Temporal trends in co-morbidities and cardiometabolic risk factors at the time of type 2 diabetes diagnosis in the UK.
To evaluate temporal patterns in co-morbidities, cardiometabolic risk factors and a high atherosclerotic cardiovascular disease (ASCVD) risk population at type 2 diabetes (T2D) diagnosis by age groups and sex. From the UK primary care database, 248,619 people with a new diagnosis of T2D during 2005-2016 were identified. Among people without ASCVD, high ASCVD risk was defined as two or more of current smoker, grade 2+ obesity, hypertension, dyslipidaemia or microvascular disease. Cardiometabolic multimorbidity (CMM) was defined as two or more of cardiovascular disease, microvascular disease, hypertension, dyslipidaemia, grade 2+ obesity or cancer. Temporal patterns in the distribution of cardiometabolic risk factors were evaluated. While the prevalence of ASCVD was stable over time (approximately 18%), 50% were identified to have a high ASCVD risk (26% and 38% in the 18-39 and 40-49 years age groups, respectively), with an increasing trend across all age groups. Overall, 51% had CMM at diagnosis, increasing during 2005-2016 for the 18-39 years age group by 14%-17%, for the 40-49 years age group by 27%-33%, for the 50-59 years age group by 41%-50%, for the 60-69 years age group by 56%-65%, and for the 70-79 years age group by 65%-80%. People with young-onset T2D had significantly higher HbA1c, body mass index and lipids at diagnosis (all p < .01). The proportions with an HbA1c of 7.5% or higher in the 18-39 and 40-49 years age groups were 58% and 54%, respectively, significantly and consistently higher over the last decade compared with those aged 50 years or older, with males having higher proportions of 15-26 and 10-18 percentage points, respectively, compared with females. CMM and high ASCVD risk have been increasing consistently across all age groups and in both sex, in particular CMM in those aged younger than 50 years. Our findings indicate that the European Society of Cardiology-European Association for the Study of Diabetes recommendations need to change to consider people with young-onset T2D as a high-risk group, as recommended in the Primary Care Diabetes Europe position statement.


Vaccination of white-tailed deer (Odocoileus virginianus) with Mycobacterium bovis bacillus Calmette Guerín.
Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis in domestic livestock. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to cattle. One approach in dealing with this wildlife reservoir is to vaccinate deer in order to interrupt the cycle of deer to deer and deer to cattle transmission. Thirty-one white-tailed deer were assigned to one of three groups; 2 SC doses of 10(7)CFU of M. bovis BCG (n=11); 1 SC dose of 10(7)CFU of M. bovis BCG (n=10); or unvaccinated deer (n=10). After vaccination, deer were inoculated intratonsilarly with 300 CFU of virulent M. bovis. Gross lesion severity scores of the medial retropharyngeal lymph node were significantly reduced in deer receiving 2 doses of BCG compared to unvaccinated deer. Vaccinated deer had fewer lymph node granulomas than unvaccinated deer, and most notably, fewer late stage granulomas characterized by coalescent caseonecrotic granulomas containing numerous acid-fast bacilli. BCG was isolated from 7/21 vaccinated deer as long as 249 days after vaccination. In one case BCG was transmitted from a vaccinated deer to an unvaccinated deer. In white-tailed deer BCG provides measurable protection against challenge with virulent M. bovis. However, persistence of vaccine within tissues as well as shedding of BCG from vaccinates remain areas for further investigation.


Overt and covert processing of left-side information in unilateral neglect investigated with chimeric drawings.
Overt and covert processing of contralesional information was investigated in 6 right-brain-damaged (RBD) patients with or without left hemispatial neglect by using three bedside tests that require the analysis of whole, half, and chimeric drawings. In the first task, patients named these stimuli. In the second task, patients designated as "same" or "different" drawings in a pair where one drawing was always whole and the other could be whole, half, or chimeric. In the third task, patients pointed to the more veridical, complete drawing that was presented with one half drawing, and two chimeric drawings. Although patients with no neglect performed without error in all conditions, patients with severe neglect based their performance on the analysis of the right side of the stimuli. In patients with mild neglect, not only did performance rely upon the right side of stimuli but it was also modulated by left-side information acquired either overtly or unconsciously.


