Lung cancer in a CF patient: combination of bad luck or is there more to say?
Patients with cystic fibrosis have increased risk for gastrointestinal cancer, lymphoid leukemia and testicular carcinomas. Chronic inflammation does not seem to be the only contributing factor. Mutations and epigenetic alterations in the CFTR gene may alter susceptibility to develop cancer. Lung cancer is up to now not frequently observed in CF patients. In lung cancer patients without CF low CFTR expression is significantly associated with advanced staging, lymph node metastasis. As the management and life expectancy of patients with cystic fibrosis have improved substantially in recent years, we expect an increased number of these patients diagnosed with lung cancer. In addition, it is possible that they, as a result of CFTR-dysfunction, will present with more aggressive lung tumors. Treating cancer in CF patients is a challenge because of multi-organ involvement and chronic colonization by resistant pathogens. The effectiveness and safety of immunotherapy in this population needs to be further evaluated.


Ligand regulation for manganese-catalyzed enantioselective epoxidation of olefins without acid.
A novel manganese catalyst bearing an l-proline-derived N4 ligand has been developed for enabling acid-free asymmetric epoxidation of olefins with tert-butyl hydroperoxide as the oxidant. A variety of olefins that are well-matched in size with the ligand pocket can be transformed to epoxides with excellent enantioselectivities. The smaller ligand pocket is also beneficial to the enantioselective epoxidation of simple olefins. Cryospray ionization mass spectrometry experiments reveal that a MnIV[double bond, length as m-dash]O species serves as an active epoxidizing species.


Diagnosis of the myeloproliferative disorders: resolving phenotypic mimicry.
With the exception of chronic myelogenous leukemia (CML), which is characterized by the constitutively active chimeric bcr-abl tyrosine kinase, the diagnosis of the myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET), and idiopathic myelofibrosis (IMF), is unaided by specific biologic markers and is complicated by phenotypic mimicry. Diagnosis is largely clinical with assistance from conventional laboratory techniques. Although the sine qua non of PV is erythrocytosis, survey data indicate that approximately 22% of American Society of Hematology members diagnose PV without the benefit of red blood cell mass and plasma volume measurements. These tests are essential in any suspected case of PV because erythrocytosis can be masked by an elevated plasma volume in this disorder. Recognition of defective platelet thrombopoietin receptor (Mpl) expression and overexpression of the PRV-1 gene in PV neutrophils has led to studies demonstrating the potential use of these molecular abnormalities as diagnostic markers for PV and for risk-stratifying patients with ET for disease conversion to PV or IMF. Enumeration of peripheral blood CD34(+) cells may prove useful in the diagnosis of IMF if current data regarding the disease-related specificity of this measurement are validated prospectively in larger numbers of patients.


Food safety guidance for older adults.
Aging is associated with loss of the physical barriers and immune efficiency that typically control pathogens' access to and multiplication within the body, thus making infection more likely in elderly persons. Chronic diseases and other health factors, such as malnutrition and immobility, may increase susceptibility to and severity of infections, including foodborne illnesses, in elderly persons, as well as associated morbidity and mortality. Prevention is the best way to avoid foodborne illnesses, but older adults have long-established food preparation and handling practices, some of which may increase the likelihood of illness. Elderly persons rely on physicians as trusted sources of health information. Physicians and other health care professionals can help prevent and control foodborne diseases by educating their patients about the risks of foodborne illness, providing sound advice on safe food-handling and consumption practices, making rapid appropriate diagnoses, and reporting cases promptly to public health authorities.


Persistent indocyanine green angiographic findings in multiple evanescent white dot syndrome.
This report describes unique findings of persistent peripapillary and posterior pole hypofluorescence on indocyanine green angiography (ICGA) in multiple evanescent white dot syndrome (MEWDS). A 38-year-old woman experienced a sudden decrease of visual acuity in the left eye. Multiple white lesions were seen on fundus examination. Fluorescein angiography, indocyanine green angiography, and automated perimetry were performed. Fundus appearance and fluorescein angiography were consistent with the diagnosis of MEWDS. Automated perimetry revealed an enlarged blind spot. ICGA revealed a zone of hypofluorescence surrounding the optic disc and throughout the posterior pole. The enlarged blind spot resolved after seven weeks along with the signs and symptoms of MEWDS. Nine months after initial presentation, ICGA revealed persistent peripapillary and posterior pole hypofluorescence. Resolution of the enlarged blind spot and return of vision does not completely correlate with the disappearance of hypofluorescent areas on ICGA. These findings suggest that MEWDS may result in persistent abnormalities in choroidal circulation even after clinical symptoms resolve.


Maturation, dystrophic changes and the continuous production of fibers in skeletal muscle regenerating in the absence of nerve.
To investigate how much skeletal muscle depends on influences coming from peripheral nerve, we studied muscle regeneration induced by bupivacaine in the permanently denervated soleus muscle of adult rats. Using light and electron microscopy, we studied the extent of maturation attained by regenerated myofibers and their ability to regenerate again after repeated bupivacaine injury. Morphometric analyses showed that within the first two weeks after injury, the regenerated denervated fibers increased in diameter, matured and then became atrophic. By electron microscopy the morphological characteristics of mature fibers are evident, but final differentiation into adult fiber types is not attained. This is in keeping with previously reported biochemical results. A new phase of massive regeneration occurred when bupivacaine treatment was repeated, thus demonstrating that regenerated myofibers devoid of innervation keep their intrinsic ability to regenerate after injury. Spontaneous though scanty regeneration also occurred in denervated regenerated muscle at late stages, when atrophy and dystrophy of fibers became prominent. Concomitantly the relative number of myosatellite cells remained high. These morphological observations further support the hypothesis that fiber regeneration participates in the maintenance of chronically denervated muscles.


Effect of soil potassium availability on soybean aphid (Hemiptera: Aphididae) population dynamics and soybean yield.
Studies were conducted to examine the effect of potassium (K) on soybean aphid, Aphis glycines Matsumura, population growth. A laboratory feeding assay examined the effect of K-deficient foliage on life table parameters of soybean aphids, and field experiments were designed to determine the effect of three soil K treatment levels on aphid populations and their impact on soybean yields. The feeding assay found that life table parameters differed between aphids feeding on the K-deficient and nondeficient soybean leaves. Soybean aphids in the K-deficient treatment exhibited significantly greater intrinsic rate of increase (r(m)), finite rate of increase (lambda), and net reproductive rate (Ro) relative to aphids feeding on nondeficient leaves. No significant difference was observed in mean generation time (T) between the two treatments. However, the field experiment repeated over 2 yr showed no effect of K on soybean aphid populations. Soybean aphid populations were high in unsprayed plots and feeding resulted in significant yield losses in 2002 at all three K treatment levels: when averaged across 2001 and 2002, unsprayed treatments yielded 22, 18, and 19.5% less than the sprayed plots in the low, medium, and high K treatments, respectively. No significant interaction was observed between aphid abundance and K level on soybean yields in either year. This study therefore suggests that although aphids can perform better on K-deficient plants, aphid abundance in the field may be dependent on additional factors, such as dispersal, that may affect final densities within plots.


Slip resistant properties of footwear on ice.
Current research on slipperiness of footwear has mainly focused on floors and lubricated floors. Slips and falls on icy and snowy surfaces involve not only outdoor workers, but also pedestrians and the general public; and occur in cold regions and in winter season in many parts of the world. However, in comparison with the size of the problem, research on slips and falls on icy and snowy surfaces has been scarce. The objective of this paper is to explore the slip resistant properties of footwear (soling materials, roughness and hardness) on ice. The coefficients of kinetic friction of four different soling materials (synthetic rubber, nitrile rubber, natural rubber and polyurethane) were measured on ice (-12 degrees C). The outsole roughness and hardness were also measured. Results showed that the polyurethane soling did not perform better than synthetic rubber, nitrile rubber and natural rubber on pure hard ice (-12 degrees C). Soling roughness was positively correlated with the coefficient of kinetic friction. The most slip resistant soling material (polyurethane) on floors and lubricated floors may not provide sufficient slip resistance on ice.


Reliability of selected antioxidants and compounds involved in one-carbon metabolism in two Dutch cohorts.
Many epidemiological studies assess nutritional status based on single blood measurements, without verifying if these remain reliable over repeated measurements. This study assessed the reliability over a period of 2 to 5 yr of plasma carotenoids, vitamin C, retinol, tocopherols, and serum compounds involved in 1-carbon metabolism in a subsample of Dutch participants of European Prospective Investigation into Cancer and Nutrition (EPIC). Blood samples from 38 men from MORGEN-EPIC and 35 women from Prospect-EPIC were collected between 1993 and 1997 and again after 2 to 5 yr. The reliability of plasma carotenoids, retinol, vitamin C, and tocopherols, and of serum folate, homocysteine, and vitamins B6 and B12 was estimated using an intraclass correlation coefficient (ICC). Serum homocysteine and vitamin B12 were highly reliable biomarkers, with ICCs of 0.91 and 0.75, respectively. All other analyzed biomarkers had a slight or fair reliability over several years (ICCs ranged from 0.17 to 0.56). Most examined biomarkers showed reliability values that may lead to considerable attenuation of the risk estimate when used as exposure assessment in a risk model. If multiple measurements are not available, the risk estimates can be adjusted for the regression dilution using the ICC as adjustment coefficient.


