Also, the use and reliability of MRI atrophy measures as a monitoring tool for GM damage in the therapeutic setting will be reviewed.


Use of metabarcoding and source tracking to identify desirable or spoilage autochthonous microorganism sources during black olive fermentations.
This study aimed at investigating the influence of the process environment and raw materials as sources of microorganisms during Nyons black table olive fermentations. Fermented olives and/or brine from spoiled fermentation tanks were analyzed and compared to good quality samples from fermentations collected during 3 consecutive harvest years. Fresh olives, salt and different process environment samples were also analyzed. Microbial diversity of all samples was analyzed using 16S and ITS2 amplicon sequencing and SourceTracker tool was used to investigate links between environment, raw materials and fermentation samples. First, comparison of microbial diversity in control and most spoiled fermentations revealed striking differences in bacterial composition with an overall higher diversity in spoiled fermentations especially for lactic acid bacteria with Lentilactobacillus buchneri, Lentilactobacillus parafarraginis dominating in brine and Pediococcus parvulus, Pediococcus ethanolidurans dominating in olive fruits. Fungal communities were similar in composition although higher abundances of Pichia membranifaciens and Penicillium carneum/roqueforti were observed in spoiled samples. Secondly, process environment samples were characterized by high bacterial and fungal diversity, especially compared to fresh olive fruits. Overall, dominant fungal species in control fermentations were also found in most environmental samples revealing a "house mycobiota". SourceTracker analysis further highlighted the contribution of brine and water from the optical sorter as a source of fungi. Most interestingly, spoilage fungi and most bacteria were retrieved in brine and environmental samples while others such as P. ethanolidurans were only found in environmental samples indicating that the studied spoilage originated from a fermentation deviation rather than a punctual contamination. Taken altogether, these results highlighted the positive and negative influence of the process environment and emphasized the relevance of studying it to better understand microbial vectors occurring during food fermentations, especially natural ones.


Executive function in Down syndrome: A meta-analysis.
Executive function (EF) refers to a set of cognitive processes involved in goal-oriented behavior-especially inhibition, attention shifting, and working memory. EF has been identified as a probable area of difficulty in Down syndrome (DS), but the exact nature of the difficulty has not been well-established. The meta-analysis sought to confirm or disconfirm EF as an area of difficulty in DS and elucidate an EF profile. A random-effects meta-analysis was conducted on 57 studies that compared a group with DS to a typically developing (TD) mental age matched group on one or more executive function tasks. Heterogeneity was examined and moderators analyzed. The overall mean weighted effect size was large (d = -0.87), indicating poorer EF in groups with DS vs TD groups. Heterogeneity was significant, and moderator analysis revealed an EF profile with a very large effect for verbal WM/STM, a large effect for shifting, and moderate effects for inhibition and nonverbal WM/STM. Skewness analysis suggested that mean effect sizes might have been dampened, especially for WM/STM and shifting. Individuals with DS display a pronounced difficulty in EFs; implications for interventions and future research are discussed.


The use of ionic and nonionic contrast agents and the effects of hydration in the post cardiac transplant patient with moderate renal insufficiency.
To determine the effects of ionic (diatrizoate) and nonionic (iopamidol) contrast and of hydration, 90 asymptomatic cyclosporine-treated cardiac transplant patients with moderate renal insufficiency (serum creatinine greater than or equal to 1.5 mg/dL) undergoing cardiac catheterization were evaluated. All patients were hydrated with intravenous fluid (5% dextrose and 0.5 normal saline) over a twelve-hour period prior to catheterization and with oral fluids thereafter. Thirty patients received iopamidol (Group I) and 60 were given diatrizoate (Group II). Renal function was determined the day before and after catheterization in all patients of Group I and in 30 patients of Group II (Group IIa). In the remaining 30 patients of Group II renal function was also determined before contrast administration (Group IIb). The dose of dye was similar in all groups (I: 139 +/- 55 mL, IIa: 140 +/- 58 mL, IIb: 128 +/- 38 mL). There was a significant decrease in BUN (I: 41 +/- 10 to 33 +/- 8 mg/dL [p less than 0.005], IIa: 42 +/- 9 to 33 +/- 8 mg/dL mg/dL [p less than 0.001], IIb: (44 +/- 12 to 34 +/- 10 mg/dL [p less than 0.005]) and a small decrease in serum cratinine after catheterization (I: 2.0 +/- 0.3 to 1.9 +/- 0.3 mg/dL, IId: 2.0 +/- 0.3 to 1.9 +/- 0.3 mg/dL, IIb: 2.1 +/- 0.4 to 1.8 +/- 0.4 mg/dL [p less than 0.005].(ABSTRACT TRUNCATED AT 250 WORDS)