Prevalence of bone loss in a population with cystic fibrosis.
The adverse effect of an increased life expectancy for people with cystic fibrosis (CF) is the increased risk of complications, such as CF-related low bone mineral density (BMD). Diagnosis of CF-related low BMD is confirmed by a dual-energy X-ray absorptiometry (DXA) scan. This study reports the results of an audit of DXA scans in 108 adults with CF in our clinic. The most common risk factors for bone loss were vitamin D deficiency (89%), CF-related diabetes (53%), low body mass index (39%) and post-lung transplant (25%); half of those with bone loss were genotype homozygous DF508. Overall fracture incidence was 5.5%; low BMD was not associated with high fracture rates. Thus BMD may not be a good predictor of fracture risk. Treatment includes bisphosphonates, which are difficult to take and have uncertain long-term effects. It is unknown whether bisphosphonate therapy is justified in this already overburdened group.


Perspectives in post-transplantation immunotherapy in breast cancer.
High risk and metastatic breast cancer remain a major therapeutic challenge. Although the role of high dose chemotherapy followed by stem cell transplantation (SCT) in the overall treatment strategy is not yet well defined, it is clear that new forms of therapy such as immunotherapy will be needed to cure the majority of patients with advanced disease. We review important considerations for immunotherapy in the post-transplantation period. Experimental and clinical data suggest that immunotherapy may be most effective in a state of minimal residual disease such as that achieved following SCT. However, high dose therapy and autologous SCT result in an iatrogenic immune deficiency, which compounds the suppression of the immune system associated with tumor itself. Understanding reconstitution of a functional immune system post transplantation is critical in devising clinically effective immune interventions. A review of the clinical studies of post transplant immunotherapy for breast cancer is presented including autologous and allogeneic strategies, as well as perspectives for future development.


Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65.
Latency-associated nuclear antigen 1 (LANA-1) of Kaposi's sarcoma-associated herpesvirus (KSHV) is the major viral latent protein and functions as a multifaceted protein. Here, we report that LANA-1 attenuates the endothelial response to tumor necrosis factor alpha (TNF-α) stimulation and inhibits consequent neutrophil chemotaxis. Reporter assays showed that LANA-1 constantly repressed nuclear factor (NF)-κB transactivity upon TNF-α stimulation. We also found that LANA-1 decreased nuclear p65 protein levels through enhancement of polyubiquitylation-mediated p65 degradation and that an elongin B/elongin C-cullin 5-LANA-1-p65 complex assembled by LANA-1 was responsible for this enhanced p65 degradation. In telomerase-immortalized human umbilical vein endothelial cells, LANA-1 was demonstrated to repress interleukin-8 expression, which was involved in neutrophil recruitment to the inflammatory site. Through an in vitro transmigration assay, we determined a suppressive effect of LANA-1 on neutrophil chemotaxis. Our work suggests that KSHV LANA-1 is a negative modulator of acute inflammation and sheds light on a new mechanism by which KSHV during the latent life cycle evades the host innate immune response.


No surgical innovation without evaluation: the IDEAL recommendations.
Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies.


Identification and analysis of the first 2009 pandemic H1N1 influenza virus from U.S. feral swine.
The first case of pandemic H1N1 influenza (pH1N1) virus in feral swine in the United States was identified in Texas through the United States Department of Agriculture (USDA) Wildlife Services' surveillance program. Two samples were identified as pandemic influenza by reverse transcriptase quantitative PCR (RT-qPCR). Full-genome Sanger sequencing of all eight influenza segments was performed. In addition, Illumina deep sequencing of the original diagnostic samples and their respective virus isolation cultures were performed to assess the feasibility of using an unbiased whole-genome linear target amplification method and multiple sample sequencing in a single Illumina GAIIx lane. Identical sequences were obtained using both techniques. Phylogenetic analysis indicated that all gene segments belonged to the pH1N1 (2009) lineage. In conclusion, we have identified the first pH1N1 isolate in feral swine in the United States and have demonstrated the use of an easy unbiased linear amplification method for deep sequencing of multiple samples.


