Detection of human elastase isoforms by the ScheBo Pancreatic Elastase 1 Test.
Determination of fecal pancreatic elastase content by ELISA is a reliable, noninvasive clinical test for assessing exocrine pancreatic function. Despite the widespread use of commercial tests, their exact molecular targets remain poorly characterized. This study was undertaken to clarify which human pancreatic elastase isoforms are detected by the ScheBo Pancreatic Elastase 1 Stool Test and whether naturally occurring genetic variants influence the performance of this test. Using recombinantly expressed and purified human pancreatic proteinases, we found that the test specifically measured chymotrypsin-like elastases (CELA) 3A and 3B (CELA3A and CELA3B), while CELA2A was not detected. Inactive proelastases, active elastases, and autolyzed forms were detected with identical efficiency. CELA3B elicited approximately four times higher ELISA signal than CELA3A, and we identified Glu154 in CELA3B as the critical determinant of detection. Common genetic variants of CELA3A and CELA3B had no effect on test performance, with the exception of the CELA3B variant W79R, which increased detection by 1.4-fold. Finally, none of the human trypsin and chymotrypsin isoforms were detected. We conclude that the ScheBo Pancreatic Elastase 1 Stool Test is specific for human CELA3A and CELA3B, with most of the ELISA signal attributable to CELA3B.NEW & NOTEWORTHY The ScheBo Pancreatic Elastase 1 Stool Test is widely used to assess pancreatic exocrine function, yet its molecular targets have been poorly defined. We demonstrate that, among the human pancreatic proteinases, the test measures the elastase isoform CELA3B and, to a lesser extent, CELA3A. Genetic variants of the human CELA3 isoforms have no significant effect on test performance.


Epidemiology and ecology of onychomycosis.
The epidemiology and ecology of onychomycosis are complex and little understood. Most is known about tinea unguium, dermatophytic nail infection, and its causative agents. This is often categorised according to the precise locus on the nail of the infection. The principal infectious propagules are thought to be the arthroconidia or chlamydospores which form within the solid substratum of invaded nail tissue. The process of infecting new hosts appears to be facilitated by abrasion, moistening and scratching. The role of the non-dermatophyte yeast Candida as an agent of onychomycosis per se may have been overestimated. The range of interactions between dermatophytes and non-dermatophytes in nails is complex and poorly understood. There may be at least six distinct ecological categories of non-dermatophyte isolations from nails. It would be of clinical interest to know which species found in mixed infections were never able to advance beyond 'secondary colonisation', as they would not require specific treatment.


Endoscopic Proximal Hamstring Tendon Repair for Nonretracted Tears: An Anatomic Approach and Repair Technique.
Proximal hamstring injuries are common, and open surgical repair with suture anchors has been the gold standard when surgical intervention is warranted. Endoscopic techniques offer the opportunity of surgical repair with smaller incisions to limit complications and expedite rehabilitation. The purpose of this technique guide is to describe a modified endoscopic technique that allows a safe and anatomic repair of proximal hamstring injuries. The patient is positioned prone with the feet at the head of the bed, table in reverse Trendelenburg, and knees flexed to 90°. Four portals are used, 3 in horizontal alignment within the gluteal fold and 1 directly superior to the ischial tuberosity. The sciatic nerve is identified, dissected, and mobilized away from the operative field. Retraction sutures help retract the gluteus maximus and further protect the sciatic nerve. Dissection is within the interval between the conjoint and semimembranosus tendons. The tendons are freed and mobilized, the ischial tuberosity is decorticated, and an anatomic repair is performed via 4 suture anchors, 2 at each tendon footprint. Advancements in arthroscopy have permitted adequate visualization and exposure of the hamstring footprint, thus allowing for an anatomic repair with increased protection of the sciatic nerve and decreased resources and cost.


The human beta-globin gene contains a downstream developmental specific enhancer.
The human beta-globin gene is part of a multigene family and is expressed specifically in adult human erythroid tissue (for review, 1). When the human beta-globin is introduced into fertilized mouse eggs, it is first activated in foetal liver and remains expressed in adult erythroid tissues. It therefore mimicks the pattern of expression of its murine counterpart. It has previously been shown in tissue culture and transgenic mice that sequences downstream from the beta-globin promoter are involved in this regulation. We now show that at least part of these sequences are located 0.5-1.2kb downstream from the poly A addition site and constitute a transcriptional enhancer element that is erythroid and developmental specific.


Analysis of combinatorial cis-regulation in synthetic and genomic promoters.
Transcription factor binding sites are being discovered at a rapid pace. It is now necessary to turn attention towards understanding how these sites work in combination to influence gene expression. Quantitative models that accurately predict gene expression from promoter sequence will be a crucial part of solving this problem. Here we present such a model, based on the analysis of synthetic promoter libraries in yeast (Saccharomyces cerevisiae). Thermodynamic models based only on the equilibrium binding of transcription factors to DNA and to each other captured a large fraction of the variation in expression in every library. Thermodynamic analysis of these libraries uncovered several phenomena in our system, including cooperativity and the effects of weak binding sites. When applied to the S. cerevisiae genome, a model of repression by Mig1 (which was trained on synthetic promoters) predicts a number of Mig1-regulated genes that lack significant Mig1-binding sites in their promoters. The success of the thermodynamic approach suggests that the information encoded by combinations of cis-regulatory sites is interpreted primarily through simple protein-DNA and protein-protein interactions, with complicated biochemical reactions-such as nucleosome modifications-being downstream events. Quantitative analyses of synthetic promoter libraries will be an important tool in unravelling the rules underlying combinatorial cis-regulation.


Leuprolide Acetate Release Study from γ-Irradiated PLGA-based In Situ Forming System.
It is well known that the properties of polymers can be altered by exposure to γ- ray. γ-irradiation has been used as a sterilization method for polymeric drug delivery devices, and its drug release profile must not be significantly changed. In this study, the effect of γ-irradiation on the release profile of leuprolide acetate from PLGA-based in situ forming system was investigated. Poly(lactide-co-glycolide) (PLGA) was dissolved in N-methylpyrrolidinone (NMP) and irradiated with a total dose of 8 kGy γ-ray emitted by a 60Co source. Then, leuprolide acetate was added to the polymer solution. PLGA-based in situ forming systems were prepared by injecting some specific amount of prepared solution into a buffer phosphate pH 7.4 at 37 °C. The effects of γ-ray on drug release profiles, morphology of matrices and thermal properties as well as stability of polymer were evaluated. The results showed that γ-irradiation causes a decrease in glass transition temperature (Tg) of PLGA from 43.4 to 38.1°C. A reduction in molecular weight of PLGA by about 17.8 % was found as consequence of radiolytic degradation. The morphological studies of PLGA matrices confirmed that the irradiated sample had higher porosity than the non-irradiated sample. It is found that the amount of released leuprolide acetate from irradiated matrix was increased by about 1.6 times after 33 days compared to the nonirradiated ones. In vitro drug release experimental data were fitted using the Gallagher- Corrigan model which indicated that diffusion and degradation were the predominant mechanisms of drug release. Accordingly, leuprolide acetate was released faster from the irradiated matrix compared to the non- irradiated matrix.


Current Pacemaker Therapy Surgical consideration involving leads and lead placement.
The implantable pacemaker, like the telephone, has evolved from a rather straightforward device, which offered virtually no choice to its early users, to a highly complex system embodying a number of choices, many of which must be made at the outset because they affect the performance of the system throughout its lifetime. The most important of these choices, is, of course, selection of the mode of pacing and its relationship to the underlying arrythmia. These considerations are discussed in considerable detail in Dr Nora Goldschlager's article on electrophysiology, and will not be repeated. The focus of this discussion will be on surgical techniques of implantation, particularly as related to the evolution of the modern lead system.


Modeling thin-film piezoelectric polymer ultrasonic sensors.
This paper presents a model suitable to design and characterize broadband thin film sensors based on piezoelectric polymers. The aim is to describe adequately the sensor behavior, with a reasonable number of parameters and based on well-known physical equations. The mechanical variables are described by an acoustic transmission line. The electrical behavior is described by the quasi-static approximation, given the large difference between the velocities of propagation of the electrical and mechanical disturbances. The line parameters include the effects of the elastic and electrical properties of the material. The model was validated with measurements of a poly(vinylidene flouride) sensor designed for short-pulse detection. The model variables were calculated from the properties of the polymer at frequencies between 100 Hz and 30 MHz and at temperatures between 283 K and 313 K, a relevant range for applications in biology and medicine. The simulations agree very well with the experimental data, predicting satisfactorily the influence of temperature and the dielectric properties of the polymer on the behavior of the sensor. Conversely, the model allowed the calculation of the material dielectric properties from the measured response of the sensor, with good agreement with the published values.


Carbapenemase Detection among Carbapenem-Resistant Glucose-Nonfermenting Gram-Negative Bacilli.
Accurate detection of carbapenemase-producing glucose-nonfermenting Gram-negative bacilli (CPNFs), including Pseudomonas aeruginosa and Acinetobacter baumannii, is necessary to prevent their dissemination within health care settings. We performed a method comparison study of 11 phenotypic carbapenemase detection assays to evaluate their accuracy for the detection of CPNFs. A total of 96 carbapenem-resistant glucose-nonfermenting isolates were included, of which 29% produced carbapenemases. All CPNFs were molecularly characterized to identify β-lactamase genes. A total of 86% of the carbapenemase-producing P. aeruginosa isolates produced class B carbapenemases. Several assays performed with a sensitivity of >90% for the detection of carbapenemase-producing P. aeruginosa, including all rapid chromogenic assays and the modified carbapenem inactivation method. Most included assays, with the exception of the Manual Blue Carba assay, the Modified Carba NP assay, the boronic acid synergy test, and the metallo-β-lactamase Etest, had specificities of >90% for detecting carbapenemase-producing P. aeruginosa Class D carbapenemases were the most prevalent carbapenemases among the carbapenemase-producing A. baumannii strains, with 60% of the carbapenemase-producing A. baumannii isolates producing acquired OXA-type carbapenemases. Although several assays achieved >90% specificity in identifying carbapenemase-producing A. baumannii, no assays achieved a sensitivity of greater than 90%. Our findings suggest that the available phenotypic tests generally appear to have excellent sensitivity and specificity for detecting carbapenemase-producing P. aeruginosa isolates. However, further modifications to existing assays or novel assays may be necessary to accurately detect carbapenemase-producing A. baumannii.