Age-Related Changes in Perirhinal Cortex Sensitivity to Configuration and Part Familiarity and Connectivity to Visual Cortex.
The perirhinal cortex (PRC) is a medial temporal lobe (MTL) structure known to be involved in assessing whether an object is familiar (i.e., meaningful) or novel. Recent evidence shows that the PRC is sensitive to the familiarity of both whole object configurations and their parts, and suggests the PRC may modulate part familiarity responses in V2. Here, using functional magnetic resonance imaging (fMRI), we investigated age-related decline in the PRC's sensitivity to part/configuration familiarity and assessed its functional connectivity to visual cortex in young and older adults. Participants categorized peripherally presented silhouettes as familiar ("real-world") or novel. Part/configuration familiarity was manipulated via three silhouette configurations: Familiar (parts/configurations familiar), Control Novel (parts/configurations novel), and Part-Rearranged Novel (parts familiar, configurations novel). "Real-world" judgments were less accurate than "novel" judgments, although accuracy did not differ between age groups. The fMRI data revealed differential neural activity, however: In young adults, a linear pattern of activation was observed in left hemisphere (LH) PRC, with Familiar > Control Novel > Part-Rearranged Novel. Older adults did not show this pattern, indicating age-related decline in the PRC's sensitivity to part/configuration familiarity. A functional connectivity analysis revealed a significant coupling between the PRC and V2 in the LH in young adults only. Older adults showed a linear pattern of activation in the temporopolar cortex (TPC), but no evidence of TPC-V2 connectivity. This is the first study to demonstrate age-related decline in the PRC's representations of part/configuration familiarity and its covariance with visual cortex.


Reclaiming the Stroop Effect Back From Control to Input-Driven Attention and Perception.
According to a growing consensus, the Stroop effect is understood as a phenomenon of conflict and cognitive control. A tidal wave of recent research alleges that incongruent Stroop stimuli generate conflict, which is then managed and resolved by top-down cognitive control. We argue otherwise: control studies fail to account for major Stroop results obtained over a century-long history of research. We list some of the most compelling developments and show that no control account can serve as a viable explanation for major Stroop phenomena and that there exist more parsimonious explanations for other Stroop related phenomena. Against a wealth of studies and emerging consensus, we posit that data-driven selective attention best accounts for the gamut of existing Stroop results. The case for data-driven attention is not new: a mere twenty-five years ago, the Stroop effect was considered "the gold standard" of attention (MacLeod, 1992). We identify four pitfalls plaguing conflict monitoring and control studies of the Stroop effect and show that the notion of top-down control is gratuitous. Looking at the Stroop effect from a historical perspective, we argue that the recent paradigm change from stimulus-driven selective attention to control is unwarranted. Applying Occam's razor, the effects marshaled in support of the control view are better explained by a selectivity of attention account. Moreover, many Stroop results, ignored in the control literature, are inconsistent with any control account of the effect.


What is the prognosis of revision total hip arthroplasty in patients 55 years and younger?
Revision THAs are expected to increase; however, few studies have characterized the prognosis of revision THAs in younger patients. We performed a case-control study to evaluate intermediate-term survivorship, complications, and hip and activity scores after revision THAs in patients 55 years and younger, compared these outcomes with the results of primary THAs in a matched patient population, and evaluated risk factors for failed revisions. Ninety-three patients (103 hips) had a minimum of 4 years after revision THA, died, or had rerevision surgery. They were matched with 98 patients (103 hips) with primary THAs. Survivorship, complications, and clinical outcomes were compared between the groups using t-tests. Risk factors for failure also were assessed with chi-square analysis. At mean followup of 6.7 years, 71 revision THAs (69%) survived, compared with 102 (99%) primary THAs (odds ratio [OR], 45.9; 95% CI, 16.5-128.4; p < 0.001). Complications occurred in 29% of the revision group and 6% of the primary group (OR, 6.64; 95% CI, 4.14-10.67; p < 0.001). After revision THA, the average improvement in Harris hip score was 19.2 compared with 34.4 after primary THA (p < 0.001). The UCLA activity score improved by an average of 0.87 after revision compared with 2.36 after primary THA (p < 0.001). Conventional polyethylene was associated with failure after revision THA (OR, 2.98; 95% CI, 1.87-4.76; p = 0.004). At intermediate-term followup, young patients undergoing revision THAs had markedly higher failure and complication rates and more modest clinical improvements compared with patients in a matched cohort who had primary THAs. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


Carbon-mixed dental cement for fixing fiber optic ferrules prevents visually triggered locomotive enhancement in mice upon optogenetic stimulation.
Optogenetics enables activation/silencing of specific neurons with unprecedented temporal and spatial resolution. The method, however, is prone to artefacts associated with biophysics of light used for illuminating opsin-expressing neurons. Here we employed Tph2-mhChR2-YFP transgenic mice, which express channelrhodopsin (ChR2) only in serotonergic neurons in the brain, to investigate behavioral effects of optogenetic stimulation of serotonergic neurons. Surprisingly, optogenetic stimulation enhanced locomotion even in ChR2-negative mice. Such unspecific effects are likely to be due to visual agitation caused by light leakage from the dental cement, which is commonly used to fixate optic fiber ferrules on the skull. When we employed black dental cement made by mixing carbons with dental cement powders, such unspecific effects were abolished in ChR2-negative mice, but not in ChR2-positive mice, confirming that enhanced locomotion resulted from serotonergic activation. The method allows extracting genuine behavioral effects of optogenetic stimulation without contamination from visual stimuli caused by light leakage.


Forecasting the onset of an allergic risk to poaceae in Nancy and Strasbourg (France) with different methods.
Pollen of Poaceae is among the most allergenic pollen in Europe with pollen of birch. It is therefore useful to elaborate models to help pollen allergy sufferers. The objective of this study was to construct forecast models that could predict the first day characterized by a certain level of allergic risk called here the Starting Date of the Allergic Risk (SDAR). Models result from four forecast methods (three summing and one multiple regression analysis) used in the literature. They were applied on Nancy and Strasbourg from 1988 to 2005 and were tested on 2006. Mean Absolute Error and Actual forecast ability test are the parameters used to choose best models, assess and compare their accuracy. It was found, on the whole, that all the models presented a good forecast accuracy which was equivalent. They were all reliable and were used in order to forecast the SDAR in 2006 with contrasting results in forecasting precision.


Students' experiences and perceptions of the use of portfolios in UK preregistration dietetic placements: a questionnaire-based study.
Reflective portfolios were introduced to dietetic practice placements in 2005, providing evidence for learning outcomes achieved and acting as a summative assessment tool. Portfolios may measure clinical competence more effectively than conventional examinations, but can be time consuming and subjective. The present study investigated current dietetic students' experiences and perceptions of the use and effectiveness of portfolio based learning and assessment during practice placements. Current UK dietetic students, who had completed a B or B and C placement, were invited to participate, via University course leaders, in an online questionnaire exploring opinions and experiences of portfolio preparation, generation, assessment, and personal and professional development and reflection. One hundred and fourteen students from 11 Universities participated. Seventy-seven percent would have liked more information about portfolio construction prior to placement. Eighty percent of students believed that reflection helped monitor their strengths and weaknesses. Perceived reflective skills were significantly positively correlated with students' perceived writing skills (P < 0.0005) and academic ability (P = 0.002). Of the respondents, 92% agreed the portfolio was a valuable learning experience; however, 76% agreed that the amount of paperwork involved was excessive and 67% felt there were inconsistencies in portfolio assessment by different supervisors. Portfolio weaknesses identified are not specific to dietetics but are inherent to portfolio assessment across many professions. The introduction of national standardised assessment processes, practices, tools and training for assessors may help improve inter-departmental and inter-rater reliability, respectively.


Stable low-pressure hydrogen clusters stored in a binary clathrate hydrate.
Thermodynamic, x-ray diffraction, and Raman and nuclear magnetic resonance spectroscopy measurements show that clusters of H2 can be stabilized and stored at low pressures in a sII binary clathrate hydrate. Clusters of H2 molecules occupy small water cages, whereas large water cages are singly occupied by tetrahydrofuran. The presence of this second guest component stabilizes the clathrate at pressures of 5 megapascals at 279.6 kelvin, versus 300 megapascals at 280 kelvin for pure H2 hydrate.


Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer.
We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was -1.8% in the SDG arm (P = 0.001) and -1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = -2.2%; P = 0.002) but not placebo (median = -1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.


Risk and pharmacoeconomic analyses of the injectable medication process in the paediatric and neonatal intensive care units.
To analyse safety risks in injectable medications. To assess the potential impact and pharmacoeconomic aspects of safety tools. The injectable drug process was prospectively assessed using a failure modes, effects and criticality analysis. Criticality indexes were estimated based on their likelihood of occurrence, detection probability and potential severity. The impact of 10 safety tools on the criticality index was calculated and extrapolated to all drugs injected daily. Yearly costs for a reduction in criticality by 1 point (=1 quali) per day were estimated. Paediatric and neonatal intensive care units in a University Hospital. Two paediatric nurses, a neonatologist, three hospital pharmacists. Qualitative and quantitative risk assessment. Failure modes, criticality indexes, cost-efficacy ratios. Thirty-one failure modes identified, with the mean of their entire criticality indexes totalling 4540. The most critical failure mode was microbial contamination. The following gains were predicted: 1292 quali (46 500 per day by extrapolation) from ready-to-use syringes, 1201 (72 060) by employing a clinical pharmacist, 996 (59 780) from double check by nurses and 984 (59 040) with computerized physician order entry. The best cost-efficacy ratios were obtained for a clinical pharmacist (1 quali = 0.54 euros), double check (1 quali = 0.71 euros) and ready-to-use syringes (1 quali = 0.72 euros). Computerized physician order entry showed the worst cost-efficacy ratio due to a very high investment costs (1 quali = 22.47 euros). Based on our risk and pharmacoeconomic analyses, clinical pharmacy and ready-to-use syringes appear as the most promising safety tools.