Pollen lipidomics: lipid profiling exposes a notable diversity in 22 allergenic pollen and potential biomarkers of the allergic immune response.
Pollen grains are the male gametophytes that deliver sperm cells to female gametophytes during sexual reproduction of higher plants. Pollen is a major source of aeroallergens and environmental antigens. The pollen coat harbors a plethora of lipids that are required for pollen hydration, germination, and penetration of the stigma by pollen tubes. In addition to proteins, pollen displays a wide array of lipids that interact with the human immune system. Prior searches for pollen allergens have focused on the identification of intracellular allergenic proteins, but have largely overlooked much of the extracellular pollen matrix, a region where the majority of lipid molecules reside. Lipid antigens have attracted attention for their potent immunoregulatory effects. By being in close proximity to allergenic proteins on the pollen surface when they interact with host cells, lipids could modify the antigenic properties of proteins. We performed a comparative pollen lipid profiling of 22 commonly allergenic plant species by the use of gas chromatography-mass spectroscopy, followed by detailed data mining and statistical analysis. Three experiments compared pollen lipid profiles. We built a database library of the pollen lipids by matching acquired pollen-lipid mass spectra and retention times with the NIST/EPA/NIH mass-spectral library. We detected, identified, and relatively quantified more than 106 lipid molecular species including fatty acids, n-alkanes, fatty alcohols, and sterols. Pollen-derived lipids stimulation up-regulate cytokines expression of dendritic and natural killer T cells co-culture. Here we report on a lipidomic analysis of pollen lipids that can serve as a database for identifying potential lipid antigens and/or novel candidate molecules involved in allergy. The database provides a resource that facilitates studies on the role of lipids in the immunopathogenesis of allergy. Pollen lipids vary greatly among allergenic species and contain many molecules that have stimulatory or regulatory effects on immune responses.


Pelvic floor muscle training using an extracorporeal biofeedback device for female stress urinary incontinence.
Extracorporeal biofeedback was developed to reduce patient discomfort when performing strengthening exercises. The efficacy and safety of extracorporeal biofeedback combined with pelvic floor muscle training (PFMT) for the treatment of female stress urinary incontinence (SUI) were evaluated. One hundred and six participants with SUI were enrolled in a 12-week PFMT program using extracorporeal biofeedback intervention. A standard pad test was performed, and pelvic floor muscle strength was assessed using the Oxford scale. Measurements were taken with a perineometer at baseline and at a 12-week follow-up visit. An objective cure was defined as less than 2 g of urine leakage by the standard pad test. The long-term effects of extracorporeal biofeedback and PFMT were investigated by interviewing the participants 12 months after treatment. Seventy-one participants completed the 12-week extracorporeal biofeedback intervention. The objective cure rate was 52.1 %, and there was a significant reduction in pad weight over the time period. The incontinence visual analogue scale, the Sandvik severity index, and the incontinence quality-of-life questionnaire domains were significantly improved after treatment (p<0.001). The strength of the PFM was significantly increased after the 12-week treatment. After PFMT, 64.3 % of 56 participants reported good treatment compliance, and 24 participants (42.9 %) had continued PFMT at home 12 months after treatment. Age and baseline pad weight were negative predictive factors for an objective cure of SUI. Pelvic floor muscle training using extracorporeal biofeedback can be an effective and safe conservative treatment option for female SUI without the discomfort caused by vaginal sensors.


Collagenase penetrates human pancreatic islets following standard intraductal administration.
: To optimize human islet isolation, it is important to improve our understanding of the collagenase digestion phase. Previous studies of collagenase action were mostly concerned with optimizing its composition, but the delivery and distribution of collagenase at the islet-exocrine interface is likely to be important for liberation of intact islets. The aim of this study was to characterize collagenase distribution in relation to islets in infused human pancreases. : Human pancreases were retrieved from multiorgan donors with appropriate consent. Tissue samples were taken from the neck, body, and tail regions before and after collagenase infusion by manual syringe-loading (n=10) or recirculating perfusion (n=8), and snap frozen in liquid nitrogen. Frozen sections were immunolabeled for collagenase, insulin, CK19, collagen VI and CD31, then assessed by confocal microscopy. : Collagenase labeling was widespread throughout the pancreas, associated with collagen VI, and adjacent to CK19-labeled ducts. Collagenase was found within 67%+/-2% of islets ("intraislet"), associated with capillaries (CD31-positive). Intraislet collagenase was observed in 70%+/-3% of islets in the pancreatic tail, compared with 58%+/-2% and 53%+/-2% of islets in the body and neck, respectively (P<0.05 tail vs. neck), and was more prevalent in islets with diameters more than 150 microm (98%+/-1% of islets >150 microm vs. 52%+/-2% of islets <150 microm, P<0.05). There was no difference in intraislet collagenase labeling between perfused and syringe-loaded pancreases. : Using current infusion techniques, collagenase penetrates the islet interior. This could cause islet fragmentation, and consequently, low islet yields. This study underlies the need to optimize collagenase delivery to preserve intact islets.


