Pathways for cervical metastasis in malignant neoplasms of the head and neck region.
There have been significant changes in the evaluation and management of lymphatic metastases in the neck during the past several decades, and knowledge of the functional anatomy of the cervical lymphatics is fundamental to the clinical management of metastasis in this region. This review provides a comprehensive description of the cervical lymphatics and discusses how this knowledge is used in the modern management of the neck lymphatics in the setting of common cancers of the head and neck. The patterns of tumor spread can be delineated based on the well-studied functional anatomy of the lymphatic networks in the cervical region. The characteristics and patterns of metastatic spread for two common cancers found in this region, squamous cell carcinoma and cutaneous malignant melanoma, are discussed in this review. Significant improvements in clinical care, namely, selective neck dissection and sentinel lymph node biopsy aided by lymphoscintigraphy, have been developed and are based upon detailed studies of the pathways of metastatic spread. These advances have significantly decreased the morbidity associated with the evaluation and treatment of metastatic disease to the neck.


Up-regulation of cyclooxygenase-2 expression in lymphocytic thyroiditis and thyroid tumors: significant correlation with inducible nitric oxide synthase.
To cast light on relations of cyclooxygenase-2 (COX-2) expression to lymphocytic thyroiditis and thyroid tumorigenesis, protein levels were immunohistochemically assessed and compared with inducible nitric oxide synthase (iNOS) in a total of 181 cases: follicular adenoma, 23; well-differentiated papillary carcinoma, 85; poorly differentiated papillary carcinoma, 25; anaplastic carcinoma, 7; and follicular carcinoma, 41. In addition, 72 specimens of normal follicular epithelia and 36 of lymphocytic thyroiditis were used as control samples. Immunohistochemical results were confirmed in 2 cases each of normal thyroid, lymphocytic thyroiditis, and well-differentiated and poorly differentiated papillary carcinoma, by Western blotting assay. Stepwise increments in overexpression of COX-2 and iNOS were revealed in epithelial cells of lymphocytic thyroiditis, follicular adenoma, and papillary carcinoma; normal thyroid epithelium showed little expression. A significant positive correlation between the 2 enzymes was found with all cases. Enhanced expression of both COX-2 and iNOS suggests important roles in the inflammatory processes underlying lymphocytic thyroiditis and thyroid tumorigenesis.


Intraocular Pressure Reduction by Femtosecond Laser Created Trabecular Channels in Perfused Human Anterior Segments.
This study investigated the initial feasibility of using femtosecond laser trabeculotomy (FLT) to create open channels through the trabecular meshwork into Schlemm's canal to lower intraocular pressure (IOP) in a perfused anterior segment model. Human anterior segments (12 eyes) were assigned to either treatment (n = 6) or sham treatment (n = 6) groups. Both groups were perfused until a baseline IOP was recorded upon which a direct FLT treatment or a sham treatment was administered. IOP was recorded before and after the treatment. Spectral domain optical coherence tomography and second harmonic generation imaging we used to investigate the FLT channels. In the FLT group, there was a significant mean decrease in the IOP of 22% compared with the pre-FLT IOP (7.13 ± 2.95 mm Hg to 5.34 ± 1.62 mm Hg; P < 0.05). In the control group, the post-sham IOP remained relatively unchanged compared with the pre-sham IOP (6.39 ± 3.69 mm Hg to 6.67 ± 4.12 mm Hg). The results of this study indicate that FLT treatment can significantly decrease the IOP in a perfusion model and may provide a potential noninvasive treatment option for primary open angle glaucoma. Investigating the use of femtosecond lasers for photodisrupting the trabecular meshwork can lead to a clinically relevant alternative to current glaucoma procedures.


Does the eHealth Literacy Scale (eHEALS) measure what it intends to measure? Validation of a Dutch version of the eHEALS in two adult populations.
The Internet increases the availability of health information, which consequently expands the amount of skills that health care consumers must have to obtain and evaluate health information. Norman and Skinner in 2006 developed an 8-item self-report eHealth literacy scale to measure these skills: the eHealth Literacy Scale (eHEALS). This instrument has been available only in English and there are no data on its validity. The objective of our study was to assess the internal consistency and the construct and predictive validity of a Dutch translation of the eHEALS in two populations. We examined the translated scale in a sample of patients with rheumatic diseases (n = 189; study 1) and in a stratified sample of the Dutch population (n = 88; study 2). We determined Cronbach alpha coefficients and analyzed the principal components. Convergent validity was determined by studying correlations with age, education, and current (health-related) Internet use. Furthermore, in study 2 we assessed the predictive validity of the instrument by comparing scores on the eHEALS with an actual performance test. The internal consistency of the scale was sufficient: alpha = .93 in study 1 and alpha = .92 in study 2. In both studies the 8 items loaded on 1 single component (respectively 67% and 63% of variance). Correlations between eHEALS and age and education were not found. Significant, though weak, correlations were found between the eHEALS and quantity of Internet use (r = .24, P = .001 and r = .24, P = .02, respectively). Contrary to expectations, correlations between the eHEALS and successfully completed tasks on a performance test were weak and nonsignificant: r = .18 (P = .09). The t tests showed no significant differences in scores on the eHEALS between participants who scored below and above median scores of the performance test. The eHEALS was assessed as unidimensional in a principal component analysis and the internal consistency of the scale was high, which makes the reliability adequate. However, findings suggest that the validity of the eHEALS instrument requires further study, since the relationship with Internet use was weak and expected relationships with age, education, and actual performance were not significant. Further research to develop a self-report instrument with high correlations with people's actual eHealth literacy skills is warranted.


The Geshiyaro Project: a study protocol for developing a scalable model of interventions for moving towards the interruption of the transmission of soil-transmitted helminths and schistosome infections in the Wolaita zone of Ethiopia.
National deworming programmes rely almost exclusively on mass drug administration (MDA) to children to control morbidity caused by these parasitic infections. The provision of other interventions, consisting of preventive chemotherapy at high population level coverage together with water, sanitation and hygiene (WaSH) and changes in risk behaviour, should enable sustainable control of soil-transmitted helminths (STH) and schistosomiasis and ultimately interrupt transmission. Two interventions will be implemented by the project: (i) community-wide biannual albendazole and annual praziquantel treatment with a target of 80-90% treatment coverage ("expanded MDA"); and (ii) provision of WaSH with behaviour change communication (BCC), within the Wolaita zone, Ethiopia. The project has three study arms: (i) expanded community-wide MDA, WaSH and BCC; (ii) expanded community-wide MDA only; and (iii) annual school-based MDA (the current National STH/schistosomiasis Control Programme). The impact of these interventions will be evaluated through prevalence mapping at baseline and endline (after four rounds of MDA), combined with annual longitudinal parasitological surveillance in defined cohorts of people to monitor trends in prevalence and reinfection throughout the project. Treatment coverage and individual compliance to treatment will be monitored by employing fingerprint biometric technology and barcoded identification cards at treatment. WaSH utilisation will be evaluated through school and household level observations and annual WaSH assessment survey. Complementary qualitative surveys will explore practices, cultural and social drivers of risk behaviours, uptake of WaSH and treatment, and assessing the impact of the BCC. The study has the potential to define an 'End Game' for STH and schistosomiasis programmes through provision of multiple interventions. Interrupting transmission of these infections would eliminate the need for long-term repeated MDA, lead to sustained health improvements in children and adults, thereby allowing health systems to focus on other disease control priorities.


Methods of analysis for anthocyanins in plants and biological fluids.
Anthocyanins are the largest group of water-soluble pigments in the plant kingdom. They are responsible for most of the red, blue, and purple colors of fruits, vegetables, flowers, and other plant tissues or products. The analysis of anthocyanins is complex as a result of their ability to undergo structural transformations and complexation reactions. In addition, they are difficult to measure independently of other flavonoids, as they have similar structural and reactivity characteristics. Anthocyanins are generally extracted with weakly acidified alcohol-based solvents, followed by concentration (under vacuum), and purification of the pigments. Paper and/or thin-layer chromatography and UV-Vis spectroscopy have traditionally been used for the identification of anthocyanins. Capillary zone electrophoresis, a hybrid of chromatography and electrophoresis, is gaining popularity for the analysis of anthocyanins; however, liquid chromatography (LC) has become the standard method for identification and separation in most laboratories and may be used for both preparative and quantitative analysis. LC with mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are possibly the most powerful methods for the structural elucidation of anthocyanins available, to date. At present, the most satisfactory method for mixture analysis is the multistep method of separation, isolation, and quantification by LC with peak identification by MS and high-field NMR.


Effect of proximal phalangeal epiphysiodesis in the treatment of macrodactyly.
The recommended treatment for macrodactyly of the foot will often include epiphysiodesis of the proximal phalanx in an attempt to halt further longitudinal growth of the toe. Nine patients who underwent open epiphysiodesis and debulking of the excess soft tissues involving 11 toes were reviewed to evaluate the effectiveness of this procedure. In 9 of 11 toes, overall length of the proximal phalanx did not change after surgery. Two toes demonstrated continued growth; one of these toes underwent a repeat epiphysiodesis of the phalanx, and the other foot underwent epiphysiodesis of the affected metatarsal. Overall, this surgical approach led to radiographic results that satisfied the surgical goals.