Role of apoptosis in the development of autosomal dominant polycystic kidney disease (ADPKD).
Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disorder in the Western world and is characterized by cystogenesis that often leads to end-stage renal disease (ESRD). Mutations in the pkd1 gene, encoding for polycystin-1 (PC1) and its interaction partner pkd2, encoding for polycystin-2 (PC2), are the main drivers of this disease. PC1 and PC2 form a multiprotein membrane complex at cilia sites of the plasma membrane and at intracellular membranes. This complex mediates calcium influx and stimulates various signaling pathways regulating cell survival, proliferation and differentiation. The molecular consequences of pkd1 and pkd2 mutations are still a matter of debate. In particular, the ways in which the cysts are initially formed and progress throughout the disease are unknown. The mechanisms proposed to play a role include enhanced cell proliferation, increased apoptotic cell death and diminished autophagy. In this review, we summarize our current understanding about the contribution of apoptosis to cystogenesis and ADPKD. We present the animal models and the tools and methods that have been created to analyze this process. We also critically review the data that are in favor or against the involvement of apoptosis in disease generation. We argue that apoptosis is probably not the sole driver of cystogenesis but that a cooperative action of cell death, compensatory cell proliferation and perturbed autophagy gradually establish the disease. Finally, we propose novel strategies for uncovering the mode of action of PC1 and PC2 and suggest means by which their dysfunction or loss of expression lead to cystogenesis and ADPKD development.


Effectiveness of trimebutine maleate on modulating intestinal hypercontractility in a mouse model of postinfectious irritable bowel syndrome.
Trimebutine maleate, which modulates the calcium and potassium channels, relieves abdominal pain in patients with irritable bowel syndrome. However, its effect on postinfectious irritable bowel syndrome is not clarified. The aim of this study was to investigate the effectiveness of trimebutine maleate on modulating colonic hypercontractility in a mouse model of postinfectious irritable bowel syndrome. Mice infected up to 8 weeks with T. spiralis underwent abdominal withdrawal reflex to colorectal distention to evaluate the visceral sensitivity at different time points. Tissues were examined for histopathology scores. Colonic longitudinal muscle strips were prepared in the organ bath under basal condition or to be stimulated by acetylcholine and potassium chloride, and consecutive concentrations of trimebutine maleate were added to the bath to record the strip responses. Significant inflammation was observed in the intestines of the mice infected 2 weeks, and it resolved in 8 weeks after infection. Visceral hyperalgesia and colonic muscle hypercontractility emerged after infection, and trimebutine maleate could effectively reduce the colonic hyperreactivity. Hypercontractility of the colonic muscle stimulated by acetylcholine and high K(+) could be inhibited by trimebutine maleate in solution with Ca(2+), but not in Ca(2+) free solution. Compared with 8-week postinfectious irritable bowel syndrome group, 2-week acute infected strips were much more sensitive to the stimulators and the drug trimebutine maleate. Trimebutine maleate was effective in reducing the colonic muscle hypercontractility of postinfectious irritable bowel syndrome mice. The findings may provide evidence for trimebutine maleate to treat postinfectious irritable bowel syndrome patients effectively.