Food restriction-like effects of dehydroepiandrosterone: decreased lymphocyte numbers and functions with increased apoptosis.
Both dietary dehydroepiandrosterone (DHEA) and food restriction can prevent or modulate the initiation or progression of a number of diseases in rodents and prolong life span. We sought to determine if these interventions have common mechanisms of action in regulating lymphocyte functions and cell numbers. We observed that male C57BL/6 mice receiving DHEA in the diet (0.45%, w/w) ate approximately 50% as much food as mice on the DHEA-free diet, and this was reflected in decreased body weights throughout a 10-week period. Mice either fed the DHEA-containing diet or pair-fed to the DHEA-treated mice had decreased spleen and thymus weights and lymphocyte cell numbers compared to mice having free access to the control diet. Mice were fed these diets for 2 weeks before and 2 weeks after exposure to sublethal irradiation (500 cGy). In mice fed DHEA or pair-fed, there was a decrease in spleen cell numbers, and B cells were the most severely affected. The frequency of apoptosis in peripheral blood cells increased from <5% in nonirradiated controls to >50% within 4 days after starting DHEA or pair-feeding. Shortly after irradiation, >87% of blood lymphocytes were hypodiploid (apoptotic) in all groups. By 9 days only 27% of lymphocytes in mice on the control diet were hypodiploid compared to 62% in DHEA and 74% in pair-fed mice. In addition, both DHEA and pair-fed mice had significant reductions in T-cell function (contact hypersensitivity to dinitrofluorobenzene), B cell function (antibody response to trinitrophenolated-lipopolysaccharide), and NK cell function (lung clearance of radiolabeled YAC-1 tumor cells) 2 weeks after irradiation. In a complementary study, peripheral blood lymphocytes from naïve mice were treated overnight with various concentrations of either DHEA or hydrocortisone 21-acetate. Only glucocorticoid-treated cells underwent apoptosis. Thus, DHEA induces apoptosis in vivo but not in vitro. We conclude that dietary DHEA induces apoptosis and decreased lymphocyte production and function in C57BL/6 mice largely by reducing food intake.


Does physical activity affect the predictive value of health-related fitness tests on walking difficulty?
Low levels of physical activity (PA) and poor fitness tend to predict a decline in mobility. The current study investigated whether PA modifies the predictive value of health-related fitness (HRF) tests on difficulty in walking 2 km (WD). PA was assessed by self-reported questionnaires in 1990 and 1996. Subjects age 55 to 69 years and free of self-reported WD participated in assessment of HRF in 1996. Occurrence of WD was assessed by questionnaire in 2002 (n=537). There were no statistically significant interactions between PA and HRF tests; thus, PA and HRF were both independent predictors of WD. Regardless of the PA level, the subjects in the poorest performing third in each HRF test had higher risk of WD than the subjects in the best performing third. PA and HRF seemed to be independent predictors of WD, although the association of PA with WD was weaker than the association of HRF. Thus, PA did not modify the predictive value of HRF on WD.


30S subunit recognition and G1405 modification by the aminoglycoside-resistance 16S ribosomal RNA methyltransferase RmtC.
Acquired ribosomal RNA (rRNA) methylation has emerged as a significant mechanism of aminoglycoside resistance in pathogenic bacterial infections. Modification of a single nucleotide in the ribosome decoding center by the aminoglycoside-resistance 16S rRNA (m7G1405) methyltransferases effectively blocks the action of all 4,6-deoxystreptamine ring-containing aminoglycosides, including the latest generation of drugs. To define the molecular basis of 30S subunit recognition and G1405 modification by these enzymes, we used a S-adenosyl-L-methionine analog to trap the complex in a postcatalytic state to enable determination of a global 3.0 Å cryo-electron microscopy structure of the m7G1405 methyltransferase RmtC bound to the mature Escherichia coli 30S ribosomal subunit. This structure, together with functional analyses of RmtC variants, identifies the RmtC N-terminal domain as critical for recognition and docking of the enzyme on a conserved 16S rRNA tertiary surface adjacent to G1405 in 16S rRNA helix 44 (h44). To access the G1405 N7 position for modification, a collection of residues across one surface of RmtC, including a loop that undergoes a disorder-to order transition upon 30S subunit binding, induces significant distortion of h44. This distortion flips G1405 into the enzyme active site where it is positioned for modification by two almost universally conserved RmtC residues. These studies expand our understanding of ribosome recognition by rRNA modification enzymes and present a more complete structural basis for future development of strategies to inhibit m7G1405 modification to resensitize bacterial pathogens to aminoglycosides.


The effects of radio frequency ablation on renal function and blood pressure.
Radio frequency ablation (RFA) is evolving as a nephron sparing treatment alternative for select patents with small renal tumors. The impact of ablated tissue on the remaining kidney parenchyma is unknown. To assess this impact we evaluated pretreatment and posttreatment serum creatinine (sCr), and blood pressure of patients treated with RFA with at least 6 months of followup. From our series of 69 tumors treated with RFA 25 patients with a total of 26 tumors and a minimum 6-month followup were identified. RFA was delivered percutaneously or laparoscopically depending on tumor location and patient preference. Blood pressure measurements and sCr levels were obtained at preoperative and postoperative office visits. Values for preoperative and postoperative systolic blood pressure, diastolic pressure and sCr were each compared. Estimated creatinine clearance was calculated for each patient before and after treatment, and compared. No patient experienced new onset hypertension or worsening of existing hypertension. Likewise no changes in mean sCr and estimated creatinine clearance were observed. Treatment with RFA does not appear to have an effect on renal function or blood pressure. RFA appears to be a medically safe therapy for patients with small renal tumors.


Causes of delayed diagnosis of scapular fractures.
To study the causes of delayed diagnosis of scapular fractures in blunt trauma cases, and to advise on early fracture detection. Between February 2003 and September 2004, 64 consecutive patients (3 females) with a median (range) age of 35 (8-60) years, treated at Al-Ain Hospital for scapular fractures, were prospectively collected. Fractures diagnosed after more than 24h from admission were considered missed; 8 people with missed scapular fractures were compared with a control group of 56 who had timely diagnosis, regarding the mechanism and distribution of injury, injury severity score, and type and quality of radiological methods used. The median (range) abbreviated injury scale scores for the missed scapular fracture group and the control group were 4 (0-5) and 2 (0-2), respectively. The missed scapular fracture group stayed significantly longer in the intensive care unit compared with the control group, with a median (range) stay of 15 (5-37) days compared with 9 (1-26) days. Associated injuries overshadowed the scapula on chest trauma radiographs. If computed tomography did not cover the whole scapula, some fractures might not be shown. Convulsive seizures were the only significantly different mechanism of injury between the missed fracture and the control groups. Delayed diagnosis of scapular fractures can be due to extensive chest injuries overshadowing the scapula on the chest trauma radiographs, inappropriately performed computer tomography or an unusual mechanism of injury.


Race by sex differences in depression symptoms and psychosocial service use among non-Hispanic black and white patients with lung cancer.
This study examined race by sex differences in depression symptoms and psychosocial service use (pastors, social workers, mental health workers, support groups) among patients with lung cancer. The multiregional Cancer Care Outcomes Research and Surveillance study surveyed black and white adults with stages I to III lung cancer (n = 1,043) about depression symptoms, interest in help for mood, and psychosocial service use. Multivariable logistic regression was used to evaluate race/sex differences in depression symptoms (modified Center for Epidemiologic Studies Depression Scale ≥ 6) and psychosocial service use, independent of demographic, clinical, psychosocial, and behavioral covariates. A total of 18.2% screened positive for depression symptoms. This proportion was highest among black men (24.7%), followed by white women (20.6%), black women (15.8%), and white men (15.0%). In adjusted analyses, white women showed greater risk for depression symptoms relative to black women (P = .01) and white men (P = .002), with no other differences among groups. Black patients were less likely than white patients to receive desired help for mood from their doctors (P = .02), regardless of sex. Among all patients, black women were most likely to have contact with pastoral care and social work. Race and sex interacted to predict risk of depression symptoms. Covariates accounted for elevated risk among black men. White women showed greater risk than black women and white men, independent of covariates. Black patients may experience greater barriers to receiving help for mood from their doctors. Race by sex differences in contact with psychosocial services highlight potential differences in the extent to which services are available, acceptable, and/or sought by patients.


Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic.
Glioblastoma, the most common primary malignant brain tumor, is among the most difficult cancers to treat. Despite the aggressive standard of care, including surgical removal followed by radiotherapy with concomitant and adjuvant chemotherapy, the often sudden onset, diffuse infiltrating nature and highly malignant features of the lesion result in a median overall survival of < 15 months. Currently employed standard- of-care therapy for glioblastoma is nonspecific, leading to premature withdrawal of treatment due to off-target toxicity. Rindopepimut is a peptide-based vaccine that elicits a potent humoral and cellular immune response specifically against cells expressing EGFRvIII, a rearranged, cell-surface tyrosine kinase receptor present exclusively in glioblastoma and other common neoplasms. Several phase I and phase II clinical trials have demonstrated that vaccination with rindopepimut is safe, well tolerated and produces a highly potent immune response that effectively eradicates EGFRvIII-expressing tumor cells, leading to a 73% increase in survival among patients with newly diagnosed glioblastoma. Furthermore, temozolomide-induced lymphopenia enhances the rindopepimut-induced immune response against EGFRvIII, allowing for enhanced vaccination responses in the context of standard-of-care chemotherapy. Rindopepimut is currently undergoing evaluation in a phase III international trial for newly diagnosed glioblastoma and is under clinical investigation for recurrent glioblastoma and pediatric brain stem gliomas.