NMR redox studies of Desulfovibrio vulgaris Cytochrome c3. Electron transfer mechanisms.
The 300-MHz proton NMR spectra of the tetrahaem cytochrome c3 from Desulfovibrio vulgaris were examined while varying the pH and the redox potential. The analysis of the complete NMR reoxidation pattern was done taking into account all the 16 redox states that can be present in the redox titration of a tetra-redox-center molecule. A network of saturation transfer experiments performed at different oxidation stages, between the fully reduced and the fully oxidized states, allowed the observation of different resonances for some of the haem methyl groups. In the present experimental conditions, some of the haems show a fast intramolecular electron exchange rate, but the intermolecular electron exchange is always slow. In intermediate reoxidation stages, large shifts of the resonances of some haem methyl groups were observed upon changing the pH. These shifts are discussed in terms of a pH dependence of the haem midpoint redox potentials. The physiological relevance of this pH dependence is discussed.


Circuit class therapy for improving mobility after stroke.
Circuit class therapy (CCT) offers a supervised group forum for people after stroke to practise tasks, enabling increased practise time without increasing staffing. To examine the effectiveness and safety of CCT on mobility in adults with stroke. We searched the Cochrane Stroke Group Trials Register (last searched October 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2009), MEDLINE (1950 to November 2008), EMBASE (1980 to November 2008), CINAHL (1982 to November 2008) and 14 other electronic databases (to November 2008). We also searched proceedings from relevant conferences, reference lists and unpublished theses; contacted authors of published trials and other experts in the field; and searched relevant clinical trials and research registers. Randomised or quasi-randomised controlled trials including people over 18 years old diagnosed with stroke of any severity, at any stage, or in any setting, receiving CCT. Two review authors independently selected trials for inclusion, assessed methodological quality and extracted data. We included six trials involving 292 participants. Participants were long-term stroke survivors living in the community or receiving inpatient rehabilitation. All could walk 10 metres with or without assistance. Four studies measured walking capacity and three measured gait speed, demonstrating that CCT was superior to the comparison intervention (Six Minute Walk Test: mean difference (MD), fixed 76.57 metres, 95% confidence interval (CI) 38.44 to 114.70, P < 0.0001; gait speed: MD, fixed 0.12 m/s, 95% CI 0.00 to 0.24, P = 004). Two studies measured balance, showing a superior effect in favour of CCT (Step Test: MD, fixed 3.00 steps, 95% CI 0.08 to 5.91, P = 0.04; activities-specific balance and confidence: MD, fixed 7.76, 95% CI 0.66 to 14.87, P = 0.03). Studies also measured other balance items showing no difference in effect. Length of stay (two studies) showed a significant effect in favour of CCT (MD, fixed -19.73 days, 95% CI -35.43 to -4.04, P = 0.01). Only two studies measured adverse events (falls during therapy): all were minor. CCT is safe and effective in improving mobility for people after moderate stroke and may reduce inpatient length of stay. Further research is required, investigating quality of life, participation and cost-benefits, that compares CCT to standard care and that also investigates the differential effects of stroke severity, latency and age.


Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results.
To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration. Prospective, multicenter, double-masked, randomized, active-controlled trial. We included 255 patients with all types of active subfoveal choroidal neovascularization. Patients were randomized 1:1 to as-needed (pro re nata; PRN) combination (standard-fluence verteporfin 6 mg/m(2) PDT and ranibizumab 0.5 mg) or PRN ranibizumab monotherapy (sham infusion [5% dextrose] PDT and ranibizumab 0.5 mg). Patients received 3 consecutive monthly injections followed by PRN retreatments based on protocol-specific retreatment criteria. Mean change in best-corrected visual acuity (BCVA) from baseline to month 12, and the proportion of patients with treatment-free interval ≥3 months at any timepoint after month 2. The mean change in BCVA at month 12 was +2.5 and +4.4 letters in the combination and monotherapy groups, respectively (P = 0.0048; difference: -1.9 letters [95% confidence interval, -5.76 to 1.86], for having achieved noninferiority with a margin of 7 letters). The proportion of patients with a treatment-free interval of ≥3 months at any timepoint after month 2 was high, but did not show a clinically relevant difference between the treatment groups. Secondary efficacy endpoints included the mean number of ranibizumab retreatments after month 2 (1.9 and 2.2 with combination and monotherapy, respectively [P = 0.1373]). The time to first ranibizumab retreatment after month 2 was delayed by 34 days (about 1 monthly visit) with combination (month 6) versus monotherapy (month 5). At month 12, mean ± standard error central retinal thickness decreased by 115.3±9.04 μm in the combination group and 107.7±11.02 μm in the monotherapy group. The mean number of verteporfin/sham PDT treatments was comparable in the 2 groups (combination, 1.7; monotherapy, 1.9). The safety profiles of the 2 groups were comparable, with a low incidence of ocular serious adverse events. The combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. The combination therapy was well tolerated.


Different immunohistochemical patterns of Fhit protein expression in renal neoplasms.
The FHIT gene on human chromosome 3p14.2 is deleted in a variety of malignant tumors, including clear cell renal carcinomas (RCCs) resulting in a loss of expression of Fhit protein. The Fhit expression in specific subtypes of renal carcinomas has not been characterized. We have investigated the association of Fhit expression with particular subtypes of renal tumors to determine the role and specificity of this putative tumor suppressor gene in renal neoplasia. The immunohistochemical expression of Fhit was tested in normal kidneys and in 109 renal neoplasms consisting of 51 clear cell RCCs, 26 papillary RCCs, two chromophobe carcinomas, six oncocytomas, four pelvic transitional cell carcinomas and 20 Wilms' tumors from formalin fixed and routinely processed tissue. Normal renal tubules expressed Fhit strongly and consistently. The majority (78%) of clear cell RCCs showed reduced or absent expression of Fhit, whereas the majority (74%) of papillary carcinomas, all chromophobe renal cell carcinomas, and oncocytomas were strongly positive. Sixty-eight percent of low-grade (G1 plus G2) but only 9% of high-grade (G3 plus G4) clear cell carcinomas were Fhit negative. Wilms' tumors demonstrated focal staining in the epithelial component in 8 of 20 cases (40%). The loss of Fhit expression in a high percentage of clear cell RCCs with conservation of Fhit in other types of tumors supports the proposed role of FHIT alterations in the genesis of clear cell carcinomas in contrast to other types of renal epithelial tumors. FHIT expression may play a role in epithelial differentiation of nephroblastomas (Wilms' tumors).


High-Power (40-50 W) Radiofrequency Ablation Guided by Unipolar Signal Modification for Pulmonary Vein Isolation: Experimental Findings and Clinical Results.
Background Although proposed to facilitate pulmonary vein isolation (PVI), high-power ablation may favor extracardiac damage. Negative component abolition of the unipolar signal reflects lesion transmurality. The present study sought to evaluate the safety and efficacy of high-power ablation using unipolar signal modification as a local end point. Methods High power and standard power were compared in 4 swine and 100 consecutive patients referred for PVI. The first 50 patients were included in the control group (25-30 W) and the last 50 patients in the study group (40-50 W). Atrial radiofrequency applications were stopped 2 s (study group and swine) or 5 s (control group) after unipolar signal modification. Ventricular radiofrequency applications of 500 J (25 W·20 s versus 50 W·10 s) were performed at the swine epicardium. Results Swine gross necropsy did not show any extracardiac damage related to atrial lesions. At equal energy of 500 J, 50 W lesions were deeper (3±0.9 versus 2.6±1.1 mm; P=0.03) and wider (6.2±2 versus 5±2.3 mm; P=0.006) than 25 W lesions. No complications occurred during the clinical study, whatever the power output used for PVI. For a similar sinus rhythm maintenance at 12 months (90% versus 88%; P=0.75), the study group displayed higher first-pass PVI (92% versus 73%; P<0.001), lower acute pulmonary vein reconnection (2% versus 17%; P<0.001), reduced procedure time (73.1±18.2 versus 107.4±21.2 min; P<0.001), and ablation time (13±2.9 versus 30.3±8.8 min; P<0.001). Conclusions High-power PVI guided by unipolar signal modification safely decreases procedural burden while ensuring robust 12-month outcomes.


Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study.
Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.


Hemodynamic Profile of Patients With Heart Failure and Preserved Ejection Fraction Vary by Age.
Patients with heart failure with preserved ejection fraction (HFpEF) exhibit a range of cardiovascular phenotypic profiles modified by several common comorbidities. In particular, patients with HFpEF tend to be older; however, it is unclear whether the effects of cardiovascular aging per se modify the expression of HFpEF. We therefore sought to investigate the interaction between age and physiologic profile in patients with HFpEF. We assessed the hemodynamic and metabolic profile of 40 patients with HFpEF. Patients underwent right heart catheterization at rest and during supine cycle ergometry, and were segregated into 2 groups by the median age of the cohort. Older patients with HFpEF demonstrated reduced resting cardiac output (4.8±1.2 L/min versus 5.7±1.1 L/min). With exercise, older patients demonstrated a marked rise in arteriovenous oxygen content difference (10.8±1.8 versus 7.9±2.4 mL, P≤0.001), driven by enhanced oxygen extraction. There was no significant difference in peak pulmonary capillary wedge pressure (30±7 mm Hg versus 27±6, P=0.135), including when indexed to workload (pulmonary capillary wedge pressure/W, 0.88 mm Hg/W versus 0.92; P=0.83). Older patients with HFpEF display a different physiological phenotype compared with younger patients, with enhanced oxygen extraction and lower increment in cardiac output to increase oxygen consumption from rest to peak supine exercise. This finding highlights the importance in considering age when considering therapeutic options in patients with HFpEF.


