Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts.
Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post-operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of olesoxime on cardiac recovery after cardioplegic arrest. Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1,500-2,000 g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30 ml 4°C cold Custodiol cardioplegia without and with 5 μmol/L olesoxime, n = 7 each) the hearts maintained arrested for 90-min. Thereafter, the hearts were re-perfused for 60 min. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2, and pCO2 were also assessed. Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the olesoxime group. Moreover, hearts of the olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the olesoxime treated hearts. Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury.


Studies on effects of co-culturing on the development of embryonic and postnatal cerebellar cells.
Experiments were conducted to compare the in vitro development of different cerebellar cells in primary surface cultures to that observed in their co-cultures. Single cultures of embryonic (E.19) and postnatal (P 7) cerebellar cells as well as their co-cultures were established. Changes in cell-size distribution and in high-affinity GABA-uptake were studied during the first three weeks in the different cultures. Morphological analyses showed that in single cultures of embryonic (E 19) cells a number of large and middle-size neurons survived on the top of confluent monolayer of large flattened astroglial cells. In cultures of postnatal (P 7) cerebellar cells small tetanus toxin positive non-GABAergic neurons proved to be the most abundant cell-constituents while no confluent feeder-layer of non-neuronal cells was formed. In co-cultures both embryonic and postnatal morphological features were observed but we could not observe any improvement in either survival or maturation of the neuronal types studied. A transient increase in glial GABA-uptake, however, was observed in both postnatal and co-cultures soon after plating of postnatal cerebellar cells.


Evaluating 5-nitrofurans as trypanocidal agents.
The nitroheterocycle nifurtimox, as part of a nifurtimox-eflornithine combination therapy, represents one of a limited number of treatments targeting Trypanosoma brucei, the causative agent of human African trypanosomiasis. The mode of action of this prodrug involves an initial activation reaction catalyzed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open-chain nitrile metabolite. Here, we evaluate the trypanocidal activities of a library of other 5-nitrofurans against the bloodstream form of T. brucei as a preliminary step in the identification of additional nitroaromatic compounds that can potentially partner with eflornithine. Biochemical screening against the purified enzyme revealed that all 5-nitrofurans were effective substrates for T. brucei NTR (TbNTR), with the preferred compounds having apparent kcat/Km values approximately 50-fold greater than those of nifurtimox. For several compounds, in vitro reduction by this nitroreductase yielded products characterized by mass spectrometry as either unsaturated or saturated open-chain nitriles. When tested against the bloodstream form of T. brucei, many of the derivatives displayed significant growth-inhibitory properties, with the most potent compounds generating 50% inhibitory concentrations (IC50s) around 200 nM. The antiparasitic activities of the most potent agents were demonstrated to be NTR dependent, as parasites having reduced levels of the enzyme displayed resistance to the compounds, while parasites overexpressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofuran class of nitroheterocycles have the potential to treat human African trypanosomiasis, perhaps as an alternative partner prodrug to nifurtimox, in the next generation of eflornithine-based combinational therapies.


Diagnostic accuracy of percent retention scores on RBANS verbal memory subtests for the diagnosis of Alzheimer's disease and mild cognitive impairment.
Previous research has supported the use of percent retention scores in the neuropsychological assessment of memory, and many widely used memory measures provide for the calculation and normative comparison of these scores. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), an increasingly utilized assessment tool for cognitive impairment, provides normative data on delayed memory total raw scores only. The current study was aimed at determining the diagnostic accuracy of a novel percent retention score calculated from RBANS verbal memory subtests (delayed recall minus last learning trial) when distinguishing between normal controls, individuals diagnosed with Mild Cognitive Impairment, and individuals diagnosed with Alzheimer's disease. Results revealed excellent diagnostic accuracy of the RBANS percent retention scores when discriminating between the three groups. Findings suggest that RBANS percent retention scores provide excellent diagnostic accuracy offering supplementary information to clinicians and researchers alike.


Clinical factors affecting symptom recurrence in patients with syncope.
Recurrent syncope leads to poor functional status and psychiatric impairment in patients with syncope. The aim of the study was to prospectively analyze the risk factors attributed to syncope recurrence. Between 2009 and 2010, 289 patients with all cause of syncope visited our institution. Syncope recurrences were followed for 1 year by telephone interview every 3 months. We diagnosed 181 (63%) patients with neurally mediated syncope (NMS), 39 (13%) with orthostatic hypotension, 34 (12%) with cardiac syncope, and 35 (12%) with unexplained syncope. During the 1-year follow-up period, 19 (6.6%) patients suffered recurrent syncope. Kaplan-Meier curves showed that recurrent syncope was observed more often in patients with unexplained syncope compared with those with NMS (p < 0.01), and also observed more often in patients with six previous syncopal episodes compared to those with fewer episodes (p = 0.02). Cox regression analysis showed that the recurrence of syncope was significantly associated with more than six previous syncopal episodes (HR 5.38, 95% CI 1.17-24.71, p = 0.03) and that there was a tendency for association between recurrence of syncope and unexplained syncope (HR 6.13, 95% CI 0.96-39.1, p = 0.05). Patients with previous frequent syncopal episodes or unexplained syncope had higher rates of syncope recurrence during the follow up period.


Molecular imaging of endocrine neoplasms with emphasis on 18F-DOPA PET: a practical approach for well-tailored imaging protocols.
6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine (18F-DOPA) PET/CT can be a useful tool for the detection of different neuroendocrine tumors (NETs). The main determinants of 18F-DOPA uptake and retention by NETs are related to expression of LAT1/LAT2 transporters, expression and activity of AADC and biochemical phenotype, all being intimately inter-connected to their embryological origin. In order to improve sensitivity of 18F-DOPA PET, it is of main importance to perform indivisualized imaging protocols across primaries. This review provides a practical approach for performing well-tailored imaging protocols and describes the clinical value of the recommended radiopharmaceuticals.


Evaluation of bilirubin displacement effect by acetaminophen in vitro.
The use of acetaminophen as a drug for pain control is expected to increase in the neonatal field. The displacement factor of acetaminophen in the reaction in the glucose oxidase peroxidase method is very high, but is also considered to be inaccurate based on physicochemical properties. Unbound bilirubin was measured using the erythrocyte-bound bilirubin measurement method and glucose oxidase peroxidase method by the addition of acetaminophen or sulfisoxazole. The displacement factor was measured using glucose oxidase peroxidase method with the addition of tert-butyl-p-hydroxyanisole. Acetaminophen did not increase erythrocyte-bound bilirubin, and the addition of tert-butyl-p-hydroxyanisole lowered its displacement factor. On the other hand, sulfisoxazole increased erythrocyte-bound bilirubin, while tert-butyl-p-hydroxyanisole did not change its displacement factor. Acetaminophen is an accelerator of the reaction in the glucose oxidase peroxidase method and does not displace bilirubin from human serum albumin.


A Current Management Strategy for Children with Chronic Viral Hepatitis B, Based on International and National Guidelines.
Peculiarities of the course of chronic viral hepatitis B in children cause an important medical and social problem of health care, despite the implementation of modern treatment and prevention protocols. Pathogenetic mechanisms of the development and progression of viral hepatitis B infection, the presence of occult poorly diagnosed form, the impossibility of completely eliminating the virus and the specificity of the immune response in children are still not fully solved scientific problems. The aim of this review is to examine current strategies for the diagnosis and treatment of chronic hepatitis B in children, based on international and national guidelines. A detailed analysis of modern guidelines on the course and pathogenesis of viral hepatitis B infection confirms the fact that chronic hepatitis B is characterised by a complex interaction between the immune system of the virus and the patient, whose dynamic balance is not only responsible for the various phases of chronic viral hepatitis B infection but also leads to the result of antiviral treatment. Despite the introduction of vaccination of children against hepatitis B, the level of viral hepatitis B vaccination of children in Ukraine remains insufficient, which leads to the further spread of the infection. Currently available antiviral drugs can provide functional treatment of viral hepatitis B infection in a limited number of patients, but today's Ukrainian realities have caused a change in approach to the treatment and monitoring of patients, which may negatively affect the implementation of the key goals of the World Health Organization Global Strategy on the prevention, diagnosis and treatment of viral hepatitis.


Regional intensity of neurosurgical care and integration of aneurysm coiling in the United States.
There is wide regional variability in the volume of procedures performed for similar surgical patients throughout the United States. We investigated the association of the intensity of neurosurgical care with the diffusion of the novel technology of cerebral aneurysm coiling. We performed a retrospective cohort study involving patients who underwent any neurosurgical procedure from 2005-2010 and were registered in the National Inpatient Sample (NIS) database. A sub-cohort of patients undergoing aneurysm clipping or coiling was also created. Regression techniques were used to investigate the association of the average risk-adjusted intensity of neurosurgical care with the average rate of coiling. There were significant disparities in the rate of coiling among several states (ANOVA, P<0.0001). It ranged from 0.24 in Maryland, where clipping was very predominant, to 0.82 in Minnesota, where coiling was the main treatment modality used. In multivariate analysis, higher coiling rate was associated with increased age, higher income, rural hospital location, and small institution size. The Midwest was association with higher rate in comparison to the Northeast, whereas the West and the South had even lower rates. Increasing rate of coiling was associated with increasing intensity of neurosurgical care. There was a positive correlation of the average risk-adjusted intensity of neurosurgical care with the average rate of coiling per state (Pearson's ρ=0.43, P<0.001). We observed significant disparities in the rate of coiling in the United States. Increased intensity of neurosurgical care was positively associated with the integration of coiling in treatment of cerebral aneurysms.