Grapevine species from varied native habitats exhibit differences in embolism formation/repair associated with leaf gas exchange and root pressure.
Drought induces xylem embolism formation, but grapevines can refill non-functional vessels to restore transport capacity. It is unknown whether vulnerability to embolism formation and ability to repair differ among grapevine species. We analysed in vivo embolism formation and repair using x-ray computed microtomography in three wild grapevine species from varied native habitats (Vitis riparia, V. arizonica, V. champinii) and related responses to measurements of leaf gas exchange and root pressure. Vulnerability to embolism formation was greatest in V. riparia, intermediate in V. arizonica and lowest in V. champinii. After re-watering, embolism repair was rapid and pronounced in V. riparia and V. arizonica, but limited or negligible in V. champinii even after numerous days. Similarly, root pressure measured after re-watering was positively correlated with drought stress severity for V. riparia and V. arizonica (species exhibiting embolism repair) but not for V. champinii. Drought-induced reductions in transpiration were greatest for V. riparia and least in V. champinii. Recovery of transpiration after re-watering was delayed for all species, but was greatest for V. champinii and most rapid in V. arizonica. These species exhibit varied responses to drought stress that involve maintenance/recovery of xylem transport capacity coordinated with root pressure and gas exchange responses.


Occurrence and Mass Loading of Synthetic Opioids, Synthetic Cathinones, and Synthetic Cannabinoids in Wastewater Treatment Plants in Four U.S. Communities.
A few new psychoactive substances (NPS) that mimic the effects of controlled neuropsychiatric and illicit drugs have been forensically identified in the U.S. Wastewater-based epidemiology (WBE) can provide a comprehensive and more cost- and time-effective method of determining the prevalence of NPSs in communities. In this study, an analytical method capable of simultaneous determination of trace-level 40 NPS residues (synthetic opioids, synthetic cannabinoids, synthetic cathinones, piperazines, indole, and amphetamine) in wastewater was developed and validated. The developed analytical method was utilized to determine the occurrence of NPSs in four rural communities in southern Illinois. Nine NPSs (carfentanil, furanyl fentanyl, methoxyacetyl fentanyl, MAB-CHMINACA, methcathinone, 4-methyl pentedrone, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP), 1-(3-chlorophenyl) piperazine (mCPP), and 5-(2-Aminopropyl) Indole (5IT) were quantified. Methcathinone was the most frequently detected NPS (detection frequency, df = 100%) followed closely by the MMMP and mCPP (df = 91%). The mass loading of methcathinone, mCPP, and 5-IT using ammoniacal nitrogen-based population were up to 21.1 ± 1.3 mg/d/1000 people, 15.0 ± 0.5 mg/d/1000 people, and 9.75 ± 2.72 mg/d/1000 people, respectively. This is the first study to determine the occurrence of NPSs including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and piperazines in the U.S. communities.


Mechanisms of CO2 capture in ionic liquids: a computational perspective.
We present computational studies of CO2 sorption in two different classes of ionic liquid. The addition of carbon dioxide to four superbase ionic liquids, [P3333][Benzim], [P3333][124Triz], [P3333][123Triz] and [P3333][Bentriz], was studied using the DFT approach and considering anions alone and individual ion pairs. The addition of CO2 to the anion alone clearly resulted in the formation of a covalently-bound carbamate function with the strength of binding correlated to experimental capacity. In the ion pair however the cation significantly alters the nature of the bonding such that the overall cohesive energy is reduced. Formation of a strong carbamate function occurs at the expense of weakening the interaction between anion and cation. In [N1111][l-ALA], a representative amino acid ionic liquid, evidence was found for a low-energy monomolecular mechanism for carbamate formation, explaining the 1 : 1 molar uptake ratio observed in some amino acid ionic liquids. The mechanism involves proton transfer to the carboxylate group of the aminate anion.


Polyarticular pigmented villonodular synovitis in a child.
Pigmented villonodular synovitis is rare in the younger child. Polyarticular involvement in this condition, regardless of patient age, is distinctly uncommon. The authors describe a case of pigmented villonodular synovitis involving multiple joints in a young boy who also had congenital anomalies of the genitourinary tract. Although rare, pigmented villonodular synovitis should be considered in the differential diagnosis of multiple joint swellings in children with congenital anomalies.


Formation and properties of reverse micellar cubic liquid crystals and derived emulsions.
The structure of the reverse micellar cubic (I2) liquid crystal and the adjacent micellar phase in amphiphilic block copolymer/water/oil systems has been studied by small-angle X-ray scattering (SAXS), rheometry, and differential scanning calorimetry (DSC). Upon addition of water to the copolymer/oil mixture, spherical micelles are formed and grow in size until a disorder-order transition takes place, which is related to a sudden increase in the viscosity and shear modulus. The transition is driven by the packing of the spherical micelles into a Fd3m cubic lattice. The single-phase I2 liquid crystals show gel-like behavior and elastic moduli higher than 104 Pa, as determined by oscillatory measurements. Further addition of water induces phase separation, and it is found that reverse water-in-oil emulsions with high internal phase ratio and stabilized by I2 liquid crystals can be prepared in the two-phase region. Contrary to liquid-liquid emulsions, both the elastic modulus and the viscosity decrease with the fraction of dispersed water, due to a decrease in the crystalline fraction in the sample, although the reverse emulsions remain gel-like even at high volume fractions of the dispersed phase. A temperature induced order-disorder transition can be detected by calorimetry and rheometry. Upon heating the I2 liquid crystals, two thermal events associated with small enthalpy values were detected: one endothermic, related to the "melting" of the liquid crystal, and the other exothermic, attributed to phase separation. The melting of the liquid crystal is associated with a sudden drop in viscosity and shear moduli. Results are relevant for understanding the formation of cubic-phase-based reverse emulsions and for their application as templates for the synthesis of structured materials.


Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) is a dimeric hormone that controls much of vascular development through binding and activation of its kinase domain receptor (KDR). We produced analogs of VEGF that show it has two receptor-binding sites which are located near the poles of the dimer and straddle the interface between subunits. Deletion experiments in KDR indicate that of the seven IgG-like domains in the extracellular domain, only domains 2-3 are needed for tight binding of VEGF. Monomeric forms of the extracellular domain of KDR bind approximately 100 times weaker than dimeric forms showing a strong avidity component for binding of VEGF to predimerized forms of the receptor. Based upon these structure-function studies and a mechanism in which receptor dimerization is critical for signaling, we constructed a receptor antagonist in the form of a heterodimer of VEGF that contained one functional and one non-functional site. These studies establish a functional foundation for the design of VEGF analogs, mimics, and antagonists.


TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma.
βIII-Tubulin, encoded by the TUBB3 gene, is a microtubule protein. Several studies have shown that overexpression of TUBB3 is linked to poor prognosis and is involved in taxane resistance in some cancers. The aim of this study was to analyze the expression and function of TUBB3 in clear cell renal cell carcinoma (ccRCC). The expression of TUBB3 was determined using immuno-histochemistry in ccRCC specimens. The effects of TUBB3 knockdown on cell growth and invasion were evaluated in RCC cell lines. We analyzed the interaction between TUBB3, p53, cancer stem cell markers, and PD-L1. In 137 cases of ccRCC, immunohistochemistry showed that 28 (20%) of the ccRCC cases were positive for TUBB3. High TUBB3 expression was significantly correlated with high nuclear grade, high T stage, and N stage. A Kaplan-Meier analysis showed that high expression of TUBB3 was associated with poor overall survival after nephrectomy. In silico analysis also showed that high TUBB3 expression was correlated with overall survival. Knockdown of TUBB3 suppressed cell growth and invasion in 786-O and Caki-1 cells. High TUBB3 expression was associated with CD44, CD133, PD-L1, and p53 in ccRCC. We generated p53 knockout cells using the CRISPR-Cas9 system. Western blotting revealed that p53 knockout upregulated the expression of TUBB3. These results suggest that TUBB3 may play an oncogenic role and could be a potential therapeutic target in ccRCC.


Association of Physical Activity with Alcohol Abuse and Dependence in a Nationally-Representative U.S. Sample.
Alcohol use is a pervasive and costly public health problem in the United States. Relapse rates from alcohol use disorders are high. Although exercise has been proposed as a strategy to prevent relapse, lifestyle modification is the least studied aspect of relapse prevention programs, especially among racial/ethnic minority populations. The current study assessed whether being physically active was associated with remission from alcohol abuse or dependence among Black (African American and Afro Caribbean) adults in the U.S. We utilized data on Black adult participants (n = 4,828) from the nationally representative National Survey of American Life (NSAL) conducted in 2001-2003. Logistic regression models were estimated to assess the odds of being in 12-month remission or currently meeting DSM-IV criteria for alcohol abuse or dependence based on level of physical activity, adjusting for socio-demographic and neighborhood characteristics. People who endorsed being physically active had higher odds of being in 12-month remission from alcohol use problems (OR: 1.67, 95% CI: 1.28, 2.17) than people who were physically inactive, adjusting for individual- and neighborhood-level characteristics. People who were physically active did not differ significantly from those who were inactive with respect to odds of currently meeting DSM-IV criteria for alcohol abuse or dependence. Conclusions/Importance: Physical activity was positively associated with being in 12-month remission from alcohol use problems. Longitudinal studies are needed to establish temporal ordering and to explore exercise as a potential relapse prevention strategy for alcohol use problems.