The colors of life: an interdisciplinary artist-in-residence project to research fungal pigments as a gateway to empathy and understanding of microbial life.
Biological pigmentation is one of the most intriguing traits of many fungi. It holds significance to scientists, as a sign of biochemical metabolism and organism-environment interaction, and to artists, as the source of natural colors that capture the beauty of the microbial world. Furthermore, the functional roles and aesthetic appeal of biological pigmentation may be a path to inspiring human empathy for microorganisms, which is key to understanding and preserving microbial biodiversity. A project focused on cross-species empathy was initiated and conducted as part of an artist-in-residence program in 2021. The aim of this residency is to bridge the current divide between science and art through interdisciplinary practice focused on fungi. The residency resulted in multiple products that are designed for artistic and scientific audiences with the central theme of biological pigmentation in fungi and other microorganisms. The first product is a video artwork that focuses on Aspergillus niger as a model organism that produces melanin pigment in a biosynthetic process similar to that of humans. The growth and morphology of this commonplace organism are displayed through video, photo, animation, and time-lapse footage, inviting the viewer to examine the likenesses and overlaps between humans and fungi. The second product is The Living Color Database, an online compendium of biological colors for scientists, artists, and designers. It links organisms across the tree of life, focusing on fungi, bacteria, and archaea, and the colors they express through biological pigmentation. Each pigment is represented in terms of its chemistry, its related biosynthesis, and its color expressions according to different indices: HEX, RGB, and Pantone. It is available at color.bio. As fungal biotechnology continues to mature into new application areas, it is as important as ever that there is human empathy for these organisms to promote the preservation and appreciation of fungal biodiversity. The products presented here provide paths for artists, scientists, and designers to understand microorganisms through the lens of color, promoting interspecies empathy through research, teaching, and practice.


Cholesterol, lipoproteins, and coronary heart disease in women.
In the United States, coronary heart disease is the major cause of death and disability in women and in men. Despite this, little is known about the risk factors, including cholesterol and lipoprotein concentrations, for coronary disease in women. In this paper we review the determinants of cholesterol and lipoprotein concentrations in women, assess whether values for total cholesterol and lipoproteins (HDL and LDL) are associated with the occurrence of coronary heart disease in women, and evaluate the evidence that suggests that modifying the concentrations of lipids in women is associated with changing the risk of coronary disease. Besides genetic determinants, dietary cholesterol, dietary fat, total caloric intake, alcohol consumption, cigarette smoking, and physical activity are known to influence concentrations of lipids in women. Some of the strongest determinants of cholesterol and lipoprotein concentrations in women are sex hormones, including estrogen and progestin. Exogenous use of both of these hormones markedly influences HDL and LDL cholesterol; additional evidence suggests that endogenous sex hormones also influence lipid and lipoprotein concentrations. The few studies that have examined the association of total cholesterol with coronary heart disease occurrence and mortality in women have consistently shown that (a) women have much lower rates of coronary heart disease than men at the same values for cholesterol, and (b) clearly elevated risk for coronary heart disease in women is evident only at relatively high values of total cholesterol (i.e., greater than 260 mg/dL). There also appears to be an age effect, with total cholesterol concentrations being more predictive in older than in younger women.


Nuclear factor of activated T cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia.
Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.


Factors influencning mitotic yields from suspension cultures of normal and acute leukaemic bone marrows.
Cytogenetic studies of bone marrow are often hampered by a paucity of dividing cells. In an attempt to improve mitotic yields we have tried to promote mitotic activity in suspension cultures of bone marrow from both normal and leukaemic subjects. Enrichment of the media always increases yield and the addition of bone marrow stimulating factor (BMSF) may do so. The best prospect for improving the yield of mitoses in acute myeloid leukaemia is to culture the marrow in an enriched medium with BMSF.


Genome-wide association between single nucleotide polymorphisms with beef fatty acid profile in Nellore cattle using the single step procedure.
Saturated fatty acids can be detrimental to human health and have received considerable attention in recent years. Several studies using taurine breeds showed the existence of genetic variability and thus the possibility of genetic improvement of the fatty acid profile in beef. This study identified the regions of the genome associated with saturated, mono- and polyunsaturated fatty acids, and n-6 to n-3 ratios in the Longissimus thoracis of Nellore finished in feedlot, using the single-step method. The results showed that 115 windows explain more than 1 % of the additive genetic variance for the 22 studied fatty acids. Thirty-one genomic regions that explain more than 1 % of the additive genetic variance were observed for total saturated fatty acids, C12:0, C14:0, C16:0 and C18:0. Nineteen genomic regions, distributed in sixteen different chromosomes accounted for more than 1 % of the additive genetic variance for the monounsaturated fatty acids, such as the sum of monounsaturated fatty acids, C14:1 cis-9, C18:1 trans-11, C18:1 cis-9, and C18:1 trans-9. Forty genomic regions explained more than 1 % of the additive variance for the polyunsaturated fatty acids group, which are related to the total polyunsaturated fatty acids, C20:4 n-6, C18:2 cis-9 cis12 n-6, C18:3 n-3, C18:3 n-6, C22:6 n-3 and C20:3 n-6 cis-8 cis-11 cis-14. Twenty-one genomic regions accounted for more than 1 % of the genetic variance for the group of omega-3, omega-6 and the n-6:n-3 ratio. The identification of such regions and the respective candidate genes, such as ELOVL5, ESSRG, PCYT1A and genes of the ABC group (ABC5, ABC6 and ABC10), should contribute to form a genetic basis of the fatty acid profile of Nellore (Bos indicus) beef, contributing to better selection of the traits associated with improving human health.


Health-Related Behavior Mediates the Association Between Personality and Memory Performance in Older Adults.
This prospective study explored the potential mediating role of health-related behavior (alcohol involvement, diet, television viewing, and physical activity) in the association between personality and change in memory performance over 2 years. A nationally representative sample of 8,376 U.K. participants aged 55 years and older (4,572 women, 3,804 men) completed self-report measures of personality and health-related behavior in 2010, and completed a memory performance task in 2010 and 2012. After removing variance associated with potential confounding variables, neuroticism and agreeableness had negative associations, and openness and conscientiousness positive associations with change in memory performance. There were no moderation effects by age, sex, education level, or ethnicity. Multiple mediator models demonstrated that physical activity, television viewing, and alcohol intake mediated associations between personality and change in memory performance. These findings provide evidence that the association between personality and memory performance in older adults can be explained, in part, through health-related behavior.


Folic acid may be a potential addition to diabetic foot ulcer treatment - a hypothesis.
Delayed wound healing in diabetes is a challenging medical and societal problem for which there is currently no efficacious treatment. One of the major contributors of this problem is nitric oxide (NO) deficiency. NO is a critical signalling molecule essential for normal wound repair. Sustained hyperglycaemia in diabetes leads to increased vascular superoxide production, which inactivates NO and causes vascular dysfunction. New therapeutic regiments and strategies to enhance endothelial NO production are a new hope to improve impaired diabetic wound healing. One of the agents that have the ability to improve endothelial NO generation in diabetic patients is folic acid. Folic acid ability to conserve NO bioactivity may be due to homocysteine-lowering effects of folates, antioxidant actions and effects on cofactor availability. Considering these data, we hypothesised that folic acid supplementation may ameliorate delayed diabetic wound healing by increasing NO bioavailability. The potential of exogenous folic acid as an inexpensive and safe oral therapy stimulates ongoing investigations.


Structural basis for adenosylcobalamin activation in AdoCbl-dependent ribonucleotide reductases.
Class II ribonucleotide reductases (RNR) catalyze the formation of an essential thiyl radical by homolytic cleavage of the Co-C bond in their adenosylcobalamin (AdoCbl) cofactor. Several mechanisms for the dramatic acceleration of Co-C bond cleavage in AdoCbl-dependent enzymes have been advanced, but no consensus yet exists. We present the structure of the class II RNR from Thermotoga maritima in three complexes: (i) with allosteric effector dTTP, substrate GDP, and AdoCbl; (ii) with dTTP and AdoCbl; (iii) with dTTP, GDP, and adenosine. Comparison of these structures gives the deepest structural insights so far into the mechanism of radical generation and transfer for AdoCbl-dependent RNR. AdoCbl binds to the active site pocket, shielding the substrate, transient 5'-deoxyadenosyl radical and nascent thiyl radical from solution. The e-propionamide side chain of AdoCbl forms hydrogen bonds directly to the α-phosphate group of the substrate. This interaction appears to cause a "locking-in" of the cofactor, and it is the first observation of a direct cofactor-substrate interaction in an AdoCbl-dependent enzyme. The structures support an ordered sequential reaction mechanism with release or relaxation of AdoCbl on each catalytic cycle. A conformational change of the AdoCbl adenosyl ribose is required to allow hydrogen transfer to the catalytic thiol group. Previously proposed mechanisms for radical transfer in B12-dependent enzymes cannot fully explain the transfer in class II RNR, suggesting that it may form a separate class that differs from the well-characterized eliminases and mutases.


