Comparison of Endothelial Function in Healthy Patients and Patients With Chronic Periodontitis and Myocardial Infarction.
The inflammatory burden as a result of severe periodontal disease acts as an insult to the endothelium. This disruption in the function of the endothelium predisposes it toward formation of atherosclerotic plaque, which may be a subsequent risk for coronary artery disease. The aim of this study is to estimate and compare endothelial function via flow-mediated dilation (FMD) assessment in periodontal health and disease. A total of 120 patients were selected and categorized equally into three groups: 1) healthy (control); 2) chronic periodontitis (CP); and 3) myocardial infarction (MI). Periodontal inflamed surface area (PISA) and FMD were assessed in all patients. Fasting blood samples were collected to estimate lipid profile. Analysis of variance was used for comparison of lipid profile, whereas Kruskal-Wallis test was used for comparison of FMD and PISA scores among the study groups with P <0.05. Comparison of FMD levels among the three groups showed statistically significant difference, with P <0.001. The value was statistically significant when the healthy group was compared with the CP and MI groups but not when the CP group was compared with the MI group. Lipid profile levels were statistically significant on comparison between the healthy and CP groups and between the CP and MI groups. Endothelial function was impaired in patients with CP compared with healthy patients, and the dysfunction observed was similar to that observed in the MI group based on FMD values.


Differential regulation of nitric oxide synthase function in aorta and tail artery from 5/6 nephrectomized rats.
Chronic renal failure (CRF) is associated with hypertension and concomitant endothelial dysfunction, enhanced vasoconstriction, and nitric oxide synthase (NOS) dysfunction. Vascular function in patients is assessed in peripheral extremity arteries like the finger arteries, whereas animal studies often use the centrally located aorta. Therefore, we examined whether peripheral tail artery and aortic NOS function are differentially regulated by blood pressure in rats with CRF. Using wire myography, arterial function was assessed in 16-week-old Sprague-Dawley rats that were subjected to 5/6 nephrectomy (Nx; arterial ligation model) 8 weeks earlier or non-Nx (control) rats. In aortas from Nx rats, endothelial-dependent vasorelaxation response to acetylcholine (ACh) was blunted and there was enhancement of phenylephrine (PE)-mediated vasoconstriction. Inversely, tail arteries from Nx rats had no change in endothelial function and reduced response to PE. Studies where arterial segments were incubated with the nonspecific NOS inhibitor, L-NAME, showed that Nx reduced NOS function in the aorta but increased NOS function in tail artery for both ACh and PE responses. Furthermore, the observed alterations in NOS function in both aorta and tail artery were abolished when mean arterial blood pressure, as assessed by telemetry, was maintained at normal levels in the 5/6 Nx rats using triple therapy: hydralazine (30 mg/kg per day), hydrochlorothiazide (10 mg/kg per day), and reserpine (0.5 mg/kg per day). In conclusion, differential changes of NOS function in central versus peripheral arteries in CRF are dependent upon hypertension.


[Resources and application of She's nationality wild medicinal plants].
To make a thorough investigation of the common She's nationality wild medicinal plants resources in our country, including the species, the distribution, the folk application and the endemic medicinal plant species, Field surveyed was conducted with 25 She people mainly lived area (county, district or city) throughout the country, the folk prescription and treatment cases provided by She's medical personnel, the drug usage and dosage, the commonly used traditional She's medicine and drug samples were collected. And the distribution, growing environment of these plants were investigated, their characteristics, photographs, GPS data and track were record , and the fresh wax leaf or plants specimens were collected. In total 1 600 varieties of folk medicine of She's nationality, 450 disease names and 1 016 prescriptions were collected. 520 kinds of these medicinal plants were commonly used, growing mainly distributed in the southeastern China, about 200 meters above sea level to 1 500 meters. There are 5 First-Grade State protection wild plants (medicinal), 15 second-Grade State protection wild plants (medicinal), and 11 She characteristic medicinal plants in our study, they belong to 144 families, 312 genera 494 species, 2 subspecies, 17 varieties, 3 forms and 1 cultivated varieties of She's nationality. Folk medicine usage is different from the traditional Chinese medicine and ethnic medicine. This survey finds out the common She's nationality wild medicinal plants resources in China, including the species, the distribution, the folk application and commonly used drugs, and found the rare and endangered medicinal plants and the She's nationality endemic medicinal plants, which provides a basis for further development and use the traditional She's medicine resources.


Severe intrauterine growth restriction is associated with higher spontaneous carbohydrate intake in young women.
Intrauterine growth restriction (IUGR) is associated with metabolic disorders in adulthood. In rats, an early adverse environment alters food preferences in adult life. We investigated whether IUGR is associated with spontaneous macronutrient preferences in humans. Two thousand sixty-three participants from a Brazilian birth cohort were evaluated at 24 y of age using a food frequency questionnaire, physical examination, anthropometric measurements, and biochemical assays (glucose, insulin, cholesterol, and triglycerides). IUGR was defined by the birth weight ratio (BWR = birth weight/mean weight for gestational age). Individuals were classified as non growth restricted (BWR > or =0.85), moderately growth restricted (0.85 > BWR > or = 0.75), and severely growth restricted (BWR <0.75). Severe IUGR women consumed a greater carbohydrate to protein ratio, even after controlling for social variables. There was a continuous association between growth restriction and later carbohydrate to protein ratio consumption in women. Women from both IUGR groups had a larger waist to hip ratio (WHR). The prevalence of metabolic syndrome was comparable between the groups. IUGR women preferred carbohydrates to protein in their regular diet, suggesting that spontaneous food choices may precede the appearance and contribute to the risk for metabolic diseases in this group.


Resonance Raman and Raman spectroscopy for breast cancer detection.
Raman spectroscopy is a sensitive method to detect early changes of molecular _composition and structure that occur in lesions during carcinogenesis. The Raman spectra of normal, benign and cancerous breast tissues were investigated in vitro using a near-infrared (NIR) Raman system of 785 nm excitation and confocal micro resonance Raman system of 532 nm excitation. A total number of 491 Raman spectra were acquired from normal, benign and cancerous breast tissues taken from 15 patients. When the 785 nm excitation was used, the dominant peaks in the spectra were characteristic of the vibrations of proteins and lipids. The differences between the normal and cancerous breast tissues were observed in both the peak positions and the intensity ratios of the characteristic Raman peaks in the spectral region of 700-1800 cm(21). With 532 nm excitation, the resonance Raman (RR) spectra exhibited a robust pattern of peaks within the region of 500-4000 cm(21). The intensities of four distinct peaks at 1156, 1521, 2854 and 3013 cm(21) detected in the spectra collected from normal breast tissue were found to be stronger in comparison with those collected from cancerous breast tissue. The twelve dramatically enhanced characteristic peaks, including the enhanced amide II peak at 1548 cm(21) in the spectra collected from cancerous breast tissue, distinguished the cancerous tissue from the normal tissue. Principal component analysis (PCA) combined with support vector machine (SVM) analysis of the Raman and RR spectral data yielded a high performance in the classification of cancerous and benign lesions from normal breast tissue.


Endoscopic findings of adenocarcinoma arising from short-segment Barrett's esophagus.
Adenocarcinoma arising from short-segment Barrett's esophagus (SSBE) is rare in Japan, although the incidence of this condition is increasing in Western countries. Four cases of early adenocarcinoma arising from SSBE were diagnosed and treated at Niigata-prefectural Yoshida Hospital. All patients were male, variously 55, 71, 73 and 79 years of age. All four patients had long-term gastroesophageal reflux disease, although one patient had erosive esophagitis and three patients did not have erosive esophagitis. Three patients were diagnosed as having Helicobacter pylori-free stomach. All adenocarcinomas occurred close to the squamocolumnar junction. Patients with SSBE should undergo detailed endoscopic examination of the squamocolumnar junction in order to detect early adenocarcinoma arising from SSBE.


Transcatheter Arterial Chemoembolization with Drug-Eluting Beads for the Treatment of Hepatocellular Carcinoma: Recommended Selection for Small-Caliber (<100 μm) Beads.
Drug-eluting beads transarterial chemoembolization (DEB-TACE) is an alternative to conventional lipiodol-based TACE (cTACE) to treat hepatocellular carcinoma (HCC). With the advancement in pharmacology, small-caliber DEB-TACE (<100 μm) has been introduced since 2016. For the treatment of hepatic neoplasms or HCC, there is a tendency to use smaller beads by DEB-TACE to achieve more extensive tumor necrosis and a significant reduction in liver toxicity in comparison with that caused by cTACE. However, the indications and potential complications of small-caliber DEB-TACE remain uncertain and have not been well established, due to lack of randomized phase III clinical trials. Instead of systematic or meta-analysis review, this narrative review article describes the suggested indications and contraindications of DEB-TACE with small DEBs, benefit of super-selective embolization of the feeding arteries and the recommended selection of small-caliber DEB. This review was approved by the institutional review board (File Number: 1-105-05-158).