A Prospective, Double-Blind, Randomized, Controlled Clinical Trial in the Gingivitis Prevention with an Oligomeric Proanthocyanidin Nutritional Supplement.
To evaluate the effectiveness on tissue response of the new nutritional supplement made of oligomeric proanthocyanidins in induced gingivitis after 21 days of use. A prospective, double-blind, randomized, controlled clinical trial was carried out on 20 patients; it is divided into an experimental group and a control group after fulfilling the selection criteria. Patients had to come 4 times during the study to register the Silness and Löe index, the gingival bleeding index, the plaque index, the inflammatory crevicular fluid study (IL6), and the changes in the brightness of the gingiva. No complementary hygiene methods were allowed during the 21 days. The Silness and Löe index was higher in the control group than in the experimental group, reaching a twofold difference between the groups (p < 0.0001). The gingival bleeding index also supports this fact, since the bleeding was lower in the experimental group (p < 0.005). However, the dental plaque on the tooth surface according to the plaque index was 33% higher in the experimental group (p < 0.006). Some differences in the IL-6 were found in the crevicular fluid (p < 0.0001). Oligomeric proanthocyanidins have an effect on the periodontal tissue's health. No effects on the accumulation of plaque on the tooth surface were found, so further studies are needed to determine the nature of the plaque.


Evaluation of adaptive immune responses and heterologous protection induced by inactivated bluetongue virus vaccines.
Eradication of bluetongue virus is possible, as has been shown in several European countries. New serotypes have emerged, however, for which there are no specific commercial vaccines. This study addressed whether heterologous vaccines would help protect against 2 serotypes. Thirty-seven sheep were randomly allocated to 7 groups of 5 or 6 animals. Four groups were vaccinated with commercial vaccines against BTV strains 2, 4, and 9. A fifth positive control group was given a vaccine against BTV-8. The other 2 groups were unvaccinated controls. Sheep were then challenged by subcutaneous injection of either BTV-16 (2 groups) or BTV-8 (5 groups). Taken together, 24/25 sheep from the 4 experimental groups developed detectable antibodies against the vaccinated viruses. Furthermore, sheep that received heterologous vaccines showed significantly reduced viraemia and clinical scores for BTV-16 when compared to unvaccinated controls. Reductions in clinical signs and viraemia among heterologously vaccinated sheep were not as common after challenge with BTV-8. This study shows that heterologous protection can occur, but that it is difficult to predict if partial or complete protection will be achieved following inactivated-BTV vaccination.


Inhaled nitric oxide: technical aspects of administration and monitoring.
Clinical applications of inhaled nitric oxide (NO) therapy resulted in the development of delivery systems and monitoring devices applicable to routine clinical care. This article presents the various components necessary for an adequate clinical use of inhaled NO, and discusses the NO gas mixture cylinders, inhaled NO delivery techniques and specifications, monitoring devices, and ending with an exhaustive description of the scavengers of nitrogen oxides (NOx). Computerized search (CURRENT CONTENTS, MEDLINE) of published original research and review articles (approximately 200), conference abstracts and compendiums up to May 1997 (approximately 50), personal files, and contact with expert informants. Technical, experimental, and clinical reports were selected from the recent English, French, German, and Spanish literature, if pertinent to the administration or monitoring of inhaled NO. The authors extracted all applicable data. The production of NO gas mixture cylinders must be certified with respect to gas purity, stability, and concentration (limits between 100 and 1000 ppm), guaranteed calibration, and specific color. An ideal inhaled NO delivery device requires a synchronized delivery, a minimal production of nitrogen dioxide (NO2), and should be simple to use (verification, calibration, convenient flushing, cylinder change possible while in use and a simple alarm setting) with full information (high and low alarms and available precision monitoring of NO, NO2, and O2). Emergency and transport systems must be readily available. The choice of the monitoring device (chemiluminescence or electrochemistry) should be made based on the knowledge of their strength and weakness for a particular clinical application. Finally, scavengers of NOx should be used with caution until specific filters are proven safe and effective. The great expectancies generated by inhaled NO action have led researchers to design personal inhaled NO delivery systems, but only with mitigated results. At present, medical companies are finding a financial interest in designing a delivery system which will suit the needs of clinicians and this, along with official governmental approval, will only then permit the use of inhaled NO safely and on a larger scale.


Lymphosarcoma in the laboratory woodchuck (Marmota monax).
From 1979 to 1999,28 cases of lymphosarcoma were identified in the Cornell University woodchuck colony (prevalence rate: 152/100,000/yr). The prevalence of lymphosarcoma was similar in woodchucks not infected with the woodchuck hepatitis virus (WHV) and in chronic carriers of WHV. Males (13) and females (15) alike were affected (mean +/- SD age 4.7 +/- 2.92 years; range, 0.5 to 9 years). On the basis of the major organ system involved, woodchuck lymphosarcoma was classified as multicentric (12 cases, 43%), alimentary (5 cases, 18%), cranial mediastinal (5 cases, 18%), and miscellaneous (6 cases, 21%). A cutaneous form was not observed. Morphologic criteria similar to those of the Kiel classification were used for light microscopic classification. All Kiel categories-except the immunoblastic form-were found: 17 cases (61%) were centroblastic, and 6 were lymphocytic (21%). Other categories (centrocytic and plasmacytoid) were recognized less frequently. Immunophenotyping of 27 cases revealed 15 (56%) B cell (CD3-/CD79a+ or CD3-/BLA.36+), 7 (26%) T cell (CD3+/CD79a-/BLA.36-), and 5 (18%) non-T non-B cell (CD3-CD79a-/BLA.36-) lymphosarcomas. Lymphosarcoma in woodchucks develops at a higher rate than that observed in humans or companion animals, and WHV infection has no effect on prevalence. The anatomic and Kiel classification used in domestic species also can be used in woodchucks. Commercially available alpha-CD3, alpha-CD79a, and alpha-BLA.36 antibodies were useful for immunophenotyping woodchuck lymphosarcomas.


Intracellular Ca2+ stores and Ca2+ influx are both required for BDNF to rapidly increase quantal vesicular transmitter release.
Brain-derived neurotrophic factor (BDNF) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity. One potential mechanism to initiate BDNF actions is through its modulation of quantal presynaptic transmitter release. In response to local BDNF application to CA1 pyramidal neurons, the frequency of miniature excitatory postsynaptic currents (mEPSC) increased significantly within 30 seconds; mEPSC amplitude and kinetics were unchanged. This effect was mediated via TrkB receptor activation and required both full intracellular Ca(2+) stores as well as extracellular Ca(2+). Consistent with a role of Ca(2+)-permeable plasma membrane channels of the TRPC family, the inhibitor SKF96365 prevented the BDNF-induced increase in mEPSC frequency. Furthermore, labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post-BDNF destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mEPSCs reflects vesicular fusion events. Indeed, BDNF application to CA3-CA1 synapses in TTX rapidly enhanced FM1-43 or FM2-10 destaining with a time course that paralleled the phase of increased mEPSC frequency. We conclude that BDNF increases mEPSC frequency by boosting vesicular fusion through a presynaptic, Ca(2+)-dependent mechanism involving TrkB receptors, Ca(2+) stores, and TRPC channels.


[A study using FRTL-5 cell for detecting thyroid stimulating antibody activity in serum in patients with Graves disease].
Using a strain of functioning rat thyroid cells (Fischer rat thyroid line-5, FRTL-5) as target cells and immunoglobin G sedimented from serum by polyethylene glycol (PEG), we studied thyroid stimulating antibody (TsAb) activity in serum of patients with Graves' disease. In a total of 92 cases, TsAb activity was detected in 92.59% (25/27) of the patients with untreated Graves' disease, 75.00% (9/12) of the patients with relapsing Graves' disease and 39.13% (18/46) of the patients with Graves' disease who were euthyroid while taking antithyroid drugs. TsAb activity was also detected in 42.86% (3/7) of the patients with ophthalmic Graves' disease and 12.50% (2/16) of the patients with Hashimoto's thyroiditis. The results showed that TsAb activity can be used as an immunologic index and is valuable in the diagnosis of Graves' disease. Remission and relapse of Graves' disease can be indicated or monitored with the measurement of TsAb activity.


Supporting the whole child through coordinated policies, processes, and practices.
The Whole School, Whole Community, Whole Child (WSCC) model provides a framework for promoting greater alignment, integration, and collaboration between health and education across the school setting and improving students' cognitive, physical, social, and emotional development. By providing a learning environment that ensures each student is emotionally and physically healthy, safe, actively engaged, supported, and challenged, the WSCC model presents a framework for school systems to evaluate, streamline, implement, and sustain policies, processes, and practices. This article examines the essential roles of the school district and of schools in aligning, developing, and implementing policy, processes, and practices to create optimal learning environments that support the whole child. Three key factors advance efforts to align policies, processes, and practices. These include hiring a coordinator at the district and school levels, having collaborative teams address health and learning at the district and school levels, and using data to make decisions and build health outcomes into school and district accountability systems. These key factors provide a road map for successfully implementing WSCC. More research is needed to determine the extent that coordinators, collaborative teams, and the inclusion of health indicators in accountability systems impact student health and learning.


Systolic Time Intervals for Diagnosis of Severe Aortic Stenosis.
Estimated frequency of aortic stenosis (AS) in those over 75 years of age is 3.4%. Symptomatic patients with severe AS have increased morbidity and mortality and aortic valve replacement should be offered to improve life expectancy and quality of life. To identify whether systolic time intervals can identify severe AS. The study comprised 200 patients (mean age 79 years, 55% men). Patients were equally divided into normal, mild, moderate, or severe AS. All patients had normal ejection fraction. Acceleration time (AT) was defined as the time from the beginning of systolic flow to maximal velocity; ejection time (ET) was the time from onset to end of systolic flow. The relation of AT/ET was calculated. Death or aortic valve intervention were documented. AT increased linearly with the severity of AS, similar to ET and AT/ET ratio (P for trend < 0.05 for all). Receiver-operator characteristic curve analysis demonstrated that AT can identify severe AS with a cutoff ≥ 108 msec with 100% sensitivity and 98% specificity, while a cutoff of 0.34 when using AT/ET ratio can identify severe AS with 96% sensitivity and 94% specificity. Multivariate analysis adjusting to sex, stroke volume index, heart rate, and body mass index showed similar results. Kaplan-Meier curve for AT ≥ 108 and AT/ET ≥ 0.34 predicted death or aortic valve intervention in a 3-year follow-up. Acceleration time and AT/ET ratio are reliable measurements for identifying patients with severe AS. Furthermore, AT and AT/ET were able to predict aortic valve replacement or death.