What is the right level of spending needed for health and care in the UK?
The health and care sector plays a valuable role in improving population health and societal wellbeing, protecting people from the financial consequences of illness, reducing health and income inequalities, and supporting economic growth. However, there is much debate regarding the appropriate level of funding for health and care in the UK. In this Health Policy paper, we look at the economic impact of the COVID-19 pandemic and historical spending in the UK and comparable countries, assess the role of private spending, and review spending projections to estimate future needs. Public spending on health has increased by 3·7% a year on average since the National Health Service (NHS) was founded in 1948 and, since then, has continued to assume a larger share of both the economy and government expenditure. In the decade before the ongoing pandemic started, the rate of growth of government spending for the health and care sector slowed. We argue that without average growth in public spending on health of at least 4% per year in real terms, there is a real risk of degradation of the NHS, reductions in coverage of benefits, increased inequalities, and increased reliance on private financing. A similar, if not higher, level of growth in public spending on social care is needed to provide high standards of care and decent terms and conditions for social care staff, alongside an immediate uplift in public spending to implement long-overdue reforms recommended by the Dilnot Commission to improve financial protection. COVID-19 has highlighted major issues in the capacity and resilience of the health and care system. We recommend an independent review to examine the precise amount of additional funds that are required to better equip the UK to withstand further acute shocks and major threats to health.


VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs.
The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.


Age- and sex-related emotional and behavioral problems in children with autism spectrum disorders: comparison with control children.
Children with autism spectrum disorders (ASD) often present with emotional and behavioral problems, which could change the clinical course, especially during childhood, and affect future quality of life. The aim of this study was to clarify the age- and sex-related differences of these problems in ASD. The study subjects were 173 patients with ASD (age: 4-16 years) and 173 age- and sex-matched community children (control group). The parent version of the Strengths and Difficulties Questionnaire was used for comparison of the emotional and behavioral problems between the two groups. The Strengths and Difficulties Questionnaire scores were significantly higher in children with ASD than controls at all ages. The score of total difficulties was significantly higher in girls with ASD than in boys, while the score in male controls was significantly higher than in female controls. Age-related differences in emotional and behavioral problems were observed both in children with ASD and controls, but the characteristics were different: in children with ASD, emotional symptoms and peer problems in both sexes and conduct problems in girls increased significantly with age, while none of the problems in the controls changed with age except for a decrease in the score of hyperactivity/inattention developmentally in both sexes. Prosocial behaviors of children with ASD and controls showed small changes with age. Emotional and behavioral problems are common in children with ASD and showed age- and sex-related differences. Our study emphasizes the importance of recognizing those differences among children with ASD for early intervention.


Prediction of Cardiovascular Parameters With Supervised Machine Learning From Singapore "I" Vessel Assessment and OCT-Angiography: A Pilot Study.
Assessment of cardiovascular risk is the keystone of prevention in cardiovascular disease. The objective of this pilot study was to estimate the cardiovascular risk score (American Hospital Association [AHA] risk score, Syntax risk, and SCORE risk score) with machine learning (ML) model based on retinal vascular quantitative parameters. We proposed supervised ML algorithm to predict cardiovascular parameters in patients with cardiovascular diseases treated in Dijon University Hospital using quantitative retinal vascular characteristics measured with fundus photography and optical coherence tomography - angiography (OCT-A) scans (alone and combined). To describe retinal microvascular network, we used the Singapore "I" Vessel Assessment (SIVA), which extracts vessel parameters from fundus photography and quantitative OCT-A retinal metrics of superficial retinal capillary plexus. The retinal and cardiovascular data of 144 patients were included. This paper presented a high prediction rate of the cardiovascular risk score. By means of the Naïve Bayes algorithm and SIVA + OCT-A data, the AHA risk score was predicted with 81.25% accuracy, the SCORE risk with 75.64% accuracy, and the Syntax score with 96.53% of accuracy. Performance of these algorithms demonstrated in this preliminary study that ML algorithms applied to quantitative retinal vascular parameters with SIVA software and OCT-A were able to predict cardiovascular scores with a robust rate. Quantitative retinal vascular biomarkers with the ML strategy might provide valuable data to implement predictive model for cardiovascular parameters. Small data set of quantitative retinal vascular parameters with fundus and with OCT-A can be used with ML learning to predict cardiovascular parameters.


Inpatient portal clusters: identifying user groups based on portal features.
Conduct a cluster analysis of inpatient portal (IPP) users from an academic medical center to improve understanding of who uses these portals and how. We used 18 months of data from audit log files, which recorded IPP user actions, of 2815 patient admissions. A hierarchical clustering algorithm was executed to group patient admissions on the basis of proportion of use for each of 10 IPP features. Post-hoc analyses were conducted to further understand IPP use. Five cluster solutions were developed for the study sample. Our taxonomy included users with high levels of accessing features that were linked to reviewing schedules, results, tutorials, and ordering food. Patients tended to stay within their clusters over multiple admissions, and the clusters had differences based on patient and clinical characteristics. Distinct groups of users exist among IPP users, suggesting that training on IPP use to enhance patient engagement could be tailored to patients. More exploration is also needed to understand why certain features were not used across all clusters. It is important to understand the specifics about how patients use IPPs to help them better engage with their healthcare. Our taxonomy enabled characterization of 5 groups of IPP users who demonstrated distinct preferences. These results may inform targeted improvements to IPP tools, could provide insights to improve patient training around portal use, and may help care team members effectively engage patients in the use of IPPs. We also discuss the implications of our findings for future research.


Costunolide induces G1/S phase arrest and activates mitochondrial-mediated apoptotic pathways in SK-MES 1 human lung squamous carcinoma cells.
Despite the availability of several therapeutic options, a safer and more effective modality strategy is required for the treatment of lung cancer. Costunolide, a sesquiterpene lactone which isolated from the Saussurea lappa, has potent anticancer properties. In the present study, the effects of costunolide on cell viability, the cell cycle and apoptosis in SK-MES-1 human lung squamous carcinoma cells were investigated. Costunolide induced morphological changes and inhibited growth of SK-MES-1 cells growth. Flow cytometric analysis data demonstrated that costunolide significantly induced apoptosis of SK-MES-1 cells and induced cell cycle arrest at G1/S phase in a dose-dependent manner. Through upregulation in the expression of p53 and Bax, and downregulation in the expression of Bcl-2 and activation of caspase-3, costunolide-induced apoptosis was confirmed by western blot analysis. In addition, the significant loss of mitochondrial membrane potential indicated that costunolide may induce apoptosis via the mitochondria-dependent pathway in SK-MES-1 cells. These results highlight the potential effects of costunolide as an anti-cancer agent in a human lung squamous carcinoma cell line.


The effects of vasopressin on endotoxin-induced attenuation of contractile responses in human gastroepiploic arteries in vitro.
We studied the effects of vasopressin on contraction in normal and endotoxin-treated human gastroepiploic arterial rings in vitro. In this tissue, vasopressin (50-500 pg/mL) produced concentration-dependent, endothelium-independent contractions. Vasopressin also potentiated the contraction elicited by 1.0 micromol/L norepinephrine (NE) in both the presence and absence of endothelium. Endotoxin (10 microg/mL) attenuated the 1.0 micromol/L NE-induced contractions, and this attenuation was reversed by 300 micromol/L N(G)-nitro-L-arginine-methyl ester (L-NAME) and by 300 micromol/L N(G)-nitro-L-arginine (L-NoArg). After 12 h endotoxin treatment, the vasopressin-induced contraction was attenuated, and the enhancing effect of vasopressin was diminished. However, both before and after endotoxin, the enhancement produced by vasopressin was larger than the vasopressin-contraction itself. An antagonist of the vasopressin V1 receptor, 1.0 micromol/L beta-mercapto-[beta,beta-cyclopentamethylenpropionyl1,O-MeTyr2+ ++,Arg8]-vasopressin, and an antagonist of V1 + V2 receptor receptor, 1.0 micromol/L des-Gly9-[beta-mercapto-beta,beta-cyclopentamethylenepropionyl1 ,O-Et-Tyr2,Val,Arg8]-vasopressin, each diminished the vasopressin-induced enhancement of the NE contraction. The results of our study suggest that, in addition to its direct vasoconstrictor effect, vasopressin strongly enhances the responses to norepinephrine through V1-receptor stimulation and that vasopressin could find a role in the management of endotoxin-induced vasodilation.


Inpatient Glycemic Management of the Pregnant Patient.
There is a rising prevalence of type 1 diabetes (T1DM), type 2 diabetes (T2DM), and gestational diabetes (GDM) in pregnancy. Reaching and maintaining glycemic targets during and after this time are important for both the health of the mother and her baby. Based on recently published guidelines from various societies, we review the diagnosis of diabetes in pregnancy, types of therapies available to maintain euglycemia, important keys to management of T1DM, T2DM, and GDM, and strategies for reaching inpatient glycemic targets during the peripartum period. Care for pregnant patients with T1DM is especially challenging, and providers should be aware of the varying insulin requirements at different stages of pregnancy and how to reduce hypoglycemia and avoid diabetic ketoacidosis. Insulin sensitivity fluctuates throughout pregnancy due to physiologic changes, especially during labor and delivery and immediately post-partum. We review recommendations regarding how to manage this dynamic time and present our own institution's inpatient management protocol. Finally, we review management of diabetes post-partum, including medications, breast-feeding, and continued monitoring and screening. With the collaborative efforts of the patient and an interdisciplinary team and in-depth knowledge of the most up-to-date management principles, it is possible to achieve euglycemia during this critical time of a mother and baby's life.


Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC).
We report four cases of Brain Metastases (BM) from non-small cell lung cancer (NSCLC) responding to ZD 1839 therapy after standard therapy failure. Four patients with BM from NSCLC, pretreated with two or more lines of chemotherapy, received ZD 1839 (Iressa), on a compassionate use basis, at the daily dose of 250 mg until disease progression. Three patients received Iressa after whole brain radiotherapy (WBRT) failure. After 3 months of ZD 1839 therapy, one patient had complete response on the brain with stabilization of extracranial disease, while the other three patients had partial response both on the brain and on extracranial sites. At the time of this analysis, two patients discontinued the treatment after 5 and 7 months for disease progression, while two patients are still on treatment with no evidence of treatment failure after 3+ and 12+ months. ZD 1839 was generally well tolerated, with skin toxicity recorded in two patients. ZD 1839 may be effective in NSCLC patients with pretreated BM. Large and prospective trials need to clarify the role of ZD 1839 in the treatment of BM from NSCLC.


Influence of nebivolol on anticonvulsant effect of lamotrigine.
The present study describes the effect of nebivolol (NBV) either alone or in combination with lamotrigine (LTG) using increasing current electroshock seizures (ICES) model in mice. Male albino mice of Swiss strain each weighing 18-30 g were used. Lamotrigine (Lamitor tablets, Torrent; 1.5 and 3.0 mg/kg) and NBV (Nebicard tablets, Torrent; 0.25 and 0.5 mg/kg) were suspended in 0.25% of carboxy methyl cellulose (CMC) in 0.9% saline and administered orally in volumes of 10 mg/kg. Control animals received an equivalent volume of 0.25% CMC in 0.9% saline suspension. The anticonvulsant effects of the drugs were measured using ICES model whereas cognitive behavior was measured by the spontaneous alternation behavior and grip-strength test. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH). Both NBV and LTG produced significantly enhanced seizure threshold (ST), decreased grip strength, inhibited lipid peroxidation, and increased brain GSH levels in acute and chronic dosages likened to control group, whereas there was no significant effect on alternation scores. The combination of NBV with LTG significantly potentiated the ST when compared to LTG. Nebivolol showed antiepileptic effects in addition to its reported antihypertensive effect, which could be attributed to action of the two drugs through different mechanisms or due to drug interaction that may be pharmacodynamic or pharmacokinetic needing elucidation.


Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.
Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05) in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P ≤ 0.05). Our integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 weeks supplementation with 200 mg/d MOF in humans. ClinicalTrials.gov NCT00742287.


Intervening sequence in the thymidylate synthase gene of bacteriophage T4.
The continuous sequence of 2.3 kilobases in a 3-kilobase DNA fragment encoding the structural gene for coliphage T4 thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 188.8.131.52) was determined by using the M13 dideoxy chain-termination method. From the coding information within this gene and that provided by sequence analysis of selected CNBr peptides from the protein product, the primary structure of T4 thymidylate synthase was determined. The most significant finding of these studies is the presence of a 1017-base-pair interruption two-thirds of the way through the nucleotide sequence of the structural gene. The 5'- and 3'-terminal ends of this intron are demarcated by an apparent stop and start codon, respectively. The corresponding methionine preceding the second coding region of the synthase is not incorporated into the final protein product. Structural evidence confirming the presence of the intervening sequence in the phage genome was obtained by restriction and hybridization analysis. Support for the presence of the intron was also obtained at the functional level by enzyme expression studies using selected td gene fragments. This work also confirms the findings of Purohit and Mathews [ Purohit , S. & Mathews , C. K. (1983) Fed. Proc. Fed. Am. Soc. Exp. Biol. 42, 1759], which reveal that the termination codon for the dihydrofolate reductase gene and the triplet initiating thymidylate synthase overlap by a four-base stretch, A-T-G-A. The implications of this unusual gene arrangement are discussed.


[Results of 25 years' research and the program of measures for improving the diagnosis and the results of treatment of patients with vasorenal hypertension].
Twenty-five years of research in the area of diagnosis and treatment of vasorenal hypertension are summed up. A total of 309 patients were investigated at the Myasnikov Institute of Clinical Cardiology, and 694 patients were operated on for vasorenal hypertension in the Bakulev Institute of Cardiovascular Surgery. Surgical treatment for vasorenal hypertension was effective in 62-88%, whereas a relapse of arterial hypertension or no effect were recorded in 12-24.9% of the cases. Plastic operations on renal arteries are associated with a 1 to 6% mortality.


Oxygen deprivation produces delayed inhibition of long-term potentiation by activation of NMDA receptors and nitric oxide synthase.
The acute and delayed effects of anoxia on synaptic transmission and long-term potentiation (LTP) were examined in the CA1 region of rat hippocampal slices. Oxygen deprivation for 20 minutes completely but reversibly depressed excitatory postsynaptic potentials mediated by both N-methyl-D-aspartate receptors (NMDAR) and non-NMDAR. Although LTP was reliably produced by a single tetanus delivered 30 minutes after reoxygenation, LTP could not be induced when a tetanus was delivered 70 to 100 minutes after reoxygenation. A tetanus delivered 100 minutes after reoxygenation produced lasting synaptic enhancement when 100 mumol/L D,L-amino-phosphonovaleric acid (APV), a competitive NMDAR antagonist, was administered during the period of oxygen deprivation. The delayed effects of oxygen deprivation were not blocked when APV was administered after oxygen deprivation. Similarly, the delayed effects on LTP induction were overcome by inhibitors of nitric oxide synthase when the nitric oxide synthase inhibitors were administered during anoxia, but not when administered after oxygen deprivation. These results suggest that untimely activation of NMDAR and nitric oxide release during anoxia produce delayed inhibition of LTP induction and may be involved in the memory defects that occur subsequent to cerebral hypoxia.


Enterobacter cloacae ventriculitis successfully treated with cefepime and gentamicin: case report and review of the literature.
A 55-year-old woman was found unresponsive and subsequently was diagnosed with a subarachnoid hemorrhage secondary to a right posterior communicating artery aneurysm. The development of hydrocephalus and decreased mental status necessitated placement of an intraventricular catheter; 18 days later she was diagnosed with Enterobacter cloacae ventriculitis. After treatment was begun with intravenous cefepime 2 g every 8 hours and intraventricular gentamicin 5 mg every 24 hours, the catheter was replaced. Cerebrospinal fluid (CSF) and plasma cefepime concentrations and a CSF trough gentamicin concentration were obtained. Intraventricular gentamicin was administered for 6 days and cefepime for 21 days; both clinical and microbiologic resolution of the ventriculitis occurred. The literature reports limited clinical experience with cefepime for the treatment of central nervous system infections in humans. This case report provides clinical evidence to support administration of intravenous cefepime in critically ill adult patients with Enterobacter ventriculitis. Because CSF is easily obtained from patients with intraventricular catheters, strong consideration should be given to monitoring CSF cefepime concentrations in concert with the minimum inhibitory concentration of the offending pathogen to help assure the efficacy of this approach to therapy.


Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women.
Pelvic floor muscle training (PFMT) is a first-line conservative treatment for urinary incontinence in women. Other active treatments include: physical therapies (e.g. vaginal cones); behavioural therapies (e.g. bladder training); electrical or magnetic stimulation; mechanical devices (e.g. continence pessaries); drug therapies (e.g. anticholinergics (solifenacin, oxybutynin, etc.) and duloxetine); and surgical interventions including sling procedures and colposuspension. This systematic review evaluated the effects of adding PFMT to any other active treatment for urinary incontinence in women To compare the effects of pelvic floor muscle training combined with another active treatment versus the same active treatment alone in the management of women with urinary incontinence. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, and handsearching of journals and conference proceedings (searched 28 February 2013), EMBASE (January 1947 to 2013 Week 9), CINAHL (January 1982 to 5 March 2013), ClinicalTrials.gov (searched 30 May 2013), WHO ICTRP (searched 3 June 2013) and the reference lists of relevant articles. We included randomised or quasi-randomised trials with two or more arms in women with clinical or urodynamic evidence of stress urinary incontinence, urgency urinary incontinence or mixed urinary incontinence. One arm of the trial included PFMT added to another active treatment; the other arm included the same active treatment alone. Two review authors independently assessed trials for eligibility and methodological quality and resolved any disagreement by discussion or consultation with a third party. We extracted and processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Other potential sources of bias we incorporated into the 'Risk of bias' tables were ethical approval, conflict of interest and funding source. Eleven trials met the eligibility criteria for inclusion, comprising women with stress urinary incontinence (SUI), urgency urinary incontinence (UUI) or mixed urinary incontinence (MUI), and they compared PFMT added to another active treatment (494 women) with the same active treatment alone (490 women). The pre-specified comparisons were reported by single trials except electrical stimulation which was reported by two trials. However, the two trials reporting electrical stimulation could not be pooled as one of the trials did not report any relevant data. We considered the included trials to be at unclear risk of bias for most of the domains, predominantly due to the lack of adequate information in a number of trials. This affected our rating of the quality of evidence. The majority of the trials did not report the primary outcomes specified in the review (cure/improvement, quality of life) or measured the outcomes in different ways. Effect estimates from small, single trials across a number of comparisons were indeterminate for key outcomes relating to symptoms and we rated the quality of evidence, using the GRADE approach, as either low or very low. There was moderate-quality evidence from a single trial investigating women with SUI, UUI or MUI that a higher proportion of women who received a combination of PFMT and heat and steam generating sheet reported cure compared to those who received the sheet alone: 19/37 (51%) versus 8/37 (22%) with a risk ratio (RR) of 2.38, 95% confidence interval (CI) 1.19 to 4.73). More women reported cure or improvement of incontinence in another trial comparing PFMT added to vaginal cones to vaginal cones alone: 14/15 (93%) versus 14/19 (75%), but this was not statistically significant (RR 1.27, 95% CI 0.94 to 1.71). We judged the quality of the evidence to be very low. Only one trial evaluating PFMT when added to drug therapy provided information about adverse events (RR 0.84, 95% CI 0.45 to 1.60; very low-quality evidence).With regard to condition-specific quality of life, there were no statistically significant differences between women (with SUI, UUI or MUI) who received PFMT added to bladder training and those who received bladder training alone at three months after treatment either on the Incontinence Impact Questionnaire-Revised scale (mean difference (MD) -5.90, 95% CI -35.53 to 23.73) or on the Urogenital Distress Inventory scale (MD -18.90, 95% CI -37.92 to 0.12). A similar pattern of results was observed between women with SUI who received PFMT plus either a continence pessary or duloxetine and those who received the continence pessary or duloxetine alone. In all these comparisons, the quality of the evidence for the reported critical outcomes ranged from moderate to very low. This systematic review found insufficient evidence to state whether or not there were additional effects of adding PFMT to other active treatment when compared with the same active treatment alone for urinary incontinence (SUI, UUI or MUI) in women. These results should be interpreted with caution as most of the comparisons were investigated in small, single trials. None of the trials in this review were large enough to provide reliable evidence. Also, none of the included trials reported data on adverse events associated with the PFMT regimen, thereby making it very difficult to evaluate the safety of PFMT.