ADP ribosylation of the specific membrane protein of C6 cells by islet-activating protein associated with modification of adenylate cyclase activity.
Islet-activating protein (IAP), one of the pertussis toxins, exerted dual actions on crude membrane preparations from rat C6 glioma cells; an Mr = 41,000 membrane protein was ADP-ribosylated while GTP (and GTP-dependent isoproterenol) activation of membrane adenylate cyclase was enhanced when membranes were incubated with IaP. Both actions of IaP were dependent on the incubation time and the concentrations of NAD and IAP, and were inhibited by nicotinamide; the one action was strictly paralleled by the other in magnitude. Tryptic digestion of the Mr = 41,000 protein was markedly influenced by the presence of guanyl-5'-yl beta-gamma-imidodiphosphate or NaF, the specific ligands of the regulatory component of the adenylate cyclase system. No ADP ribosylation occurred in the membranes prepared from intact C6 cells that had been incubated with IAP, suggesting that the IAP substrate had already been ADP-ribosylated by the intracellular NAD during incubation of the intact cells. Cholera toxin catalyzed ADP ribosylation of other proteins with Mr = 45,000 and 48,000/49,000 (doublet). It is concluded that IAP, added to intact cells or isolated membranes, causes unique modification of the receptor-adenylate cyclase coupling mechanism as a result of ADP ribosylation of the Mr = 41,000 protein which is presumably one of the subunits, other than the cholera toxin substrates, of the guanine nucleotide regulatory component of the cyclase system.


Low-dose heparin therapy in the long-term management of venous thromboembolism.
The efficacy of a six-month course of low-dose heparin therapy was compared to a conventional warfarin regimen by a prospective, controlled trial in 48 patients with pulmonary embolism or deep venous thrombosis of the legs. All subjects had complicated medical illnesses and a high risk of recurrent thromboembolism. Bleeding complications were virtually negligible during heparin therapy and occurred significantly more frequently in patients receiving warfarin. Heparin was as effective as warfarin in the prevention of recurrent thromboembolism. Patient compliance with the two treatment regimens was comparable. Self-administered, low-dose heparin therapy is a useful alternative to warfarin in the long-term management of complicated thromboembolic disorders.


New species, new records and notes in Cerambycidae from Colombia.
A new species from Colombia is described: Ectenessa caputnigra sp. nov. Taxonomic notes on Adiposphaerion rubrum Martins Napp, 1992, new geographical records to 11 species and the specific locality in Colombia for five species are provided.


Prevalence of osteoporosis among cancer patients in Germany: prospective data from an oncological rehabilitation clinic.
In this prospective study, we measured bone mineral density (BMD) in 1,041 cancer patients undergoing an oncological rehabilitation program in an inpatient rehabilitation clinic. There was an osteoporosis prevalence of approximately 16%, independent of sex, which is considerably higher than in the community-dwelling population. There is evidence that cancer patients are at risk of an increased BMD-loss following the disease and its therapy. Nevertheless, there is only little data available about the prevalence of osteoporosis in German cancer patients. Therefore, we measured BMD in 1,041 oncological inpatients undergoing rehabilitation. From February 2006 to September 2009, BMD was measured in oncological patients with dual-energy x-ray absorptiometry (DXA; femur and spine). Statistical analysis for prevalence of osteoporosis was done in descriptive manner calculating means, standard deviation, frequencies, and 95% confidence intervals. To compare the prevalence of osteoporosis in different subgroups, χ (2) tests were done with p < 0.05. To create a risk profile, odds ratios were calculated using uni- and multivariate logistic regression. In 1,041 patients with a mean age of 57.1 years (11.0 years), DXA-measures were performed. Of them, 22% were male and 78% were female. The osteoporosis prevalence was about 16% (13.8, 18.2), independent of sex (p = 0.9722) or cancer type (p = 0.7174). As risk factors influencing the development of osteoporosis, age, weight, menopausal state, and hormone replacement therapy were identified in women and weight only in men. Compared to the general population, the rate of osteoporosis is distinctly elevated in German cancer patients independent of sex or cancer type. Hence, a general recommendation for a DXA screening in these patients appears to be justified.