The organ allocation controversy: how did we arrive here?
The Department of Health and Human Services (HHS) recently issued a final regulation governing the Organ Procurement and Transplantation Network (OPTN) that directs the allocation of organs to the sickest patients first without regard to a host of medical, geographic, and social factors that members of the transplant community view as an essential part of a sound organ allocation policy.Current organ allocation mechanisms are based on policies that reflect a broad consensus of medical experts and provide equal consideration for both the needs of the sickest patients and the efficient use of organs. This system also reduces potential waste of organs by minimizing cold ischemic time, increases access to transplantation for patients in local communities, provides positive incentives for local citizens and medical professionals to support organ donation initiatives, and decreases the cost of organ transplantation.Representatives of the American Society of Transplant Surgeons have testified before Congress that "giving priority to the sickest patients first over broad geographic areas would be wasteful and dangerous, resulting in fewer patients transplanted, increased death rates, increased retransplantation due to poor organ function, and increased overall cost of transplantation." In response, Congress enacted a 1-year moratorium on the implementation of the HHS rule and provided for a study of the current organ allocation policy and HHS regulation by The Institute of Medicine.


Uric acid as a marker for renal dysfunction in hypertensive women on diuretic and nondiuretic therapy.
Hyperuricemia is a common finding in hypertensive patients, especially among those who are on diuretic therapy. However, its clinical relevance regarding cardiovascular and chronic kidney disease (CKD) has not clearly been established. The authors assessed whether, in a population of 385 hypertensive women categorized according to diuretic therapy, the stratification in quartiles by uric acid levels would identify a gradient of changes in renal function and in risk factors for cardiovascular disease. The following were evaluated: serum uric acid, glycemia, total and fractional cholesterol, triglycerides, apolipoprotein (Apo) B, Apo A-I, and C-reactive protein. Renal function was assessed by serum creatinine, albuminuria, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation, whereas cardiovascular risk was estimated through the Framingham score. A total of 246 women were on diuretic therapy; 139 were taking other antihypertensive medications. There was a reduction in eGFR parallel to the increase in uric acid levels, regardless of diuretic use and without a concomitant increase in albuminuria. In both groups, higher uric acid levels translated into an increase in metabolic syndrome components, in markers of insulin resistance, triglyceride / high-density lipoprotein levels, and Apo B/Apo A-I ratios, as well as in Framingham scores. Hyperuricemia was associated with an increase in inflammatory markers only in patients on diuretic therapy. In a binary logistic regression, hyperuricemia (uric acid >6.0 mg/ dL) was independently associated with CKD (eGFR <60 mL/ min / 1.73 m(2)) (odds ratio, 2.63; 95% confidence interval, 1.61-4.3; P<.001). In hypertensive women, the presence of hyperuricemia indicated a substantial degree of kidney dysfunction as well as a greater cardiovascular risk profile.


Breast Cancer Survivorship: Patient Characteristics and Plans for High-Quality Care.
The number of breast cancer survivors has increased and this increase is expected to continue, likely as a result of population and age growth, the implementation of earlier detection strategies, and the development of more effective therapies. Breast cancer treatment requires a multidisciplinary approach with surgery, radiation, chemotherapy, targeted therapy, and hormonal therapy. Breast cancer survivors may develop various long-term adverse effects from these therapies. Care of the survivor may transition eventually to the primary care physician. Survivorship care plans have been developed to facilitate care transition, guide the content and coordination of posttreatment care, and engender greater self-management of health by cancer survivors. Guidelines for posttreatment follow-up care are discussed in this article, and interventions that patients may practice to promote a healthy lifestyle also are presented.


[Absorptive capacity of upper gastrointestinal tract with Chinese herbal medicine].
285 reports on the intoxication of Chinese herbal medicine per os were reviewed. The toxic symptoms occurred after oral administration for less than 10 min in about 110 reports. Some components of these herbal medicines might be absorbed and then reach effective level more rapidly. By segmental ligation of GI tract, experiments in rabbits, cats, rats or mice were conducted, in which principal ingredients of Rheum palmatum, Coptis chinensis, Veratrum nigrum, and aconitine were absorbed in esophagus or stomach within short period of time was observed. It suggested that the absorptive capacity of upper GI tract might have universal significance. The treatment of acute diseases by oral administration of Chinese herbal medicines is feasible.


Prognostic Significance of Tumor Regression in Locally Advanced Rectal Cancer after Preoperative Radiochemotherapy.
The majority of rectal cancers are discovered in locally advanced forms (UICC stage II, III). Treatment consists of preoperative radiochemotherapy, followed by surgery 6-8 weeks later and finally by postoperative chemotherapy. The aim of this study was to find out if tumor regression affected long-term survival in patients with localy advanced rectal cancer, treated with neoadjuvant radiochemotherapy. Patients with rectal cancer stage II or III, treated between 2006 and 2010, were included in a retrospective study. Clinical and pathohistologic data were acquired from computer databases and information about survival from Cancer Registry. Survival was estimated according to Kaplan-Meier method. Significance of prognostic factors was evaluated in univariate analysis; comparison was carried out with log-rank test. The multivariate analysis was performed according to the Cox regression model; statistically significant variables from univariate analysis were included. Two hundred and two patients met inclusion criteria. Median follow-up was 53.2 months. Stage ypT0N0 (pathologic complete response, pCR) was observed in 14.8% of patients. Pathohistologic stage had statistically significant impact on survival (p = 0.001). 5-year survival in patients with pCR was>90%. Postoperative T and N status were also found to be statistically significant (p = 0.011 for ypT and p < 0.001 for ypN). According to multivariate analysis, tumor response to neoadjuvant therapy was the only independent prognostic factor (p = 0.003). Pathologic response of tumor to preoperative radiochemotherapy is an important prognostic factor for prediction of long-term survival of patients with locally advanced rectal cancer.


Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells.
Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.


Adrenergic reactions of sheep rumen in vivo.
Pharmacodynamical analysis of alpha-adrenergic and beta-adrenergic reactions of sheep rumen was performed in vivo after administration of agonists and antagonists of alpha-adrenergic and beta-adrenergic receptors. It was found that phenylephrine, and in a lower degree propranolol, stimulated the motor activity of sheep rumen, while adrenaline, noradrenaline, isoprenaline, phenoxybenzamine and regitine depressed this activity. Propranolol abolished atonia produced by catecholamines in sheep rumen, and previous blockade of beta-adrenergic receptors with propranolol reversed the relaxing action of catecholamines on the muscular elements in the rumen. The experiments in vivo confirmed the adrenergic effects on the motor activity of the rumen of sheep obtained in earlier investigations on isolated muscles of the rumen. It is suggested that noradrenaline exerts an ambireceptro effect (similar to that of adrenaline) on the motor activity in sheep rumen.


Hovenia dulcis Thunb. and its active compound ampelopsin inhibit angiogenesis through suppression of VEGFR2 signaling and HIF-1α expression.
Specific inhibition of angiogenesis has been considered a powerful strategy for the treatment of cancer and other angiogenesis-related human diseases. Hovenia dulcis Thunb., Japanese raisin tree or Oriental raisin tree, is a hardy tree found in Asia, Eastern China and Korea and has been known to possess various biological activities, including antifatigue, antidiabetic, neuroprotective and hepatoprotective activity. In the present study, for the first time, we evaluated whether a 100% ethanol extract of Hovenia dulcis Thunb. (HDT) inhibits the angiogenesis of human umbilical vein endothelial cells (HUVECs) using in vitro angiogenesis assays. HDT suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion and tube formation of HUVECs at subtoxic doses. In addition, HDT significantly inhibited in vivo angiogenesis of the chorioallantoic membrane from growing chick embryos without exhibiting cytotoxicity. Furthermore, HDT downregulated not only VEGF receptor 2 (VEGFR2) signaling in HUVECs, but also hypoxia-inducible factor (HIF)-1α expression in hepatocarcinoma cell line HepG2. Ampelopsin is a bioactive flavanonol found in Hovenia dulcis Thunb. Our data showed that ampelopsin inhibited angiogenesis with no cytotoxicity by suppressing both VEGFR2 signaling and HIF-1α expression. These results suggest that Hovenia dulcis Thunb. and its active compound ampelopsin exhibit potent antiangiogenic activities and therefore could be valuable for the prevention and treatment of angiogenesis-related diseases including cancer.


A polyunsaturated fatty acid diet lowers blood pressure and improves antioxidant status in spontaneously hypertensive rats.
gamma-Linolenic acid [GLA, 18:3(n-6)], eicosapentaenoic acid [EPA, 20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)] have been reported to prevent cardiovascular diseases. However, they are highly unsaturated and therefore more sensitive to oxidation damage. We investigated the effects of a diet rich in these polyunsaturated fatty acids (PUFA) on blood pressure, plasma and lipoprotein lipid concentrations, total antioxidant status, lipid peroxidation and platelet function in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Five-week-old SHR and WKY rats were fed for 10 wk either a diet containing Isio 4 oil or a diet rich in GLA, EPA and DHA (5.65, 6.39 and 4.94 g/kg dry diet, respectively). The total antioxidant status was assayed by monitoring the rate of free radical-induced hemolysis. VLDL-LDL sensitivity to copper-induced lipid peroxidation was determined as the production of thiobarbituric acid reactive substances. After dietary PUFA supplementation, a significant decrease in blood pressure of SHR rats (-20 mm Hg) was observed and the total antioxidant status was enhanced. VLDL-LDL resistance to copper-induced peroxidation was increased in both strains. The PUFA supplementation did not change platelet maximum aggregation in SHR rats, but it decreased the aggregation speed. In hypertensive rats, GLA + EPA + DHA supplementation lowers blood pressure, enhances total anti-oxidant status and resistance to lipid peroxidation, diminishes platelet aggregation speed and lowers plasma lipid concentrations. Thus, it enhances protection against cardiovascular diseases. Therefore, nutritional recommendations for cardiovascular disease prevention should take into account the pharmacologic properties of GLA, EPA and DHA.