[Staging of esophageal cancer using ultrasound].
The early diagnosis of esophageal cancer is crucial for the prognosis of the disease. In contrast to cancer of the upper aerodigestive tract, the mucosa of the esophagus is not visible without the appropriate equipment. In addition to endoscopy, imaging of the esophagus is crucial for early detection of the esophageal cancer. Ultrasound of the esophagus can be performed easily and--in contrast to other imaging techniques--without side effects. Different modes of ultrasound can be performed. First, transcutaneous ultrasound allows one to detect tumors of the upper esophagus and its passage into the hypopharynx. Second, endosonography allows one to detect pathologies of the other esophageal regions including the passage into the stomach. The present review discusses the impact of both techniques against the background of the international literature.


Antigens in penicillin allergy. V. On the relative allergenic potency of antigens carrying penicilloyl determinants derived from azidocillin, ampicillin and benzylpenicillin.
The effects of the different acyl side chains of azidocillin, ampicillin and benzylpenicillin on the immunogenic potency of penicilloylated antigens as well as on the specificity of the developed antibodies were investigated in CBA mice. The antigens used were penicilloylated bovine gammaglobulin (BGG), bovine serum albumin (BSA) and human serum albumin (HSA). Immunization was performed with injection of high doses of antigens together with adjuvant or by injection of minute amounts of antigen over periods of 10 days. IgE antibodies were recorded with PCA in rats and IgG antibodies were measured with a double antibody assay. The nature of the carrier as well as the number of epitopes was found to influence the development of antibodies irrespective of the immunization schedule used. The immunogenic activity of the PO-BSA antigens was related to the epitope density. The PO-BSA antigens were, in contrast to the PO-BGG antigens, weak immunogens in the CBA mice. The acyl side chains of the different penicillins influenced the induction and specificity of the IgE antibody responses obtained after daily treatment.


Noninvasive Evaluation of Liver Fibrosis in a Sample of Putative Inactive HBV Carriers in Rome, Italy.
Noninvasive methods are useful for investigating patients with chronic HBV infection. The severity of liver disease in inactive HBsAg carriers can be noninvasively assessed by transient elastography (TE) alone or in association with biochemical markers of fibrosis. The study evaluates the effectiveness of the TE compared to common fibrosis scores (FSs), APRI, Forns Index, and FIB4, for identifying significant fibrosis in Italian and foreigner HBsAg carriers. To investigate the risk of progression of the liver disease, liver stiffness (LS) and HBV-DNA were monitored over time. Viral load, biochemical parameters, and LS have been retrospectively evaluated in 125 putative inactive HBV carriers, who visited two outpatient departments (Colleferro Hospital and INMP) from 01/03/2014 to 31/12/2019. Differences in clinical, biochemical, and demographic variables between Italians and foreigners were analyzed. 66 of 125 patients were followed up for 24 months by monitoring liver stiffness and HBV-DNA. Mean overall LS was 5.55 ± 1.92 kPa; 18 (14.4%) patients had a LS ≥7.5 kPa. Mean of APRI, Forns, and FIB4 was 0.29 ± 0.11, 4.15 ± 1.63, and 1.16 ± 0.59, respectively. FS did not differ between the patients with LS <7.5 kPa and those with LS ≥7.5 kPa. Italians displayed a significant lower ALT (0.53 ± 0.18 vs. 0.67 ± 0.33, p < 0.05) and AST (0.59 ± 0.16 vs. 0.70 ± 0.21, p < 0.01) value than foreigners. No differences in LS and HBV-DNA levels were observed. In 66 patients followed up for 24 months, HBV-DNA increased by ≥2000 UI/ml after 12 months in 15 individuals and remained ≥2000 UI/ml after 24 months in 10/15 individuals. 7/10 patients showed LS ≥ 7.5 kPa after 24 months, and 4 of them underwent antiviral therapy for HBV. Patients with HBV-DNA <2000 IU/ml had a significantly lower LS than those with HBV-DNA ≥2000 IU/ml (5.30 ± 1.43 vs. 7.69 ± 1.07, p < 0.0001). Analysis shows lower effectiveness of FS vs. TE in the assessment of putative inactive HBV carriers. Furthermore, using FibroScan® and HBV-DNA can identify "false" inactive carriers.


Abnormal social behaviors in mice lacking Fgf17.
The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediate-early gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.


Pulmonary Artery Aneurysm Associated with Bicuspid Pulmonary Valve.
A 73-year-old Japanese man was admitted with an asymptomatic pulmonary artery aneurysm. However, chest X-ray and contrast-enhanced thoracic computed tomography revealed a protrusion at the second left branch that in fact was a pulmonary artery aneurysm with a diameter of 50 mm. Transesophageal echocardiography showed a bicuspid pulmonary valve, and cardiac catheterization revealed pulmonary stenosis with a pressure gradient of 45 mmHg, but no other heart diseases were noted. An extremely rare pulmonary artery aneurysm associated with an isolated bicuspid pulmonary valve was diagnosed.


Carotid artery stenting: which stent for which lesion?
The different geometries and working principles of carotid stents (nitinol or cobalt chromium, open- or closed-cell configuration) provide each product with unique functional properties. The individual characteristics of each device may make it an attractive choice in one circumstance but render it less desirable in other situations. In approximately 75% of all procedures, all types of stents will achieve similar outcomes, making adequate device selection unnecessary. For the remaining quarter, careful preoperative screening is mandatory. In addition to eventual access issues, the choice of the optimal carotid stent depends mainly on arterial anatomy and lesion morphology. When treating a tortuous anatomy, stents with a flexible and comformable open-cell configuration are preferred. In arteries with a significant mismatch between common carotid artery and internal carotid artery diameter, cobalt chromium (Elgiloy) or tapered nitinol stents are selected. Lesions with suspected high emboligenicity are best covered with stents with a closed-cell configuration, whereas highly calcified lesions need treatment with nitinol stents. Thorough knowledge of the characteristics, advantages and disadvantages, and working principles of the different available stents is mandatory to optimally select the materials to be used for patients eligible for carotid revascularization.


Sorafenib induces autophagy and suppresses activation of human macrophage.
Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and other malignancies, has been shown as a modulator for dendritic cells. This study was designed to examine the effects of sorafenib on macrophages, the major ontogeny of innate immunity. Macrophages were derived from sorted CD14(+) monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by trypan blue analysis. Autophagy was characterized by light microscopy and transmission electron microscopy for morphology, Western blotting for microtubule associated light chain protein 3B (LC-3B) I lipidation, and acridine orange staining for acidic component vacuoles. Soluble factors contained in culture medium and serum were measured by ELISA. We found that sorafenib inhibited the viability of macrophages accompanied by morphological changes characteristic of autophagy. This autophagy-inducing effect was validated by LC3B-I lipidation and autophagosome accumulation. The surface antigen expression and the function of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. The secretion of IL-10, but not IL-6, TNF-α nor TGF-β, was reduced by sorafenib. Sorafenib, in addition to being a cancer targeted therapeutic agent, can induce autophagy and modulate the function of human macrophages.


Therapeutic vaccination with TNF-Kinoid in TNF antagonist-resistant rheumatoid arthritis: a phase II randomized, controlled clinical trial.
Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA. This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection. The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not. TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement. ClinicalTrials.gov NCT01040715.


A model system that demonstrates interactions among extracellular matrix macromolecules.
Binding interactions among fibronectin (FN), glycosaminoglycan chains (GAG) and hyaluronate binding proteins (HABP) have been examined using a bead aggregation assay. 3H-FN binds to Dowex beads coated with chondroitin sulfate GAG chains (CS) but not to beads coated with hyaluronic acid (HA). Assays of bead agglutination indicate that FN has multiple binding sites for CS. Binding of 3H-FN to HA-beads is slightly promoted by exogenous divalent cations but this interaction does not aggregate Dowex-HA. The interaction between FN and CS reduces the previously reported ability of Dowex-CS to associate with HA-beads (Turley, E.A. and Roth, S. 1980, Nature Vol. 283, 268-271). HABP bind to HA and to a lesser extent CS. These proteins both stabilize the interaction between HA- and CS-beads in a manner reminiscent of the stabilization of HA-proteoglycan interactions by link protein and permit aggregation of Dowex-CS-FN with Dowex-HA. This simple bead aggregation assay allows rapid characterization of properties that may help to clarify how macromolecular constituents spontaneously assemble into an interstitial matrix.


Lower-limb muscle strength according to bodyweight and muscle mass among middle age patients with type 2 diabetes without diabetic neuropathy.
[Purpose] This study assessed the effects of type 2 diabetes without diabetic polyneuropathy on muscle strength according to body composition in middle age patients. [Subjects and Methods] This study included 45 non-diabetic individuals (control group) and 50 patients with type 2 diabetes (DM group), 40 to 64 years of age. The body composition was examined, including the leg muscle volume (LMV), which was the sum of the lower-limb muscle mass. The muscle strength was also examined, and the knee extension force (KEF), ankle dorsiflexion force (ADF). The KEF and ADF were normalized to the bodyweight, and the total leg muscle force (TLMF) were calculated by combining the KEF and ADF. The leg muscle quality (LMQ) was calculated as the TLMF normalized with the LMV. [Results] While no significant differences were found in the LMV between groups, the body mass index were higher in the DM group than in the control group. Significant differences were observed in %KEF, %ADF, and the LMQ in the DM group, with 15.8%, 18.7%, and 11.5% lower values than those in the control group, respectively. [Conclusion] The results of this study may demonstrate that muscle weakness occurs before diabetes progresses to a severe condition.