Controversies in the treatment of early-stage oral squamous cell carcinoma.
The treatment of early-stage oral squamous cell carcinoma (OSCC) is still a controversial issue. Thanks to the 8th edition of TNM by AJCC there is a better distinction between the stages of OSCC. However, Stages I and II still share the same treatment protocol, even if the prognosis is radically different. A retrospective study has been conducted including 70 previously untreated patients with Stage I or II OSCC, treated with tumorectomy and selective neck dissection. The study focuses on the link between pT1/2 and various other factors, particularly histological grading, vascular and perineural invasion, local and cervical recurrence, surgical margins and overall survival. These data reveal significant differences between pT1 and pT2 in histological grade, perineural invasion, cervical recurrence, surgical margins, and overall survival, emphasizing the necessity of different treatment protocols for T1 and T2 OSCC. Distinct strategies should be proposed to treat Stage I and II OSCC, with Stage II patients possibly benefitting from more aggressive treatments: following these data, a wait-and-see strategy should only be considered in Stage I, while certain treatments at the cervical level - such as prophylactic neck dissection and sentinel node biopsy - should always be considered for Stage II tumors.


Photoelectrochemical polymerization of thiophene on self-assembled RuL2(NCS)2/di(3-aminopropyl)viologen on indium thin oxide.
Polythiophene layers were formed on self-assembled monolayers (SAMs)/indium tin oxide (ITO) using photoelectrochemical polymerization. The SAMs on ITO was prepared using Ru(4,4'-dicarboxylic acid-2,2'-bipyridine)2(NCS)2 and di(3-aminopropyl)viologen. The photoelectrochemically polymerized polythiophene layers on SAMs/ITO were characterized using UV-vis. absorption spectroscopy, atomic force microscopy, scanning electron microscopy, and cyclic voltammetry. The polymer layers have thickness of 360 nm, a dense surface morphology, optical gap of 2.38 eV, highest occupied molecular orbital of -5.2 eV and lowest unoccupied molecular orbital of -2.82 eV. In photoelectrochemical cells, the polythiophene on SAMs/ITO electrode showed a photocurrent of 5 microA/cm2.


Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib.
Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.


Activity and directional sensitivity of leg campaniform sensilla in a stick insect.
1. The mechanoreceptive campaniform sensilla, which are arranged in groups on insect legs, were studied in the stick insect Cuniculina impigra. In middle and rear legs, the most posterior trochanteral campaniform group (group 1) is oriented so as to be stimulated by compressional cuticular forces acting on the posterior articulation of the trochanter with the coxa. 2. Recordings from nerve Tr2, which innervates this campaniform group, confirmed that the sensilla were directionally sensitive to cuticular stress generated by imposed or active movements of the femur. Different individual sensilla had different thresholds of response, but all responded qualitatively in the same way to a given stimulus. 3. Posteriorward horizontal deflection of the femur-trochanter relative to the coxa (at right angles to the normal plane of movement) produced a strong excitation of the group 1 sensilla. Anteriorward horizontal deflection caused a sharp reduction of on-going background activity in the group. Imposed vertical movements of the femur usually had little effect on the activity of the campaniform sensilla. 4. Active depression of the femur-trochanter by the animal reduced on-going background activity in proportion to the strength of the depression movement. Elevation that simulated muscle-generated lifting of the leg strongly increased activity. 5. It is concluded that campaniform group 1 functions to signal passive horizontal and active vertical movements around the trochantero-coxal joint of the leg. This dual pattern of response means that the animal cannot interpret signals from this campaniform group without also having information about muscle activity.


Laryngeal Framework Surgical Anatomy: A Radiological Study.
Awareness of variations in laryngeal anatomy among different age and gender groups is crucial during laryngeal framework surgery. The aim of this study is to demonstrate the relationship between gender and laryngeal radiologic morphometrics among different age groups and the applicability of important anatomical landmarks of laryngeal surgery. Laryngeal images of 180 adult patients older than 18 years of age were obtained by computed tomography and assessed. A total of 11 measurements of important laryngeal landmarks were taken from the patients' computed tomography images. Results were subgrouped according to gender and age, and these groups were compared for each measurement. The majority of laryngeal measurements obtained in the study were higher in males than females, with the exception of the interlaminar angle. The mean interlaminar angle value was 88.27°± 14.99 for males and 103.04°± 14.81 for females (P <0.005). The distance from the anterior commissure to the inferior border of the thyroid cartilage was 10.46 ± 2.5 mm for males and 7.72 ± 1.9 mm for females. The anterior commissure locates slightly higher than the midpoint of the distance from the thyroid notch to the thyroid inferior border. The shortest distance between the muscular process of the arytenoid cartilage and the thyroid cartilage was found to be 9.60 ± 3.47 mm for males and 7.72 ± 2.33 mm for females (P <0.001). Observation of obvious diversities in the size and distance of the important laryngeal structures between the gender groups is an important factor to be considered for successful laryngeal framework surgery. Also, using the midpoint of the thyroid cartilage as a landmark for anterior commissure is a practical method during surgery, especially for thyroplasty.