Subtractive hybridization yields a silver resistance determinant unique to nosocomial pathogens in the Enterobacter cloacae complex.
The heterogeneity and the increasing clinical importance of the Enterobacter cloacae complex have often been discussed. However, little is known about molecular factors causing pathogenicity within this nomenspecies. Here, we analyzed the genetic differences between an avirulent plant isolate and a pathogenic strain causing an outbreak with septicemia in three patients. We identified an IncHI-2 plasmid as a major difference between these two strains. Besides resistance to several antibiotics, this plasmid encoded a silver resistance determinant. We further showed that this sil determinant was present not only in the analyzed outbreak strain but also in the vast majority of clinical isolates of the E. cloacae complex, predominantly in (sub)species that frequently cause nosocomial infections. The identified sil determinant was highly conserved within the E. cloacae complex and mediated resistance to up to 600 μM silver nitrate. As silver is often used as a disinfectant and treatment for burn wounds, we present here an important fitness factor within the clinically most prevalent subspecies of the E. cloacae complex. This provides a possible explanation for their unequal involvement in nosocomial and especially burn wound infections.


Marginal zinc intake reduces the protective effect of lactation on mammary gland carcinogenesis in a DMBA-induced tumor model in mice.
Breastfeeding can reduce breast cancer risk; however, unknown factors modify this protective effect. Zinc (Zn) modulates an array of cellular functions including oxidative stress, cell proliferation, motility and apoptosis. Marginal Zn intake is common in women and is associated with breast cancer. We reported that marginal Zn intake in mice leads to mammary gland hypoplasia and hallmarks of pre-neoplastic lesions. In the present study, we tested the hypothesis that marginal Zn intake confounds the protective effect of lactation on breast cancer. Nulliparous mice fed control (ZA, 30 mg Zn/kg) or a marginal Zn diet (ZD, 15 mg Zn/kg), were bred and offspring were weaned naturally. Post-involution, mice were gavaged with corn oil or 7,12-dimethylbenz(a)anthracene (DMBA, 1 mg/wk for 4 weeks) and tumor development was monitored. A ZD diet led to insufficient involution, increased fibrosis and oxidative stress. Following DMBA treatment, mice fed ZD had higher oxidative stress in mammary tissue that correlated with reduced levels of peroxiredoxin-1 and p53 and tended to have shorter tumor latency and greater incidence of non-palpable tumors. In summary, marginal Zn intake creates a toxic mammary gland microenvironment and abrogates the protective effect of lactation on carcinogenesis.


Assessment of monacolin in the fermented products using Monascus purpureus FTC5391.
Monacolins, as natural statins, form a class of fungal secondary metabolites and act as the specific inhibitors of HMG-CoA reductase. The interest in using the fermented products as the natural source of monacolins, instead of statin drugs, is increasing enormously with its increasing demand. In this study, the fermented products were produced by Monascus purpureus FTC5391 using submerged and solid state fermentations. Two commercial Monascus-fermented products were also evaluated for comparison. Improved methods of monacolins extraction and identification were developed for the assessment of monacolins in the fermented products. Methanol and ethanol were found to be the most favorable solvents for monacolins extraction due to their ability to extract higher amount of monacolin K and higher numbers of monacolin derivatives. Problem related to false-positive results during monacolins identification was solved by adding monacolin lactonization step in the assessment method. Using this improved method, monacolin derivatives were not detected in all Monascus-fermented products tested in this study, suggesting that their hypocholesterolemic effects may be due to other compounds other than monacolins.


Analysis of the appropriate age and weight for pediatric patient sedation for magnetic resonance imaging.
Sedatives with a long duration are required for pediatric magnetic resonance imaging (MRI) in the emergency department. The success rate of chloral hydrate for pediatric sedation is 80% to 100% according to some studies. However, the success rate varies by age, weight, and underlying disease. To identify factors affecting the success rate, we compared the chloral hydrate sedation success rate and adverse event rate by age, weight, and underlying disease. Compared with patients in the failure group, patients in the successful group were younger (23.8 vs 36.9 months, P < .01) and weighed less (11.4 vs 14.4 kg, P < .01). No differences in neurological problems, reasons for MRI, or adverse events were observed between the 2 groups. Patients 18 months old had a success rate greater than 95%, but the success rate decreased in children older than 18 months. The adverse event rate was about 10% in patients 18 months old and increased to 20% in patients older than 36 months. Patients 24 months of age who had a neurological problem (seizure disorder or developmental delay) had a success rate greater than 95%, but the adverse event rate increased after 24 months of age. Chloral hydrate sedation was appropriate for pediatric MRI in patients younger than 18 months. Although we observed no fatal adverse events, it is necessary to monitor patients until full recovery from sedation.


[Empirical, free of genetic model, estimation of recurrence risks in multifactorial diseases: conditional probability approach].
Conditional probability approach in estimation of recurrence risks in sibships of different parental phenotypic matings with the different set of affected and normal siblings is considered. The formulae are presented for calculation of recurrence risks in cases of equal and different susceptibility of two sexes under different ways of sampling of family data: direct selection of offsprings through the parents; indirect selection of offsprings through affected siblings--the probands, under different ascertainment probability--from pi = 1.0 ("exhaustive selection") up to pi----0 ("single selection"); for the case of different susceptibility of the two sexes a possibility of the differences in the ascertainment probabilities of men (pi m) and of women (pi w) is allowed, unlike "independent ascertainment model", which requires the constancy of pi. The case of multiple incompatible subforms is considered for estimation of the recurrence risks of the specified subforms. The methods of the risks estimation proposed are free of genetic models being universal both for classical mendelian traits (with the constant risks) and for multifactorial ones (with variable risks).


A high-accuracy theoretical study of the CH(n)P systems n = 1-3.
We have performed high-level electronic structure computations on the most important species of the CH(n)P systems n = 1-3 to characterize them and provide reliable information about the equilibrium and vibrationally averaged molecular structures, rotational constants, vibrational frequencies (harmonic and anharmonic), formation enthalpies, and vertical excitation energies. Those chemical systems are intermediates for several important reactions and also prototypical phosphorus-carbon compounds; however, they are often elusive to experimental detection. The present results significantly complement their knowledge and can be used as an assessment of the experimental information when available. The explicitly correlated coupled-cluster RCCSD(T)-F12 method has been used for geometry optimizations and vibrational frequency calculations. Vibrational configuration interaction theory has been used to account for anharmonicity effects. Basis-set limit extrapolations have been carried out to determine accurate thermochemical quantities. Electronic excited states have been calculated with coupled-cluster approaches and also by means of the multireference configuration interaction method.


[Mutagenicity of rice-straw and -husk ashes by Ames test].
In the rice-producing district of Japan, environmental pollution by smoke from burnt rice straws has become a matter of concern. The mutagenicity of fly- and bottom-ashes of rice-straw and -husk was assayed by the Ames test, TA100 +/- S9 and TA98 +/- S9, and the relationship of combustion temperature to mutagenicity was investigated. Fly ash showed weak mutagenicity at 300 degrees C, with no remarkable change in mutagenic activity between 300 degrees C and 500 degrees C. Above 500 degrees C the mutagenic activity increased with a rise of temperature. The increasing rate of mutagenicity was much higher in the test system with S9 mix than that without S9. Moreover, the mutagenicity with TA100 was stronger than with TA98. With respect to bottom ash, weak mutagenic activity was observed at 300 degrees C, but at 400 degrees C decreased and at 500 degrees C or above could not be observed. Fly ash derived from burning 1 g of rice straw at 600 degrees C showed about 14 times and 2.5 times higher mutagenicity than main stream smoke condensates from the burning of 1 g of cigarette in TA100 + S9 and TA98 + S9 test systems respectively.


Postural Disorders and Antiparkinsonian Treatments in Parkinson Disease: An Exploratory Case-Control Study.
The aim of this study was to evaluate the relationship between antiparkinsonian treatments, especially dopamine agonist (DAs) and the development of postural disorders in patients with Parkinson's disease (PD). We performed an exploratory case-control study. Cases were PD patients with camptocormia, Pisa syndrome, or anterocollis. Control subjects were PD patients without postural disorders matched by sex and age. Demographic and clinical data including pharmacologic treatments history were collected retrospectively. Characteristics of cases and control subjects were compared using parametric and nonparametric tests accordingly, and logistic regression models were used to analyze correlations. We included 63 patients with PD and postural disorders and 63 control subjects. Cases were more exposed to DAs (74.60% vs 58.73%, P = 0.05) and amantadine (30.16% vs 7.94%, P < 0.05) than control subjects. Cases showed longer disease duration (7.63 ± 7.83 vs 4.27 ± 3.87 years, P < 0.05), higher Hoehn and Yahr stage (2.83 ± 0.80 vs 2.15 ± 0.73, P < 0.05), higher Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score (29.61 ± 1.39 vs 20.76 ± 10.94, P = 0.05), and more dyslipidemia (28.57% vs 12.70%, P < 0.05) than control subjects, as well as lower prevalence of depression (46.03% vs 28.57%, P < 0.05). We found no clinical predictors for the development of postural disorders after multivariable adjusted regression. Our results suggest a possible association between the use of DAs and amantadine and the development of postural disorders in PD and suggest potential risk factors including advanced disease and more severe motor symptoms. These results support the need of a cautious use of these medications in patients with advanced disease due to the possibility of increasing the risk-benefit ratio.