Effect of conventional and household water treatment technologies on the removal of pesticide residues in drinking water, Jimma town, Southwestern, Ethiopia.
Water resources have been contaminated by pesticides due to the different activities of human beings. Different studies documented that advanced water treatment systems can eliminate pesticides while conventional and household treatment technologies are not well studied. The main aim of the present study is to determine the effect of conventional and household water treatment technologies on the removal of pesticide residue in drinking water. Water samples were collected from the Gibe River (intake point), from each treatment process, and from the distribution system. To determine the effect of the household water treatment process (solar disinfection and boiling), pesticides were spiked into distilled water and then passed through solar disinfection (SODIS) and boiling. The extraction of samples was conducted by following a low-density-based dispersive liquid-liquid microextraction procedure. The result of the study revealed that almost all studied pesticides except o´p-DDT were detected in water samples. Most pesticides that were detected in water samples from our study areas exceeded the maximum residue limits (MRLs), except for p,p'-DDE. The percent reduction of pesticide residue after post-chlorination by conventional water treatment ranges from 11.7% (from 70.83 μg/L to 62.54 μg/L) for p´p-DDD to 97.29% (5510.1μg/L to 149.5μg/L) for Dimethachlor, and the percent reduction of pesticide residue by SODIS and boiling ranges from 2.31% (o´p-DDT) to 54.45% (Cypermethrin) and 27.13% (γ-Chlordane) to 38.9% (p´p-DDE) respectively. This indicates that treatment technologies are important for the reduction of pesticides in water. Since studied pesticides are persistent and the resides were exceed MRL (have a health impact), monitoring of pesticides in treatment plant units is necessary and treatment technology improvement is important to allow further removal of pesticides.


TaqI polymorphism in the 3' flanking region of the PI gene among Kuwaiti Arabs and Russians.
The Taq1 polymorphism in the 3' flanking region of the PI gene has been reported to be associated with chronic obstructive pulmonary disease (COPD). We have studied the frequency of the Taq1 polymorphism in 117 Kuwaiti Arabs and 110 Russians using PCR/RFLP. The frequency of this polymorphism was found to be 0.235 in the Arabs and 0.027 in the Russians. Such a striking difference in allele frequencies could be due to a 'founder effect' in the Kuwaiti population. However: it may also be that this mutation provides a selective advantage, thus accounting for its fixation at a rather high frequency in some populations. Our results suggest that ethnic composition is a very important factor which should be taken into consideration when studying the association of the Taq1 polymorphism with COPD.


Morphometry of cat's pulmonary arterial tree.
Morphometic data of the pulmonary artery in the cat's right lung are presented. Silicone elastomer casts of cat's right lung were made, and measured, counted and analyzed. The Strahler system is used to describe the branching pattern of the arterial vascular tree. These data are needed for any quantitative approach to the study of the pulmonary circulation. For all the pulmonary blood vessels of the cat lying between the main pulmonary artery and the capillary beds, there are a total of 10 orders of vessels in the right upper lobe, 9 orders of vessels in the right middle lobe and 11 orders of vessels in the right lower lobe. The ratio of the number of branches in successive orders of vessels or the branching ratio, is 3.58. The corresponding average diameter ratio is 1.72, whereas the average length ratio is 1.81.


Anesthetic management for separation of craniopagus twins.
We report the anesthetic management of a case of separation of craniopagus twins with unbalanced cross circulation and one twin with renal dysfunction. After intravenous induction, anesthesia was maintained with isoflurane inhalation and propofol infusion. Twin A survived but Twin B died after the surgery. The anesthetic problems during the operation are discussed.


Successful en bloc endoscopic full-thickness resection of a giant cervical esophageal leiomyoma originating from muscularis propria.
Esophageal leiomyomas, the most common benign primary tumors of the esophagus, are esophageal subepithelial lesions treated by surgery traditionally. In recent years, endoscopic submucosal dissection and related endoscopic treatment techniques are adopted by endoscopists to resect gastrointestinal submucosal tumors. But if a giant esophageal leiomyoma approaches the esophagus entrance and originates from the deep layer of muscularis propria, it will be difficult for both endoscopic resection and surgical treatment. Especially, endoscopic resection has a high risk of huge perforation difficult to be sutured. A 72-year-old man with dysphagia underwent gastroscopy examination which indicated a large submucous eminence lesion, about 18-24 cm from the incisors. Endoscopic ultrasonography revealed the lesion was hypoechoic and originated from the muscularis propria with a clear boundary. The patient refused invasive surgical resection. Then, an en bloc endoscopic full-thickness resection was performed, which perforation was successfully closed with purse-string sutures using a novel endoloop device through standard single-channel endoscopy. Histopathologic examination showed an esophageal leiomyoma. This endoscopic procedure may be an alternative to avoid surgery for the removal of a giant upper esophagus tumor from muscularis propria layer.


Multi-color RGB marking enables clonality assessment of liver tumors in a murine xenograft model.
We recently introduced red-green-blue (RGB) marking for clonal cell tracking based on individual color-coding. Here, we applied RGB marking to study clonal development of liver tumors. Immortalized, non-tumorigenic human fetal hepatocytes expressing the human telomerase reverse transcriptase (FH-hTERT) were RGB-marked by simultaneous transduction with lentiviral vectors encoding mCherry, Venus, and Cerulean. Multi-color fluorescence microscopy was used to analyze growth characteristics of RGB-marked FH-hTERT in vitro and in vivo after transplantation into livers of immunodeficient mice with endogenous liver damage (uPA/SCID). After initially polyclonal engraftment we observed oligoclonal regenerative nodules derived from transplanted RGB-marked FH-hTERT. Some mice developed monochromatic invasive liver tumors; their clonal origin was confirmed both on the molecular level, based on specific lentiviral-vector insertion sites, and by serial transplantation of one tumor. Vector insertions in proximity to the proto-oncogene MCF2 and the transcription factor MITF resulted in strong upregulation of mRNA expression in the respective tumors. Notably, upregulated MCF2 and MITF expression was also observed in 21% and 33% of 24 human hepatocellular carcinomas analyzed. In conclusion, liver repopulation with RGB-marked FH-hTERT is a useful tool to study clonal progression of liver tumors caused by insertional mutagenesis in vivo and will help identifying genes involved in liver cancer.


Benefits of a narrative culture.
LOOKING BACK over the past 20 years, the healthcare challenges we faced then are similar to those we face now. They may be heightened, but they still concern quality and safety, healthcare equity, cost constraints, and regulatory requirements.


Comparison of Endovascular Aneurysm Repair with Open Repair in Patients with Abdominal Aortic Aneurysm in Our Own Material in Years 2002-2011.
Endovascular abdominal aortic aneurysm repair has become an alternative to open surgical repair of abdominal aortic aneurysm since the early 1990s. The conventional method remains the gold standard in the treatment of Abdominal Aortic Aneurysm (AAA); however, a large percentage of patients do not qualify for this treatment due to the high risk of perioperational death and complications. The objective of this work was to compare AAA surgeries performed by both classical and endovascular methods in years 2002-2011. Medical documentation of elective AAA patients undergoing surgical treatment was retrospectively analyzed on the basis of archive- and computer database data. The analysis included the patients' demographics, internal disease burden, as well as causes of deaths and complications within 30 days after the procedure and 1 year follow-up. Thirty-day and 1-year mortality rates in patients treated in the elective setting were 1.5% and 8.7% for endovascular method and 4.0% and 15.7% for the open method. The comparison of mortality rates in 115 high-risk patients undergoing elective OR treatment with 275 high-risk treatment patients undergoing EVAR surgery (7.8% vs. 1.5%, 8.7% vs. 15.7%, p<.01) showed that the endovascular method significantly reduced the mortality in the latter group. Endovascular treatment is an attractive option in AAA; especially in heavily burdened patients, because it definitely reduces mortality. EVAR was found to be advantageous over OR in case of high-risk patients.


Anti-inflammatory effects of ursolic acid-3-acetate on human synovial fibroblasts and a murine model of rheumatoid arthritis.
Ursolic acid (UA), a pentacyclic triterpenoid, is a common natural substance known to be effective in the treatment of inflammation, oxidative stress, and ulcers in arthritis. This study examined the effects of ursolic acid-3-acetate (UAA), a derivative of UA, on rheumatoid arthritis (RA) and verified the underlying mechanism of action by using a type-II collagen-induced arthritis (CIA) mice model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. The oral administration of UAA showed a decrease in clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. UAA administration reduced Th1/Th17 phenotype CD4+ T lymphocyte expansion and inflammatory cytokine production in draining lymph nodes. In addition, UAA effectively reduced the expression and production of inflammatory mediators, including cytokines and matrix metalloproteinase-1/3 in the knee joint tissue and RA synovial fibroblasts, through the downregulation of IKKα/β, ΙκBα, and nuclear factor-κB. Our findings showed that UAA modulated helper T cell immune responses and matrix-degrading enzymes. The effects of UAA were comparable with those of the positive control drug, dexamethasone. In summary, all the evidence presented in this paper suggest that UAA could be a therapeutic candidate for the treatment of RA.


Efficacy and tolerability of fitostimoline in two different forms (soaked gauzes and cream) and citrizan gel in the topical treatment of second-degree superficial cutaneous burns.
A total of 227 patients (mean age 41.3 years, 52% females) with at least one second-degree superficial cutaneous burn of thermal origin of a smallest transverse diameter ≥20 mm and a largest transverse diameter ≤90 mm were randomised to receive the topical application of aqueous extract of Triticum vulgare (Fitostimoline) in two different forms (soaked gauzes and cream) or catalase of horse origin in form of gel (Citrizan Gel), given up to healing or to a maximum of 20 days. The rate of lesion healing at end of study was significantly higher in patients treated with Fitostimoline (gauzes 97.3%, cream 91.5%) than in those receiving catalase (84.5%). The pooled Fitostimoline groups were also significantly more effective than catalase gel in reducing total symptoms score, pain at medication, pain at rest, and burning at end of study. Both formulations of Fitostimoline and catalase gel were well tolerated in terms of adverse effects in the site of application.


Hypoosmotic stress stimulates growth in HepG2 cells via protein kinase B-dependent activation of activator protein-1.
Although hypoosmotic stress-induced cell swelling activates phosphatidylinositol-3-kinase, its impact on the downstream signal protein kinase B and cell growth is unknown. Activator protein-1 is in part phosphatidylinositol-3-kinase dependent, and is important in proliferation. We hypothesized that cell swelling modulates proliferation in HepG2 cells via the protein kinase B-dependent activation of activator protein-1. HepG2 cells pretreated with or without LY294002 were exposed for up to 30 minutes to hypoosmotic medium (160 mOsm/L). Tumor necrosis factor-alpha (1.4 nmol/L) or normoosmolar medium (270 mOsm/L) served as positive and negative controls, respectively. Western immunoblots measured cytoplasmic phosphorylated and total protein kinase B. Electromobility shift assays measured nuclear activator protein-1. Methylene blue assays measured cell proliferation at 24, 48, and 72 hours after stimulation. Hypoosmotic stress phosphorylated protein kinase B by 10 minutes. Subsequently, hypoosmotic exposure stimulated activator protein-1 by 30 minutes. Pulse exposure to hypoosmotic stress potentiated HepG2 proliferation by 72 hours as compared to both negative controls and LY-inhibited cells (n = 4 per group, P = 0.009 and P = 0.004, respectively; P <0.001 analysis of variance. All three activation events were abolished with LY294002 pretreatment. In HepG2 cells, hypoosmotic stress-induced swelling stimulates proliferation via protein kinase B-mediated activation of activator protein-1. These data delineate a possible mechanism linking changes in cell volume to growth in human liver cancer.