Lymphoblastoid cell lines and Burkitt-lymphoma-derived cell lines differ in the expression of a second Epstein-Barr virus encoded nuclear antigen.
Twenty-seven Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and 27 EBV-carrying Burkitt-lymphoma-derived lines were analyzed for expression of the second EBV-encoded nuclear antigen (EBNA-2) by immunoblotting and anticomplement immunofluorescence with EBNA-2-specific sera. While all lymphoblastoid cell lines expressed EBNA-2, only 10 of the 27 BL lines were EBNA-2-positive. Comparison of the EBNA-2 coding BamHI W-, Y- and H-fragments of EBV-DNA in the different cell lines by restriction enzyme analysis suggests that EBNA-2 negativity is due either to sequence diversity or to a deletion in the BamHI WYH region.


Stimulating program implementation via a Community of Practice: a responsive evaluation of care programs for frail older people in the Netherlands.
Evaluation is often used as a vehicle to improve program implementation. To evaluate the implementation of programs that provide care for frail older people a Community of Practice (CoP) was developed in the Netherlands. The purpose of this paper is to describe and reflect on the role of a CoP in the implementation of these programs. Using a responsive evaluation approach this study was based on interviews with participating stakeholders and transcripts of the CoP meetings with 13 professionals, project managers and patient representatives. Findings showed that CoP members had unanticipated concerns regarding the pro-active approach of the programs and older people not being open to receiving care. The heterogenic composition was appreciated and fostered learning. A social infrastructure was created for active learning inside and outside the CoP. We conclude that a CoP is a useful strategy as part of an evaluation aimed at improving program implementation. Lessons learned include the importance of creating ownership among CoP members by sharing responsibilities and paying attention to the heterogenic group composition and professional language spoken to involve all members.


FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation.
Increasing evidence suggests that FBXW7 has a high frequency of mutations in esophageal squamous cell carcinoma (ESCC). However, the function of FBXW7, especially the mutations, is not clear. This study was designed to investigate the functional significance of FBXW7 loss of function and underlying mechanism in ESCC. Immunofluorescence was applied to clarify the localization and main isoform of FBXW7 in ESCC cells. Sanger sequencing were performed to explore mutations of FBXW7 in ESCC tissues. Proliferation, colony, invasion and migration assays were performed to examine the functional roles of FBXW7 in ESCC cells in vitro and in vivo. Real-time RT-PCR, immunoblotting, GST-pulldown, LC-MS/MS and co-immunoprecipitation assay were used to explore the molecular mechanism underlying the actions of FBXW7 functional inactivation in ESCC cells. Immunohistochemical staining were used to explore the expression of FBXW7 and MAP4 in ESCC tissues. The main FBXW7 isoform in ESCC cells was the β transcript in the cytoplasm. Functional inactivation of FBXW7 led to activation of the MAPK signaling pathway and upregulation of the downstream MMP3 and VEGFA, which enhanced tumor proliferation cell invasion and migration. Among the five mutation forms screened, S327X (X means truncated mutation) had an effect similar to the FBXW7 deficiency and led to the inactivation of FBXW7 in ESCC cells. Three other point mutations, S382F, D400N and R425C, attenuated but did not eliminate FBXW7 function. The other truncating mutation, S598X, which was located outside of the WD40 domain, revealed a tiny attenuation of FBXW7 in ESCC cells. Notably, MAP4 was identified as a potential target of FBXW7. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. Immunohistochemical staining indicated that FBXW7 loss of function was associated with tumor stage and shorter survival of patients with ESCC. Univariate and multivariate Cox proportional hazards regression analyses showed that high FBXW7 and low MAP4 was an independent prognostic indicator and prospective longer survival. Moreover, a combination regimen that included MK-8353 to inhibit the phosphorylation of ERK and bevacizumab to inhibit VEGFA produced potent inhibitory effects on the growth of FBXW7 inactivation xenograft tumors in vivo. This study provided evidence that FBXW7 loss of function promoted ESCC via MAP4 overexpression and ERK phosphorylation, and this novel FBXW7/MAP4/ERK axis may be an efficient target for ESCC treatment.