Research on nursing practice. Stress.
Clearly, there is not agreement among nurse researchers regarding a definitional orientation to stress that best fits nursing's orientation to human experiences. Varying theoretical orientations are used to explain stress or stress-related phenomena, for example, stress as a stimulus, stress as a response, and stress as a transaction. The studies are fairly evenly distributed among the four definitional categories. The various approaches do not represent expanding theoretical explanations of stress, but rather are incompatible approaches to explaining stress. More disconcerting than the lack of direction in research efforts, however, is that all too commonly the measurement of the variables and the methodology were not "linked" or consistent with the theoretical framework. For the most part the research efforts reviewed fell short of theory testing. Even for those studies that were designed to contribute to theory development, it was rare to find research reports that included implications regarding theory in the discussion sections. Additionally, discussion sections of the reports typically did not identify alternative explanations for the findings. Quasi-experimental, ex post facto, and causal comparative studies typically were flawed with validity problems. If nursing is to strengthen its contribution to knowledge in the area of stress, more emphasis will need to be placed on congruence between design and measurement, and on issues of statistical rigor, validity, and reliability. Although some might argue that it is too early to expect a coalescing of definitional orientations, it is important to point out that considerable confusion regarding stress phenomena results from a nonsystematic or nondeliberative mixture of incompatible orientations to or definitions of stress. It is little wonder that the vast number of opinion articles that appear in the nursing literature include varied definitions of stress, often making conflicting recommendations regarding the nursing assessment of stress and nursing intervention strategies to assist a person in stress management efforts.


A nationwide survey of adenovirus-associated encephalitis/encephalopathy in Japan.
Adenovirus is a major pathogen causing febrile illness among children. It may also cause acute encephalitis/encephalopathy. This study aimed to elucidate the clinical features of adenovirus-associated encephalitis/encephalopathy (AdVE) among children in Japan. A nationwide survey of children with AdVE was conducted. An initial survey was distributed among pediatricians to obtain information about children with AdVE treated between January 2014 and March 2019. A second survey was used to obtain the clinical information of children with AdVE from hospitals that responded to the initial survey and those identified from a literature search of the reported cases. We collected demographic data and information about symptoms of infection, neurological symptoms, laboratory parameters, treatment, and outcomes. Outcomes were determined using the Pediatric Cerebral Performance Category Score. Clinical information was available for 23 children with a median age of 39 months. Two had preexisting neurological disorders and six had a history of febrile seizures. The outcome was good in 15 patients and poor in eight patients. Serum lactate dehydrogenase, glucose, and ammonia levels were higher among children with a poor outcome compared to those with a good outcome. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion was the most common type (n = 8), followed by acute encephalopathy with biphasic seizures and late reduced diffusion (n = 7). A prior history of febrile seizures was frequent in children with AdVE. Several different subtypes of acute encephalopathy were seen in children with AdVE, and the outcome was poor in those with acute encephalopathy with biphasic seizures and late reduced diffusion and hemorrhagic shock and encephalopathy syndrome. Elevated lactate dehydrogenase, glucose, and ammonia levels on admission were found to correlate with a poor outcome.


Replicating prediction algorithms for hospitalization and corticosteroid use in patients with inflammatory bowel disease.
Previous work had shown that machine learning models can predict inflammatory bowel disease (IBD)-related hospitalizations and outpatient corticosteroid use based on patient demographic and laboratory data in a cohort of United States Veterans. This study aimed to replicate this modeling framework in a nationally representative cohort. A retrospective cohort design using Optum Electronic Health Records (EHR) were used to identify IBD patients, with at least 12 months of follow-up between 2007 and 2018. IBD flare was defined as an inpatient/emergency visit with a diagnosis of IBD or an outpatient corticosteroid prescription for IBD. Predictors included demographic and laboratory data. Logistic regression and random forest (RF) models were used to predict IBD flare within 6 months of each visit. A 70% training and 30% validation approach was used. A total of 95,878 patients across 780,559 visits were identified. Of these, 22,245 (23.2%) patients had at least one IBD flare. Patients were predominantly White (87.7%) and female (57.1%), with a mean age of 48.0 years. The logistic regression model had an area under the receiver operating curve (AuROC) of 0.66 (95% CI: 0.65-0.66), sensitivity of 0.69 (95% CI: 0.68-0.70), and specificity of 0.74 (95% CI: 0.73-0.74) in the validation cohort. The RF model had an AuROC of 0.80 (95% CI: 0.80-0.81), sensitivity of 0.74 (95% CI: 0.73-0.74), and specificity of 0.72 (95% CI: 0.72-0.72) in the validation cohort. Important predictors of IBD flare in the RF model were the number of previous flares, age, potassium, and white blood cell count. The machine learning modeling framework was replicated and results showed a similar predictive accuracy in a nationally representative cohort of IBD patients. This modeling framework could be embedded in routine practice as a tool to distinguish high-risk patients for disease activity.


[Autonomy or compassion? Values to be taken into account in the treatment of patients suffering Alzheimer's disease].
Advance directives applied to decision making in assisting people with neurodegenerative disorders like Alzheimer disease faces professionals with an ethical dilemma that seems to have a pole on the autonomy enjoyed by the subject when gave such directions and in the other the compassion that awakens the individual at the time of their implementation. In this paper we take the concepts of R. Dworkin of experiential interests(i.e. things that people do just because they like the experience of doing them) and critical interests (interests, which if not satisfied, people would think they were worse off in some way or that their life had been wasted) to discuss about autonomy of persons with dementia. To what extent the subject that provides advance directives knows about his or her future experience? Is it enough to have a statistical knowledge about the evolution of certain conditions to make early decisions about our own very existence? When a disease like Alzheimer bursts into the life of a person, is personal identity disrupted in such a way that decisions taken before lose strength or is there a continuum that should guide the actions of those who attend?


Implication of antibiotic referents in complex bone and joint infections.
One of the main objectives of antibiotic referents in French hospitals is to promote the nationwide antibiotic stewardship program. National guidelines for complex bone and joint infection management (CBJI) issued in 2009, and expert and associated hospital centres were chosen. Our aim was to determine the role of antibiotic referents in CBJI treatment modalities, in 2012. A questionnaire was proposed to participants at the seventh national meeting of antibiotic referent in June 2012. Ninety-seven questionnaires were completed. Antibiotic referents were mainly infectious diseases doctors working in public hospitals with more than 300 hundreds beds. Twenty-eight units dedicated to CBJI were reported, as well as 35 multidisciplinary team meetings, 57% of which including physicians from both private and public hospitals. The 2009 national recommendations were the reference for 81% of responders, while referring to expert and associated centres was reported by 80%. Patient transfer to a reference center was rare, for both geographic reason and divergent medical and surgical habits. Most antibiotic referents suggested a 6-week course of antibiotic therapy and 12 months of follow-up. Twenty-two percent of the responders participated in morbidity and mortality audits. The 2009 national guidelines were rapidly taken into account. Their implementation led to more homogeneous clinical practices as reported by antibiotic referents. Reference centres are used for advice but patient transfer to these centres is still rare.