Single-dose pharmacokinetics of ceftibuten (SCH 39720) in infants and children.
Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12- to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cmax) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (+/- standard deviations) were as follows: apparent elimination half-life, 2.0 +/- 0.5 h; mean residence time, 3.9 +/- 1.1 h; apparent steady-state volume of distribution, 0.4 +/- 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 +/- 0.9 ml/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to less than or equal 5 years of age (3.1 +/- 1.1 ml/min/kg) than in children > 10 years of age (2.0 +/- 0.6 ml/min/kg; P < 0.005). The increased CL/f for CFB (3.0 +/- 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (1.0 +/- 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 +/- 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.


Structure-function analysis of hepatitis C virus envelope-CD81 binding.
Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease. We have recently found that the large extracellular loop (LEL) of human CD81 binds HCV. This finding prompted us to assess the structure-function features of HCV-CD81 interaction by using recombinant E2 protein and a recombinant soluble form of CD81 LEL. We have found that HCV-E2 binds CD81 LEL with a K(d) of 1.8 nM; CD81 can mediate attachment of E2 on hepatocytes; engagement of CD81 mediates internalization of only 30% of CD81 molecules even after 12 h; and the four cysteines of CD81 LEL form two disulfide bridges, the integrity of which is necessary for CD81-HCV interaction. Altogether our data suggest that neutralizing antibodies aimed at interfering with HCV binding to human cells should have an affinity higher than 10(-9) M, that HCV binding to hepatocytes may not entirely depend on CD81, that CD81 is an attachment receptor with poor capacity to mediate virus entry, and that reducing environments do not favor CD81-HCV interaction. These studies provide a better understanding of the CD81-HCV interaction and should thus help to elucidate the viral life cycle and to develop new strategies aimed at interfering with HCV binding to human cells.


Cellular uptake and reactive oxygen species modulation of cerium oxide nanoparticles in human monocyte cell line U937.
Cerium oxide nanoparticles (nanoceria) are promising materials for intracellular oxygen free radical scavenging providing a potential therapy for reactive oxygen species (ROS)-mediated inflammatory processes. In this study rhombohedral-shaped nanoceria were synthesized by flame spray pyrolysis with tuneable particle diameters between 3 and 94 nm by changing the liquid precursor flow rate. Monocytes and macrophages are major players in inflammatory processes as their production of ROS species has important downstream effects on cell signalling. Therefore, this study examined the ability of the nanoceria to be internalised by the human monocytic cell line, U937, and scavenge intracellular ROS. U937 cells activated in the presence of phorbol 12-myristate 13-acetate (PMA) were found to be more responsive to the nanoceria than U937 cells, which may not be surprising given the role of monocyte/macrophages in phagocytosing foreign material. The smaller particles were found to contain more crystal lattice defects with which to scavenge ROS, however a greater proportion of both the U937 and activated U937 cell populations responded to the larger particles. Hence all nanoceria particle sizes examined in this study were equally effective in scavenging intracellular ROS.


Primary hyperparathyroidism with cardiac abnormalities: a case report.
Primary hyperparathyroidism, characterized by hypersecretion of parathyroid hormone (PTH) leading to hypercalcemia and relative hypophosphatemia, is quite common in the elderly. Most patients with primary hyperparathyroidism have only mild hypercalcemia and are symptomless. But others experience various other organ diseases. Primary hyperparathyroidism is also associated with cardiovascular abnormalities, including QT interval shortening, heart block, cardiac arrhythmias, hypertension, myocardial hypertrophy, myocardial calcification and, though rarely, with valvular heart disease. We described a case of primary hyperparathyroidism associated with cardiac abnormalities. An 82-year-old male presented with the complaints of chest discomfort, fatigue, general weakness, nausea and vomiting over a period of months and was admitted in July 1996. Physical examination with heart auscultation showed a pansystolic murmur over the right sternal border and apex region, and a blowing diastolic murmur over the left sternal border. Biochemistry profiles revealed elevations of serum calcium (14.3 mg/dl) and chloride/phosphate ratio (> 33). Endocrinological studies showed elevations of serum PTH-C (4.8 ng/ml) and PTH-intact (705 pg/ml) concentrations. Kidney ultrasonography revealed a left renal stone. A spine X-ray revealed spondylosis and a compression fracture of the lumbar-spine with osteoporotic change. Thyroid ultrasonography and Thallium (Tl201)-technetium (Tc99m) subtraction scan showed parathyroid adenoma in the low pole of the right thyroid bed. Parathyroid aspiration cytology revealed few and discrete cells. Echocardiogram revealed moderate to severe aortic valvular calcification as well as stenosis with moderate aortic regurgitation, mitral regurgitation and myocardial calcification. The patient received parathyroidectomy one month later. During his postoperative days, he suffered from muscle twitching with positive Trousseau's sign and Chvostek's sign. The patient received calcium carbonate and vitamin D for hypocalcemia, diltiazem and capoten for his heart problems. A repeated echocardiogram two months after surgery showed no improvement of valvular calcification.


Neuropsychological outcome in adolescents/young adults with childhood ADHD: profiles of persisters, remitters and controls.
This study examined neuropsychological functioning in a longitudinal sample of adolescents/young adults with attention deficit/hyperactivity disorder (ADHD) and controls as a function of the persistence of ADHD. We hypothesized that measures of executive processes would parallel adolescent clinical status, with ADHD-persisters, but not remitters, differing significantly from controls. In contrast, persisters and remitters were hypothesized to perform similarly, and different from controls, on tasks requiring less effortful processing. Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, and sex distribution served as a comparison group. Participants were administered a psychiatric interview and neuropsychological test battery. Those with childhood ADHD demonstrated broad neuropsychological deficits relative to controls. When the group with childhood ADHD was subdivided based on adolescent ADHD status, compared to controls, both persisters and remitters showed deficient perceptual sensitivity and response variability, and increased ankle movements recorded by a solid-state actigraph. Only persisters differed from controls on several measures of more effortful executive processes. Findings provide preliminary support to the hypothesis that ADHD is associated with early-appearing and enduring subcortical dysfunction, while recovery over the course of development is associated with improvements in executive control functions.


Microbial and chemical markers: runoff transfer in animal manure-amended soils.
Fecal contamination of water resources is evaluated by the enumeration of the fecal coliforms and Enterococci. However, the enumeration of these indicators does not allow us to differentiate between the sources of fecal contamination. Therefore, it is important to use alternative indicators of fecal contamination to identify livestock contamination in surface waters. The concentration of fecal indicators (, enteroccoci, and F-specific bacteriophages), microbiological markers (Rum-2-bac, Pig-2-bac, and ), and chemical fingerprints (sterols and stanols and other chemical compounds analyzed by 3D-fluorescence excitation-matrix spectroscopy) were determined in runoff waters generated by an artificial rainfall simulator. Three replicate plot experiments were conducted with swine slurry and cattle manure at agronomic nitrogen application rates. Low amounts of bacterial indicators (1.9-4.7%) are released in runoff water from swine-slurry-amended soils, whereas greater amounts (1.1-28.3%) of these indicators are released in runoff water from cattle-manure-amended soils. Microbial and chemical markers from animal manure were transferred to runoff water, allowing discrimination between swine and cattle fecal contamination in the environment via runoff after manure spreading. Host-specific bacterial and chemical markers were quantified for the first time in runoff waters samples after the experimental spreading of swine slurry or cattle manure.


[Therapy of Parkinson disease. 1: Standard therapy of motor and non-motor symptoms].
Early diagnosis is important for satisfactory pharmacotherapy of idiopathic Parkinson's disease (PD). L-Dopa therapy is still the gold standard in the treatment of PD, but due to complications of long term L-Dopa application, a combination therapy of levodopa with various dopamine agonists and putative neuroprotective drugs, like e.g. selegiline, is becoming increasingly important and attracts more and more attention, especially in the early phases of PD. Moreover, disturbances of the autonomic nervous system and the mind have to be considered and treated besides pharmacotherapy of motor symptoms in idiopathic Parkinson's disease (PD). Hypersalivation, seborrhoea, dysregulation of the cardiovascular system and disturbances of gastrointestinal and bladder motility and sleep are common mainly in the context of autonomic failure in PD. Moreover, Parkinsonian patients often complain of psychopathological features like depression, dementia and psychosis, which may also be due to dopaminergic Parkinsonian therapy. This review surveys possible therapeutic approaches of these disturbances of the psyche and the autonomic nervous system in PD.


Intracellular fate of carbon nanotubes inside murine macrophages: pH-dependent detachment of iron catalyst nanoparticles.
Carbon nanotubes (CNT) are a family of materials featuring a large range of length, diameter, numbers of walls and, quite often metallic impurities coming from the catalyst used for their synthesis. They exhibit unique physical properties, which have already led to an extensive development of CNT for numerous applications. Because of this development and the resulting potential increase of human exposure, an important body of literature has been published with the aim to evaluate the health impact of CNT. However, despite evidences of uptake and long-term persistence of CNT within macrophages and the central role of those cells in the CNT-induced pulmonary inflammatory response, a limited amount of data is available so far on the CNT fate inside macrophages. Therefore, the overall aim of our study was to investigate the fate of pristine single walled CNT (SWCNT) after their internalization by macrophages. To achieve our aim, we used a broad range of techniques that aimed at getting a comprehensive characterization of the SWCNT and their catalyst residues before and after exposure of murine macrophages: X-ray diffraction (XRD), High Resolution (HR) Transmission Electron Microscopy (TEM), High Angle Annular Dark Field-Scanning TEM (HAADF-STEM) coupled to Electron Energy Loss Spectroscopy (EELS), as well as micro-X-ray fluorescence mapping (μXRF), using synchrotron radiation. We showed 1) the rapid detachment of part of the iron nanoparticles initially attached to SWCNT which appeared as free iron nanoparticles in the cytoplasm and nucleus of CNT-exposed murine macrophages, and 2) that blockade of intracellular lysosomal acidification prevented iron nanoparticles detachment from CNT bundles and protected cells from CNT downstream toxicity. The present results, while obtained with pristine SWCNT, could likely be extended to other catalyst-containing nanomaterials and surely open new ways in the interpretation and understanding of CNT toxicity.