A microdiffraction set-up for nanoporous metal-organic-framework-type solids.
For the past decade, the emerging class of porous metal-organic frameworks has been becoming one of the most promising materials for the construction of extralarge pore networks in view of potential applications in catalysis, separation and gas storage. The knowledge of the atomic arrangements in these crystalline compounds is a key point for the understanding of the chemical and physical properties. Their crystal size limits the use of single-crystal diffraction analysis, and synchrotron radiation facilities may allow for the analysis of tiny crystals. We present here a microdiffraction set-up for the collection of Bragg intensities, which pushes down the limit to the micrometre scale by using a microfocused X-ray beam of 1 mum. We report the structure determination of a new porous metal-organic-framework-type aluminium trimesate (MIL-110) from a single crystal of a few micrometres length, showing very weak scattering factors owing to the composition of the framework (light elements) and very low density. Its structure is built up from a honeycomb-like network with hexagonal 16 A channels, involving the connection of octahedrally coordinated aluminium octameric motifs with the trimesate ligands. Solid-state NMR (27Al,13C,1H) and molecular modelling are finally considered for the structural characterization.


Stromal interaction molecule 1 modulates blood pressure via NO production in vascular endothelial cells.
In vascular endothelial cells, store-operated calcium entry (SOCE) activates endothelial NO synthase (eNOS) and regulates nitric oxide (NO) production as well as flow-dependent mechanical stimuli. Stromal interaction molecule 1, or STIM1, was recently identified to be essential for SOCE, acting as a calcium sensor for intracellular calcium stores. However, how STIM1 affects endothelial function and blood pressure (BP) remains unclear. We generated STIM1 fl/fl mice and vascular endothelial cell-specific STIM1 knockout mice using the Cre-loxP system, and conducted experiments using these mice to clarify the physiological role of STIM1 in vascular endothelial function and BP as follows: (1) SOCE was analyzed in isolated aortic endothelial cells by calcium add-back with fluorescent Ca2+ indicators. Phosphorylation of eNOS and NO production were evaluated by immunoblotting and the NO indicator, respectively. (2) Tension of aortic rings was measured in 10-week-old mice in response to acetylcholine. (3) BP was measured in 10-week-old mice by the telemetry system. The results were: (1) SOCE, eNOS activation, and NO production were suppressed by ~50-60% in endothelial cells from STIM1 knockout. (2) Endothelium-dependent vasodilation was decreased in aortic rings from STIM1 knockout mice, whereas endothelium-independent relaxation was not altered. (3) STIM1 knockout mice exhibited significant BP elevation, especially in nighttime. (124.3 ± 2.5/99.2 ± 3.9 vs. 114.1 ± 3.2/83.6 ± 1.7 (nighttime, mmHg), 109.7 ± 1.7/83.0 ± 3.0 vs. 104.8 ± 3.3/73.7 ± 1.6 (daytime, mmHg), knockout vs. control, respectively). In conclusion, STIM1 in vascular endothelial cell modulates vascular function through NO production and has a major role in regulating BP, especially in the active time.


Growth inhibition of tubercle bacilli after pulsed exposures to combinations of antituberculous drugs.
All possible pairs of drugs chosen from the primary antituberculous agents including isoniazid, streptomycin, rifampin, and ethambutol were compatible and inhibited growth after administration to tubercle bacilli in a single 7 hr pulsed exposure. In general, combined drug effects could be best described as additive.