Determination of therapeutic agents efficiencies of microsatellite instability high colon cancer cells in post-metastatic liver biochip modeling.
Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


[Clinical observation of 85 patients with Behçet's uveitis treated with immunosuppressive agents combined with steroids].
To investigate the effect and safety of immunosuppressive treatment (IMT) combined with steroids in patients with Behçet's uveitis. Case-series study. Eighty-five patients (167 eyes) were enrolled in this study from June 2010 to June 2011 at the Beijing Tongren Hospital. The patients were examined before the initiation of IMT and were followed up once every 3 months after the therapy. The corrected visual acuity, inflammation score, ocular complications and side effects of IMT and steroid use were recorded. The rate of positive outcomes was reported in person years (PY) or eye years (EY). The intervals between the episodes of ocular inflammation were analyzed using Kaplan-Meier survival analysis. The difference of the proportion of stable cases before and after treatment was analyzed by Log-rank test. There were 67 males and 18 females. The mean age of diagnosis with Behçet's disease was (30.4 ± 9.5) years. The total follow-up period was 255.5 EY and 129.67 PY. The percentages of eyes with inflammation that had been stable for at least 3 months (91.6%, 153/167) or more than 1 year (22.3%, 37/167) after treatment were significantly higher than those before treatment [34.7% (58/167) and 1.0% (2/167), respectively] (χ(2) = 137.80, P < 0.01). The incident rate of a decrease in visual acuity was 0.11 per EY, and the incident rate of an increased in visual acuity was 0.22 per EY. The incident rates of cataracts, an intraocular pressure greater than 30 mm Hg (1 mm Hg = 0.133 kPa) or a severe vitreous haze were 0.39 per EY, 0.07 per EY and 0.79 per EY, respectively. The incident rates of obesity, osteoporosis and hypertension caused by steroid use were 0.4 per PY, 0.22 per PY and 0.13 per PY, respectively. The common side effects of IMT were reversible leukopenia (0.26 per PY by chlorambucil and 0.46 per PY by methotrexate), hepatotoxicity (0.21 per PY by cyclophosphamide, 0.13 per PY by azathioprine), hematuria (0.21 per PY by cyclophosphamide) and gum hyperplasia caused by cyclosporine (0.15 per PY). Although the use of IMT combined with steroids is effective for the control of intraocular inflammation in patients with Behçet's uveitis, the occurrence of complications is still high, and the vision prognosis is poor. We should pay attention to the side effects of the long-term use of steroids, such as hypertension, obesity and osteoporosis. The initiation of IMT is recommended over the long-term administration of large doses of steroids. The side effects of IMT should be monitored.


The progress of patients in the European Working Party on Hypertension in the Elderly trial.
792 hypertensive patients above the age of 60 have entered the double-blind multicentre trial of the European Working Party on High blood pressure in the Elderly (EWPHE). Half were treated with hydrochlorothiazide and triamterene and half were given placebo and a second capsule was given and if necessary up to 2 g of methyldopa/day. The measurements in a sample of 157 patients suggested 80-86% compliance rate. A significant blood pressure difference of 25/10 mm Hg was obtained between the groups and maintained during five years of follow-up. The increase in serum creatinine found in the actively treated group was related to the decrease in sitting systolic blood pressure. Changes in serum uric acid correlated with changes in serum creatinine both in the placebo and in the actively treated group. Fasting blood glucose changed significantly in the active treatment group. The balance between this decreased risk on the basis of the blood pressure reduction and the increase produced by the rise in blood glucose and the other treatment effects remains to be determined. The trial continues and more patients are being admitted.


[A new virus: the human herpesvirus 6].
Human herpesvirus 6 (HHV-6) was discovered in 1986. This novel virus is genetically related to cytomegalovirus. HHV-6 mainly infects T lymphocytes but its tropism appears to be much wider and probably involves some epithelial cells. Two HHV-6 variants, designated as A and B, can be distinguished by genetical and immunological analysis. HHV-6 infection is ubiquitous and widespread; it occurs most often during infancy and it is life-long. During primary infection, HHV-6 is the causative agent of exanthem subitum and fever episodes without rash in infants. HHV-6 is suspected to be the causative agent of opportunistic infections such as pneumonitis and retinitis in immunocompromised subjects. Its role in human immunodeficiency virus infection, lymphomas and chronic fatigue syndrome is controversial. In vitro, HHV-6 is sensitive to ganciclovir and foscarnet.


Cutibacterium avidum Osteomyelitis Associated With Pediatric Hip Reconstruction.
Cutibacteria are gram-positive, non-sporulating, anaerobic, or microaerophilic bacilli that are increasingly recognized in the setting of indolent post-operative infection. Clinically significant infection with Cutibacterium avidum in the pediatric population is rarely encountered. Herein, we report our experience with two pediatric cases of osteomyelitis and soft tissue abscess after femoral derotational osteotomy for congenital hip dysplasia.


A New Method for Characterization of Natural Zeolites and Organic Nanostructure Using Atomic Force Microscopy.
In order to study and develop an economical solution to environmental pollution in water, a wide variety of materials have been investigated. Natural zeolites emerge from that research as the best in class of this category. Zeolites are natural materials which are relatively abundant and non biodegradable, economical and serve to perform processes of environmental remediation. This paper contains a full description of a new method to characterize the superficial properties of natural zeolites of exotic provenience (Caribbean Islets) with atomic force microscopy (AFM). AFM works with the simplicity of the optical microscope and the high resolution typical of a transmission electron microscope (TEM). If the sample is conductive, structural information of mesoporous material is obtained using scanning and transmission electron microscopy (SEM and TEM), otherwise the sample has to be processed through the grafitation technique, but this procedure induces errors of topography. Therefore, the existing AFM method, to observe zeolite powders, is made in a liquid cell-head scanner. This work confirms that it is possible to use an ambient air-head scanner to obtain a new kind of microtopography. Once optimized, this new method will allow investigation of organic micelles, a very soft nanostructure of cetyltriammonium bromide (CTAB), upon an inorganic surface such as natural zeolites. The data also demonstrated some correlation between SEM microphotographies and AFM 3D images.


Migration and healing of ligament cells under inflammatory conditions.
It is well documented that the adult human medial collateral ligament has a functional healing response, whereas the anterior cruciate ligament does not. The differential healing responses of the medial collateral and anterior cruciate ligaments could be due to factors caused by different biological conditions and locations in vivo. In addition, different intrinsic properties of the constituent cells of these ligaments may contribute to their different healing abilities. Ligament healing follows an orderly process of hemorrhage, inflammation, proliferation, and remodeling. At the cellular level, healing involves a cell's detachment from and attachment to the matrix adjacent to the wound area, migration, and proliferation. This study sought to investigate whether, during migration, the responses of the medial collateral and anterior cruciate ligament fibroblasts are intrinsically different under the same inflammatory conditions. Human medial collateral and anterior cruciate ligament fibroblast cells were cultured, and in vitro wounds were simulated by streaking the cells with an inoculating loop, creating a cell-free area. The migration of the cells into this gap, thus filling the cell-free area, was observed. Two sets of experiments were conducted; one varied the wound width and the other added the inflammatory factors tumor necrosis factor-alpha, complement C5a, and lipopolysaccharide. As the width of the wound increased, the rate of recovery decreased for both types of ligament cells (slope: anterior cruciate ligament, 0.13 hour/micron and medial collateral ligament, 0.10 hour/micron). Also, the three inflammatory factors used all inhibited the recovery rates of both ligaments to ones that were 1.4-2.3 times slower than controls. However, in both sets of experiments, the anterior cruciate ligament fibroblasts were more sensitive to inflammatory factors, and the medial collateral ligament fibroblasts had faster recovery rates (anterior cruciate ligament, 1.2-3.4 times slower than rates for medial collateral ligament fibroblasts, excluding those under lipopolysaccharide treatment). The results showed that medial collateral and anterior cruciate ligament fibroblasts responded differently under the same inflammatory conditions. This may suggest that these differences in intrinsic properties contribute to their different healing responses and abilities.


Triangular ZnO nanosheets: synthesis, crystallography and cathodoluminescence.
ZnO nanosheets with triangular morphology have been synthesized on an Au-coated silicon substrate through a facile thermal evaporation process. The morphologies and microstructures of the nanosheets were studied by a scanning electron microscope (SEM) and a high-resolution transmission electron microscope (HR-TEM). These studies show that a nanosheet is commonly composed of two parts: a triangular ZnO sheet and an Au nanoparticle attached on its tip-end. Detailed crystallography analyses conclude that the formation of the highly crystalline nanostructures can be assigned to a combination of a vapor-liquid-solid (VLS) process that is believed to be responsible for its initial nucleation and subsequent crystallization along the growth direction, and a vapor-solid (VS) process that is responsible for its further radial growth. The spatially-resolved cathodoluminescence (CL) spectra exhibit a sharp strong near-band-edge (NBE) emission in the ultraviolet range and a negligible green emission.


Tula hantavirus in Belgium.
European common voles (Microtus arvalis), captured in Belgium in 1999, were proven by molecular as well as by serological techniques to be infected with Tula hantavirus (TULV). This is the first evidence for the presence of TULV in this country. No indication of spill-over infections of Puumala virus, known to be highly endemic among bank voles (Clethrionomys glareolus) within the same geographical regions as the trapped TULV-infected common voles, was observed. Together with previous reports on the circulation of TULV in eastern/central Europe, this finding suggests a more wide-spread circulation of this hantavirus serotype throughout the continent.