Some critical remarks on the problem of HLA association with disease.
The results concerning the association of HLA antigens with ITP, pernicious anaemia, hemangiomas and Alzheimer's disease are compared with those of other authors and the causes for differences are discussed. The different number of examined patients does not seem to be the main cause of those differences. Selecting of the correct method for statistical evaluation and the differences in the criteria for diagnosing the disease are more important. The unsubstantial differences in the homogeneity of the patients group and controls are negligible.


Unusual site of spontaneous first-rib fracture: case report.
Spontaneous fractures of the first rib are uncommon and are usually thought to be associated with a malignant process. However, fatigue fractures of the first rib are being encountered increasingly in association with various physical activities. Typically, the fractures occur at the subclavian groove, but in the 48-year-old woman described in this report the fracture was unexpectedly situated in the posterior portion of the rib and was the result of snow shovelling, which was a new activity for the patient.


[Metabonomics profile of urine from rats administrated with different treatment period of isoniazid].
To study the effect of different treatment period, of isoniazid (INH) on the metabonomic profile of rat urine and its relationship with traditional toxicity evaluation of blood biochemical indicators and histopathology and to explore the feasibility of metabonomics in the application of drug toxicity. Sixty male Wistar rats were orally administrated with 0, 50, 100, 200, and 400 mg x kg(-1) INH for 3, 7, and 14 days, respectively. Rat urine was then collected and its 1H nuclear magnetic resonance (NMR) spectra were acquired. All animals underwent traditional toxicity evaluation. Hepatotoxicity was revealed by traditional toxicity evaluation in rats treated with higher dosage and longer treatment of INH. Time-response relationship existed during the treatment. Time-dependent metabonomics changes conformed with the results of traditional toxicity evaluation. The urine metabonomics showed a trajectory bias from those of the controls or pre-administration, and such bias exaggerated along with the prolongation of treatment, indicating a severer toxic injury. Along with the increase of the concentrations of urinary taurine and glucose and the decrease of the concentrations of urinary citrate and 2-oxoglutarate, the 1H NMR spectra of urine in rats treated with INH also changed. The metabonomics technique can distinguish the onset and development of toxicity, which helps track and identify biomarkers. The hepatic toxicity induced by INH is related to the injury of mitochondrial function, reduction of energy metabolism in tricarboxylic acid cycle, and perturbations in the metabolism of glucose and lipid. The effect of INH on the rat urine metabonomic profile is related with INH toxicology. Therefore, metabonomics can be recognized as an ideal technique to explore and evaluate the drug toxicities.


B16 Membrane-Coated Vesicles for Combined Photodynamic Therapy and Immunotherapy Shift Immune Microenvironment of Melanoma.
Coating of nanomedicine with cell membranes has attracted increasing attention as it can boost biocompatibility and improve the efficiency of treatment. Herein, we prepared innovative tumor cell-membrane-coated vesicles based on photodynamic therapy (PDT) drug indocyanine green (ICG) and explore the effect on melanoma in vitro and in vivo. ICG was coated with B16 cell membranes (I@BM NVs) by sonication and extrusion, and the morphological characteristics of I@BM NVs were evaluated by transmission electron microscopy (TEM) and NP-tracking analysis. Homologous cellular uptake was evaluated by flow cytometry (FCM) after staining by DiD dye. Cellular cytotoxicity was evaluated by cell counting kit-8 assay and the anti-tumor effect in vitro was assessed by FCM and western blotting. The anti-tumor effect in vivo was evaluated in a B16 xenograft model in mice. The tumor micro-environment was investigated by FCM and real-time PCR. The vesicles are stable and uniform in nature, and show strong homologous targeting in vivo and in vitro. The vesicles can generate reactive oxygen species to induce apoptosis of B16 cells under near-infrared irradiation. Furthermore, the I@BM NVs induce a significant anti-tumor response in vivo, and perform better with respect to both tumor growth inhibition and lifespan extension. Analysis of immunocytes in the tumor microenvironment showed significant reductions in numbers of myeloid-derived suppressor cells and tumor-associated M2 macrophages in mice in the I@BM NVs group. This was accompanied by significant increases in numbers of M1 macrophages and proliferative CD4+/CD8+ T cells. Expression levels of IFN-γ and IL-2 increased in the I@BM NVs group, while expression of TGF-β and IL-10 decreased. The results show that the I@BM NVs are feasible drugs for the treatment of melanoma by inducing cell apoptosis under NIR and shifting the immunosuppressive tumor microenvironment in vivo.


Optimization of electroactive hydrogel actuators.
To improve actuation of hydrogels, we utilized an emulsion polymerization to engineer porous structures into polyelectrolyte hydrogels. Porous hydrogels generated large deformation as a result of enhanced deswelling mechanisms; for instance, the decreased number of COO(-) groups that must be protonated in porous hydrogels to initiate bending. Measurements of the mechanical properties revealed that porous hydrogels also bend to a larger extent because of their increased flexibility. Overall, our results demonstrate that the fast and large actuation of polyelectrolyte hydrogels can be accomplished by increasing the hydrogel porosity.


The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics.
Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.


[Complications after spinal cord injuries and their influence on the effectiveness of rehabilitation].
In this article, literature data on complications after spinal cord injuries and their influence on the efficiency of rehabilitation are analyzed. The spinal cord injury is associated with physical and psychological disorder that causes disability and requires intensive treatment. Authors in their articles indicate that many people after spinal cord injuries have complications. The most common complications are: skin breakdown, urinary tract infection, pulmonary complications, spasticity, pain, autonomic dysreflexia, cardiovascular disease, osteoporosis and fractures, heterotopic ossification, deep vein thrombosis. These complications make patients' rehabilitation more difficult and limit their self-care independence, and the treatment of such complications is very expensive.


Effects of the inhibitors on glutamate uptake by nerve terminals after exposure of rats to centrifuge-induced hypergravity.
L-[14C]glutamate uptake process by nerve terminals has been investigated using glutamate analogs (nontransportable and transportable inhibitors of glutamate transporters) as tools. The effects of L-threo-beta-benzyloxyaspartate (DL-TBOA) and L-threo-beta-hydroxyaspartate (L-TBHA) on uptake of L-[14C] glutamate have been evaluated after exposure of rats to centrifuge-induced hypergravity. Both glutamate analogs potently inhibited L-[14C] glutamate uptake in dose-dependent manner. The IC50 values for DL-TBOA (nontransportable analog) calculated on the basis of curves of non-linear regression kinetic analysis was 18 +/- 2 micromoles and 11 +/- 2 micromoles (P < or = 0.05) before and after exposure to artificial gravity, respectively. Inhibition caused by 10 micromoles DL-TBOA was significantly increased from 38.0 +/- 3.8% in control group to 51.0 +/- 4.1% in animals, exposed to hypergravity (P < or = 0.05). L-TBHA, transportable analog, exhibited similar inhibitory characteristics.


Influence of initial length of uterus per embryo and gestation stage on prenatal survival, development, and sex ratio in the pig.
The effects of uterine length per embryo and stage of gestation on prenatal survival, development, and sex ratio were determined by systematically restricting embryos to 5, 10, 15, 20, 25, 30, 35, 40, 45, or > 50 cm of initial uterine length per potential embryo and examining the reproductive tracts at d 17, 23, 29, 35, or 41 of gestation. At d 3 the mean length of a uterine horn was 169 +/- 35 cm, with a range of 80 to 255 cm. The mean total number of corpora lutea (CL) was 12.4 +/- 2.34. Ovulation rate tended to be correlated with the length of uterine horns (r = .38; P > .1). Prenatal survival was highly correlated with initial assigned uterine space from 5 to 25 cm/CL (r = .95; P < .05). Prenatal survival was not affected by space (r = .53; P < .1) when space was > 25 cm/CL. In all groups, regardless of space available, some prenatal loss occurred before d 17. In sections with < 25 cm/CL, a second loss took place between d 29 and 35. Before d 35, there was no significant effect of restriction on either fetal length or weight, but after d 35, fetuses from sections with > 25 cm/CL were longer and heavier than those from sections with less space (P < .05). Greater uterine space was occupied by larger fetuses (P < .05). Male fetuses occupied more uterine space than female fetuses did in both crowded and roomy sections (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)


The story of the missing canine.
Odontomas are usually associated with permanent teeth and rarely with primary dentition. The consequences of their presence are several clinical complications. Presented here is a case where diagnosis and management of an odontome causing impaction of primary tooth is discussed thus emphasising need for alertness in a clinician using the aid of radiological examination for early detection and subsequent intervention.


Increased ceruloplasmin expression caused by infiltrated leukocytes, activated microglia, and astrocytes in injured female rat spinal cords.
Ceruloplasmin (Cp), an enzyme containing six copper atoms, has important roles in iron homeostasis and antioxidant defense. After spinal cord injury (SCI), the cellular components in the local microenvironment are very complex and include functional changes of resident cells and the infiltration of leukocytes. It has been confirmed that Cp is elevated primarily in astrocytes and to a lesser extent in macrophages following SCI in mice. However, its expression in other cell types is still not very clear. In this manuscript, we provide a sensible extension of these findings by examining this system within a female Sprague-Dawley rat model and expanding the scope of inquiry to include additional cell types. Quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that the Cp mRNA and protein in SCI tissue homogenates were quite consistent with prior publications. However, we observed that Cp was expressed not only in GFAP+ astrocytes (consistent with prior reports) but also in CD11b+ microglia, CNPase+ oligodendrocytes, NeuN+ neurons, CD45+ leukocytes, and CD68+ activated microglia/macrophages. Quantitative analysis proved that infiltrated leukocytes, activated microglia/macrophages, and astrocytes should be the major sources of increased Cp.


Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women.
Menstrual cycle characteristics and ovulatory infertility were evaluated in relation to breast cancer risk among 116,678 women in the Nurses' Health Study II, a prospective cohort study of female registered nurses who were aged 25-42 years and living in 14 US states at enrollment in 1989. During 396,299 person-years of follow-up between return of the baseline questionnaire and June 1993, 251 cases of breast cancer were identified in this cohort. The multivariate relative risk (RR) associated with age at menarche > 13 years compared with age < or = 12 years was 0.66 (95% confidence interval (CI) 0.44-0.99). Short and long menstrual cycle lengths at ages 18-22 years were associated with reduced risk. Compared with menstrual cycle length 26-31 days, the multivariate relative risks (95% CIs) for more extreme cycle lengths were: < 26 days, 0.50 (0.25-0.98); 32-39 days, 0.81 (0.51-1.28); and > 39 days or too irregular for estimation of a usual cycle length, 0.41 (0.18-0.94). The multivariate relative risk associated with a history of ovulatory infertility, compared with no such history, was 0.41 (95% CI 0.18-0.93). These results are consistent with the hypothesis that reduced exposure to ovulatory menstrual cycles provides a protective effect against breast cancer.


Neurosteroids and Postpartum Depression: The Mechanism, Efficacy, and Approval of Brexanolone and Zurzuvae.
Postpartum depression (PPD) affects 10-15% of new mothers globally. Marking a pivotal shift in treatment, the U.S. Food and Drug Administration approved Zurzuvae (zuranolone) as the first oral medication for PPD in adults. This major depressive episode can emerge after childbirth or in pregnancy's later stages. Previously, PPD treatments were restricted to IV injections administered in select healthcare facilities. Childbirth instigates hormonal, physiological, and emotional shifts, with a stark drop in mood-regulating hormones like estrogen and progesterone possibly triggering depression. The role of serotonin in PPD is undeniable. Psychosocial stressors, such as neonatal care burdens and societal pressures, further amplify the risk. This Patent Highlight underscores the introduction of zuranolone as a beacon of hope for an effective and accessible treatment, which may benefit many postnatal women worldwide.


Analyses of promoter hypermethylation for RUNX3 and other tumor suppressor genes in nasopharyngeal carcinoma.
Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.


Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.
A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects.


Cockade naevus: an unusual variant of the benign cellular naevus.
A patient with benign cellular naevi with unusual target-like morphology is described. Histological and histochemical examination of the lesions showed Dopa oxidase positive cells in the epidermal portion of the tumour but only the naevus cells and keratinocytes at the periphery of the tumour stained for melanin. It is suggested that failure of melanin synthesis is the cause of the target-like appearance.


Electroacupuncture alleviates stress-induced visceral hypersensitivity through an opioid system in rats.
To investigate whether stress-induced visceral hypersensitivity could be alleviated by electroacupuncture (EA) and whether EA effect was mediated by endogenous opiates. Six to nine week-old male Sprague-Dawley rats were used in this study. Visceral hypersensitivity was induced by a 9-d heterotypic intermittent stress (HIS) protocol composed of 3 randomly stressors, which included cold restraint stress at 4°C for 45 min, water avoidance stress for 60 min, and forced swimming stress for 20 min, in adult male rats. The extent of visceral hypersensitivity was quantified by electromyography or by abdominal withdrawal reflex (AWR) scores of colorectal distension at different distention pressures (20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg). AWR scores either 0, 1, 2, 3 or 4 were obtained by a blinded observer. EA or sham EA was performed at classical acupoint ST-36 (Zu-San-Li) or BL-43 (Gao-Huang) in both hindlimbs of rats for 30 min. Naloxone (NLX) or NLX methiodide (m-NLX) was administered intraperitoneally to HIS rats in some experiments. HIS rats displayed an increased sensitivity to colorectal distention, which started from 6 h (the first measurement), maintained for 24 h, and AWR scores returned to basal levels at 48 h and 7 d after HIS compared to pre-HIS baseline at different distention pressures. The AWR scores before HIS were 0.6 ± 0.2, 1.3 ± 0.2, 1.9 ± 0.2 and 2.3 ± 0.2 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg distention pressures, respectively. Six hours after termination of the last stressor, the AWR scores were 2.0 ± 0.1, 2.5 ± 0.1, 2.8 ± 0.2 and 3.5 ± 0.2 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg distention pressures, respectively. EA given at classical acupoint ST-36 in both hindlimbs for 30 min significantly attenuated the hypersensitive responses to colorectal distention in HIS rats compared with sham EA treatment [AWRs at 20 mmHg: 2.0 ± 0.2 vs 0.7 ± 0.1, P = 4.23,711 E-4; AWRs at 40 mmHg: 2.6 ± 0.2 vs 1.5 ± 0.2, P = 0.00,163; AWRs at 60 mmHg: 3.1 ± 0.2 vs 1.9 ± 0.1, P = 0.003; AWRs at 80 mmHg: 3.6 ± 0.1 vs 2.4 ± 0.2, P = 0.0023; electromyographic (EMG) at 20 mmHg: 24 ± 4.7 vs 13.8 ± 3.5; EMG at 40 mmHg: 60.2 ± 6.6 vs 30 ± 4.9, P = 0.00,523; EMG at 60 mmHg: 83 ± 10 vs 39.8 ± 5.9, P = 0.00,029; EMG at 80 mmHg: 94.3 ± 10.8 vs 49.6 ± 5.9, P = 0.00,021]. In addition, EA at the acupuncture point BL-43 with same parameters did not alleviate visceral hypersensitivity in HIS rats. EA in healthy rats also did not have any effect on AWR scores to colorectal distention at distention pressures of 20 and 40 mmHg. The EA-mediated analgesic effect was blocked by pretreatment with NLX in HIS rats [AWR scores pretreated with NLX vs normal saline (NS) were 2.0 vs 0.70 ± 0.20, 2.80 ± 0.12 vs 1.50 ± 0.27, 3 vs 2.00 ± 0.15 and 3.60 ± 0.18 vs 2.60 ± 0.18 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg; P = 0.0087, 0.0104, 0.0117 and 0.0188 for 20, 40, 60 and 80 mmHg, respectively]. Furthermore, EA-mediated analgesic effect was completely reversed by administration of m-NLX, a peripherally restricted opioid antagonist (EMG pretreated with m-NLX vs NS were 30.84 ± 4.39 vs 13.33 ± 3.88, 74.16 ± 9.04 vs 36.28 ± 8.01, 96.45 ± 11.80 vs 50.19 ± 8.28, and 111.59 ± 13.79 vs 56.42 ± 8.43 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg; P = 0.05,026, 0.00,034, 0.00,005, 0.000,007 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg, respectively). EA given at classical acupoint ST-36 alleviates stress-induced visceral pain, which is most likely mediated by opioid pathways in the periphery.


Preservation of Hypermobile Teeth by Establishing Posterior Occlusal Support Using Implant Prostheses: A 5-Year Follow-Up.
For patients with periodontally compromised, hypermobile teeth, implant-supported fixed dental prostheses (FDPs) or removable dentures are often used after extracting mobile teeth. The loss of native teeth may carry social consequences, depending upon the patient's age, state of health, and degree of social functioning. This report represents successful stabilization and preservation of questionable, hypermobile teeth that have been damaged by traumatic occlusion due to the loss of posterior support with a cross-arch splinted FDP, as well as the implementation of posterior support using implant-supported prostheses.


Cogan's syndrome: a rare systemic vasculitis.
A 4 year old girl presented with keratitis and ataxia. Over the next two months she developed profound hearing loss, arthritis, and polychondritis. A diagnosis of Cogan's syndrome was made. The literature on the condition is reviewed and the importance of early diagnosis to prevent hearing loss is highlighted.


A new oxathiolane from Enterobacter cloacae.
Enterobacter cloacae is a versatile bacterial species inhabiting a wide variety of niches and is capable of metabolising a wide variety of substances as energy resources. The fermentation culture of this bacterial species has successfully yielded one new compound, Rimboxa (1) and three known compounds, i.e. indole-3-carboxaldehyde (2), indole-3-acetic acid (3) and 3,4-di-t-butylaniline (4). Rimboxa (1) is shown to possess the 1,2-oxathiolane core structure. 3,4-Di-t-butylaniline (4) is isolated for the first time from a natural resource. These compounds were isolated and characterised using extensive chromatographic and spectroscopic methods, and were subjected to cytotoxicity evaluations.


Finding synergies in fuels properties for the design of renewable fuels--hydroxylated biodiesel effects on butanol-diesel blends.
This article describes the effects of hydroxylated biodiesel (castor oil methyl ester - COME) on the properties, combustion, and emissions of butanol-diesel blends used within compression ignition engines. The study was conducted to investigate the influence of COME as a means of increasing the butanol concentration in a stable butanol-diesel blend. Tests were compared with baseline experiments using rapeseed methyl esters (RME). A clear benefit in terms of the trade-off between NOX and soot emissions with respect to ULSD and biodiesel-diesel blends with the same oxygen content was obtained from the combination of biodiesel and butanol, while there was no penalty in regulated gaseous carbonaceous emissions. From the comparison between the biodiesel fuels used in this work, COME improved some of the properties (for example lubricity, density and viscosity) of butanol-diesel blends with respect to RME. The existence of hydroxyl group in COME also reduced further soot emissions and decreased soot activation energy.


Preparation of a Facilitated Transport Membrane Composed of Carboxymethyl Chitosan and Polyethylenimine for CO2/N2 Separation.
The miscibility of carboxymethyl chitosan/polyethylenimine (CMCS/PEI) blends was analyzed by FT-IR, TGA and SEM. Defect-free CMCS/PEI blend membranes were prepared with polysulfone (PSf) ultrafiltration membranes as support layer for the separation of CO(2)/N(2) mixtures. The results demonstrate that the CMCS/PEI blend is miscible, due to the hydrogen bonding interaction between the two targeted polymers. For the blended membrane without water, the permeability of CO(2) gas is 3.6 × 10-7 cm3 cm-2 s-1 cmHg-1 and the corresponding separation factor for CO(2) and N(2) gas is about 33 at the pressure of 15.2 cmHg. Meanwhile, the blended membrane with water has the better permselectivity. The blended membrane containing water with PEI content of 30 wt% has the permeance of 6.3 × 10-4 cm3 cm-2 s-1 cmHg-1 for CO(2) gas and a separation factor of 325 for CO(2)/N(2) mixtures at the same feed pressure. This indicates that the CO(2) separation performance of the CMCS/PEI blend membrane is higher than that of other facilitated transport membranes reported for CO(2)/N(2) mixture separation.