Crystal Perfection of Particle Monolayer at the Air-Water Interface.
Crystal growth in colloidal particle monolayers fabricated by Langmuir-Blodgett method on 4 in. sapphire wafers was investigated under the condition of two techniques, that is, ultrasonic annealing at 1.2 to 1.5 MHz and barrier-sway process at 0.2 to 0.5 Hz. Significant increases of the ordered area were obtained by the both techniques and more than 60 times growth was confirmed. The remaining crystal defects after the growth were categorized as grain boundary, vacancy, and line defect. Both techniques exhibited different features regarding the component ratio of the defects, and different mechanisms for the reorientation of particles are discussed. The driving force of these re-orientations is thought to be associated with the 2D Ostwald ripening of colloidal crystals.


Antibiofilm Activity of Azadirachta indica and Catharanthus roseus and Their Synergistic Effects in Combination with Antimicrobial Agents against Fluconazole-Resistant Candida albicans Strains and MRSA.
The rapid emergence and spread of antimicrobial resistance has become a global public health concern that threatens the effective treatment of infectious diseases. One major approach adopted to overcome antimicrobial resistance is the use of plant extracts individually and/or with combination of antibiotics with plant extracts, which may lead to new ways of treating infectious diseases and essentially representing a potential area for further future investigations. In this study, the antifungal activities of Azadirachta indica leaf and Catharanthus roseus flower extracts against fluconazole-resistant Candida albicans strains (isolated from pregnant women with vulvovaginal candidiasis) and anti-methicillin-resistant Staphylococcus aureus (MRSA) were evaluated by agar well diffusion, microdilution, and biofilm inhibition assays. Subsequently, the determination of the combined antimicrobial activity of the individual plant extracts with (fluconazole and voriconazole) and (ampicillin, tetracycline, and streptomycin) against C. albicans strains and MRSA, respectively, was evaluated by checkerboard microdilution assay. Results from the study showed that the antimicrobial activity of the two plant extracts determined by time-kill kinetics was fungistatic with their MICs ranging from 0.1 to 4 mg/mL. Interestingly, all extracts were proved as good biofilm inhibitors of resistant C. albicans and MRSA from 10.1 to 98.82%. Their combination interaction with fluconazole, voriconazole, ampicillin, tetracycline, and streptomycin ranged from synergy to antagonism as per the parameters used. Overall, these results showed that A. indica leaf and C. roseus flower extracts have significant antifungal property. Furthermore, A. indica leaf and C. roseus flower extracts alone or in combination with fluconazole and voriconazole could provide a promising approach to the management of candidiasis caused by drug-resistant strains as well as their interaction with the antibacterial agents to combat the common infections caused by MRSA.


Evaluation of in vitro dissolution rates of thorium in uranium mill tailings.
Dissolution rates of thorium from the uranium mill tailings piles at two Department of Energy Uranium Mill Tailings Remedial Action Project (UMTRAP) sites have been evaluated. The thorium dissolution rates were evaluated in vitro using simulated lung fluid. The former uranium mills at the UMTRAP sites employed different chemical processes (acid leach and alkaline pressure leach) to extract the uranium from the ore, and the thorium dissolution rates at these sites were found to be markedly different. A site specific annual limit on intake (ALI) value for 230Th was calculated for the UMTRAP site that was associated with a multiple component dissolution curve.


Toward development of a screen to identify randomly encoded, foldable sequences.
The ability to identify sequences in a randomly encoded polypeptide library that are capable of acquiring unique and stably folded structures would be valuable in the examination of protein-folding issues. The quality control system of the yeast secretory pathway prevents the release of incompletely folded polypeptides. Earlier work has shown that this feature can be used in a screen to identify mutations that increase the stability of a protein. We sought to extend this strategy for use with random sequence libraries by combining a quality-control system-based screen with generic tag-based immunodetection that can be applied to any sequence. To test this method, we screened a library encoding random mutations in a bovine pancreatic trypsin inhibitor variant containing a small generic tag. Initial on-plate screening resulted in a large number of false positives: sequences that were secreted but not foldable. These false positives were excluded successfully in additional screening steps that used a liquid-culture secretion screen and a gel electrophoresis assay. Three positive clones were obtained that showed midpoint thermal denaturation temperatures 10-16 degrees C higher than the original bovine pancreatic trypsin inhibitor variant. Thus, this multistep screening method may be useful for finding novel, foldable sequences.


Diagnosis of Internal Derangement of the Knee: Volume Isotropic Turbo Spin-Echo Acquisition MRI With Fat Suppression Versus Without Fat Suppression.
The purpose of this study was to compare 3D volume isotropic turbo spin-echo acquisition (VISTA) MRI with and without fat suppression for use in evaluating ligaments, menisci, and cartilage. Two radiologists retrospectively and independently reviewed 71 MRI studies. Each study consisted of 3D intermediate-weighted VISTA images with fat suppression and without fat suppression. The presence of tears of the anterior cruciate and posterior cruciate ligaments, tears of the medial and lateral menisci, and cartilaginous defects was evaluated. Arthroscopic surgical findings were used as the standard of reference. Statistical analysis was performed to calculate the sensitivity, specificity, and accuracy of the two methods. Mean specificity and accuracy for medial meniscal tears were significantly higher with VISTA (specificity, 95.0%; accuracy, 94.4%) than with fat-suppressed VISTA (FS-VISTA) (specificity, 81.3%; accuracy, 85.9%), and the difference was statistically significant (specificity, p = 0.003; accuracy, p = 0.004). Mean specificity for cartilaginous defects was also significantly higher with VISTA than with FS-VISTA (99.1% vs 96.8%, p = 0.039). There were no other significant differences between the two methods. Three-dimensional VISTA MRI has higher specificity than FS-VISTA imaging for evaluation of medial meniscal tears and cartilaginous defects.


Trans-unsaturated fatty acids in human skin surface lipids.
Methyl esters of the fatty acids obtained by saponification of human skin surface lipids were subjected to thin-layer chromatography on silica gel-silver nitrate revealing the presence of trans-monounsaturated components constituting approximately 0.3% of the total fatty acids. The positions of unsaturation in the 18-carbon trans-unsaturated acids in 2 subjects resembled those present in the corresponding acids from margarine, although this was not a component of the diet of one of the subjects. Dietary origin is possible for these components, which could also arise from bacterial action in the pilosebaceous follicle.


Genome Sequence of Mycobacterium Phage CrystalP.
Mycobacteriophage CrystalP is a newly isolated phage infecting Mycobacterium smegmatis strain mc2155. CrystalP has a 76,483-bp genome and is predicted to contain 143 protein-coding and 2 tRNA genes, including repressor and integrase genes consistent with a temperate lifestyle. CrystalP is related to the mycobacteriophages Toto and Kostya and to other Cluster E phages.


Genomic research, publics and experts in Latin America: Nation, race and body.
The articles in this issue highlight contributions that studies of Latin America can make to wider debates about the effects of genomic science on public ideas about race and nation. We argue that current ideas about the power of genomics to transfigure and transform existing ways of thinking about human diversity are often overstated. If a range of social contexts are examined, the effects are uneven. Our data show that genomic knowledge can unsettle and reinforce ideas of nation and race; it can be both banal and highly politicized. In this introduction, we outline concepts of genetic knowledge in society; theories of genetics, nation and race; approaches to public understandings of science; and the Latin American contexts of transnational ideas of nation and race.


Experiences of a mobile phone delivered brief intervention for hazardous drinking: A qualitative study nested in the AMBIT trial from Goa, India.
This study explores the experiences of participants receiving a mobile-based brief intervention (BI) for hazardous drinking in India, to determine characteristics that influenced engagement and examine perceived reasons for change in alcohol consumption. Semi-structured interviews were conducted with 10 adult hazardous drinkers who received a mobile-based BI in the intervention arm of a pilot randomised control trial. Data were coded through an iterative process and analysed using thematic analysis. Study participants reported a positive experience, with factors such as customised intervention delivery and personal motivation facilitating their engagement. Participants reported a reduction in quantity and frequency of alcohol use. This was credited to the intervention, particularly, its provision of health-related information, goal-setting content and strategies to manage drinking. Apart from alcohol reduction, participants reported improvements in diet, lifestyle, wellbeing, and familial relations. By providing a context to explain the impact of the intervention, the learnings from this study can be used to strengthen the implementation of mobile-based interventions. This study outlines the scope for further research in digital health, such as Internet-based health interventions, and incorporating digital interventions within the ambit of existing health care programmes.


Single-dose intramuscular iron dextran in pregnancy for anaemia prevention in urban Zambia.
One hundred and thirty-three pregnant Zambians from a low socio-economic group had 5 ml of iron dextran complex injected into each buttock at their first antenatal visit. The haemoglobin change between then and delivery was measured and compared with a similar group of 142 patients who served as controls. Of the treated group 84% showed a rise in haemoglobin level (mean change 1.025 g/dl) compared with 56% of the control group (mean change 0.26 g/dl). This regimen may be appropriate for areas where general health is poor, iron deficiency is common and antenatal care is hindered by distance, acceptance or compliance with tablet taking.