COVID 19 Pandemic and biomedical waste management practices in healthcare system.
The whole world was shaken with the pandemic of Coronavirus Disease (COVID-19) in end of the year 2019. Due to its novel origin, it was required to follow all precautions possible. Dealing with the massive amount of infectious healthcare waste became an enormous challenge. This review identifies the impacts of the pandemic on biomedical waste management. This systematic review was made by using keywords "biomedical waste" and "COVID 19" in open access databases like PubMed, Science Direct, Scopus, Google Scholers etc. 2124 articles downloaded and 765 found duplicate and 634 not related to the topic. after scrutiny with inclusion criteria 102 articles were considered to analyze the practices related to biomedical waste management during pandemic using PRISMA guideline.. The COVID-19 waste segregation, collection, storage, transportation, and disposal are a big challenge with all stakeholders. In order to control the virus spread, strict monitoring of the complete waste management cycle is required. Adoption of appropriate guidelines is paramount to worker safety and containment of infection. Sustainable recycling methods are needed to deal with the ever-increasing plastic waste resulting from mandatory personal protective equipment (PPE) usage. The situation also demands a rethinking of the healthcare system. Overall, there was an increase in BMW generation, and municipal waste had increased globally. Pandemic preparedness requires a global public health strategy and long-term investments. This will be vital for making a robust community capable enough to fight against any public health pressures in the future, as well as the pandemic tremors. Systematized efforts from all stakeholders, at all levels, not only refines epidemic preparation but also helps to attain a sustainable development of health for a healthier future.


Investigation of Repeat Client Drop-Out and Re-Enrolment Cycles in Fourteen Methadone Maintenance Treatment Clinics in Guangdong, China.
Client adherence is vital for effective methadone maintenance treatment (MMT). This study explores the pattern and associated factors of client adherence, drop-out and re-enrolment in the Chinese MMT programme over the period of 2006-2013. This retrospective study was conducted in 14 MMT clinics in Guangdong Province, China. We employed Kaplan-Meier survival analysis to estimate the rates of drop-out and re-enrolment of MMT clients and multivariate Cox regression to identify associated factors. Among 1,512 study participants, 79% have experienced 'drop-out' during the 7-year study period. However, 82% 'dropped-out' clients resumed treatment at a later time. Low education level (junior high or below versus otherwise, HR = 1.21, 1.05-1.40), low methadone dosage in the first treatment episode (<50 ml versus ≥50 ml, HR = 1.84, 1.64-2.06) and higher proportion of positive urine test (≥50% versus<50%, HR = 3.72, 3.30-4.20) during the first treatment episode were strong predictors of subsequent drop-outs of the participants. Among the 'dropped-out' clients, being female (HR = 1.40, 1.23-1.60), being married (HR = 1.19, 1.09-1.30), and having a higher proportion of positive urine tests in the first treatment episode (≥50% versus<50%, HR = 1.35, 1.20-1.51) had greater likelihood of subsequent re-enrolment in MMT. Clients receiving lower methadone dosage (first treatment episode <50 ml versus ≥50 ml, HR = 1.12, 1.03-1.23; the last intake before drop-out <50 ml versus ≥50 ml, HR = 1.16, 1.04-1.30) were also more likely to re-enrol. Persistent cycling in-and-out of clients in MMT programmes is common. Insufficient dosage and higher proportion of positive urine samples in the first treatment episode are the key determinants for subsequent client drop-out and re-enrolment. Interventions should target clients in their early stage of treatment to improve retention in the long term.


Information Propagation in Prior-Image-Based Reconstruction.
Advanced reconstruction methods for computed tomography include sophisticated forward models of the imaging system that capture the pertinent physical processes affecting the signal and noise in projection measurements. However, most do little to integrate prior knowledge of the subject - often relying only on very general notions of local smoothness or edges. In many cases, as in longitudinal surveillance or interventional imaging, a patient has undergone a sequence of studies prior to the current image acquisition that hold a wealth of prior information on patient-specific anatomy. While traditional techniques tend to treat each data acquisition as an isolated event and disregard such valuable patient-specific prior information, some reconstruction methods, such as PICCS[1] and PIR-PLE[2], can incorporate prior images into a reconstruction objective function. Inclusion of such information allows for dramatic reduction in the data fidelity requirements and more robustly accommodate substantial undersampling and exposure reduction with consequent benefits to imaging speed and reduced radiation dose. While such prior-image-based methods offer tremendous promise, the introduction of prior information in the reconstruction raises significant concern regarding the accurate representation of features in the image and whether those features arise from the current data acquisition or from the prior images. In this work we propose a novel framework to analyze the propagation of information in prior-image-based reconstruction by decomposing the estimation into distinct components supported by the current data acquisition and by the prior image. This decomposition quantifies the contributions from prior and current data as a spatial map and can trace specific features in the image to their source. Such "information source maps" can potentially be used as a check on confidence that a given image feature arises from the current data or from the prior and to more quantitatively guide the selection of parameter values affecting the strength of prior information in the resulting image.


Activated virus-specific T cells are early indicators of anti-CMV immune reactions in liver transplant patients.
Cytomegalovirus (CMV) infection represents the most common infectious complication after liver transplantation. Because CMV-associated complications in liver transplantation patients are often liver-restricted and clinically unrecognized, diagnosis of early infection or reactivation is still very difficult. Because cytotoxic T cells (CTLs) are crucial for the immune control of CMV, analysis of virus-specific CTLs could contribute to diagnosis and management of CMV infection. Major histocompatibility complex class I tetramers and intracellular cytokine staining were used to determine frequencies and phenotypes of peripheral blood CMV/pp65-specific CD8(+) T cells in HLA-A2, -B7, and -B35 positive liver transplantation patients and in healthy individuals. After liver transplantation (6-33 months after liver transplantation), frequencies of CMV-specific T cells were significantly elevated compared with healthy individuals. In contrast to immunoglobulin (Ig) M-negative patients and healthy blood donors, patients with increasing CMV IgM titers or IgG seroconversion had high percentages of activated (CD38(high)) CMV-specific T cells. In recently transplanted patients, activation of CMV-specific T cells was associated with increased transaminases and histopathological abnormalities in the absence of positive CMV-polymerase chain reaction results from peripheral blood. These data indicate that T-cell analysis based on MHC tetramer staining may be a valuable parameter in the early diagnosis of CMV-induced, liver-restricted complications after liver transplantation.


Technical efficiency and productivity of public district hospitals in KwaZulu-Natal province, South Africa.
Background: District hospitals (DHs) constitute a significant proportion of public hospitals and consume a more substantial percentage of the government's total hospital budget. With the level of resources disbursed to DHs, it is essential to ensure efficient allocation and utilization. Hence, this study set out to assess the technical efficiency and productivity of public DHs in KwaZulu- Natal province, South Africa. Methods: Data envelopment analysis (DEA) and Malmquist total factor productivity (MTFP) were used to assess technical efficiency, identify adjustments required to make inefficient facilities more efficient, and determine overall productivity growth. Input data such as medical personnel and output information such as outpatient visits were retrieved from the databases of the district health information system (DHIS), and personnel salary systems (PERSAL) for three consecutive financial years (2014/15, 2015/16 and 2016/17). A total of 38 district hospitals were included in the study. Results: The proportion of technically efficient facilities according to constant return to scale (CRS) were 12 (31.6%), 16 (42.1%) and 14 (36.8%) in 2014/15, 2015/16 and 2016/17 respectively while according to the variable return to scale (VRS) technically efficient facilities were 22 (57.9%), 19 (50.0) and 21 (55.2%) respectively for the three consecutive years. On average, the total productivity of DHs increased by 4.8 percent over the three years, which is attributed majorly to technical growth of 6.9 percent. Conclusion: This study showed that a significant proportion of the district hospitals were technically inefficiency. Also, steps that could enable more efficient use of healthcare resources to yield optimal health service delivery were recommended.


[Current status of treatment of renal cell carcinoma and future problems].
An account was given of the current status of treatment of renal cell carcinoma and reference made to problems that remain unsolved as follows: (1) Failure to keep biological characteristics of renal cell carcinoma in mind may be misleading in deciding on a therapeutic policy, (2) already established as it may appear, operation for renal cell carcinoma is still open to discussion, (3) indication for operation upon metastatic lesions, (4) widespread use of interferon based on insufficient theoretical grounds to provide ample justification, (5) future development and possible usefulness of multiple drug combination therapy including interferon as a main component and (6) how to make best use of neo-adjuvant therapy for renal cell carcinoma.


Renal effects of bunazosin, a new alpha 1-adrenoceptor blocker, in patients with mild-to-moderate essential hypertension.
Renal effects of 4-week fixed maintenance doses of bunazosin three times daily (2.0 mg t.i.d., n = 8) and propranolol (40 mg t.i.d., n = 8) were evaluated in patients with mild-to-moderate essential hypertension [World Health Organization (WHO) stages I and II]. Both bunazosin and propranolol decreased blood pressure (BP) significantly (p less than 0.05), but the magnitude of reduction in diastolic BP (DBP) was greater with bunazosin (p less than 0.05) than with propranolol. Bunazosin produced a nonsignificant increase in renal blood flow (RBF) by 14%, a significant increase in glomerular filtration rate (GFR) 11% (p less than 0.05), and a decrease in total renal vascular resistance (TRR) by 15% (p less than 0.05), whereas propranolol caused no significant changes in these parameters. Urinary sodium excretion rate and the fractional excretion of sodium were unchanged by either of the drugs. The results of this short-term study suggest that bunazosin may be a drug that will increase RBF and GFR and decrease TRR with a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. Whether these renal functional effects of the drug would benefit such patients must be determined in long-term studies.