Correlation between the BACTEC MGIT 960 culture system with Genotype MTBDRplus and TB-SPRINT in multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil.
The accurate detection of multidrug-resistant tuberculosis (MDR-TB) is critical for the application of appropriate patient treatment and prevention of transmission of drug-resistant Mycobacterium tuberculosis isolates. The goal of this study was to evaluate the correlation between phenotypic and molecular techniques for drug-resistant tuberculosis diagnostics. Molecular techniques used were the line probe assay genotype MTBDRplus and the recently described tuberculosis-spoligo-rifampin-isoniazid typing (TB-SPRINT) bead-based assay. Conventional drug susceptibility testing (DST) was done on a BACTECTM MGIT 960 TB. We studied 80 M. tuberculosis complex (MTC) clinical isolates from Minas Gerais state, of which conventional DST had classified 60 isolates as MDR and 20 as drug susceptible. Among the 60 MDR-TB isolates with MGIT as a reference, sensitivity, specificity, accuracy, and kappa for rifampicin (RIF) resistance using TB-SPRINT and MTBDRplus, were 96.7% versus 93.3%, 100.0% versus 100.0%, 97.5% versus 95.0% and 0.94 versus 0.88, respectively. Similarly, the sensitivity, specificity, accuracy, and kappa for isoniazid (INH) resistance were 85.0% and 83.3%, 100.0% and 100.0%, 88.8% and 87.5% and 0.74 and 0.71 for both tests, respectively. Finally, the sensitivity, specificity, accuracy, and kappa for MDR-TB were 85.0% and 83.3%, 100.0% and 100.0%, 88.8% and 87.5% and 0.74 and 0.71 for both tests, respectively. Both methods exhibited a good correlation with the conventional DST. We suggest estimating the cost-effectiveness of MTBDRplus and TB-SPRINT in Brazil.


Assessment of GABAA benzodiazepine receptor (GBzR) sensitivity in patients with alcohol dependence.
The aim of this study was to measure GABAA benzodiazepine receptor (GBzR) sensitivity in alcohol-dependent patients and compare with matched non-dependent drinkers. Nine abstinent alcohol-dependent male patients, age matched with nine male non-dependent social drinkers, received an intravenous infusion of midazolam. Objective (saccadic eye movement slowing) and subjective (visual analogue scales) measurements were recorded at 15-min intervals for 2 h. There were no differences in objective or subjective measures. Our hypothesis that patients with alcohol dependence would have less slowing of their eye movements in response to this challenge, reflecting reduced GBzR sensitivity, was not confirmed. The reasons for this could mean that GBzR function returns to normal with abstinence, or that this paradigm is unable to measure the subtle subtype-specific changes in GBzR sensitivity that occur following dependent alcohol use.


The DNMT3A R882H mutant displays altered flanking sequence preferences.
The DNMT3A R882H mutation is frequently observed in acute myeloid leukemia (AML). It is located in the subunit and DNA binding interface of DNMT3A and has been reported to cause a reduction in activity and dominant negative effects. We investigated the mechanistic consequences of the R882H mutation on DNMT3A showing a roughly 40% reduction in overall DNA methylation activity. Biochemical assays demonstrated that R882H does not change DNA binding affinity, protein stability or subnuclear distribution of DNMT3A. Strikingly, DNA methylation experiments revealed pronounced changes in the flanking sequence preference of the DNMT3A-R882H mutant. Based on these results, different DNA substrates with selected flanking sequences were designed to be favored or disfavored by R882H. Kinetic analyses showed that the R882H favored substrate was methylated by R882H with 45% increased rate when compared with wildtype DNMT3A, while methylation of the disfavored substrate was reduced 7-fold. Our data expand the model of the potential carcinogenic effect of the R882H mutation by showing CpG site specific activity changes. This result suggests that R882 is involved in the indirect readout of flanking sequence preferences of DNMT3A and it may explain the particular enrichment of the R882H mutation in cancer patients by revealing mutation specific effects.


Team effectiveness model for science (TEMS): Using a mutual learning shared mindset to design, develop, and sustain science teams.
In this paper, we introduce the Team Effectiveness Model for Science (TEMS) and describe a multiphase set of interventions for forming a new team or developing an existing team. TEMS uses a shared mutual learning mindset as the model's central and guiding element. It shows how team mindset leads to behavior and to results and how this affects the characteristics of effective team functioning. TEMS addresses two related questions: What are the variables that contribute to effective teams? and How do the variables need to be designed to make their relevant contributions? Team models often answer the first question without fully answering the second. By addressing three gaps, TEMS contributes to enhancing science team effectiveness. Gap 1 is the absence of explicit core values, assumptions, and norms that serve as the foundation for developing and maintaining science team effectiveness. Gap 2 is the absence of a process for integrating the science and relationship aspects of a science team. Gap 3 is the absence of team processes and structures that are derived from the team's values, assumptions, and norms. Using TEMS to design new or intervene with existing teams focuses on shifting mindset, developing behavioral skills, and designing processes and structures congruent with the new mindset.


Intraocular pressure following intravitreal injection of triamcinolone acetonide.
To investigate the intraocular pressure (IOP) response following intravitreal injection of triamcinolone acetonide. This retrospective consecutive non-comparative case series study included 41 patients (52 eyes) (19 male, 22 female, mean age 64.1 ± 13.44; range 22 - 85 years) with progressive exudative ARMD (n = 10 eyes) or diffuse diabetic macular oedema (42 eyes), who received one or more intravitreal injection(s) of 4 mg triamcinolone acetonide. IOP increased significantly (p<0.001) from 16.08 (±3.28) mm Hg (range 12-26 mm Hg) preoperatively to a mean maximum of 26.1 (±11.79) mmHg (range 15-80 mm Hg) postoperatively (p<0.001). An IOP rise to values higher than 21 mm Hg was observed in 28 (53.8%) eyes. Elevation of IOP occurred 7.5 weeks (±7.07) after the injection. All five patients (11.9%) with a family history of glaucoma developed an IOP rise above the mean maximum level. The post-injection rise of IOP was statistically independent of gender (p=0.37), but the presence of diabetes mellitus demonstrated a marked influence on the rate of a postoperative elevation of IOP (p=0.05). The IOP response following IVTA was consistent with previous studies. A family history of glaucoma and a history of diabetes mellitus may predispose patients to a greater than average IOP rise following IVTA. Careful IOP assessment for at least 6 months post injection is recommended.


Photoactivation enhances the mitochondrial toxicity of the cationic rhodacyanine MKT-077.
In this study, the mitochondrial phototoxicity of the cationic rhodacyanine MKT-077 was investigated by comparing its effects on the inhibition of mitochondrial respiration and the structural integrity of mitochondrial DNA (mtDNA) in the presence and absence of added high-intensity visible light (7.5 J/cm2). Results indicate that photoirradiation significantly enhances the mitochondrial toxicity of MKT-077 at both the biochemical and DNA levels. For example, the concentration of MKT-077 required to achieve one-half maximal inhibition of ADP-stimulated respiration was observed to be 6-fold lower in the presence versus absence of high-intensity light (one-half maximal inhibition at 2.5 versus 15 microg MKT-077/ mg, respectively). In addition, photoirradiation produced a 25-fold increase in inhibition of succinate-cytochrome c reductase activity by MKT-077 (one-half maximal inhibition at 2 versus 50 microg MKT-077/ml, +/-light, respectively) and a 6-fold increase in inhibition of cytochrome oxidase activity (one-half maximal inhibition at 5 versus 30 microg MKT-077/ml, +/-light, respectively). Furthermore, the combination of 25 microg/ml MKT-077 and 7.5 J/cm2 visible light caused significant degradation of mtDNA in isolated rat liver mitochondria, whereas the same concentration of dye in the absence of light had only a modest effect on mtDNA. Evaluation of light-induced MKT-077 lipid peroxidation in mitochondrial membrane fragments by the thiobarbituric acid test and by measurement of nonrespiratory-linked oxygen uptake suggests that mitochondrial phototoxicity by MKT-077 may be the result of lipid peroxidation via reactive oxygen species. These results have important implications with regard to the potential use of MKT-077 in photochemotherapy.


Delayed skin hypersensitivity reaction in normal children.
The delayed skin hypersensitivity reaction was assessed in normal children using candida, PPD and sterptokinase/streptodornase antigens. There was an increase in reactivity from 20 percent in children under three years to 90 percent in the 12--16 age group which approximates adult levels. The conclusion is that this test of cell-mediated immunity is unsatisfactory in young children.


[Vaccination against IBR: a recommendation for dairy herds].
In view of the results of previous serological studies on the presence of SN antibodies to IBR virus in a minimum of ten per cent of the herd, the following procedure is suggested: (1) Vaccination of serologically negative herds in areas menaced by IBR virus. (2) Vaccination of IBR-negative groups of animals in herds in which serologically IBR-positive animals are present. When sampling shows that IBR-negative animals are present in every age group, vaccination of the entire herd should be contemplated. (3) Vaccination of all animals which are added to dairy herds including animals showing antibodies to IBR virus.


Hematology of neonatal Japanese quail.
The hematologic development of Japanese quail was studied as a function of time through the first 49 hr post-hatching. Packed cell volumes, hemoglobin levels, erythrocyte and leukocyte numbers, as well as differential percentages of lymphocytes, heterophils, basophils, eosinophils, and monocytes were determined. Additionally, the mean corpuscular volumes, mean corpuscular hemoglobins, and mean corpuscular hemoglobin concentrations were calculated. Of particular interest are the increasing mean corpuscular volume and the increasing number of erythrocytes which were observed as the birds aged. Between the 13th and 19th hr after hatching, an almost 2-fold increase in the erythrocyte number was detected with a concomitant decrease in the mean corpuscular volume. These findings indicate that the state of the hematologic system in quail is highly dependent on the stage of post-embryonic maturation.