Creating accountable care for carotid angioplasty and stenting: A multidisciplinary carotid revascularization board.
We tested the feasibility of a mandated multidisciplinary carotid revascularization board (MDCB) to review, approve and monitor all carotid artery and stenting (CAS) procedures and outcomes at our institution. The board was composed of vascular surgeons, cardiologists, interventional neuroradiologists, neurosurgeons, and neurologists, who met weekly to facilitate an evidence-based, consensus recommendation to ensure appropriate CAS referral. The board successfully reviewed and continues to review and approve all CAS procedures at our center. Of the 69 patients considered high risk for standard surgical treatment, 42 patients were symptomatic and 27 patients were asymptomatic. Their mean age was 70.5-year-old and the median degree of stenosis was 79%. In the 74 procedures, periprocedural complications occurred at the following rates: 2.7% death, 2.7% major stroke, 2.7% minor stroke, and 2.7% myocardial infarction (MI) within 30 days of the procedure. At 1 year the primary endpoints of ipsilateral stroke and neurovascular-related death were observed in 8.1% and 2.7% of the patients, respectively. At mean follow-up of 21 months, 18.8% of the patients (13/69) had died (including all causes), and 14.5% (10/69) experienced stroke (including nontarget strokes). Target vessel revascularization was needed in 2.9% patients. A mandated multidisciplinary carotid revascularization board MDCB is feasible and potentially advantageous in real clinical practice. It establishes a model for accountable care by providing a mechanism for institutional oversight, credentialing operators, quality review, standardizing care, cost containment and eliminating the "subspecialty silo mentality."


Serum and Plasma Metabolomic Biomarkers for Lung Cancer.
In drug invention and early disease prediction of lung cancer, metabolomic biomarker detection is very important. Mortality rate can be decreased, if cancer is predicted at the earlier stage. Recent diagnostic techniques for lung cancer are not prognosis diagnostic techniques. However, if we know the name of the metabolites, whose intensity levels are considerably changing between cancer subject and control subject, then it will be easy to early diagnosis the disease as well as to discover the drug. Therefore, in this paper we have identified the influential plasma and serum blood sample metabolites for lung cancer and also identified the biomarkers that will be helpful for early disease prediction as well as for drug invention. To identify the influential metabolites, we considered a parametric and a nonparametric test namely student׳s t-test as parametric and Kruskal-Wallis test as non-parametric test. We also categorized the up-regulated and down-regulated metabolites by the heatmap plot and identified the biomarkers by support vector machine (SVM) classifier and pathway analysis. From our analysis, we got 27 influential (p-value<0.05) metabolites from plasma sample and 13 influential (p-value<0.05) metabolites from serum sample. According to the importance plot through SVM classifier, pathway analysis and correlation network analysis, we declared 4 metabolites (taurine, aspertic acid, glutamine and pyruvic acid) as plasma biomarker and 3 metabolites (aspartic acid, taurine and inosine) as serum biomarker.


Advanced Glycation End Products are Increased in the Skin and Blood of Patients with Severe Psoriasis.
Psoriasis is frequently associated with metabolic comorbidities. Advanced glycation end products (AGEs) are highly oxidant, biologically active compounds that accumulate in tissues in association with hyperglycaemia, hyperlipidaemia and oxidative stress. This is a cross-sectional case-control study involving 80 patients with mild/severe psoriasis and 80 controls matched for age, sex and body mass index (40 with severe eczema, 40 healthy individuals). Patients and healthy individuals with a smoking habit, diabetes, dyslipidaemia, hypercholesterolaemia, hypertension or who were under systemic treatment were excluded from the study. Skin AGEs were measured in normal-appearing skin by a standard fluorescence technique, and blood AGEs (total AGEs, pentosidine and AGEs receptor) by enzyme-linked immunosorbent assay. Levels of cutaneous AGEs (p < 0.04), serum AGEs (p < 0.03) and pentosidine (p <0.05) were higher in patients with severe psoriasis. Cutaneous AGEs correlated well with serum AGEs (r = 0.93, p < 0.0001) and with Psoriasis Area and Severity Index score (r = 0.91, p < 0.0001). Receptor levels were lower (p < 0.001) in severe psoriasis, and inversely correlated with disease severity (r = -0.71, p < 0.0002). Patients with severe psoriasis have accumulation of skin and serum AGEs, independent of associated metabolic disorders.


Isothiocyanates: mechanism of cancer chemopreventive action.
Dietary and synthetic isothiocyanates have cancer chemopreventive activity. Dietary isothiocyanates are formed from glucosinolate precursors of ingested green vegetables. Isothiocyanates are absorbed across intestinal cell membranes by passive diffusion and bind reversibly to plasma protein thiols by thiocarbamoylation. Free isothiocyanate enters cells and is converted to the glutathione conjugate by glutathione S-transferases (GSTs). The glutathione conjugate is exported from cells by multidrug resistance proteins (MRPs), and metabolized in the mercapturic acid pathway to the corresponding mercapturic acid. The isothiocyanate is reformed by fragmentation of mercapturic acid pathway metabolites; it is inactivated by slow hydrolysis to the corresponding amine that is inactive in chemoprevention. Depletion of cellular glutathione and protein thiocarbamoylation activates signal transduction for cancer chemoprevention. Isothiocyanates inhibited and inactivated cytochrome P450 isoforms. They induced increased expression of GST, NADPH: quinone oxidoreductase, aldo-keto reductase and gamma-glutamylcysteine synthetase. These responses were coordinated at the transcription level by nuclear factor-erythroid 2 p45-related factor-2 acting through the antioxidant/electrophile enhancer response element and stimulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1 and c-Jun N-terminal kinase-1 (JNK1) pathway. Isothiocyanates also induced apoptosis of pre-cancerous cells and tumor cells activated by caspase-8 and potentiated by JNK1. The chemopreventive activity of isothiocyanates is influenced by the isothiocyanate bioavailability-as is toxicity, GST polymorphism, protein thiocarbamoylation and probably also by MRP expression. These features of isothiocyanate metabolism and chemoprevention deserve further investigation.


Decision-making at the time of parasitism: cowbirds prefer to peck eggs with weaker shells.
Interspecific avian brood parasites, like cuckoos and cowbirds, lay their eggs in nests of other species, the hosts, which take over the entire parental care of the parasite's eggs and chicks. This breeding strategy requires decisions that may affect the parasite's reproductive success. During the breeding season, cowbirds search for host nests and revisit them to monitor its progress and parasitize at the time host laying begins. When visiting hosts nests, they repeatedly peck the nest contents trying to destroy one or more eggs. This behaviour favours parasite's offspring by reducing the competition for food with nestmates. We evaluated if the egg-pecking behaviour of female shiny (Molothrus bonariensis) and screaming (M. rufoaxillaris) cowbirds is affected by the strength and the size of the eggs they find in the nest. We presented to wild-caught females artificial clutches with two natural eggs that differ in size and shell strength. We found that female shiny and screaming cowbirds adjusted egg-pecking behaviour based on the strength but not on the size of the eggs. When differences in strength between eggs were high, both cowbird species pecked more frequently the egg with the weaker shell, increasing the probability of a successful puncture. Our results indicate that female cowbirds can discriminate eggs through the strength of the shell, and by choosing the weaker egg to peck, they increase the probability of puncturing.


Pharmacokinetics, central nervous system uptake, and lipid solubility of propranolol, acebutolol, and sotalol.
The relation of in vitro lipophilicity, based on octanol:buffer partition ratio and on reverse-phase liquid chromatographic retention, to in vivo pharmacokinetics and central nervous system entry was evaluated for the beta-blockers propranolol, acebutolol, and sotalol. Anesthetized cats received single intravenous doses, following which plasma kinetics, cerebrospinal fluid (CSF) kinetics and brain tissue uptake were determined over the next 4 h. Propranolol, by far the most lipophilic beta-blocker in vitro, had the highest in vivo metabolic clearance and volume of distribution (Vd), the most rapid entry into CSF, and the highest brain:plasma uptake ratio (38.0). Sotalol, the most hydrophilic drug in vitro, had the lowest in vivo clearance and Vd, the slowest CSF entry, and the lowest brain:plasma ratio (0.52). Acebutolol had slightly greater in vitro lipophilicity than sotalol, intermediate values of in vivo plasma kinetics and CSF entry rate, and a slightly greater brain:plasma uptake ratio (0.71). Thus, differences among beta-blockers in lipid solubility are associated with predictable differences in plasma kinetics, and rate of entry into CSF. Furthermore, the relative extent of entry into brain is lower for hydrophilic as opposed to lipophilic beta-blockers.


Looking for trouble: a search for developmental defects of the hypothalamus.
The hypothalamus is a critical integrator of several homeostatic processes that are required for the survival of vertebrates. Disruption of the development of the hypothalamus thus has the potential of perturbing important physiological processes with lifelong consequences. We review current knowledge about how cell types are specified and circuits are formed within the developing hypothalamus. We emphasize the potential clinical impact of the perturbations of these pathways using the regulation of energy balance as a model. We predict that disruption of hypothalamic development is a common, previously unsuspected cause of disorders of homeostatic processes such as obesity and high blood pressure.


Negative findings in search for a transmissible agent in Crohn's disease.
Affected lymph nodes from 3 patients with Crohn's disease were homogenised and inoculated intramurally into the distal ileum of five piglets. The homogenates were also inoculated intramurally in the distal ileum of 15 rats and also by percutaneous injection intraabdominally in 15 rats and compared with the same number of animals of each species inoculated in the same manner with homogenates prepared from 3 patients with caecal cancer. There was no difference in weight increase between the animals inoculated with Crohn's tissue homogenate or control tissue homogenate. Neither did we find any macroscopic or microscopic changes in the animals inoculated with Crohn's tissue homogenate. We found a rather high frequency of mammary tumors in the rats inoculated with Crohn's tissue homogenate, although compared to the rats inoculated with control tissue homogenate there was no statistically significant difference. The negative results may be due to the method of preparing the tissue homogenate or to the use of lymph nodes instead of the bowel in preparing the homogenate, but may also be taken as support against the suggestion that a transmissible agent is present in Crohn's disease.