PTSD as a consequence of past conflict experience, recent exposure to violence and economic marginalization in post-conflict contexts: A study from Nepal, Guatemala and Northern Ireland.
Exposure to war and conflict increases the risk of mental health problems. Poor living conditions are known to negatively impact mental health. It is hypothesized that exposure to negative events after armed conflict interacts with past negative experiences, socioeconomic factors and current mental health problems. A cross-sectional survey was carried out in three contexts of previous internal armed conflict: Nepal, Guatemala and Northern Ireland. Three nationally representative samples were drawn, comprising a net sample of 3,229 respondents. Both recent negative events and past negative events linked to the previous conflicts were found to be associated with elevated risk of post-traumatic stress syndrome (PTSD). Economic marginalization and urban residency also contributed to current risk of PTSD. The results support the study hypothesis that both past and recent negative events in combination with economic marginalization contribute to explain current risk of PTSD. It is necessary both to improve living conditions more broadly and to establish and develop health services that have the capacity to screen, prevent and treat mental health problems also in poor contexts, in particular against a background of previous armed conflict.


Bioinformatic identification of candidate genes induced by trichostatin A in BGC-823 gastric cancer cells.
The aim of the present study was to identify the candidate genes induced by trichostatin A (TSA) in BGC-823 gastric cancer (GC) cells and to explore the possible inhibition mechanism of TSA in GC. Gene expression data were obtained through chip detection, and differentially expressed genes (DEGs) between GC cells treated with TSA and untreated GC cells (control group) were identified. Gene ontology analysis of the DEGs was performed using the database for annotation, visualization and integrated discovery. Then sub-pathway enrichment analysis was performed and a microRNA (miRNA) regulatory network was constructed. We selected 76 DEGs, among which 43 were downregulated genes and 33 were upregulated genes. By sub-pathway enrichment analysis of the DEGs, the propanoate metabolism pathway was selected as the sub-pathway. By constructing a miRNA regulatory network, we identified that DKK1 and KLF13 were the top hub nodes. The propanoate metabolism pathway and the genes DKK1 and KLF13 may play significant roles in the inhibition of GC induced by TSA. These genes may be potential therapeutic targets for GC. However, further experiments are still required to confirm our results.


The voice of Primary Care patients in the Lisbon and Tagus Valley region of Portugal.
This article was the result of a study aimed at determining the degree of user satisfaction with the care provided in the 125 Family Health Units (Unidades de Saúde Familiar - USF) and in some of the 127 Personalized Health Care Units (Unidades de Cuidados de Saúde Personalizados - UCSP) of the Region of Lisbon and Tagus Valley (LVT). A total of 20,118 questionnaires were distributed and 16,965 received (89.0% response rate). The data collection instrument used was the Europep questionnaire, essentially measuring four dimensions: medical care, non-medical care, organization of care and quality of premises. 65.3% of the respondents were women, the average age was 50.8 years, 35% had a maximum of six years of schooling, and to 5.2% this had been their first contact. There was an overall average satisfaction of 77.4%, higher in what regards the care and attention provided by professionals. Women had slightly lower satisfaction than men, the same as for the younger compared to the older ones. Those with less literacy were the ones that presented better satisfaction rates. USF had always more satisfaction than the UCSP, and models B a satisfaction greater than models A. Users penalize units with more than 12 GP and there was a great regional disparity.


Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease.
We report a fatal case of coxsackievirus B4 chronic infection in a 30-year-old woman with a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disorder controlled by rituximab monotherapy for 3 years. Initially presenting as self-limited meningitis, the infection remained silent for 8 months before the sudden onset of fulminant myocarditis. Analysis of the complete genome showed that the same virus was responsible for both episodes.


Language and internalizing and externalizing behavioral adjustment: developmental pathways from childhood to adolescence.
Two independent prospective longitudinal studies that cumulatively spanned the age interval from 4 years to 14 years used multiwave designs to investigate developmental associations between language and behavioral adjustment (internalizing and externalizing behavior problems). Altogether 224 children, their mothers, and teachers provided data. Series of nested path analysis models were used to determine the most parsimonious and plausible paths among the three constructs over and above stability in each across age and their covariation at each age. In both studies, children with poorer language skills in early childhood had more internalizing behavior problems in later childhood and in early adolescence. These developmental paths between language and behavioral adjustment held after taking into consideration children's nonverbal intellectual functioning, maternal verbal intelligence, education, parenting knowledge, and social desirability bias, as well as family socioeconomic status, and they applied equally to girls and boys.


Genetic analysis for quality of frozen embryos produced by Holstein cattle donors in Canada.
The number of embryos produced by Holstein donors has been shown to be heritable, so it could be possible to genetically select for this trait to improve the efficiency of the assisted reproductive technology (ART) in dairy cattle. Another important parameter to consider for achieving good results from ART is embryo quality because embryos of good quality have more chance of producing live offspring. The possibility of using genetic selection for increasing the quality of embryo produced from ART has yet to be assessed. The objective of this study was, therefore, to perform a genetic analysis of embryo quality of Holstein donors in Canada using data recorded by Holstein Canada. The data set used was missing quality score data for embryos transferred fresh into a recipient, so the analyses were only performed for frozen embryos. With most traits in the Canadian dairy industry being evaluated with linear models, embryo quality was also evaluated with this class of models. However, considering the categorical nature of embryo quality, a threshold model was also evaluated. Embryo quality data were analyzed with either a univariate linear animal model or a univariate binomial threshold animal model. Genetic parameters estimated from the different models were comparable. A low heritability was found for the donor (0.04 ± <0.01) and the service sire (0.02 ± <0.01), but the repeatability estimate for the donor was higher (0.17), indicating that it was worthwhile to use a repeated records model. Overall, considering the low genetic parameters estimated, slow genetic progress is expected for the quality of frozen embryos produced by Canadian Holstein donors. Rank correlations were calculated between breeding values estimated from different models. High correlations were found between all models, indicating that no substantial re-ranking of the animals is expected from the different models. So, even though a threshold model is better suited for the analysis of categorical data, a linear model could be used for the analysis of embryo quality because it is less computationally demanding.


Novel Abscisic Acid Antagonists Identified with Chemical Array Screening.
Abscisic acid (ABA) signaling is involved in multiple processes in plants, such as water stress control and seed dormancy. Major regulators of ABA signaling are the PYR/PYL/RCAR family receptor proteins, group A protein phosphatases 2C (PP2Cs), and subclass III of SNF1-related protein kinase 2 (SnRK2). Novel ABA agonists and antagonists to modulate the functions of these proteins would not only contribute to clarification of the signaling mechanisms but might also be used to improve crop yields. To obtain small molecules that interact with Arabidopsis ABA receptor PYR1, we screened 24 275 compounds from a chemical library at the RIKEN Natural Products Depository by using a chemical array platform. Subsequent SnRK2 and PP2C assays narrowed down the candidates to two molecules. One antagonized ABA in a competitive manner and inhibited the formation of the PYR1-ABA-PP2C ternary complex. These compounds might have potential as bioprobes to analyze ABA signaling.


Functional outcome and complications following two types of dorsal plating for unstable fractures of the distal part of the radius.
There is a paucity of data in the literature documenting the functional outcomes for patients who have been managed with a dorsal plate because of a distal radial fracture. The purpose of the present study was to determine the functional outcome and complications following dorsal plating for dorsally displaced, unstable fractures of the distal part of the radius. The records of all patients who had been managed at our institution with dorsal plating because of a comminuted, dorsally displaced fracture of the distal part of the radius were reviewed. Patients with less than twelve months of follow-up were excluded from the study. Outcomes were evaluated at the time of the latest follow-up with use of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and the Gartland and Werley scoring system. Twenty-eight patients (nineteen women and nine men) with a mean age of forty-two years formed the basis of the study. The mean duration of follow-up was twenty-one months. Nineteen patients had been treated with a Synthes pi plate, and nine had been treated with a low-profile plate. There were no instances of loss of reduction, malunion, or nonunion. The mean score on the DASH questionnaire was 14.5 points. All patients had an excellent (nineteen patients) or good (nine patients) result according to the scoring system of Gartland and Werley. Nine patients had postoperative complications requiring repeat surgical treatment for hardware removal or extensor tendon reconstruction. All nine reoperations were performed in patients who had been treated with a Synthes pi plate, while none were performed in patients who had been treated with a low-profile plate (p < 0.025). Four complications occurred in patients who had been treated with a titanium plate, and five complications occurred in patients who had been treated with a stainless-steel plate (p = 0.71). Patients in whom a dorsally displaced distal radial fracture is treated with a titanium or stainless-steel Synthes pi plate have a significantly increased risk of complications compared with those in whom such a fracture is treated with a low-profile plate. Regardless of the type of plate used, all of the patients in the present study had a good or excellent long-term functional outcome.