Does release of encapsulated nutrients have an important role in the efficacy of xylanase in broilers?
The non-starch polysaccharides (NSPs) in cell walls can act as a barrier for digestion of intracellular nutrients. This effect is called "cage effect." Part of the success of fibrolytic enzymes in broiler feed is assumed to be attributed to cage effect reduction. Further, changes in viscosity and potential prebiotic action should also be considered. The aim of this study was to gain insight into the relative importance of the cage effect in xylanase efficacy in broilers. Using a 2×2 factorial design, 24 pens with 30 Ross 308 male chicks were fed corn-soy based diets consisting of normal and freeze-thawed (5 d at -18°C) corn, both with and without xylanase. The freeze-thaw method was used to eliminate the cage effect, whereas a corn-based diet was used to exclude viscosity effects. Body weights (BW), feed intake (FI), and feed conversion ratio (FCR) were determined at d 13, 26, and 39. A balance study was executed at the end of the growing phase. These birds were euthanized at d 34 (non-fasted) to determine the viscosity of digesta, blood metabolites, intestinal morphology, and microbiota composition. During the finisher period, there was a significant interaction between enzyme supplementation and freeze-thawing for FCR, in which FCR was improved by freeze-thawed corn and tended to be improved by normal corn+enzyme compared with the control group. The improvement in performance (finisher period) of freeze-thawed corn and xylanase coincided with increased gut absorption of glucose (based on postprandial plasma concentrations) and increased number of Clostridiumcluster IV in the caecum, and agreed with the higher gut villus height. In addition, xylanase inclusion significantly increased the postprandial plasma glycine and triglycerides concentration, and led to elevated bacterial gene copies of butyryl CoA:acetate CoA-transferase, suggesting a prebiotic effect of xylanase addition through more than just the cage effect reduction. The applied model managed to rule out viscosity by using corn, and it was possible to isolate the cage effect by freeze-thawing the dietary corn.


Merkel cell carcinoma: Is there a role for 2-deoxy-2-[f-18]fluoro-D-glucose-positron emission tomography/computed tomography?
2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is becoming widely available as a powerful imaging modality, combining the ability to detect active metabolic processes and their morphologic features in a single study. The role of FDG-PET/CT is proven in lymphoma, melanoma, colorectal carcinoma, and other cancers. However, there are rare malignancies such as Merkel cell carcinoma that can potentially be evaluated with PET/CT. We were therefore prompted to review our experience with FDG-PET/CT in the management of patients with Merkel cell carcinoma. This is a retrospective case series of six patients with Merkel cell carcinoma, 58-81 years old (average 69 +/- 8.3), who had whole-body PET/CT at our institution from January 1st, 2003 to August 31st, 2005. Two patients were women and four were men. Reinterpretation of the imaging studies for accuracy and data analysis from medical records were performed. Twelve examinations were acquired for the six patients (one patient had six PET/CT, one patient had two PET/CT, and four patients had one PET/CT). The injected FDG doses ranged 381.1-669.7 MBq (average 573.5 +/- 70.3). Four patients had the PET/CT as part of initial staging, and two patients had the exam for restaging (after surgery and XRT). A total of six Merkel lesions (pancreas, adrenal, lip, submandibular lymph nodes, cervical lymph nodes, and parapharyngeal soft tissue) were identified in three patients and confirmed on histopathological examination. The FDG uptake in these areas was intense, with maximum standardized uptake value (SUVmax) values of 5-14 (average 10.4 +/- 3.8). In one patient, the PET/CT scan identified abnormal focal distal sigmoid uptake that was biopsied and diagnosed as adenocarcinoma. Two patients had negative scans and had no clinical evidence of disease on follow-up office visits (up to one year after PET/CT). This case series suggests that FDG-PET/CT may have a promising role in the management of patients with Merkel cell carcinoma.