Sealed sources in synthetic absorbable suture: a new method for permanent interstitial implantation.
Inactive gold grains are embedded at 1-cm intervals along a synthetic, absorbable surgical suture, then subjected to neutron irradiation in a nuclear reactor, forming a new material for permanent interstitial implant therapy. Assembling and activating the sealed sources in an absorbable carrier, the physical properties of the irradiated suture, its behavior in tissue, and the methods and results of implantation in the dog are described.


Ambulatory blood pressure monitoring.
During the past decade, ambulatory blood pressure monitoring has risen rapidly as a diagnostic technique used in clinical research trials and, more recently, in clinical practice. Blood pressure monitors have become smaller, technologically improved, and quiet during recordings--all features that have increased patient compliance. During the past year, research has focused on establishing population norms for ambulatory blood pressure levels, improving methods of validating devices, enhancing our ability to reduce the ambulatory blood pressure data and provide clinically meaningful methods of statistical analysis, and evaluating the role of blood pressure monitoring in the management of hypertension in ambulatory care.


"Being" an Older Adult Skier: The Phenomenology of Masters Alpine Ski Racers.
This research examined the lived experience of older adult Alpine skiers in their continued participation in competitive ski racing. The aim was to gain an understanding of the meaning of the experiences for older adults as they continued to compete in Alpine ski racing. Masters skiers between the ages of 69 and 82 years participated in individual interviews. Data collection and analysis were iterative processes informed by phenomenological methods and visual mind mapping. The overarching theme identified in participants' accounts was the significance of the identity of "Being" a Ski Racer. Supporting subthemes were Enjoying the Feeling of Ski Racing, Adapting in the Sport, and Skiing as a Lifestyle. These insights offer the opportunity to encourage and support the holistic experiences of older adults who maintain their athletic identity as they age. This research highlights how inclusion of older adults' stories may foster critical reflexivity and challenge assumptions about aging.


[Pre- and postoperative color Doppler ultrasonography of myocutaneous flaps in reconstructive surgery of the breast].
The authors present their experience in the study of blood supply of flaps. The machine used to study both pre and postoperatively the myocutaneous flap is the echo-color Doppler, a brand new device which has recently been used in investigating the morphology and the blood supply. The use of such method has provided us with the following information: detailed ultrasound structure of the skin, subcutaneous and muscular tissues of the examined flap; localization of vessels within the flap; size of the vessel in its whole length; quality and speed of both the arterial and venous flow. Such information is very important for the surgeon to plan in detail the reconstruction by knowing the blood supply of myocutaneous flap.


Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ.
It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.


Obesity, hypertension, social determinants of health and the epidemiologic transition among traditional Amazonian populations.
The health and nutritional situation of adults from three rural vulnerable Amazonian populations are investigated in relation to the Social Determinants of Health (SDH) and the epidemiologic transition. To investigate the role of the environment and the SDH on the occurrence of chronic-degenerative diseases in these groups. Anthropometric, blood pressure and demographic data were collected in adults from the RDS Mamirauá, AM (n = 149), Flona Caxiuanã, PA (n = 148) and quilombolas, PA (n = 351), populations living in a variety of socio-ecological environments in the Brazilian Amazon. Adjusting for the effect of age, quilombola men are taller (F = 9.85; p < 0.001) and quilombola women present with higher adiposity (F = 20.43; p < 0.001) and are more overweight/obese. Men from Mamirauá present higher adiposity (F = 9.58; p < 0.001). Mamirauá women are taller (F = 5.55; p < 0.01) and have higher values of waist circumference and subscapular/triceps index. Quilombolas present higher prevalence of hypertension in both sexes and there are significant differences in rates of hypertension among the women (χ(2) = 17.45; p < 0.01). The quilombolas are more dependent on government programmes, people from Mamirauá have more economic resources and the group from Caxiunã have the lowest SES. In these populations, the SDH play a key role in the ontogeny of diseases and the 'diseases of modernity' occur simultaneously with the always present infectoparasitic pathologies, substantially increasing social vulnerability.


DNA polymorphisms of apolipoprotein B in the population of Senegal.
Three apolipoprotein B (apoB) genetic polymorphisms, the XbaI, MspI and EcoRI restriction fragment length polymorphisms (RFLPs), were analysed for 221 individuals in Senegal by polymerase chain reaction. Allelic frequency determination revealed that this population has 0.79 XbaI- (X-), 0.96 MspI+ (M+), and 0.89 EcoRI+ (E+). Major genotypes were X-/X- (0.62), M+/M+ (0.92) and E+/E+ (0.80). The XbaI allele frequency is different (p < 10(-9)) from that in Caucasians (0.47) and from that in Mongoloids (0.98). Significant differences between Senegalese and Caucasians, and between Senegalese and Mongoloids were also observed for the EcoRI and MspI alleles of the apoB genes.


Experimental study of the mutual interactions between waves and tailored turbulence.
When surface waves interact with ambient turbulence, the two affect each other mutually. Turbulent eddies get redirected, intensified and periodically stretched and compressed, while the waves suffer directional scattering. We study these mutual interactions experimentally in the water channel laboratory at the Norwegian University of Science and Technology (NTNU) Trondheim. Long groups of waves were propagated upstream on currents with identical mean flow but different turbulence properties, created by an active grid at the current inlet. The subsurface flow in the spanwise-vertical plane was measured with stereo particle-image velocimetry. Comparing the subsurface velocity fields before and after the passage of a wave group, a strong enhancement of streamwise vorticity is observed which increases rapidly towards the surface for k0z ≳ -0.3 (z: vertical distance from still surface; k0: carrier wavenumber) in qualitative agreement with theory. Next, we measure the broadening of the directional wave spectrum at increasing propagation distance. The rate of directional diffusion is greatest for the turbulent case with the highest energy at the longest length scales whereas the highest total turbulent kinetic energy overall did not produce the most scattering. The variance of directional spectra is found to increase linearly as a function of propagation time.


Mapping drivers of second-generation South Asian American eating behaviors using a novel integration of qualitative and social network analysis methods.
This study explores a novel, mixed qualitative method to deconstruct the diet of second-generation South Asian Americans (SAAs). Online interviews of 32 second-generation SAAs were conducted usingintegrated free-listing and mind-mapping. Ranked free-lists were aggregated to identify salient drivers, while connections made within mind-maps were analyzed using social network analysis (SNA) methods. Overall, 34 distinct drivers and 247 unique connections were identified. Taste, family, and health had the highest adjusted rankings, while health displayed the strongest network centrality. Interventions aimed at second-generation SAA dietary behaviors may benefit from family-based or multi-level interventions, which consider the complex, unique dietary norms identified.


Essential amino acids improve insulin activation of AKT/MTOR signaling in soleus muscle of aged rats.
Essential amino acids (EAA) improve basal muscle protein synthesis in the elderly. Nevertheless, in settings of prolonged supplementation, putative signal pathways of EAA are currently unknown. The purpose of this study was to test the effects of prolonged supplementation of EAA enriched mixture (12-L-Amin) on Insulin/Insulin-like Growth Factor-1 (IGF1) pathway by measuring total and phosphorylated Akt (Ser473) and its upstream (IRS1 at Ser636) and downstream (mTOR at Ser2448, p70S6K at Thr389) targets in basal conditions and following acute insulin (0.1 U/L) incubation in vitro. To this aim, soleus muscles were dissected from male Wistar rats divided in three groups of 7 each: adults (AD, 10 mo of age), elderly (EL, 22 mo of age) and elderly supplemented (EL-AA, 12-L-Amin 1.5gr/Kg die in drinking water for 3 mo). EL showed reduced basal and post-insulin mTOR and p70S6K activation and reduced post-insulin IRS1 degradation relative to AD. EL-AA showed an increase of post-insulin Akt activation, no change in basal and post-insulin phospho-mTOR, lower reduction of phospho-p70S6K and increased post-insulin IRS1 degradation relative to AD. These results demonstrate that chronic 12-LAmin administration exerts anti-ageing effects on the activation/inactivation of the Insulin/IGF1/mTOR pathway which is identified as putative target of EAA in the elderly.


Magnetostructural relationship for μ2-phenoxido bridged ferric dimers.
Three Fe(iii) dimers, [Fe2(L-H)2]·2CH3CN (1), [Fe2(L-OCH3)2] (2) and [Fe2(L-OC2H5)2]·2CH3CN (3), containing the pentadentate O,N,N,O,O-donor Schiff-base ligands with variable size pendants, were synthesized and structurally characterized. The three ligands were generated in situ from 2-(iminomethyl)phenol, 2-methoxy-6-(iminomethyl)phenol and 2-ethoxy-6-(iminomethyl)phenol, respectively. All three crystal structures contain centrosymmetric dimers of edge-sharing octahedra of Fe(iii) ions through a pair of μ2-phenoxido bridges. The exchange coupling is ferromagnetic for 1 (J = +0.47(1) cm-1, ∠Fe-O-Fe = 98.02°) and 2 (J = +0.86(1) cm-1, ∠Fe-O-Fe = 97.17°), but antiferromagnetic for 3 (J = -0.72(1) cm-1, ∠Fe-O-Fe = 98.53°), which are correlated by high-field electron paramagnetic resonance revealing moderate magneto-anisotropy of D = -0.24(3) cm-1, E = 0.08(1) cm-1 for 1, D = -0.38(1) cm-1, E = 0.11(1) cm-1 for 2, and D = 0.30(3) cm-1, E = 0.02(1) cm-1 for 3. The exchange couplings were further estimated by DFT calculations, which gave the finest Fe-O-Fe angle of 97.83° for the ferromagnetic-antiferromagnetic crossover.