Subinhibitory Concentrations of Antibiotics Alter the Response of Klebsiella pneumoniae to Components of Innate Host Defense.
Carbapenem-resistant Klebsiella pneumoniae isolates classified as multilocus sequence type 258 (ST258) are a problem in health care settings in many countries globally. ST258 isolates are resistant to multiple classes of antibiotics and can cause life-threatening infections, such as pneumonia and sepsis, in susceptible individuals. Treatment strategies for such infections are limited. Understanding the response of K. pneumoniae to host factors in the presence of antibiotics could reveal mechanisms employed by the pathogen to evade killing in the susceptible host, as well as inform treatment of infections. Here, we investigated the ability of antibiotics at subinhibitory concentrations to alter K. pneumoniae capsular polysaccharide (CPS) production and survival in normal human serum (NHS). Unexpectedly, pretreatment with some of the antibiotics tested enhanced ST258 survival in NHS. For example, a subinhibitory concentration of mupirocin increased survival for 7 of 10 clinical isolates evaluated and there was increased cell-associated CPS for 3 of these isolates compared with untreated controls. Additionally, mupirocin pretreatment caused concomitant reduction in the deposition of the serum complement protein C5b-9 on the surface of these three isolates. Transcriptome analyses with a selected ST258 isolate (34446) indicated that genes implicated in the stringent response and/or serum resistance were upregulated following mupirocin treatment and/or culture in NHS. In conclusion, mupirocin and/or human serum causes changes in the K. pneumoniae transcriptome that likely contribute to the observed decrease in serum susceptibility via a multifactorial process. Whether these responses can be extended more broadly and thus impact clinical outcome in the human host merits further investigation. IMPORTANCE The extent to which commensal bacteria are altered by exposure to subinhibitory concentrations of antibiotics (outside resistance) remains incompletely determined. To gain a better understanding of this phenomenon, we tested the ability of selected antibiotics (at subinhibitory concentrations) to alter survival of ST258 clinical isolates in normal human serum. We found that exposure of ST258 to antibiotics at low concentrations differentially altered gene expression, capsule production, serum complement deposition, and bacterial survival. The findings were isolate and antibiotic dependent but provide insight into a potential confounding issue associated with ST258 infections.


Temperature-Dependent Tip-Induced Motion of Ga Adatom on GaAs (110) Surface.
The temperature-dependent tip-induced-motion of a Ga adatom on a GaAs (110) surface is experimentally demonstrated using scanning tunneling microscopy (STM). The surface adsorption energy profile obtained by first-principle electronic structure calculations reveals that the origin of the Ga motion observed at 78 K is attributable to the tip-induced Ga adatom hopping between the most stable potential minima among the three local minima, whereas that observed at 4.2 K is attributable to the tip-induced hopping and sliding motions through the next stable minima as well as the most stable minima. Furthermore, it is shown that a slight progressive modification of the adatom motion observed only at 4.2 K resulting from repeated STM line scans is consistent with the overall picture taking account of the heating of the adatom owing to the tip current.


A study to determine if changes to an undergraduate orthodontic course improved course quality and student satisfaction.
A study was carried out to determine if changes to the undergraduate orthodontic course at Leeds Dental Institute resulted in increased student satisfaction. The study was based on a questionnaire distributed to dental students comprising statements related to the undergraduate orthodontic course. Questionnaires were distributed in 1993 and 1995 to 2 groups of 4th year undergraduate dental students at the same stage of their course on both occasions. Questions were in the form of 16 statements with which students expressed a level of agreement, ranging from strongly agree to strongly disagree. The numbers of responses at each level of agreement were compared between the 2 groups. Statistical differences were determined using a Mann Whitney-U test. 8 of the 16 statements had more favourable responses in 1995 than in 1993. No statement received a less favourable response in 1995 than in 1993. It is concluded that changes in the undergraduate orthodontic course at Leeds Dental Institute aimed at increased problem-based learning and clinician-led tutorials, have resulted in improved student satisfaction with the teaching.


Targeting Self-Binding Peptides as a Novel Strategy To Regulate Protein Activity and Function: A Case Study on the Proto-oncogene Tyrosine Protein Kinase c-Src.
Previously, we have reported a new biomolecular phenomenon spanning between protein folding and binding, termed as self-binding peptides (SBPs), where a short peptide segment in monomeric protein functions as a molecular switch by dynamically binding to/unbinding from its cognate domain in the monomer (Yang et al. J. Chem. Inf. 2015, 55, 329-342). Here, we attempt to raise the SBP as a new class of druggable targets to regulate the biological activity and function of proteins. A case study was performed on the proto-oncogene nonreceptor tyrosine kinase, c-Src, which contains two SBPs that bind separately to SH3 and SH2 domains of the kinase. State-of-the-art molecular dynamics (MD) simulations and post binding energetics analysis revealed that disrupting the kinase-intramolecular interactions of SH3 and SH2 domains with their cognate SBP ligands can result in totally different effects on the structural dynamics of c-Src kinase architecture; targeting the SH2 domain unlocks the autoinhibitory form of the kinase-this is very similar to the pTyr527 dephosphorylation that functionally activates the kinase, whereas targeting the SH3 domain can only release the domain from the tightly packed kinase but has a moderate effect on the kinase activity. Subsequently, based on the cognate SBP sequence we computationally designed a number of SH2-binding phosphopeptides using a motif grafting strategy. Fluorescence polarization (FP) assay observed that most of the designed phosphopeptides have higher binding affinity to SH2 domain as compared to the native SBP segment (Kd = 53 nM). Kinase assay identified a typical dose-response relationship of phosphopeptides against kinase activation, substantiating that disruption of SH2-SBP interaction can mimic c-Src dephosphorylation and activate the kinase. Two rationally designed phosphopeptides, namely EPQpYEEIEN and EPQpYEELEN, were determined as strong binders of SH2 domain (Kd = 8.3 and 15 nM, respectively) and potent activators of c-Src kinase (EC50 = 3.2 and 41 μM, respectively).


A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.
Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.


A cost evaluation of treatment alternatives for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil.
The first-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil is currently activated prothrombin complex concentrate (aPCC), with recombinant activated factor VII (rFVIIa) used as second-line therapy or as a last resort. The aim of this study was to determine the cost and effectiveness of these treatments from the perspective of the Brazilian National Health Service. A decision analysis model was constructed to assess total direct medical costs (including drug costs, costs of outpatient or inpatient care, ambulance transportation and cost of concomitant medications) of first-line treatment with aPCC or rFVIIa. Clinical outcome and resource utilization data were obtained both retrospectively and prospectively and validated by the consensus of an expert panel of Brazilian haematologists. A total of 103 bleeds in 25 patients were included in the analysis. rFVIIa resolved bleeds more quickly (4.4 h) than aPCC (62.6 h) and was more effective (100% vs. 56.7% respectively). Mean total direct medical costs (from initiation to cessation of bleed) were estimated to be US$13 500 (aPCC) and US$7590 (rFVIIa). Extensive sensitivity analyses confirmed the cost-effectiveness of rFVIIa. Compared with aPCC, rFVIIa was more effective and less expensive when used as first-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil. rFVIIa should be considered a first-line treatment for the management of these patients.


N-acetylprocainamide induced changes in refractoriness and monophasic action potentials of the dog heart in situ.
The major metabolite of procainamide (PA) is N-acetylprocainamide (NAPA). The effect of this drug on the electrophysiology of the right ventricle was studied in the dog heart in situ by means of programmed electrical stimulation and monophasic action potential (MAP) recordings. A decrease in the beat interval caused a progressive decrease in refractoriness and MAP duration. Intravenous injection of NAPA 50 mg.kg-1 body weight increased refractoriness to a greater extent than MAP duration at shorter, while the opposite was observed at longer beat intervals. These observations are compatible with delayed recovery of excitability. On the basis of these findings, it is concluded that NAPA belongs to antiarrhythmic drugs of type I according to Vaughan Williams' classification, and NAPA may be an alternative drug for treatment of cardiac arrhythmias.


A photochemical one-pot three-component synthesis of tetrasubstituted imidazoles.
Tetrasubstituted imidazoles can be formed in a photochemical one-pot synthesis from aldehydes, α-aminonitriles, and isoxazoles. Condensation of the first two components produces α-(alkylideneamino)nitriles which react under basic conditions with the acylazirines formed in situ by photochemical ring transformation of the isoxazole component. This process includes an unusual cleavage of the C(2)-C(3) bond of the acylazirine. The reaction mechanism was studied by DFT calculations.


Estimation of gait parameter using sonoelastography in children with cerebral palsy.
We aimed to study the relationship between neuromuscular abnormalities associated with spasticity and gait impairments in spastic children with hemiplegia cerebral palsy (CP). Neuromuscular abnormalities of the tibialis anterior and medial gastrocnemius muscles of the spastic ankle were quantified using sonoelastography with two major features; i.e. entropy and histogram ratio of sonoelastography images. Gait impairments were evaluated in the gait laboratory using motion capture system, and the spatial and temporal features were extracted. The correlation analysis showed a significant relation between both the entropy and histogram ratio of sonoelastography images with walking speed and step time. The findings demonstrate that the neuromuscular abnormalities associated with spasticity may contribute to gait impairments in children with CP.


Nucleic acid homologies of selected bacteria, L forms, Mycoplasma species.
Rogul, M. (Walter Reed Army Institute of Research, Washington, D.C.), Z. A. McGee, R. G. Wittler, and Stanley Falkow. Nucleic acid homologies of selected bacteria, L forms, and Mycoplasma species. J. Bacteriol. 90:1200-1204. 1965.-The molar per cent of guanine plus cytosine (G + C) in the deoxyribonucleic acids (DNA) of Proteus mirabilis, strain 9, and its stable L form was determined by thermal denaturation and found to be approximately 39.5% G + C. The DNA homologies of this bacterium and its L form were estimated by the agar-column technique and were equivalent in their abilities to anneal and form specific duplexes. The next series of comparisons were performed between two Mycoplasma species and their often suggested bacterial parent. The G + C ratios of M. gallisepticum (32.7%), M. gallinarum (28.1%), and Haemophilus gallinarum (41.9%) varied to a high degree. In the homologous system, the denatured DNA of H. gallinarum trapped in agar bound approximately 40% of its sheared, denatured, and H(3)-labeled DNA. In comparison, the nucleic acids of M. gallinarum and M. gallisepticum were incapable of binding the labeled DNA of H. gallinarum. These findings provided evidence that the two strains of Mycoplasma were not derived from H. gallinarum.