Inducible nitric oxide synthase (iNOS) in endotoxemia: chimeric mice reveal different cellular sources in various tissues.
The aim of these experiments was to determine the contribution of leukocyte-derived iNOS to total iNOS expression induced by lipopolysaccharide (LPS). By transferring bone marrow between iNOS+/+ and iNOS-/- mice, we created chimeric mice in which iNOS expression was limited to either circulating leukocytes (leukocyte-iNOS mice) or parenchymal cells (parenchyma-iNOS mice). Analysis of congenic markers demonstrated that >95% of thymocytes in chimeric mice were of donor origin. Also, following LPS treatment, iNOS mRNA was detectable in blood from leukocyte-iNOS mice but not parenchyma-iNOS mice. Together these findings indicated that the host marrow had been replaced entirely by donor cells. In the lung, at least 50% of the LPS-induced iNOS mRNA was derived from leukocytes, and immunohistochemical analysis indicated that leukocytes were the main source of iNOS protein. In contrast in the liver, colon, and muscle, iNOS expression was derived predominantly from parenchymal cells. This divergence is potentially explained by the high level of leukocyte recruitment to the lung, relative to the other tissues. Plasma levels of NOS byproducts indicated that parenchymal iNOS was the dominant source of systemic iNOS activity. These findings indicate that in tissues other than the lung, parenchymal cells are the principal source of iNOS during endotoxemia.


Role of the inferior frontal cortex in coping with distracting emotions.
The role of inferior frontal cortex in coping with emotional distracters presented concurrently with a working memory task was investigated using event-related functional magnetic resonance imaging. The study yielded two main findings: (i) processing of emotional distracters was associated with enhanced functional coupling between the amygdala and the inferior frontal cortex and (ii) the inferior frontal cortex showed a left-lateralized activation pattern discriminating successful from unsuccessful trials in the presence of emotional distraction. These findings provide evidence that coping with emotional distraction entails interactions between brain regions responsible for detection and inhibition of emotional distraction, and identified a hemispheric specialization in the inferior frontal cortex in controlling the impact of distracting emotions on cognitive performance (left hemisphere) vs. controlling the subjective feeling of being distracted (right hemisphere).


Immunoblastic lymphadenopathy with pulmonary lesions and positive sputum cytology.
A case of immunoblastic lymphadenopathy is presented. The patient's diagnosis was made from his clinical findings and lymph node pathology. Of particular note are long-standing pulmonary lesions of undetermined etiology and the exfoliation in sputum specimens of large numbers of immunoblasts identical to those seen in histologic sections of lymph node. Although other cases of immunoblastic lymphadenopathy with pulmonary findings have been published, 4, 5 only the histomorphology of these lesions has been described. This is the first reported case of immunoblastic lymphadenopathy with positive pulmonary cytology. Diagnosis of this condition requires histopathologic evaluation of diagnostic lymph nodes. Immunoblasts may be identified cytologically in sputum preparations and in this context are suggestive of but not diagnostic of this entity. The use of methyl green-pyronine stain to better differentiate immunoblasts is recommended.


[Erlotinib plus gemcitabine combination therapy in patients with unresectable advanced pancreatic cancer - a single-institution experience].
Pancreatic adenocarcinoma is one of the leading causes of cancer deaths in Japan. Erlotinib plus gemcitabine( GEM) combination therapy provided significant improvements in the overall and progression-free survival in a phase III trial in Canada and a phase II trial in Japan. As a result, this combination therapy was approved for use in Japan. We evaluated the efficacy of erlotinib plus GEM in patients with unresectable pancreatic cancer. GEM at a dose of 1,000 mg/m2 was administered on days 1, 8, and 15 in a 4-week cycle. Erlotinib was taken orally at 100 mg/day until disease progression or unmanageable toxicity. Between October 2011 and April 2013, 9 patients were enrolled. The mean age was 62.3 years (range, 48-70 years), and 66.7% of patients were men. Eight patients had no prior therapy. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0. Eight patients had metastatic and 1 had locally advanced disease. Five patients had a history of smoking. The median duration of erlotinib administration was 133 days, and the median dose intensity was 100 mg/day, with the majority of patients( 88.9%) receiving 100% of the relative dose intensity. The median duration of GEM treatment was 5 cycles, and its median dose intensity was 890 mg/m2/week, with approximately half of the patients (66.7%) receiving >85% of the relative dose intensity. The most frequently reported adverse event was skin rash, which occurred in 44.4% of the patients. Other common non-hematological adverse events included facial edema, diarrhea, nausea, depilation, pruritus, and cholangitis. Most patients experienced some degree of hematological toxicity, with Grade 3 or 4 neutropenia, leukopenia, and anemia. Interstitial lung disease was not observed. The median overall survival was 7.63 months, and the 1-year survival rate was 15%. The median progression-free survival was 5.60 months. The overall response rate was 11.1%,and the disease control rate was 88.9% [complete response (CR), n =0; partial response( PR), n=1; stable disease( SD), n=7]. In conclusion, erlotinib plus GEM combination therapy is well tolerated and associated with efficacy and survival outcomes.


Association of single nucleotide polymorphisms in the nuclear respiratory factor-2 beta subunit-encoding the GABPB1 gene within the occupational environment.
GABPB1, known as nuclear respiratory factor 2 (Nrf2), activates the mitochondrial genes that are responsible for antioxidant action and detoxification. Two single nucleotide polymorphisms (SNPs) of GABPB1, such as rs7181866 and rs8031031, were reported to be associated with the prevention of the increasing cancer risk caused by environmental deterioration. Between March 1 and May 1, 2018, human peripheral blood mononuclear cells (PBMCs) from a cohort of 300 volunteers working in adverse occupational environments were genotyped for the two SNPs in the present study. The SNP rs7181866 was found to be significantly greater in the male group than in the female group. Frequencies of SNP rs7181866 and bi-allele SNPs (rs7181866 + rs8031031) were significantly different between the <35-year-old group and the ≥35-year-old group. Further, multinomial logistic regression analysis of the occupational environments revealed the highest predictive frequency of SNPs for four environmental factors, of which chemical factors accounted for 15.33% rs7181866, physical factors accounted for 34.79% rs7181866 + rs8031031, physical + chemical factors accounted for 39.5% rs8031031, and unknown factors accounted for 26.5% rs7181866 + rs8031031. In conclusion, the G allele of rs7181866 was found to be significantly more susceptible than the rs8031031 allele under adverse occupational environmental factors, and physical factors such as noise, which appear to play vital roles in causing SNP mutations.


Induction of intestinal tumors in rats by dextran sulfate sodium.
The carcinogenicity of dextran sulfate sodium was studied in inbred ACI rats. In group 1, 10 male rats were fed a 10% dextran sulfate sodium diet; in group 2, 14 male and 12 female rats were fed a 5% dextran sulfate sodium diet; and in the control group, 9 male and 9 female rats were given the basal diet without dextran sulfate sodium. After the start of the feeding regimen, all rats given the 10% dextran sulfate sodium diet died of severe diarrhea and anemia within 14 days and 15 of 23 surviving rats fed a 5% dextran sulfate sodium diet developed intestinal tumors between 134 and 215 days. These tumors were induced in the colon and cecum and consisted of adenomas, adenocarcinomas, and papillomas.


Calorimetric study of magnetic fluids under a magnetic field.
In our past study, it was found that the strong magneto-optical effect of a magnetic fluid (MF) under a magnetic field is due to the second-order phase transition from colloidal particles' monodispersed phase to the particles' anisotropically agglomerated microclusters phase. These results, however, contradicted the Landau criterion. In the present study, in order to clarify whether the transition is of first order or second order, we performed differential scanning calorimetry (DSC) experiments on three different MFs to look for the existence of a phase transition latent heat. The DSC measurement was performed in the temperature range 22-150 degrees C with zero magnetic field and under approximately 10 kA/m magnetic field, respectively. No phase transition heat was observed within an experimental error of 0.03 kJ/kg for all the samples whether or not the field was applied.


Studies on the role of opiate peptides in two forms of genetic obesity: ob/ob mouse and fa/fa rat.
Recent reports have indicated that genetically obese hyperinsulinemic mice (ob/ob) and Zucker rats (fa/fa) compared with their lean controls have elevated levels of pituitary and plasma B-endorphins, opiates that can stimulate insulin secretion. In this study we have measured opiate levels by a radio-receptor assay in gastro-intestinal tissues and pancreas in ob/ob and fa/fa animals and their controls. Ob/ob mice showed significantly higher levels than control mice (+/+) in most gastro-intestinal tissues and pancreas. Levels in fa/fa rats did not differ from their controls. Radioimmunoassay of pancreas for B-endorphins, revealed higher levels in ob/ob vs +/+ mice, while there was no difference in the obese and lean rats. Fasting tended to decrease gastro-intestinal opioids in mice, while B-endorphin levels rose. It is concluded that opiates may play a significant role in the obesity of the ob/ob mouse and that this genetic obesity differs from that in Zucker rats.


Alz 50 recognizes abnormal filaments in Alzheimer's disease and progressive supranuclear palsy.
The monoclonal antibody Alz 50 recognizes a 68-kDa protein present in large amounts in cerebral tissue of patients with Alzheimer's disease (AD). We used light and electron microscopic as well as quantitative immunochemical techniques to compare distribution, characteristics, and amount of Alz 50 antigen in the tegmental nuclei of the pons of subjects with progressive supranuclear palsy (PSP) and subjects with AD. In both conditions Alz 50 antigen was found in neurons with and without neurofibrillary tangles (NFT). In NFT-bearing neurons the antigen was located in the filamentous components of NFT in both diseases, i.e., in straight filaments forming the NFT in PSP and in paired helical filaments components of the NFT in AD. In neurons lacking NFT the antigen was associated with straight filaments of various sizes, but the straight filaments were generally thinner than those of PSP. On immunoblots of both PSP and AD tissues, Alz 50 recognized a set of bands between 68 and 35 kDa which were not present in control tissue. The amount of Alz 50 antigen in AD tissue was estimated to be 10 times higher than that present in PSP tissue. The higher amount of Alz 50 antigen in AD tissue correlates with the more severe fibrillary pathology in this disease than in PSP. We propose that the Alz 50 antigen, although possibly related to tau proteins, distinguishes neurons that are forming abnormal filaments.


[Practice-related diagnostic classification of orofacial pain].
In this article, a practical diagnostic classification of orofacial pain for use in the general dental practice is presented. In contrast to the detailed taxonomy proposed by Okeson (1995), this classification is limited to those pain conditions dentists are confronted with most frequently. Furthermore, the fundamental differences of somatic versus neuropathic pain, localized versus widespread pain, and acute versus chronic pain are emphasized. Principles of managing the different pain entities are suggested.