Avascular Necrosis Is Associated With Increased Transfusions and Readmission Following Primary Total Hip Arthroplasty.
Avascular necrosis (AVN) may confer an increased risk of complications and readmission following total hip arthroplasty (THA). However, current risk-adjustment models do not account for AVN. A total of 1706 patients who underwent THA for AVN from 2011 to 2013 were selected from the American College of Surgeon's National Surgical Quality Improvement Program database and matched 1:1 to controls using a predetermined propensity score algorithm. Rates of 30-day medical and surgical complications, readmissions, and reoperations were compared between cohorts. Propensity-score logistic regression was used to determine independent associations between AVN and outcomes of interest. Patients with AVN had a higher rate of medical complications than those without AVN (20.3% vs 15.3%, respectively; P<.001). Bleeding transfusion was the most common medical complication, occurring at a significantly higher rate in patients with AVN than those without AVN (19.6% vs 13.9%, respectively; P<.001). Patients with AVN were also twice as likely to experience a readmission after THA (odds ratio, 2.093; 95% confidence interval, 1.385-3.164). Avascular necrosis of the femoral head is an independent risk factor for transfusion up to 72 hours postoperatively and readmission up to 30 days following total hip replacement. [Orthopedics. 2017; 40(3):171-176.].


Regulation of TL antigen expression. Analysis of the T18d promoter region and responses to IFN-gamma.
Type I (alpha/beta) and type II (gamma) IFN enhance MHC class I gene expression through an IFN-responsive element (IRE) present in the 5' flanking region of the class I-a genes. Comparison of the 5' sequences between classical class I-a genes and T region class I-b genes reveals little homology except for presence of a potential IRE. We have found that cell surface expression of thymus leukemia Ag (TL) was up-regulated by IFN-gamma to a greater extent than H-2K,D in all TL+ T cell lines tested. In contrast, IFN-alpha/beta, which significantly increased H-2K and H-2D Ag expression, had only minor effects on TL expression. Resting peripheral T cells, which were considered to be TL- from previous studies, were found to express TL at a low level as determined by flow cytometry, immunoprecipitation, as well as polymerase chain reaction; the level of expression also could be elevated by IFN-gamma. To examine the control of TL gene transcription and its regulation by IFN-gamma, varying lengths of the T18d 5' flanking region were analyzed in chloramphenicol acetyl transferase assays. By deletion analysis, promoter activity and IFN-gamma responsiveness were localized to an 86-bp fragment that contains the IRE. Both responses were localized further to a 32-bp fragment that contained the IRE at its 3' end. RNase protection assays revealed two major transcription initiation sites, one immediately 5' of the IRE and another approximately 60 bp downstream. Furthermore, polymerase chain reaction analysis of mRNA from resting T cells, thymocytes, and T cell tumor lines confirmed the RNase protection data. Thus, transcription of T18d initiates much further upstream than the classical class I genes, can utilize an unusual promoter element, and can be elevated by IFN-gamma.


Cancer immunotherapy with mRNA-transfected dendritic cells.
Bone marrow-derived dendritic cells (DCs) are the most potent antigen-presenting cells capable of activating naïve T cells. Loading DCs ex vivo with tumor antigens can stimulate potent antitumor immunity in tumor-bearing mice. This review describes the use of mRNA-encoded tumor antigens as a form of antigen loaded onto DCs, including our early experience from clinical trials in urological cancers. Transfection of DCs with mRNA is simple and effective. Comparative studies suggest that mRNA transfection is superior to other antigen-loading techniques in generating immunopotent DCs. The ability to amplify RNA from microscopic amounts of tumor tissue extends the use of DC vaccination to virtually every cancer patient. The striking observation from two phase I clinical trials, in patients with prostate cancer immunized with prostate-specific antigen mRNA-transfected DCs and patients with renal cancer immunized with autologous tumor RNA-transfected DCs, was that the majority of patients exhibited a vaccine-induced T-cell response. Suggestive evidence of clinically related responses was seen in both the trials. Immunization with mRNA-transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.


Theophylline disposition in cystic fibrosis.
The disposition of intravenously and orally administered theophylline was compared in 10 patients with cystic fibrosis (CF) and 10 healthy volunteers. The mean total body clearance of the patients with CF was twice that of the control subjects (p less than 0.001). The volume of distribution of theophylline was also greater in the patients with CF (p less than 0.05). These observations indicate that if theophylline is used in patients with CF, doses larger than those commonly given to asthmatics may be required to maintain therapeutic serum concentrations.


Male sex workers' (in)visible risky bodies in international health development: now you see them, now you don't.
International health development discourse constructs and regulates male sex workers as risky bodies in need of interventions for HIV. Drawing on ethnographic research among male sex workers and interviews with development sector actors in Nairobi, Kenya, this paper shows how the identification of male sex workers as a high-risk group for HIV offers a singular conceptualisation of their bodies as risky and renders invisible broader everyday struggles for security and wellbeing. Within these everyday struggles, male sex workers experience bodily risk as they are exposed not only to HIV, but also to being outed or outing themselves as gay. Interview findings show that development actors recognise and are empathic to male sex workers' security risks but have limited opportunity to address these due to restrictive donor regimes. To contribute to enduring change and develop appropriate and effective programmes, it is important for donors to continue funding HIV activities in relation to male sex work, while broadening their understandings of risk.


Stanniocalcin 2 alters PERK signalling and reduces cellular injury during cerulein induced pancreatitis in mice.
Stanniocalcin 2 (STC2) is a secreted protein activated by (PKR)-like Endoplasmic Reticulum Kinase (PERK) signalling under conditions of ER stress in vitro. Over-expression of STC2 in mice leads to a growth-restricted phenotype; however, the physiological function for STC2 has remained elusive. Given the relationship of STC2 to PERK signalling, the objective of this study was to examine the role of STC2 in PERK signalling in vivo. Since PERK signalling has both physiological and pathological roles in the pancreas, STC2 expression was assessed in mouse pancreata before and after induction of injury using a cerulein-induced pancreatitis (CIP) model. Increased Stc2 expression was identified within four hours of initiating pancreatic injury and correlated to increased activation of PERK signalling. To determine the effect of STC2 over-expression on PERK, mice systemically expressing human STC2 (STC2Tg) were examined. STC2Tg pancreatic tissue exhibited normal pancreatic morphology, but altered activation of PERK signalling, including increases in Activating Transcription Factor (ATF) 4 accumulation and autophagy. Upon induction of pancreatic injury, STC2Tg mice exhibited limited increases in circulating amylase levels and increased maintenance of cellular junctions. This study links STC2 to the pathological activation of PERK in vivo, and suggests involvement of STC2 in responding to pancreatic acinar cell injury.


The cryoprotectant trehalose could inhibit ERS-induced apoptosis by activating autophagy in cryoprotected rat valves.
Valvular diseases are common health problems that are strongly related to high morbidity and mortality; aortic valve allograft transplantation may be a promising way to improve survival and relieve symptoms. However, ideal tissue viability has not been observed with common valve cryopreservation methods, which could lead to apoptosis and necrosis in cryopreserved tissue. It has been observed that trehalose plays a positive role by acting to maintain cell structures and protect cells from stress responses. In this study, we studied the effects of trehalose in protecting rat valve tissue from the cooling process. We found improved higher cell function in rat valves treated with trehalose during cryopreservation than in those treated with dimethyl sulphoxide (DMSO). To further explore the mechanisms, we found that trehalose could down-regulate the expression of cleaved caspase-3, an important molecule involved in cell apoptosis. In addition, treatment with trehalose also decreased Glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP), the key proteins in the endoplasmic reticulum stress (ERS) process. Intriguingly, we observed that trehalose promotes cryoprotected rat valve cell autophagy via an mTOR-independent but p38 MAPK-dependent signaling pathway. Additionally, miR-221 and miR-32 have been implicated in such cell activities. In summary, our study offers a new and meaningful cryopreservation approach for valve allograft storage.


Genotypic resistance profile of HIV-1 protease gene: a preliminary report from Vellore, south India.
HIV-1 subtypes other than B are responsible for most new HIV infections worldwide; virus sequence data for drug resistance is described only from a limited number of non-B subtype HIV-1. This study is on mutations and polymorphisms of HIV-1 protease gene that can predict drug resistance in subtype C. The genotypic resistance assay was carried out on 38 HIV-1 strains with their plasma RNA and in nine, the proviral protease gene was sequenced. The treatment naïve strains showed minor resistance mutations, there were no major resistance mutations in the protease gene. We suggest the use of resistance testing to monitor individuals on therapy and also before initiation of therapy, gathering more sequence information for a data bank of Indian strains.


Collaboration of Dental Hygiene and Nursing Students on Hospital Units: An Interprofessional Education Experience.
The aims of this study were to implement and evaluate an innovative collaborative event with hospitalized patients to help develop dental hygiene and nursing students' interprofessional competence. The Interprofessional Collaborative Competency Attainment Survey (ICCAS) was used to assess the students' perceptions of interprofessional skill acquisition. Participants were 24 dental hygiene and 25 nursing students at the University of Southern Indiana in spring 2016. The results showed that all students had statistically significant improvement on the ICCAS items from pretest to posttest. There were no significant differences in improvement between the two groups on any single posttest item as the impact of the responses was similar. These results suggest that incorporating collaborative experiences in hospital settings can be an effective means to develop students' skills in interprofessional competence.