Combined treatment of tetrahydrocurcumin and chlorogenic acid exerts potential antihyperglycemic effect on streptozotocin-nicotinamide-induced diabetic rats.
We have shown that separate dose of tetrahydrocurcumin (THC) at a dose of 80 mg/kg body weight (b.w.) and chlorogenic acid (CGA) at a dose of 5 mg/kg b.w. exerts antidiabetic potential in streptozotocin (STZ) (45 mg/kg b.w.) nicotinamide induced diabetic rats. In the present study we have attempted to compare the antihyperglycemic activity exerted by the combined treatment of THC/CGA with THC and CGA alone treated diabetic rats. After the experimental period of 45 days we observed that supplementation with combined dose of THC/CGA significantly decreased glycosylated hemoglobin (HbA(1C)) and increased the levels of plasma insulin, C-peptide, hemoglobin and glycogen which were decreased upon STZ treatment and also significantly reversed the altered activities of gluconeogenic enzymes such as glucose-6-phosphatase, fructose-1,6-bisphosphatase, and of glycolytic enzymes such as glucokinase and hexokinase in the tissues of experimental rats as compared to their individual supplementation. Thus our results substantiate that though THC and CGA alone found to exert hypoglycemic activity the maximum hypoglycemic effect was always observed in diabetic rats treated THC/CGA and this summed effect seems to have a promising value for the development of a potent phytomedicine for diabetes.


Modified leaves with disk-shaped nectaries of Macaranga sinensis (Euphorbiaceae) provide reward for pollinators.
Nectar is the most common reward provided by animal-pollinated flowers. Diversity in position and structure of floral nectaries suggests that floral nectar production evolved repeatedly, but the evolutionary origins are not well known. Flowers of the genus Macaranga (Euphorbiaceae) are apetalous and lack floral nectar. Nevertheless, many Macaranga species possess disk-shaped nectaries on their leaves, sought by ants that defend plants from herbivory. In some Macaranga species, similar glands also occur on the bracteoles-modified leaves subtending the flowers. We investigated whether these glands on the bracteoles of M. sinensis are involved in pollination. • Flower visitors were captured, and body pollen was examined. The behavior of flower visitors on inflorescences was also observed. Sugar composition of the nectar from bracteoles and leaves was collected and analyzed using high-performance liquid chromatography. • Various bees and flies with body pollen visited both male and female inflorescences, feeding on nectar from the bracteoles and touching anthers and stigmas in the process. Sugar composition of nectar from the bracteoles and the leaves did not differ. • Macaranga sinensis was pollinated by insects foraging on the disk-shaped nectaries on bracteoles. The similar appearance, position, and sugar composition of nectar suggest that disk-shaped nectaries on bracteoles and leaves are homologous and that nectaries on leaves were recruited to inflorescences to serve floral function in M. sinensis. Having protective mutualism with ants has likely opened an unusual route for the evolution of floral nectar in otherwise non-nectar-producing flowers of M. sinensis.


Power Doppler imaging and color Doppler flow imaging for the evaluation of normal and pathological vertebral arteries.
Recently, an ultrasound method for vascular applications using the amplitude of the reflected echosignal for the generation of intravascular color signals has been introduced. We compared the utility of this power Doppler imaging (PDI) with conventional color Doppler flow imaging (CDFI) for examination of vertebral arteries (VA). Forty-nine patients with signs and symptoms suggesting ischemia within the posterior circulation were evaluated. Quality of blood flow visualization by PDI and CDFI at the different VA segments was classified according to a four point scale. Furthermore, combined sonographic findings were correlated with the results of digital substraction and/or magnetic resonance angiography (DSA, MRA). Power Doppler imaging provided a significantly superior visualization of the intertransversal VA, whereas display of the intracranial V4 segment was superior significantly on CDFI. Both methods were complementary for the evaluation of the VA at the origin. With respect to the angiographic findings, combined CDFI and PDI achieved a sensitivity of 90.63% and a specificity of 97.22% for the differentiation of healthy and pathologic VAs. Power Doppler imaging is complementary to CDFI for the sonographic assessment of VA disease. Combined use of PDI and CDFI achieves a high sensitivity and specificity, thus increasing diagnostic confidence.


Evolutionary microdivergence of chick and rat liver ribosomal proteins.
We have set out to establish a nomenclature for ribosomal proteins which transcends, as far as is possible, the species from which the ribosomes were isolated. Initally, we identified individual proteins of rat liver by two-dimensional polyacrylamide gel electrophoresis and comparison with the classification system established by others (Sherton, C.C., and Wool, I.G. (1972) J. Biol. Chem. 247, 4460-4467). This was possible with minor modifications. We carried out a detailed comparison of the rat liver proteins with those of chick liver; parallel separate and mixed preparations of ribosomal subunits from the two species were made. Spots on the two-dimensional gels were carefully scrutinized for possible species differences. Proteins which gave congruent spots for the separate and the mixed preparations were tentatively assumed to be identical between the two species. For these proteins, a species-independent nomenclature was adopted. Contrary to earlier reports, a number of proteins were found which were not identical between the two species. These were assigned a species-specific nomenclature. In all, 7 proteins in the small subunit and 17 from the large subunit of the rat liver ribosome were found to be significantly different in the chick. The evolutionary implications of this are discussed.


Genome-wide association studies for the number of teats and teat asymmetry patterns in Large White pigs.
The number of teats is a morphological trait that influences the mothering ability of the sows and thus their reproduction performances. In this study, we carried out GWASs for the total number of teats and other 12 related parameters in 821 Italian Large White heavy pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip array. For four investigated parameters (total number of teats, the number of teats of the left line, the number of teats of the right line and the maximum number of teats comparing the two sides), significant markers were identified on SSC7, in the region of the vertnin (VRTN) gene. Significant markers for the numbers of posterior teats and the absolute difference between anterior and posterior teat numbers were consistently identified on SSC6. The most significant SNP for these parameters was an intron variant in the TOX high mobility group box family member 3 (TOX3) gene. For the other four parameters (absolute difference between the two sides; anterior teats; the ratio between the posterior and the anterior number of teats; and the absence or the presence of extra teats) only suggestively significant markers were identified on several other chromosomes. This study further supported the role of the VRTN gene region in affecting the recorded variability of the number of teats in the Italian Large White pig population and identified a genomic region potentially affecting the biological mechanisms controlling the developmental programme of morphological features in pigs.


The effect of polymyxin B on steroidogenesis from adrenocortical cells.
The action of the cyclic peptide polymyxin B (a well known inhibitor of protein kinase C) on adrenal steroid synthesis was examined with Y-1 adrenal tumor cells. Polymyxin B produces a biphasic effect on the stimulation of steroid synthesis by 2 nM ACTH in these cells, with inhibition at low concentrations (less than 10 microM) and a return to control levels at high concentrations (greater than 100 microM). Polymyxin B does not inhibit the stimulatory effect of Bu2cAMP on steroidogenesis. Inhibition of the steroidogenic response to ACTH by a fixed concentration (20 microM) of polymyxin B is overcome by high concentrations of ACTH. Polymyxin B causes a concentration-dependent stimulation of steroid synthesis by Y-1 cells and, over the same concentration range, increases the production of cAMP by these cells. Polymyxin B also partially inhibits the increased production of the cyclic nucleotide produced by ACTH. In addition, polymyxin B inhibits binding of [125I](Phe2,Nle4)ACTH-(1-38) to Y-1 cells. Polymyxin B, like ACTH, promotes rounding of Y-1 cells and partially inhibits rounding produced by ACTH. These effects of polymyxin B are specific to the extent that polymyxins E1 and E2 do not exert similar effects. The actions of polymyxin B are not confined to transformed cells, since responses similar to those seen with Y-1 cells were also observed with cultured rat fasciculata cells. On the other hand, the effect of polymyxin B is specific for adrenal cells, since the cyclic peptide does not influence the steroidogenic response of rat Leydig cells to LH. It is concluded that polymyxin B is a partial agonist of ACTH which is likely to prove useful in studying the molecular basis of the interaction between ACTH and its adrenal receptor.


Effect of partially depolymerized guar gum on acute metabolic variables in patients with non-insulin-dependent diabetes.
Fourteen patients with non-insulin-dependent diabetes (NIDDM) attended the study centre on 4 mornings separated by at least 3 days, to receive in random order 75 g carbohydrate breakfast meals of control or guar breads with jam and butter. Guar gum flours of low, medium, and high molecular weight (MW) were incorporated into wheat bread rolls to provide 7.6 g guar per meal. Venous blood samples were taken via an indwelling cannula in a forearm vein at fasting and at eight postprandial times and then analysed for blood glucose, plasma insulin, C-peptide, and gastric inhibitory polypeptide (GIP). Guar gum bread significantly reduced the postprandial rise in blood glucose, plasma insulin, and, except for bread containing low MW guar gum, plasma GIP levels compared to the control. Thus, the partial depolymerization of guar gum does not diminish its physiological activity. No reductions in postprandial plasma C-peptide levels were seen after any of the guar bread meals. This suggests that guar gum attenuates the insulin concentration in peripheral venous blood in patients with NIDDM by increasing the hepatic extraction of insulin.


Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy.
The MTHFR C677T single nucleotide polymorphism TT genotype is associated with increased levels of plasma homocysteine and possibly an effect on cardiovascular mortality. We evaluated the effect of C677T genotype on mortality in a large end-stage renal disease (ESRD) cohort. C677T genotype was determined in 439 Caucasians with end-stage diabetic nephropathy (DNP) (cases) recruited from 30 dialysis centres in Southern Germany. A total of 482 type 2 diabetes patients without DNP (no microalbuminuria) at inclusion served as a genotype control collective. Patients were prospectively followed for 4 years. Primary endpoint was all-cause mortality. In contrast to controls, the genotype distribution in cases was not in Hardy-Weinberg equilibrium (HWE, P = 0.003), due to a less than expected number of patients with the TT genotype. The requirements of HWE were met in cases with < 2 years dialysis therapy prior to study inclusion (n = 219). TT genotype was associated with a decreased body mass index (P = 0.002) and long diabetes duration in dialysis patients (P = 0.03). However, TT genotype was not associated with an increased risk of all-cause or cardiac mortality in the total dialysis collective or the subgroup. Also, we observed no association of MTHFR genotype with cardiovascular morbidity in cases or controls (P > 0.05), or with an increased rate of progression to novel microalbuminuria. MTHFR 677TT genotype was significantly underrepresented in patients with ESRD in our study, but was not associated with premature mortality in these patients. We found no evidence for survival bias due to C677T genotype in the ESRD cohort, or bias due to genetically determined accelerated progression to novel microalbuminuria in the controls. However, we cannot exclude that the TT genotype protects from progression from microalbuminuria to more advanced stages of DNP, or that TT genotype is associated with premature mortality before a patient progresses to ESRD.


OmpL1 DNA vaccine cross-protects against heterologous Leptospira spp. challenge.
Available leptospirosis vaccines made up of inactivated bacteria or their membrane components elicit immunity which is serovar specific and unsatisfactory immunological memory. A vaccine that protects across Leptospira serogroups/serovars, i.e. broad spectrum, and induces long-lasting memory is needed for both human and veterinary uses. In this study, a plasmid DNA vaccine was constructed from cloning gene encoding a transmembrane porin protein, OmpL1, of pathogenic Leptospira interrogans, serogroup Icterohaemorrhagiae, serovar Copenhageni into a mammalian expression vector pcDNA3.1(+). The protective efficacy of the ompL1-pcDNA3.1(+) plasmid DNA vaccine was studied by immunizing hamsters intramuscularly with three doses of the vaccine (100 microg per dose) at two week intervals. The empty pcDNA3.1(+) and PBS were used as mock as negative vaccine controls, respectively. All animals were challenged with the heterologous Leptospira interrogans, serogroup Pomona, serovar Pomona (10 LD50), at one week after the last vaccine booster. The ompL1-pcDNA3.1(+) plasmid DNA vaccine rescued some vaccinated animals from the lethal challenge and delayed death time, reduced morbidity, e.g. fever, and/or the numbers of Leptospira in the tissues of the vaccinated animals. While the results are encouraging, further studies are needed to optimize the immunization schedule, vaccine dosage and formulation in order to maximize the efficacy of the vaccine.


Ligand- and structure-based drug design strategies and PPARδ/α selectivity.
Peroxisome-proliferator-activated receptors are a class of nuclear receptors with three subtypes: α, γ and δ. Their main function is regulating gene transcription related to lipid and carbohydrate metabolism. Currently, there are no peroxisome-proliferator-activated receptors δ drugs being marketed. In this work, we studied a data set of 70 compounds with α and δ activity. Three partial least square models were created, and molecular docking studies were performed to understand the main reasons for peroxisome-proliferator-activated receptors δ selectivity. The obtained results showed that some molecular descriptors (log P, hydration energy, steric and polar properties) are related to the main interactions that can direct ligands to a particular peroxisome-proliferator-activated receptors subtype.


Acute exposure to sulfur dioxide and mortality: Historical data from Yokkaichi, Japan.
We examined the association between acute exposure to sulfur dioxide (SO2) and mortality, using historical data from 1972-1991 in Yokkaichi, Japan. We used a time-stratified case-crossover study design. We included all causes of death, excluding external causes, between 1972 and 1991 in Yokkaichi and the neighboring town, Kusu of the Mie Prefecture (N = 29,839). We obtained daily estimations of SO2 concentrations during the study period. We then conducted conditional logistic regression analysis to examine association between SO2 exposure and all-cause and cause-specific mortality. Exposure to SO2 increased the risk of all-cause and cause-specific mortality in a non-linear manner. The relationship between SO2 exposure and mortality outcomes remained after adjustment for co-pollutants such as particulate matter and nitrogen dioxide. Historical data from Yokkaichi, Japan, showed that SO2 exposure increased the risk of all-cause and cause-specific mortality.


Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids.
A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects affected the potency of the AII antagonistic action. Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect. The representative compound, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 1.1 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0 x 10(-10) M). Oral administration of CV-11974 to conscious normotensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.


Stereodirectional images of molecules oriented by a variable-voltage hexapolar field: Fragmentation channels of 2-bromobutane electronically excited at two photolysis wavelengths.
The asymmetric-top molecule 2-bromobutane is oriented by means of a hexapole state selector; the angular distribution of the bromine atom photofragment, for the two fine-structure components, is acquired by velocity-map ion imaging. The molecular beam, spatially oriented along the time-of-flight axis, is intersected with a linearly polarized laser, whose polarization is tilted by 45° with respect to the detector surface. To obtain the mixing ratio of the perpendicular and parallel transitions, the fragment ion images and angular distributions can be appropriately simulated to give insight on the population mechanism of the specific electronic state involved at each selected excitation wavelength. The photofragment images obtained at 238.6 nm yielded an asymmetry factor β1 of 0.67, indicative of the extent of molecular orientation, and an anisotropy parameter β2 of 1.03, which is a signature of a prevailing parallel transition along the C-Br axis. When the photolysis wavelength is tuned to 254.1 nm, the corresponding angular distribution is less asymmetric (β1 = 0.24) and the obtained small value β2 = 0.12 is a characteristic of a predominantly perpendicular transition. The photofragment angular distributions are also affected by hexapole voltage, especially regarding the asymmetry factor, and this aspect provides information on the effect of molecular orientation.


Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart.
Cl-/HCO3- exchange contributes to regulation of pHi and [Cl-] in cardiac muscle, with possible effects on excitability and contractility. We have isolated human heart cDNAs, which encode two isoforms of the anion exchanger AE3. These clones share long portions of common sequence but have different 5' ends encoding distinct amino-terminal amino acid sequences. The longer AE3 polypeptide of 1232 amino acids, bAE3, displays nearly 96% amino acid sequence identity to the rat and mouse AE3 "brain isoforms." The shorter cAE3 polypeptide of 1034 amino acids in length corresponds to the rat AE3 "cardiac isoform." The unique N-terminal 73 amino acids of the cAE3 sequence are less well conserved between rat and human. Northern blot analysis with isoform-specific probes revealed the presence of both cAE3 and bAE3 mRNAs in human heart tissue. Both AE3 protein isoforms were overexpressed in Chinese hamster ovary cells and detected by immunoblot with antipeptide antibodies. Immunoblot studies of human cardiac membranes detected only cAE3 polypeptides, which were apparently not susceptible to enzymatic deglycosylation. Injection into Xenopus oocytes of cRNAs encoding either cAE3 or bAE3 produced increased 36Cl- uptake into the oocytes, confirming the ability of both AE3 isoforms to transport Cl-. The human AE3 gene was localized to chromosome 2. AE3 may provide a new pharmacologic target for antiarrhythmic and cardioprotective drugs.


Sequential study of macrophage migration inhibition factor in renal cell carcinoma patients.
Preliminary investigation of cell-mediated immunity (CMI) in 49 patients harboring renal cell carcinoma (RCC) by the migration inhibition factor (MIF) tests as compared to 47 patients with simple renal cysts or normal kidneys established the specificity (85%) and reproducibility of this test. A retrospective analysis of the results of the MIF test was conducted in 35 patients followed for a minimum 20-month period. A marked difference was observed between the group of patients with localized disease who remained disease free and those with metastatic lesions and disease progression. The first group sustained their positive response of the MIF tests for a longer time during the study period, while the latter had a decrease of the MIF test response shortly after surgery. This difference may indicate that immune response as reflected in the positive MIF test has a role in RCC patients' defense mechanism.


Induction of DNA fragmentation, chromosome aberrations and micronuclei by cisplatin in rat bone-marrow cells: protective effect of recombinant human erythropoietin.
Cisplatin (Cisp) is one of the most effective chemotherapeutic agents. However, at higher doses several side effects may occur. Recombinant human erythropoietin (rhEPO), a glycoprotein regulating haematopoiesis, has recently been shown to exert an important cyto-protective effects in many tissues. The purpose of this study was to explore whether rhEPO protects against Cisp-induced genotoxicity in rat bone-marrow cells. Adult male Wistar rats were divided into six groups of 18 animals each: control group, rhEPO-alone group, Cisp-alone group and three rhEPO+Cisp-groups (pre-, co- and post-treatment condition, respectively). Our results show that Cisp induced a noticeable genotoxic effect in rat bone-marrow cells. In all types of treatment, rhEPO significantly decreased the frequency of micronuclei, the percentage of chromosome aberrations and the level of DNA damage. The protective effect of rhEPO was more efficient when it was administrated 24h before exposure to Cisp.


The RAB GTPase RAB18 modulates macroautophagy and proteostasis.
Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positive modulator of autophagy and is relevant for the maintenance of cellular proteostasis.