Should we use standard survival models or the illness-death model for interval-censored data to investigate risk factors of chronic kidney disease progression?
In studies investigating risk factors of chronic kidney disease (CKD) progression, one may be interested in estimating factors effects on both a fall of glomerular filtration rate (GFR) below a specific level (i.e., a CKD stage) and death. Such studies have to account for the fact that GFR is measured at intermittent visit only, which implies that progression to the stage of interest is unknown for patients who die before being observed at that stage. Our objective was to compare the results of an illness-death model that handles this uncertainty, with frequently used survival models. This study included 1,519 patients from the NephroTest cohort with CKD stages 1-4 at baseline (69% males, 59±15 years, median protein/creatinine ratio [PCR] 27.4 mg/mmol) and subsequent annual measures of GFR (follow-up time 4.3±2.7 years). Each model was used to estimate the effects of sex, age, PCR, and GFR at baseline on the hazards of progression to CKD stage 5 (GFR<15 mL/min/1.73 m2, n = 282 observed) and death (n = 168). For progression to stage 5, there were only minor differences between results from the different models. The differences between results were higher for the hazard of death before or after progression. Our results also suggest that previous findings on the effect of age on end-stage renal disease are more likely due to a strong impact of age on death than to an effect on progression. The probabilities of progression were systematically under-estimated with the survival model as compared with the illness-death model. This study illustrates the advantages of the illness-death model for accurately estimating the effects of risk factors on the hazard of progression and death, and probabilities of progression. It avoids the need to choose arbitrary time-to-event and time-to-censoring, while accounting for both interval censoring and competition by death, using a single analytical model.


Comprehensive Behavioral Therapy of Trichotillomania: A Multiple-Baseline Single-Case Experimental Design.
Despite rapidly increasing knowledge about Trichotillomania (TTM), no gold-standard evidence-based psychological intervention has been identified. In the current study, we evaluated the potential efficacy of an eight-session psychological intervention for TTM, namely the Comprehensive Behavioral Model (ComB) treatment, using a multiple-baseline single-case experimental design with three Italian women with TTM. The study included three phases: baseline, intervention, and 3-month follow-up. We assessed the intervention using daily self-monitoring of number of hair-pulling episodes, number of pulled hairs per episode, degree of resistance to pulling urges, and degree of associated distress. We also assessed for reliable improvement in general distress from baseline to post-intervention. All participants completed treatment and showed improvements on those symptom measures that were most relevant to their individualized case conceptualization. However, no participants recovered completely or demonstrated reliable improvement in general distress. Our results provide initial evidence for the utility of the ComB treatment for TTM in an Italian clinical setting. Furthermore, they support the delivery of individualized and flexible psychological treatments when treating TTM.


Research note: changes in the concentration of beta-carotene, alpha-tocopherol and retinol in the bovine corpus luteum during the ovarian cycle.
Causes and possible consequences of the accumulation of beta-carotene during the development of the corpus luteum in cattle are still unknown. Therefore, in a descriptive study a total of 43 corpora lutea from ovaries of non-pregnant cows representing four stages of the ovarian cycle the concentration of beta-carotene, alpha-tocopherol and retinol was determined. Beta-carotene and alpha-tocopherol continuously increased from stage I to stage IV (beta-carotene: 14 +/- 8 vs. 175 +/- 117 microg/g, P < 0.05; alpha-tocopherol: 15 +/- 7 vs. 132 +/- 66, P < 0.001). In contrast, retinol decreased from highest values at stage I (250 +/- 160 ng/g) to lowest (90 +/- 80 ng/g tissue) at stage III (P < 0.05). The results support the concept, that both beta-carotene and alpha-tocopherol accumulation in the corpus luteum secondary to the uptake of lipoprotein-bound cholesterol during steroid synthesis. Lowest retinol levels were observed at highest metabolic activity of the corpus luteum indicating a possible consumption of retinol during stereogenesis. In conclusion assuming an importance of a local conversion of beta-carotene into retinol in the corpus luteum dietary supplementation should be sufficient enough to support such an accumulation of beta-carotene in the corpus luteum as local precursor of retinol.


Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in sub-Saharan Africa.
Heart failure in sub-Saharan Africans is mainly due to non-ischaemic causes, such as hypertension, rheumatic heart disease, cardiomyopathy and pericarditis. The two endemic diseases that are major contributors to the clinical syndrome of heart failure in Africa are cardiomyopathy and pericarditis. The major forms of endemic cardiomyopathy are idiopathic dilated cardiomyopathy, peripartum cardiomyopathy and endomyocardial fibrosis. Endomyocardial fibrosis, which affects children, has the worst prognosis. Other cardiomyopathies have similar epidemiological characteristics to those of other populations in the world. HIV infection is associated with occurrence of HIV-associated cardiomyopathy in patients with advanced immunosuppression, and the rise in the incidence of tuberculous pericarditis. HIV-associated tuberculous pericarditis is characterised by larger pericardial effusion, a greater frequency of myopericarditis, and a higher mortality than in people without AIDS. Population-based studies on the epidemiology of heart failure, cardiomyopathy and pericarditis in Africans, and studies of new interventions to reduce mortality, particularly in endomyocardial fibrosis and tuberculous pericarditis, are needed.


Continuing diabetes care--Rhode Island, 1991.
The annual economic impact of diabetes mellitus in the United States is an estimated $92 billion, primarily reflecting the treatment of both acute (e.g., diabetic ketoacidosis and hypoglycemic coma) and chronic (e.g., atherosclerotic cardiovascular disease, blindness, renal failure, neuropathy, and amputation of extremities) complications. The complications of diabetes may be prevented or delayed through intensive treatment and through early detection and treatment of complications. To characterize continuing care of diabetes in Rhode Island in 1991, the Rhode Island Department of Health initiated a Diabetes Care Survey (DCS) in conjunction with its statewide Health Interview Survey (HIS) in 1990. This report summarizes the results of that survey.


Degradation of ochratoxin A by Bacillus amyloliquefaciens ASAG1.
Ochratoxin A (OTA) is widely found in food and feed products as a mycotoxin contaminant. It is produced by Penicillium species and several Aspergillus species. The identification OTA detoxification microorganisms is believed to be the best approach for decontamination. In this study, we isolated ASAG1, a bacterium with the ability to degrade OTA effectively, from grain depot-stored maize. A 16S rDNA sequencing approach was used to identify this strain as Bacillus amyloliquefaciens ASAG1. The degradation of OTA was detected in both medium and cell-free extracts after incubation with a culture of B. amyloliquefaciens ASAG1 cells. Subsequently, a hydrolysed enzyme (carboxypeptidase) related to the enzymatic conversion of OTA was cloned from the B. amyloliquefaciens ASAG1 genome. Using the Escherichia coli Expression System, we successfully expressed and purified this carboxypeptidase. When this enzyme was incubated with the engineered recombinant E. coli cells, the concentration of OTA was dramatically degraded. Our data therefore indicate that the carboxypeptidase produced by B. amyloliquefaciens ASAG1 is likely responsible for the biodegradation of OTA.


Implantation of three-piece silicone toric additive IOLs in challenging clinical cases with high astigmatism.
To analyze the refractive outcomes and safety of three-piece silicone toric sulcus-fixated add-on intraocular lenses (IOLs) (HumanOptics/Dr.Schmidt Intraocularlinsen, Erlangen, Germany) in complex clinical cases with high astigmatism such as in cases with previous penetrating keratoplasty. Interventional case series of 21 eyes of 20 patients enrolled at two German centers. Functional results including power vector analysis, accuracy of IOL power calculation, rotational stability, and postoperative complications were evaluated from 2 months to 6 years postoperatively. The preoperative subjective cylinder exceeded or was equal to -6.00 diopters (D) in 81% of eyes (range: -2.00 to -17.00 D). The median follow-up period was 7.6 months (range: 57 days to 6 years). The efficacy analysis focused on the 2 to 6 months follow-up visit. Postoperatively, there was a median reduction of astigmatism by 70.59% (subjective cylinder range: 0.00 to -5.00 D), improvement of uncorrected distance visual acuity, and unchanged median corrected distance visual acuity. The attempted spherical equivalent was achieved within ± 0.50 D in 45% and within ± 1.00 D in 65% of cases. Five eyes received secondary surgical alignment of axis. Other complications related to the surgical procedure were mainly transient shortly after implantation, such as intraocular pressure elevation (2 of 21 eyes) or corneal edema (2 of 21 eyes). Persisting changes were seen only in rare cases and included pigment dispersion (1 of 21 eyes) or corneal edema requiring a second keratoplasty within 9 months after surgery (2 of 21 eyes). Toric add-on IOLs may be useful in reducing high astigmatism and anisometropia and increasing spectacle independence even in complex clinical conditions with high refractive errors.


Questionable diagnostic benefit of the commercially available panel of bee venom components.
For many years, only the major allergen rApi m 1 has been available on the ImmunoCAP system for routine diagnosis of bee venom (BV) allergy. Now, there are five components available, and we aimed to detect the sensitivity and specificity of rApi m 1, 2, 3, 5, and 10 in BV-allergic patients. We further evaluated the sensitivity of rApi m 1 and 2 of an alternative platform and investigated possible differences in the sensitization profile between monosensitization and clinically relevant double sensitization. Analysis of the whole panel of BV allergens of the CAP system still resulted in a lower sensitivity than analysis of the combination of rApi m 1 and 2 of the Immulite (71.6% vs 85.8%). Sensitization rate of rApi m 5 was more than doubled in double-sensitized patients, while there was no difference for rApi m 2. The benefit of the commercially available panel of BV components is questionable, due to the insufficient sensitivity and still unavailable important cross-reacting allergens.