Confirmation of efficacy in providing relief from the pain of dentin hypersensitivity of an anhydrous dentifrice containing 0.454% with or without stannous fluoride in an 8-week randomized clinical trial.
To compare the efficacy of an anhydrous dentifrice containing 0.454% w/w stannous fluoride and a negative control dentifrice containing 1,000 ppm fluoride, as sodium monofluorophosphate, at reducing dentin hypersensitivity over 8 weeks with twice-daily brushing. This was a randomized, examiner-blind, parallel, two treatment group, stratified (by maximum baseline Schiff sensitivity score), 8-week clinical study carried out at a single site in 119 healthy subjects with at least two sensitive teeth, who met all study criteria at the screening and baseline visits. Clinical assessments of sensitivity to evaporative (air) [with Schiff sensitivity score and visual analogue scale (VAS)] and tactile (Yeaple probe) stimuli were employed to compare the efficacy of the test dentifrice containing 0.454% w/w stannous fluoride to the negative control dentifrice at reducing sensitivity after 4 and 8 weeks treatment. Of the 119 subjects randomized to study treatment, 113 completed the study. At 4 and 8 weeks, between treatment analyses found the test dentifrice to be significantly better than the negative control dentifrice in relieving dentin hypersensitivity for all measures (Schiff: P < 0.0001 at 4 and 8 weeks; VAS score: P = 0.0003 at 4 weeks, P < 0.0001 at 8 weeks; tactile threshold: P = 0.0138 at 4 weeks, P < 0.0001 at 8 weeks).


The injustice of it all: caring for the chronically ill.
... While Spiegelberg emphasizes these "cosmic" -- perhaps more accurately, ontological -- features of birth and undeserved inequalities, it seems to us not inappropriate to suggest that what Douard terms "outrage" and Annas "instinct" go in the same direction. When impairment occurs without desert, something should be done to help. This is all the more true when, as in cases of chronic affliction that concern Douard or the case of the Siamese twins that fascinates Annas, something helpful can be done. Then, in Spiegelberg's words, what is "undeserved" demands redress. In these terms, each of these authors points to a deeply rooted sense of our common human lot. Or, in Albert Schweitzer's apt phrase, to witness such undeserved misfortune is to awaken "a moral sense that is usually dormant but that on special occasions can be brought to the surface." Chronic illnesses, we suggest -- no less than the "accidents of birth" that concern Spiegelberg -- are just such "special occasions" for awakening that "moral sense" suggested by Douard in his appeal to the "outrage" of doing nothing for, or refusing to help, the chronically ill.


Spectral properties of the polarizing devices at SRRC.
User requirements at SRRC for high-brilliance synchrotron light in various polarization states will be fulfilled in the near future by the implementation of two types of polarizing devices in the storage ring: the elliptically polarizing undulator (EPU) and the elliptically polarized bending magnet (EPBM). The EPBM provides a broadband polarized spectrum up to the soft X-ray range with rapid alternation of the left and right helicities. The EPU, which has a magnetic period length of 56 mm, generates a high-brilliance harmonic spectral intensity in the range 80-1400 eV with abundant polarization states, including circular ones. The optimal merit flux is evaluated for the operation of these two polarizing devices in the SRRC 1.5 GeV storage ring. The available polarization states are also surveyed.


DNV granted deeming authority from CMS.
DNV first organization to be granted deeming authority in 30 years. Now hospitals can get accreditation from Joint Commission or DNV, which bases its program on ISO 9000 standards. ISO 9000, which originated in manufacturing industry, focuses on processes for quality improvement.


Bromperidol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in psychoses.
Bromperidol is a close structural analogue of haloperidol. Both agents possess similar pharmacodynamic properties which are consistent with central antidopaminergic activity. The available clinical data from non-comparative and comparative trials have shown that bromperidol possesses antipsychotic activity. Its overall efficacy was slightly greater than chlorpromazine and perphenazine, and similar to or slightly better than haloperidol in a small number of comparative studies. Bromperidol frequently displayed a faster onset of action than these comparative agents and there have been reports of bromperidol causing an activating effect. However, extrapyramidal side effects occurred with similar frequency and severity after bromperidol compared with the 3 reference drugs. Data from additional controlled clinical trials are required to confirm the comparative antipsychotic efficacy of bromperidol and to assess whether it possesses any advantages in certain sub-types of schizophrenia.


Transfer of sensorimotor learning reveals phoneme representations in preliterate children.
Reading acquisition is strongly intertwined with phoneme awareness that relies on implicit phoneme representations. We asked whether phoneme representations emerge before literacy. We recruited two groups of children, 4 to 5-year-old preschoolers (N = 29) and 7 to 8-year-old schoolchildren (N = 24), whose phonological awareness was evaluated, and one adult control group (N = 17). We altered speakers' auditory feedback in real time to elicit persisting pronunciation changes, referred to as auditory-motor adaptation or learning. Assessing the transfer of learning at phoneme level enabled us to investigate the developmental time-course of phoneme representations. Significant transfer at phoneme level occurred in preschoolers, as well as schoolchildren and adults. In addition, we found a relationship between auditory-motor adaptation and phonological awareness in both groups of children. Overall, these results suggest that phoneme representations emerge before literacy acquisition, and that these sensorimotor representations may set the ground for phonological awareness.


The role of differential diagnosis in intravascular papillary endothelial hyperplasia of the sinonasal cavity mimicking angiosarcoma: A case report.
Intravascular papillary endothelial hyperplasia (IPEH), also known as Masson's tumour, is an unusual vascular lesion characterized by the proliferation of endothelial cells. The principal significance of IPEH is its clinical and radiological resemblance to angiosarcoma, resulting in a potential misdiagnosis and overtreatment. The aim of the present study is to report a rare case of IPEH of the right maxillary sinus, focusing on the radiological and histopathological features of the neoplasm and their role in the differential diagnosis with angiosarcoma. Herein we present a case of a 67-year-old woman with history of right-sided nasal obstruction. A computed tomography scan indicated opacity in the right maxillary sinus and significant bony erosion, and an magnetic resonance imaging revealed a highly vascularized polylobed neoplasm, suggesting a malignant neoplasm. The mass was removed surgically through a combined open and endoscopic approach. A perioperative biopsy excluded malignancy and histological examination was consistent with IPEH. IPEH in the sinonasal cavity is an extremely rare condition in which differential diagnosis serves a central role due to its close clinical and radiological resemblance to angiosarcoma. Awareness of IPEH is recommended for a correct diagnosis, and in order to avoid unnecessarily aggressive treatment.


Framework for the development and application of environmental biological monitoring guidance values.
Human biomonitoring (HBM) is widely recognised as a useful tool to aid assessment of exposure to chemical substances, but our ability to detect hazardous substances (or their metabolites and health effects) often exceeds our understanding of their biological relevance. There are only a few established frameworks for developing and using occupational and environmental biological guidance values (BGVs), mostly for data-rich substances that have been in use for some time. BGVs for new substances and those with unknown dose-response relationships are difficult to derive. An accepted framework based on current scientific knowledge and best practice is therefore urgently needed to help scientists, regulators, and stakeholders to design appropriate HBM studies, interpret HBM data (both for groups and individuals) understand the limitations and to take appropriate action when required. The development and application of such a tool is described here. We derived a conceptual framework that was refined by consultation with an advisory group and workshop. The resulting framework comprised four levels defined by increasing data, with increasing confidence for human health risk assessment. Available data were used for 12 chemicals with expert judgement to illustrate the utility of the framework.


Current concepts in the imaging of uterine sarcoma.
Recent advances in genetics and pathology have improved our understanding of diagnosis and staging of uterine sarcomas. The major types of uterine sarcomas include leiomyosarcoma, low-grade endometrial stromal sarcoma, undifferentiated endometrial sarcoma, adenosarcoma and carcinosarcoma. The distinctive biological behavior and poor overall survival of uterine sarcoma create challenges in the management of these tumors. We herein present a comprehensive review of taxonomy, epidemiology, pathology, imaging findings and natural history of a wide spectrum of uterine sarcomas.


Pro-oxidant and antioxidant processes in aquatic invertebrates.
Most aquatic organisms behave as conformers with respect to environmental variables, including changes in O2 availability. Aquatic species that show tolerance to hypoxia/anoxia or hyperoxia can be excellent models for investigating physiological and biochemical adaptations that deal with changing O2 and consequent changes in metabolic rate and production of reactive oxygen species (ROS). Here, I summarize selected data on ROS production and antioxidant defenses in a model marine invertebrate, the bivalve Mytilus, under different environmental and physiological conditions. An example of other bivalves adapted to particular environments (the Antarctic Sea) is also reported. These studies contributed to the knowledge on pro-oxidant and antioxidant processes in aquatic invertebrates from comparative and environmental perspectives. A common role for metallothioneins in antioxidant protection in mammals and aquatic invertebrates is underlined in different conditions, from human disease to responses to environmental exposure to heavy metals.


Inhibitory effects of antagonists of bombesin/gastrin releasing peptide (GRP) and somatostatin analog (RC-160) on growth of HT-29 human colon cancers in nude mice.
Nude mice bearing xenografts of HT-29 human colon cancer cell line were treated for 4 weeks with somatostatin analog (RC-160), bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095 and RC-3440). In three separate experiments somatostatin analog RC-160 (50 micrograms/day) released from microgranules significantly reduced tumor growth. Bombesin/GRP antagonists, RC-3095 and RC-3440 injected subcutaneously (s.c.) twice daily at a dose of 10 micrograms had the greatest and consistently significant inhibitory effect on tumor growth. RC-3095 given once daily s.c. at a dose of 20 micrograms was less effective. RC-3095 also inhibited metastatic tumor growth after intrasplenic injection of HT-29 cells in nude mice. Specific binding sites of somatostatin, bombesin and epidermal growth factor (EGF) were detected on intact HT-29 cells or on the membranes from HT-29 tumor xenografts. The inhibitory effects of bombesin antagonists on tumor growth were consistently linked with a significant down-regulation of EGF receptors. Bombesin/GRP antagonists and somatostatin analogs could be considered for the development of new hormonal therapies for colon cancer.