Generation and Implementation of a Patient-Centered and Patient-Facing Genomic Test Report in the EHR.
Communication of genetic laboratory results to patients and providers is impeded by the complexity of results and reports. This can lead to misinterpretation of results, causing inappropriate care. Patients often do not receive a copy of the report leading to possible miscommunication. To address these problems, we conducted patient-centered research to inform design of interpretive reports. Here we describe the development and deployment of a specific patient-centered clinical decision support (CDS) tool, a multi-use patient-centered genomic test report (PGR) that interfaces with an electronic health record (EHR). A PGR with a companion provider report was configured for implementation within the EHR using locally developed software (COMPASS™) to manage secure data exchange and access. We conducted semi-structured interviews with patients, family members, and clinicians that showed they sought clear information addressing findings, family implications, resources, prognosis and next steps relative to the genomic result. Providers requested access to applicable, available clinical guidelines. Initial results indicated patients and providers found the PGR contained helpful, valuable information and would provide a basis for result-related conversation between patients, providers and family. Direct patient involvement in the design and development of a PGR identified format and presentation preferences, and delivery of relevant information to patients and providers, prompting the creation of a CDS tool. Research and development of patient-centered CDS tools designed to support improved patient outcomes, are enhanced by early and substantial engagement of patients in contributing to all phases of tool design and development.


Development of a New Container for Storage and Release of the Parasitoid Cotesia flavipes (Hymenoptera: Braconidae).
In Brazil, the parasitoid Cotesia flavipes (Cameron) has been used as a biological control agent against Diatraea saccharalis (F.) since 1976, because of its effectiveness in reducing populations of this pest. Three million plastic cups are used annually to release C. flavipes, which remain in the environment. This study aimed to develop fully biodegradable packaging, so that releases occur without damaging the environment. The biological characteristics of C. flavipes were studied for five generations in the packaging developed (biodegradable boxes) and in the packaging currently used (non-biodegradable plastic cups and biodegradable cups), as were the costs. The results demonstrated the feasibility of using completely biodegradable and inexpensive packaging for the rearing, transport, and release of adult C. flavipes in the field.


Tumor targeting of protein through poly(ethylene glycol) conjugation with metal coordination.
The objective of this study is to introduce a new and simple conjugation method of protein with poly(ethylene glycol) (PEG) based on metal coordination. A chelating residue N,N-bis(carboxymethyl)-L-lysine (NTA) was chemically introduced into one terminal of PEG with another terminal of methoxy group (MeO-PEG). Cu2+ or Zn2+ ions were chelated into the NTA residue of MeO-PEG-NTA prepared. Chromatographic experiments revealed that transferrin (Tf) was conjugated to the MeO-PEG-NTA based on Cu2+ ions coordination. The amount of PEG conjugated increased with an increase in that added. Fluorescently labeled Tf was conjugated by the MeO-PEG-NTA with Cu2+ or Zn2+ coordination and injected intravenously into tumor-bearing mice. The Tf conjugated with the MeO-PEG-NTA based on Cu2+ coordination was accumulated in the tumor site to a significantly great extent compared with the free Tf and Tf conjugated with the Zn2+ coordinated MeO-PEG-NTA. A body distribution assay with radiolabeled Tf demonstrated that PEG conjugation with Cu2+ coordination enabled Tf to prolong the blood circulation and enhance the tumor accumulation. When interferon (IFN) was conjugated with the Cu(2+)-coordinated MeO-PEG-NTA and subcutaneously injected into tumor-bearing mice, the in vivo tumor growth was significantly suppressed compared with the injection of free IFN and IFN conjugated by Zn(2+)-coordinated MeO-PEG-NTA. It is concluded that the Cu(2+)-coordinated PEG conjugation can modify the body distribution of protein only by simple mixing in aqueous solution. The PEG conjugation with metal coordination could increase the in vivo half-life period of proteins in the blood, and consequently enhance the accumulation amount at the tumor site.


Role of TPMT and ITPA variants in mercaptopurine disposition.
To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPALA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001). TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.


The use of high pressure for separation and production of bioactive molecules.
Due to its action on the forces governing inter- and intramolecular interactions, the application of high pressure to biopurification or bio-elaboration of a product are of interest. The two closely thermodynamically related parameters, pressure and temperature, render processes based on their action clean, as no chemical reagents have to be added (and thus further removed) when they are applied. The use of high pressure in the development of desorption methods for the purification of bioactive molecules, particularly in the immunoaffinity field, is reviewed and discussed. Also mentioned is the application of the pressure parameter during the synthesis of a bioreagent. Finally, integrated processes relative to the synthesis and purification of these compounds are proposed.


Long non-coding RNA PVT1 functions as an oncogene in human colon cancer through miR-30d-5p/RUNX2 axis.
Recently, long noncoding RNAs (lncRNAs) have caught more attention for their role in tumor progression. Colon cancer is one of these ordinary malignant tumors. This study aimed to identify how lnc RNA PVT1 affects the progression of colon cancer. PVT1 expression of both colon cancer cell tissue and 60 paired cancer and peri-tumoral tissue samples was detected by real-time quantitative polymerase chain reaction (RT-qPCR). The associations between lnc RNA PVT1 expression level and clinicopathological characteristics and patients' disease-free survival rate were evaluated. Furthermore, function assays containing cell proliferation assay, colony formation and transwell assay were conducted. Mechanism-associated experiments included western blot assay, luciferase assay and RNA immunoprecipitation assay. PVT1 expression was significantly higher in tumor tissues than in peritumoral tissues, and was associated with lymph node metastasis, tumor stage and survival time of these patients. Moreover, knockdown of PVT1 promoted tumor growth and invasion in vitro. In addition, further experiments revealed that miR-30d-5p was a direct target of PVT1 and its expression in tumor tissues negatively correlated to PVT1 expression. Moreover, RUNX2 was identified as the direct target spot of miR-30d-5p according to the mechanism experiments. Besides, RUNX2 expression was positively correlated with PVT1 in cancer tissues and cells. These results indicate that PVT1 could promote metastasis and proliferation of colon cancer via suppressing miR-30d-5p/RUNX2 axis, which may offer a new way for interpreting the mechanism of colon cancer development.


Evaluation of bronchial air leaks by auscultation and phonopneumography.
Bronchial fistulae in communication with atmospheric pressure can be identified by the presence of a squeaking sound heard over the chest wall during a Valsalva maneuver. Furthermore, these leak sounds can help identify the size, location, and communications of the bronchial fistulae. The size of the leak can be inferred by the pitch of the leak sound. Large leaks produce low pitched sounds, smaller leaks (or partially obstructed leaks) produce high pitched squeaks , and multiple leaking sites produce polyphonic leak squeaks . The bronchus responsible for the leak can be identified by cessation of the leak sound during balloon occlusion of the correct bronchial stump. A communication of a bronchial fistula with the chest wall facial plane produces massive subcutaneous emphysema and an early inspiratory click. This click suggests a check valve mechanism of air exiting the leaking bronchus.


[Effects of repeated firing on microleakage of selective laser melting ceramic crowns].
To investigate the effects of repeated firing on microleakage of selective laser melting ceramic crowns. Fifty molars were randomly divided into 2 groups (25 teeth in each group). Teeth in group A received a chamfer finish line preparation, whereas teeth in group B received a shoulder finish line. After SLM metal crowns were fabricated, all the crowns received initial oxidation step, opaque firing, dentin firing and glaze firing, then crowns in each group were randomly divided into 5 sub-groups according to different time of clinical firings. Glass ionomer was applied for bonding. After 5000 thermocycles ranging from 5degrees centigrade to 55degrees centigrade, all the specimens was evaluated by dye penetration and then microleakage was examined under light microscopy. The data were analyzed with SPSS 20.0 software package. Microleakage between all specimens of group A were not statistically significant (P>0.05) whereas that of group B were statistically significant (P<0.05); After the fifth time of clinical firing, microleakage of specimens in group B(B5) were significantly higher than that of group A(A5). Repeated firings had no significant influence on marginal microleakage of SLM ceramic crowns whereas the crowns of chamfer finish lines result in better clinical performance after repeated firings.


Effect of time interval between capecitabine intake and radiotherapy on local recurrence-free survival in preoperative chemoradiation for locally advanced rectal cancer.
The concentration of capecitabine peaks at 1-2 hours after administration. We therefore assumed that proper timing of capecitabine administration and radiotherapy would maximize radiosensitization and influence survival among patients with locally advanced rectal cancer. We retrospectively reviewed 223 patients with locally advanced rectal cancer who underwent preoperative chemoradiation, followed by surgery from January 2002 to May 2006. All patients underwent pelvic radiotherapy (50 Gy/25 fractions) and received capecitabine twice daily at 12-hour intervals (1,650 mg/m2/day). Patients were divided into two groups according to the time interval between capecitabine intake and radiotherapy. Patients who took capecitabine 1 hour before radiotherapy were classified as Group A (n = 109); all others were classified as Group B (n = 114). The median follow-up period was 72 months (range, 7 to 149 months). Although Group A had a significantly higher rate of good responses (44% vs. 25%; p = 0.005), the 5-year local recurrence-free survival rates of 93% in Group A and 97% in Group B did not differ significantly (p = 0.519). The 5-year disease-free survival and overall survival rates were also comparable between the groups. Despite the better pathological response in Group A, the time interval between capecitabine and radiotherapy administration did not have a significant effect on survivals. Further evaluations are needed to clarify the interaction of these treatment modalities.