LLC-PK1 cells: cloning of phenotypically stable subpopulations.
The LLC-PK1 pig kidney-derived cell line is morphologically and functionally heterogeneous. We have clonally derived three sublines that differ in their response to calcitonin and in their ability to form domes. The three clones were analyzed for their basal and hormonally induced plasminogen activator production. In contrast to the D + Sc clone, in which calcitonin induced a greater than 100-fold increase in plasminogen activator synthesis, the D + Rc clone did not respond to the hormone; this was related to a deficiency of the cells in calcitonin binding. Transepithelial electrical resistance measurements revealed a direct correlation with the capacity of the cells to form domes; in one of the isolated clones (D-), the lack of dome formation coincided with a low electrical resistance; the D + Sc clone, in which all single cell-derived colonies formed domes, showed a higher electrical resistance than that developed by the original cell line. Thus the LLC-PK1 clones provide a useful in vitro model for the study of epithelial properties.


Strepsirrhine Primate Training Programs in North American Institutions: Status and Implications for Future Welfare Assessment.
Many articles have shown the benefits of operant conditioning training techniques in the care and welfare of several species of nonhuman primates; however, the information regarding their use in strepsirrhine species is scarce. We assessed the development and current status of training programs with these species in North American institutions. An online survey was distributed through members of the Association of Zoos and Aquariums using a multiple-choice format. We collected information related to training program details; animals, behaviors, and techniques; the evaluation process; and the impact of training. Seventy-one organizations completed the survey, with the results showing that 97% of respondents trained their strepsirrhines with the main objective of husbandry and veterinary care (around 80%). Sixty-eight percent of organizations did not report any risk in training these species. The benefits reported include increases in positive human-animal interactions (97%), psychological well-being (88%), and staff awareness of animal behaviors (90%). However, a multi-dimensional approach to measure the efficacy of training could provide a deeper understanding of its impact on the welfare of strepsirrhine primates. We hope that the data offered in this survey can help in this future assessment.


Design and evaluation of inhibitors of enkephalin degrading enzymes.
The endogenous opioid peptides enkephalins are degraded in vitro by several metallopeptidases (aminopeptidases, enkephalinase, dipeptidylaminopeptidases). Selective and mixed inhibitors of these enzymes were obtained by a rational approach taking into account crystallographic data on Thermolysin, a bacterial enzyme, used as model of metallopeptidase active site. This strategy is supported by recent cloning of enkephalinase. As expected, a physiological analgesia is produced by administration of inhibitors, especially kelatorphan and analogues, demonstrating unambiguously the implication of enkephalinase and aminopeptidase M in enkephalin metabolism. The intensive studies on endogenous opioid system have shown that inhibitors of enkephalin metabolism represent very useful probes and promising new analgesics.


Tpr Misregulation in Hippocampal Neural Stem Cells in Mouse Models of Alzheimer's Disease.
Nuclear pore complexes (NPCs) are highly dynamic macromolecular protein structures that facilitate molecular exchange across the nuclear envelope. Aberrant NPC functioning has been implicated in neurodegeneration. The translocated promoter region (Tpr) is a critical scaffolding nucleoporin (Nup) of the nuclear basket, facing the interior of the NPC. However, the role of Tpr in adult neural stem/precursor cells (NSPCs) in Alzheimer's disease (AD) is unknown. Using super-resolution (SR) and electron microscopy, we defined the different subcellular localizations of Tpr and phospho-Tpr (P-Tpr) in NSPCs in vitro and in vivo. Elevated Tpr expression and reduced P-Tpr nuclear localization accompany NSPC differentiation along the neurogenic lineage. In 5xFAD mice, an animal model of AD, increased Tpr expression in DCX+ hippocampal neuroblasts precedes increased neurogenesis at an early stage, before the onset of amyloid-β plaque formation. Whereas nuclear basket Tpr interacts with chromatin modifiers and NSPC-related transcription factors, P-Tpr interacts and co-localizes with cyclin-dependent kinase 1 (Cdk1) at the nuclear chromatin of NSPCs. In hippocampal NSPCs in a mouse model of AD, aberrant Tpr expression was correlated with altered NPC morphology and counts, and Tpr was aberrantly expressed in postmortem human brain samples from patients with AD. Thus, we propose that altered levels and subcellular localization of Tpr in CNS disease affect Tpr functionality, which in turn regulates the architecture and number of NSPC NPCs, possibly leading to aberrant neurogenesis.


Superparallel holographic correlator for ultrafast database searches.
We describe a superparallel holographic optical correlator that performs two-dimensional spatial and angular multiplexing simultaneously. The key step in this architecture is the use of a holographic multiplexer to split a query image into many copies before it applies them to the holographic database. A holographic demultiplexer, in conjunction with an aperture, is used to identify the location and the angle of the brightest correlation peak. This architecture uses only O(square root of N) detector elements to search through N unsorted images in a single query. We demonstrate the basic features of this architecture, using three spatial locations with eight angle-multiplexed images in each location.


Surface contacts strongly influence the elasticity and thermal conductivity of silica nanoparticle fibers.
Granular materials are often encountered in science and engineering disciplines, in which controlling the particle contacts is one of the critical issues for the design, engineering, and utilization of their desired properties. The achievable rapid fabrication of nanoparticles with tunable physical and chemical properties facilitates tailoring the macroscopic properties of particle assemblies through contacts at the nanoscale. Models have been developed to predict the mechanical properties of macroscopic granular materials; however, their predicted power in the case of nanoparticle assemblies is still uncertain. Here, we investigate the influence of nanocontacts on the elasticity and thermal conductivity of a granular fiber comprised of close-packed silica nanoparticles. A complete elastic moduli characterization was realized by non-contact and non-destructive Brillouin light spectroscopy, which also allowed resolving the stiffness of the constituent particles in situ. In the framework of effective medium models, the strong enhancement of the elastic moduli is attributed to the formation of adhesive nanocontacts with physical and/or chemical bondings. The nanoparticle contacts are also responsible for the increase in the fiber thermal conductivity that emphasizes the role of interface thermal resistance, which tends to be ignored in most porosity models. This insight into the fundamental understanding of structure-property relationships advances knowledge on the manipulation of granular systems at the nanoscale.


Orphan receptor DAX-1 is a shuttling RNA binding protein associated with polyribosomes via mRNA.
The DAX-1 (NR0B1) gene encodes an unusual member of the nuclear hormone receptor superfamily which acts as a transcriptional repressor. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). We have studied the intracellular localization of the DAX-1 protein in human adrenal cortex and mouse Leydig tumor cells and found it to be both nuclear and cytoplasmic. A significant proportion of DAX-1 is associated with polyribosomes and is found complexed with polyadenylated RNA. DAX-1 directly binds to RNA, two domains within the protein being responsible for cooperative binding activity and specificity. Mutations in DAX-1 found in AHC-HHG patients significantly impair RNA binding. These findings reveal that DAX-1 plays multiple regulatory roles at the transcriptional and posttranscriptional levels.


PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer.
Polysialic acid (polySia) is expressed on several malignant tumors of neuroendocrine origin, including small cell lung cancer. In this study, we investigated the therapeutic efficacy of tumor-directed T-cell responses, elicited by polySia-retargeted oncolytic adenovirus infection, in an orthotopic murine model of disseminated polySia-positive lung cancer. In several cell lines, we demonstrated highly polySia-selective retargeting of adenoviral infection using a bispecific adapter comprising the ectodomain of the coxsackievirus/adenovirus receptor and a polySia-recognizing single-chain antibody domain. PolySia-dependent systemic infection in vivo facilitated effective uptake of viruses in subcutaneous polySia-expressing human tumors, whereas hepatic viral load and hepatotoxicity were significantly reduced. The impact and nature of antitumoral immune responses triggered by systemic delivery of polySia-retargeted oncolytic adenoviruses were investigated in an orthotopic model of disseminated lung cancer. Interestingly, improved transduction by polySia-retargeted oncolytic adenoviruses led to CD45-positive cell infiltrates in close association with large lytic areas. Consistently, enhanced tumor regression and prolonged survival was only observed in immunocompetent mice, but not in T-cell-deficient mice. To investigate whether improved systemic infection by polySia retargeting would elicit a tumor-specific T-cell response, we screened the used lung cancer cells for mutated oncogenes by complete exon sequencing. In agreement with our other results, only retargeted oncolysis was able to induce a significant response specific for the tumor-associated neoepitope Gsta2-Y9H. In conclusion, we demonstrated that effective retargeting of oncolytic adenovirus against polySia-expressing tumors elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer.


Lymphangitic spread from the appendiceal adenocarcinoma to the ileocecal valve, mimicking Crohn's disease.
Due to the anatomical peculiarity of the appendix, diagnosis of tumors arising from this area can be challenging by clinicoradiologic means. We report a case of a rare primary appendiceal signet ring carcinoma with an uncommon presentation. An 86-year-old woman was admitted to our hospital with subacute epigastric pain. Computed tomography demonstrated bowel wall thickening with fat stranding in the ileocecal region. The leading diagnostic consideration was inflammatory bowel disease. Upon colonoscopy, a swollen, distorted ileocecal valve was identified. The remaining colon was otherwise unremarkable. Extensive biopsy sampling of the ileocecal region and colon was performed. A lymphangitic signet ring carcinoma within the ileocecal region was diagnosed on biopsy; there was no dysplasia or carcinoma of the remaining biopsies. By cytomorphology and immunoprofile, a lymphangitic signet ring carcinoma of appendiceal origin was the primary consideration, further confirmed upon subsequent laparotomy. This case represents an unusual pattern of appendiceal tumor spread with localized, lymphangitic involvement, creating a milieu which closely simulates Crohn's disease on imaging modalities.