Molecular dynamics study on the influence of quencher concentration on the reaction rate for ionic systems.
The influence of concentrations of reagents on the rate of reaction: A+B-->C+B for low density equimolar mixtures of spherically symmetric ions immersed in the Brownian medium has been investigated by performing large scale molecular dynamics simulations. The Coulomb potential of ion-ion interactions is truncated at the cutoff distance large enough to make the kinetics of the reaction independent of its value. The simulations have been performed at conditions close to that for quenching reactions for fluophores. One of the simulation results is that the excess in the rate coefficient Delta k is always positive and converges to a constant value which is two to three orders in magnitude higher than that for the soft spheres immersed in the Brownian medium [Litniewski, J. Chem. Phys. 124, 114502 (2006)]. Delta k is approximately proportional to c however, if the concentration is high, positive deviations [O(c(2))] are noticeable. The simulation results are compared with simple model that bases on the superposition approximation. The model predicts most of the properties of Delta k. The predicted values are about 30%-40% lower than that from the simulations.


Phosphene induction by microstimulation of macaque V1.
Non-human primates are being used to develop a cortical visual prosthesis for the blind. We use the properties of electrical microstimulation of striate cortex (area V1) of macaque monkeys to make inferences about phosphene induction. Our analysis is based on well-established properties of V1: retino-cortical magnification factor, receptive-field size, and the characteristics of hypercolumns. We argue that phosphene size is dependent on the amount of current delivered to V1 and on the retino-cortical magnification factor. We suggest that to improve the correspondence between the site of stimulation within V1 and the visual field location of an elicited phosphene both eyes must be put under experimental control given that phosphene location is retinocentric and given that the vergence angle between the eyes might affect the position of a phosphene in depth. Knowing how electrical microstimulation interacts with cortical tissue to evoke percepts in behaving macaque monkeys is fundamental to the establishment of an effective cortical visual prosthesis for the blind.


[New therapeutic perspectives for arsenic: from acute promyelocytic leukemia to autoimmune diseases].
Since 1996, arsenic trioxide (As2O3) is used to treat patients with acute promyelocytic leukemia. We have recently shown that As2O3 is a novel promising therapeutic agent for the autoimmune diseases (human lupus-like syndrome) and the massive lymphoproliferation (human autoimmune lymphoproliferative-like syndrome) developed by MRL/lpr mice. As2O3 is able to achieve an almost complete regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions. This treatment also markedly reduced anti-DNA autoantibodies, rheumatoid factor, IL-18, IFN-gamma, nitric oxide metabolites, TNF-alpha, Fas ligand and IL-10 levels, and immune-complex deposits in glomeruli, leading to significantly prolonged survival rates.


Conjugated anionic PEG-citrate G2 dendrimer with multi-epitopic HIV-1 vaccine candidate enhance the cellular immune responses in mice.
Multi-epitope vaccines might cause immunity against multiple antigenic targets. Four immunodominant epitopes of HIV-1 genome were used to construct a polytope vaccine, formulated by dendrimer. Two regimens of polytopes mixture with dendrimer were utilized to immunize BALB/c mice. Adjuvants were also used to boost immune responses. The conjugated polytope could arouse significant cellular immune responses (P < 0.05) and Th1 response showed higher intensity compared to Th2 (P < 0.05). Our study depicted that conjugated dendrimer with multi-epitopic rHIVtop4 would efficiently induce cell-mediated immune responses and might be considered as promising delivery system for vaccines formulation.


[The design of smart data collection system for EHR].
This paper presents the design of smart data collection system to deal with the drawbacks like EHR data second hand input which is time-consuming and EHR's poor usability. The system comprises security certification, information management and data transmission modules. Through WLAN, EHR data can transmit between smart terminals and server. Also it provides a real-time communication platform for both terminal users and medical care personnel.


Quantifying and Reducing Ion Migration in Metal Halide Perovskites through Control of Mobile Ions.
The presence of intrinsic ion migration in metal halide perovskites (MHPs) is one of the main reasons that perovskite solar cells (PSCs) are not stable under operation. In this work, we quantify the ion migration of PSCs and MHP thin films in terms of mobile ion concentration (No) and ionic mobility (µ) and demonstrate that No has a larger impact on device stability. We study the effect of small alkali metal A-site cation additives (e.g., Na+, K+, and Rb+) on ion migration. We show that the influence of moisture and cation additive on No is less significant than the choice of top electrode in PSCs. We also show that No in PSCs remains constant with an increase in temperature but μ increases with temperature because the activation energy is lower than that of ion formation. This work gives design principles regarding the importance of passivation and the effects of operational conditions on ion migration.


Cloning and characterization of the first serine carboxypeptidase from a plant parasitic nematode, Radopholus similis.
Radopholus similis is an important parasitic nematode of plants. Serine carboxypeptidases (SCPs) are peptidases that hydrolyse peptides and proteins and play critical roles in the development, invasion, and pathogenesis of certain parasitic nematodes and other animal pathogens. In this study, we obtained the full-length sequence of the SCP gene from R. similis (Rs-scp-1), which is 1665 bp long and includes a 1461-bp open reading frames encoding 486 amino acids with an 18-aa signal peptide. This gene is a double-copy gene in R. similis. Rs-scp-1 was expressed in the procorpus, esophageal glands and intestines of females and in the esophageal glands and intestines of juveniles. Rs-scp-1 expression levels were highest in females, followed by juveniles and males, and lowest in eggs. Rs-scp-1 expression levels were significantly suppressed after R. similis was soaked in Rs-scp-1 dsRNA for 12 h. Nematodes were then inoculated into Anthurium andraeanum after RNAi treatment. Compared with water treatment, R. similis treated with RNAi were reduced in number and pathogenicity. In summary, we obtained the first SCP gene from a plant parasitic nematode and confirmed its role in the parasitic process.


Biogenesis of Leishmania-harbouring parasitophorous vacuoles following phagocytosis of the metacyclic promastigote or amastigote stages of the parasites.
Protozoan parasites Leishmania alternate between a flagellated promastigote form and an amastigote form. In their mammalian hosts, Leishmania survive and multiply in macrophages. Both forms can be internalized by these host cells at different stages of the infectious process and eventually establish themselves within parasitophorous vacuoles exhibiting phagolysosomal properties. To determine whether the biogenesis of these organelles differs according to the parasitic stage used to initiate infection, we compared their formation kinetics after phagocytosis of either metacyclic promastigotes or amastigotes of L. amazonensis or of L. major by mouse bone-marrow-derived macrophages pre-exposed or not to IFN-gamma. After 10 minutes of contact, an accumulation of F-actin was observed around the promastigotes and amatigotes undergoing phagocytosis or those that had already been internalized. This accumulation was transient and rapidly disappeared at later times. At 30 minutes, most of the promastigotes were located in long, narrow organelles that were exactly the same shape as the parasites. The latter were elongated with their cell bodies near to the macrophage nucleus and their flagella towards the periphery. This suggests that promastigote phagocytosis mainly occurs in a polarized manner, with the cell body entering the macrophages first. Most, if not all, of the phagocytosed promastigotes were located in organelles that rapidly acquired phagolysosomal properties. At 30 minutes, lamp-1, macrosialin, cathepsins B and D were detected in 70-98% of these compartments and about 70% of them were surrounded by rab7p. These late endosome/lysosome 'markers' were recruited through fusion with late endocytic compartments. Indeed, when late endosomes/lysosomes were loaded with fluorescein dextran, 81-98% of the promastigote-harbouring compartments contained the endocytic tracer 30 minutes after infection. Electron microscopy of infected macrophages previously loaded with peroxidase confirmed that the phagosomes rapidly fused with late endocytic compartments. When the amastigote stage of L. amazonensis was used to initiate infection, the kinetics of acquisition of the different late endosome/lysosome 'markers' by the phagosomes were similar to those measured after infection with metacyclics. However, more rab7p(+)-phagosomes were observed at early time points (e.g. 90% were rab7p(+) at 30 minutes). The early endosome 'markers', EEA1 and the transferrin receptor, were hardly detected in parasite-containing compartments regardless of the parasitic stage used to infect macrophages and the time after infection. In conclusion, both metacyclic- and amastigote-containing phagosomes fuse with late endosomes/lysosomes within 30 minutes. However, with L. amazonensis, the time required for the formation of the huge parasitophorous vacuoles, which are characteristic of this species, was much shorter after infection with amastigotes than after infection with metacyclic promastigotes. This indicates that the initial fusions with late endosomes/lysosomes are followed by a stage-specific sequence of events.


CONTINUING STUDIES ON THE SOUTH AMHERST DROSOPHILA MELANOGASTER NATURAL POPULATION DURING THE 1970'S AND 1980'S.
Continuing investigations on the South Amherst Drosophila melanogaster natural population following the significant decline and recovery of lethal (le) and semilethal (sle) frequencies in the late 1960's (Ives, 1970) show that the population has been remarkably stable although it contains MR (male recombination) and/or P DNA elements (Kidwell et al., 1977a; Green, 1980). A 13-year study affirms that the lethals present are nonrandomly distributed along the second chromosome and deficient on the right; they differ significantly in distribution from spontaneous (Ives, 1973) and δ-induced lethals (Minamori and Ito, 1971). Between 1970 and 1977, a total of 4,083 second chromosomes from the Markert subpopulation were analyzed; 28.9% of the chromosomes were lethal and 7.25% were semilethal in homozygous condition. Frequencies are similar for early summer and late fall collections although the rate of allelism among lethals is significantly higher in early summer than in late fall. For the large fall (1970-1979) Porch site population, 2,519 second chromosomes were analyzed; 29.5% were lethal and 8.0% were sublethal as homozygotes; the rate of allelism among lethals was 1.50%. At Hockanum, 1977-1983, lethal and semilethal frequencies were lower; the rate of allelism among lethals was 1.43%. The chromosome map distribution of lethals does not change between summer and late fall at Markert. The overall distributions of lethals at the Markert and Hockanum sites are similar. In tests for male recombination (MR) activity in the population over a 6-year period, a total of 0.47% recombinants were observed; these were uniformly distributed along the second chromosome. Comparisons are made with other long studied D. melanogaster populations.


Pharmacological investigation of trimetazidine in models of inflammation, pain and gastric injury in rodents.
The antinociceptive, anti-inflammatory and gastric effects of trimetazidine (2,3,4-trimethoxybenzyl-piperazine dihydrochloride), a novel anti-ischaemic compound, were evaluated in various animal models. In acute pain models, namely acetic acid-induced writhing, hot-plate assay, tail electric stimulation test, capsaicin-induced pain and the formalin test, trimetazidine (1.8-7.2 mg/kg, i.p.) showed marked antinociceptive effects. Trimetazidine did not produce any behavioural impairment as revealed by the mouse rotarod. The inhibition of writhing response by trimetazidine was reduced by yohimbine, theophylline (and to a certain extent by sulpiride) but not by prazosin, guanethidine, naloxone, atropine, propranolol, haloperidol, domperidone, clozapine, glibenclamide or caffeine. The carrageenan-evoked acute paw oedema was reduced by 19.2-21.2 and 17-18.6% by 3.6 and 7.2 mg/kg trimetazidine, respectively. The drug did not alter the oedema-suppressive effect of indomethacin or dexamethasone, but reduced that of rofecoxib. Trimetazidine at 7.2 mg/kg reduced immobility time in Porsolt's forced-swimming test by 28.9%. The acute gastric mucosal lesions evoked by indomethacin in the rat were inhibited in a dose-dependent manner by co-administration of trimetazidine. In anesthetized rats, trimetazidine potentiated the gastric acid secretory response. This study indicates that trimetazidine possesses antinociceptive and gastric protective properties. The antinociceptive properties of trimetazidine are likely to be centrally mediated, but do not involve opioid pathways.


Construction of pMEKm12, an expression vector for protein production in Pseudomonas syringae.
Characterization of the biological roles of proteins is essential for functional genomics of pseudomonads. Heterologous proteins overproduced in Escherichia coli frequently fail to exhibit biological function. To circumvent this problem, vector pMEKm12 was constructed and used to overexpress proteins in Pseudomonas. The vector contains the pRO1600 replication origin, the maltose-binding protein (MBP) fusion system, and an inducible tac promoter. The pMEKm12 was successfully used to overexpress the syringomycin synthetase SyrB1 protein fused to MBP in Pseudomonas syringae pv. syringae. Furthermore, expression of the MBP-SyrB1 protein in the syrB1 mutant BR132A1 resulted in the restoration of syringomycin production. This vector will facilitate confirmation of the biochemical roles of nonribosomal peptide synthetase genes in Pseudomonas syringae, and studies of gene function from a wide spectrum of pseudomonads.


An incremental EM-based learning approach for on-line prediction of hospital resource utilization.
Inpatient length of stay (LOS) is an important measure of hospital activity, health care resource consumption, and patient acuity. This research work aims at developing an incremental expectation maximization (EM) based learning approach on mixture of experts (ME) system for on-line prediction of LOS. The use of a batch-mode learning process in most existing artificial neural networks to predict LOS is unrealistic, as the data become available over time and their pattern change dynamically. In contrast, an on-line process is capable of providing an output whenever a new datum becomes available. This on-the-spot information is therefore more useful and practical for making decisions, especially when one deals with a tremendous amount of data. The proposed approach is illustrated using a real example of gastroenteritis LOS data. The data set was extracted from a retrospective cohort study on all infants born in 1995-1997 and their subsequent admissions for gastroenteritis. The total number of admissions in this data set was n = 692. Linked hospitalization records of the cohort were retrieved retrospectively to derive the outcome measure, patient demographics, and associated co-morbidities information. A comparative study of the incremental learning and the batch-mode learning algorithms is considered. The performances of the learning algorithms are compared based on the mean absolute difference (MAD) between the predictions and the actual LOS, and the proportion of predictions with MAD < or = 1 day (Prop(MAD < or = 1)). The significance of the comparison is assessed through a regression analysis. The incremental learning algorithm provides better on-line prediction of LOS when the system has gained sufficient training from more examples (MAD = 1.77 days and Prop(MAD < or = 1) = 54.3%), compared to that using the batch-mode learning. The regression analysis indicates a significant decrease of MAD (p-value = 0.063) and a significant (p-value = 0.044) increase of Prop(MAD < or = 1) with the incremental learning algorithm. The incremental learning feature and the self-adaptive model-selection ability of the ME network enhance its effective adaptation to non-stationary LOS data. It is demonstrated that the incremental learning algorithm outperforms the batch-mode algorithm in the on-line prediction of LOS.


Stereoselective bioreduction of bulky-bulky ketones by a novel ADH from Ralstonia sp.
Ketones with two bulky substituents, named bulky-bulky ketones, as well as less sterically demanding ketones were successfully reduced to the corresponding optically highly enriched alcohols using a novel identified recombinant short-chain alcohol dehydrogenase RasADH from Ralstonia sp. DSM 6428 overexpressed in E. coli.


Engineering Single Nanopores on Gold Nanoplates by Tuning Crystal Screw Dislocation.
Compared with the large variety of solid gold nanostructures, synthetic approaches for their hollow counterparts are limited, largely confined to chemical and irradiation-based etching of preformed nanostructures. In particular, the preparation of through nanopore structures is extremely challenging. Here, a unique strategy for direct synthesis of gold nanopores in solution without the need for sacrificial templates or postsynthesis processing is reported. By controlling the degree of crystal screw dislocation, a single through pore with diameter ranging from sub-nanometer to tens of nanometers, in the center of large gold nanoplates, can be engineered with precision. Ionic current rectification behaviors are observed using the gold nanopore, potentially enabling new capabilities in biosensing, sequencing, and imaging.


Laminin-511 and -521-based matrices for efficient ex vivo-expansion of human limbal epithelial progenitor cells.
Optimization of culture conditions for human limbal epithelial stem/progenitor cells (LEPC) that incorporate the in vivo cell-matrix interactions are essential to enhance LEPC ex vivo-expansion and transplantation efficiency. Here, we investigate the efficacy of laminin (LN) isoforms preferentially expressed in the limbal niche as culture matrices for epithelial tissue engineering. Analyses of expression patterns of LN chains in the human limbal niche provided evidence for enrichment of LN-α2, -α3, -α5, -β1, -β2, -β3, -γ1, -γ2 and -γ3 chains in the limbal basement membrane, with LN-α5 representing a signature component specifically produced by epithelial progenitor cells. Recombinant human LN-521 and LN-511 significantly enhanced in vitro LEPC adhesion, migration and proliferation compared to other isoforms, and maintained phenotype stability. The bioactive LN-511-E8 fragment carrying only C-terminal domains showed similar efficacy as full-length LN-511. Functional blocking of α3β1 and α6β1 integrins suppressed adhesion of LEPC to LN-511/521-coated surfaces. Cultivation of LEPC on fibrin-based hydrogels incorporating LN-511-E8 resulted in firm integrin-mediated adhesion to the scaffold and well-stratified epithelial constructs, with maintenance of a progenitor cell phenotype in their (supra)basal layers. Thus, the incorporation of chemically defined LN-511-E8 into biosynthetic scaffolds represents a promising approach for xeno-free corneal epithelial tissue engineering for ocular surface reconstruction.


Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect?
Cognitive impairment in schizophrenia is frequent, involves multiple domains, and is enduring. Numerous recent clinical trials have suggested that second-generation antipsychotic medications significantly enhance cognition in schizophrenia. However, none of these studies included healthy controls undergoing repeated testing to assess the possibility that improvements might reflect simple practice effects. To report the results on cognition of a randomized comparison of 2 widely prescribed second-generation antipsychotic medications, olanzapine and risperidone, in patients with first-episode schizophrenia and a healthy control group. Randomized clinical trial. Hospital-based research units. Patients A total of 104 participants with first-episode schizophrenia and 84 healthy controls. Cognitive assessment of all study participants occurred at baseline, 6 weeks later, and 16 weeks later. Neurocognitive tests included measures of working memory and attention, speed, motor function, episodic memory, and executive function. No differential drug effects were observed. Of 16 cognitive measures, 9 demonstrated improvement over time and only 2 demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment. The composite effect size for cognitive change was 0.33 in the healthy control group (attributed to practice) and 0.36 in the patients with first-episode schizophrenia. Improvements in cognition in the first-episode schizophrenia group could not be accounted for by medication dose, demographic variables, or intellectual level. The cognitive improvements observed in the trial were consistent in magnitude with practice effects observed in healthy controls, suggesting that some of the improvements in cognition in the first-episode schizophrenia group may have been due to practice effects (ie, exposure, familiarity, and/or procedural learning). Our results also indicated that differential medication effects on cognition were small. We believe that these findings have important implications for drug discovery and the design of registration trials that attempt to demonstrate cognitive enhancement.


Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures.
Farming has been associated with rheumatoid arthritis (RA), but the role of pesticides is not known. We examined associations between RA and pesticides or other agricultural exposures among female spouses of licensed pesticide applicators in the Agricultural Health Study. Women were enrolled between 1993 and 1997 and followed through 2010. Cases (n = 275 total, 132 incident), confirmed by a physician or by self-reported use of disease modifying antirheumatic drugs, were compared with noncases (n = 24,018). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusted for age, state, and smoking pack-years. Overall, women with RA were somewhat more likely to have reported lifetime use of any specific pesticide versus no pesticides (OR = 1.4; 95% CI: 1.0, 1.6). Of the 15 pesticides examined, maneb/mancozeb (OR = 3.3; 95% CI: 1.5, 7.1) and glyphosate (OR = 1.4; 95% CI: 1.0, 2.1) were associated with incident RA compared with no pesticide use. An elevated, but non-statistically significant association with incident RA was seen for DDT (OR = 1.9; 95% CI: 0.97, 3.6). Incident RA was also associated with the application of chemical fertilizers (OR = 1.7; 95% CI: 1.1, 2.7) and cleaning with solvents (OR = 1.6; 95% CI: 1.1, 2.4), but inversely associated with lifetime livestock exposure as a child and adult (OR = 0.48; 95% CI: 0.24, 0.97) compared with no livestock exposure. Our results suggest that specific agricultural pesticides, solvents, and chemical fertilizers may increase the risk of RA in women, while exposures involving animal contact may be protective. Citation: Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. 2016. Rheumatoid arthritis in Agricultural Health Study spouses: associations with pesticides and other farm exposures. Environ Health Perspect 124:1728-1734; http://dx.doi.org/10.1289/EHP129.