Roles for ORC in M phase and S phase.
The origin recognition complex (ORC), a six-subunit protein, functions as the replication initiator in the yeast Saccharomyces cerevisiae. Initiation depends on the assembly of the prereplication complex in late M phase and activation in S phase. One subunit of ORC, Orc5p, was required at G1/S and in early M phase. Asynchronous cells with a temperature-sensitive orc5-1 allele arrested in early M phase. In contrast, cells that were first synchronized in M phase, shifted to the restrictive temperature, and then released from the block arrested at the G1/S boundary. The G1/S arrest phenotype could not be suppressed by introducing wild-type Orc5p during G1. Although all orc2 and orc5 mutations were recessive in the conventional sense, this dominant phenotype was shared with other orc5 alleles and an orc2 allele. The dominant inhibition to cell-cycle progression exhibited by the orc mutants was restricted to the nucleus, suggesting that chromosomes with mutant ORC complexes were capable of sending a signal that blocked initiation on chromosomes containing functional origins.


AGE metabolites: a biomarker linked to cancer disparity?
Socioeconomic and environmental influences are established factors promoting cancer disparity, but the contribution of biologic factors is not clear. We report a mechanistic link between carbohydrate-derived metabolites and cancer that may provide a biologic consequence of established factors of cancer disparity. Glycation is the nonenzymatic glycosylation of carbohydrates to macromolecules, which produces reactive metabolites called advanced glycation end products (AGE). A sedentary lifestyle and poor diet all promote disease and the AGE accumulation pool in our bodies and also increase cancer risk. We examined AGE metabolites in clinical specimens of African American and European American patients with prostate cancer and found a higher AGE concentration in these specimens among African American patients when compared with European American patients. Elevated AGE levels corresponded with expression of the receptor for AGE (RAGE or AGER). We show that AGE-mediated increases in cancer-associated processes are dependent upon RAGE. Aberrant AGE accumulation may represent a metabolic susceptibility difference that contributes to cancer disparity.


Development of the Wheelchair outcomes Assessment Tool for Children (WATCh): A patient-centred outcome measure for young wheelchair users.
To develop a patient-centred outcome measure (PCOM) for use with children and young people accessing National Health Service (NHS) wheelchair and posture services. Identifying and addressing outcomes of most importance to young wheelchair users (≤ 18 years) will help services maximise the benefits achievable within available resources. A mixed-methods approach was used, involving questionnaire surveys and qualitative interviews, and building on previous work identifying how young wheelchair users define health-related quality of life (HRQoL). Framework analysis was used to analyse the interview transcripts. Survey questionnaires seeking views on the importance of a range of outcomes were completed by 21 young wheelchair users or their parents. Subsequent face-to-face interviews with 11 parents or dyads of parents and young wheelchair users explored these responses and identified novel outcomes. Interviewees also scored and recorded satisfaction levels for their key outcomes. All outcomes proposed in the survey were rated as 'extremely important' by at least one respondent, as were additional outcomes uncovered in the qualitative data. In consultation with the service providers and service users, the Wheelchair outcomes Assessment Tool for Children (WATCh) was developed to allow service users and providers to identify, score and monitor individual users' most important outcomes. The final WATCh tool comprises 16 outcome options, of which service users select five to be monitored. The tool will be used to measure key outcomes identified by service users before and after wheelchair provision.


Characterization of the Anti-Inflammatory Capacity of IL-10-Producing Neutrophils in Response to Streptococcus pneumoniae Infection.
Neutrophils are immune cells classically defined as pro-inflammatory effector cells. However, current accumulated evidence indicates that neutrophils have more versatile immune-modulating properties. During acute lung infection with Streptococcus pneumoniae in mice, interleukin-10 (IL-10) production is required to temper an excessive lung injury and to improve survival, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during S. pneumoniae infection remain unknown. Here we show that neutrophils are the main myeloid cells that produce IL-10 in the lungs during the first 48 h of infection. Importantly, in vitro assays with bone-marrow derived neutrophils confirmed that IL-10 can be induced by these cells by the direct recognition of pneumococcal antigens. In vivo, we identified the recruitment of two neutrophil subpopulations in the lungs following infection, which exhibited clear morphological differences and a distinctive profile of IL-10 production at 48 h post-infection. Furthermore, adoptive transfer of neutrophils from WT mice into IL-10 knockout mice (Il10-/- ) fully restored IL-10 production in the lungs and reduced lung histopathology. These results suggest that IL-10 production by neutrophils induced by S. pneumoniae limits lung injury and is important to mediate an effective immune response required for host survival.


Cutaneous basophil (Jones-Mote) hypersensitivity after "tolerogenic" doses of intravenous ovalbumin in the guinea pig.
Cutaneous basophil hypersensitivity (CBH) was studied for tolerogenic requirements. Graded doses of intravenous ovalbumin (OA) were given to guinea pigs which were subsequently immunized appropriately to produce CBH, classic delayed hypersensitivity (classic DH), and/or antibodies of both passive cutaneous anaphylaxis (PCA) and hemolytic types. Results showed that doses of intravenous antigen sufficient to induce subsequent tolerance for classic DH and hemolytic antibody actually stimulate CBH reactivity and PCA antibody production. Other studies of dose-route relationships for CBH production demonstrated that optimal immunogenic dosage requirements for CBH varied widely with route of antigen employed. OA in incomplete Freund's adjuvant (IFA) injected into footpads had low dosage requirements, intravenous OA had high dose requirements, and intradermal soluble OA dosage requirements were intermediate. The observation that blatant immunogenic responses occur during the early period of tolerance induction amplifies the significant heterogeneity of the cellular immune response and may be of importance in understanding tolerogenesis. Similar immunogenic-tolerogenic requirements and the prime role played by the basophil suggest a developmental or functional relationship between CBH and PCA antibody response.


Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3.
We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer, dentate nuclei and inferior olives, thinning of cerebellopontine tracts, demyelination of posterior and lateral columns in the spinal cord, as well as ubiquitin-positive intranuclear inclusions in nigral neurons that were considered to be Marinesco bodies. Data obtained from the genome-wide linkage analysis revealed a maximal lod score of 3.46 at = 0.00 for marker D20S199. This new SCA locus, on chromosome region 20p13-p12.3, was designated SCA23 after approval by the HUGO Nomenclature Committee. Currently, candidate genes are being screened for mutations within the SCA23 interval. In addition to the recently identified SCA14, SCA19 and FGF14 families, SCA23 is yet another novel SCA locus in the Dutch ADCA population, which further defines the genetic heterogeneity of ADCA families in the Netherlands.


In-sewer stability of 31 human health biomarkers and suitability for wastewater-based epidemiology.
Monitoring urinary markers of dietary, disease, and stress by wastewater-based epidemiology (WBE) is a promising tool to better understand population health and wellbeing. However, common urinary biomarkers are subject to degradation in sewer systems and their fates have to be assessed before they can be used in WBE. This study investigated the stability of 31 urinary biomarkers (12 food biomarkers, 8 vitamins, 9 oxidative stress biomarkers, and 1 histamine biomarker) in a laboratory sewer sediment reactor and evaluated their suitability for WBE, considering their detectability in real wastewater and in-sewer stability. These biomarkers showed various transformation patterns, among which 16 compounds had half-lives <2 h while other 15 compounds presented moderate to high stability (2 to >500 h). Thirteen biomarkers showed potential for WBE because of their consistently measurable concentrations in untreated wastewater and sufficient in-sewer stability. Eighteen biomarkers were unsuitable due to their rapid in-sewer degradation and/or undetectable concentration levels in untreated wastewater using previous methods. Transformation rates of these biomarkers showed generally weak relationships with molecular properties but relatively higher correlations with biological activities in sewers. Overall, this study determined in-sewer stability of 31 health-related biomarkers through laboratory experiments, providing new findings to WBE for population health assessment.


[Rejection antigens of tumors and specific immunotherapy of cancer].
Human tumors carry antigens that are recognized by the patients' cytolytic T lymphocytes. An important group of antigens is coded by the MAGE family of genes. These antigens are expressed in a significant proportion of tumors of numerous histological types but not in normal tissues. Clinical trials are underway in an attempt to immunize patients suffering from metastatic melanomas using peptides coded by the MAGE genes. Regressions have been observed in 5 of the 17 immunized patients.


Multifunctional mesoporous composite microspheres with well-designed nanostructure: a highly integrated catalyst system.
The precise control of the size, morphology, surface chemistry, and assembly process of each component is important to construction of integrated functional nanocomposites. We report here the fabrication of multifunctional microspheres which possess a core of nonporous silica-protected magnetite particles, transition layer of active gold nanoparticles, and an outer shell of ordered mesoporous silica with perpendicularly aligned pore channels. The well-designed microspheres have high magnetization (18.6 emu/g), large surface area (236 m(2)/g), highly open mesopores (approximately 2.2 nm), and stably confined but accessible Au nanoparticles and, as a result, show high performance in catalytic reduction of 4-nitrophenol (with conversion of 95% in 12 min), styrene epoxidation with high conversion (72%) and selectivity (80%), especially convenient magnetic separability, long life and good reusability. The unique nanostructure makes the microsphere to be a novel stable and approachable catalyst system for various catalytic industry processes.