Helicobacter pylori adherence to gastric epithelial cells: a role for non-adhesin virulence genes.
Helicobacter pylori is a major aetiological agent in gastroduodenal disorders and adherence of the bacteria to the gastric mucosa is one of the initial stages of infection. Although a number of specific adhesins has been identified, other H. pylori virulence factors may play a role in adherence to gastric epithelial cells directly or through interaction with other adhesins. This study assessed the effect of 16 H. pylori virulence factors on the adherence of the bacteria to gastric AGS cells and on gastric epithelial cell cycle distribution. Defined isogenic H. pylori SS1 mutants were used. After co-incubation of gastric AGS cells and bacteria, adherence of H. pylori to AGS cells was visualised by immunofluorescence microscopy and quantified by flow cytometry. Cell cycle phase distribution was analysed by flow cytometry with propidium iodide staining. Mutants were tested for their ability to adhere to AGS cells and compared with the wild-type SS1 strain. Mutations in genes in the cag pathogenicity island showed that cagP and cagE mutants adhered less than the wild-type strain to AGS cells, whereas a cagF mutant showed no reduction in adherence. Mutations in genes involved in flagellar biosynthesis showed that the adherence ability of fliQ, fliM and fliS mutants was reduced, but a flhB mutant possessed wild-type levels of adherence. Mutations in genes coding for the urease (ureB) and phospholipase (pldA) enzymes did not affect adherence, but mutation of the tlyA gene encoding an H. pylori haemolysin resulted in a reduced adherence. A fliQ mutant, with reduced adherence to AGS cells, was less able to induce AGS cell apoptosis than SS1. The ability to induce G0G1 cell cycle arrest was also abolished in the fliQ mutant. However, an increased cell number in S phase was observed when AGS cells were exposed to the fliQ mutant compared with SS1, suggesting that unattached bacteria may still be able to stimulate cell proliferation. In addition to known adhesins, other bacterial virulence factors such as CagE, CagP, FliQ, FliM, FliS and TlyA appear to play a role in H. pylori adherence to gastric epithelial cells. Mutations in these genes may affect H. pylori pathogenicity by reducing either the ability of the bacteria to attach to gastric epithelial cells or the intensity of bacteria-host cell interactions.


Phase-amplitude response functions for transient-state stimuli.
The phase response curve (PRC) is a powerful tool to study the effect of a perturbation on the phase of an oscillator, assuming that all the dynamics can be explained by the phase variable. However, factors like the rate of convergence to the oscillator, strong forcing or high stimulation frequency may invalidate the above assumption and raise the question of how is the phase variation away from an attractor. The concept of isochrons turns out to be crucial to answer this question; from it, we have built up Phase Response Functions (PRF) and, in the present paper, we complete the extension of advancement functions to the transient states by defining the Amplitude Response Function (ARF) to control changes in the transversal variables. Based on the knowledge of both the PRF and the ARF, we study the case of a pulse-train stimulus, and compare the predictions given by the PRC-approach (a 1D map) to those given by the PRF-ARF-approach (a 2D map); we observe differences up to two orders of magnitude in favor of the 2D predictions, especially when the stimulation frequency is high or the strength of the stimulus is large. We also explore the role of hyperbolicity of the limit cycle as well as geometric aspects of the isochrons. Summing up, we aim at enlightening the contribution of transient effects in predicting the phase response and showing the limits of the phase reduction approach to prevent from falling into wrong predictions in synchronization problems. PRC phase response curve, phase resetting curve.PRF phase response function.ARF amplitude response function.


Role of structural order and excess energy on ultrafast free charge generation in hybrid polythiophene/Si photovoltaics probed in real time by near-infrared broadband transient absorption.
Despite the central role of light absorption and the subsequent generation of free charge carriers in organic and hybrid organic-inorganic photovoltaics, the precise process of this initial photoconversion is still debated. We employ a novel broadband (UV-Vis-NIR) transient absorption spectroscopy setup to probe charge generation and recombination in the thin films of the recently suggested hybrid material combination poly(3-hexylthiophene)/silicon (P3HT/Si) with 40 fs time resolution. Our approach allows for monitoring the time evolution of the relevant transient species under various excitation intensities and excitation wavelengths. Both in regioregular (RR) and regiorandom (RRa) P3HT, we observe an instant (<40 fs) creation of singlet excitons, which subsequently dissociate to form polarons in 140 fs. The quantum yield of polaron formation through dissociation of delocalized excitons is significantly enhanced by adding Si as an electron acceptor, revealing ultrafast electron transfer from P3HT to Si. P3HT/Si films with aggregated RR-P3HT are found to provide free charge carriers in planar as well as in bulk heterojunctions, and losses are due to nongeminate recombination. In contrast for RRa-P3HT/Si, geminate recombination of bound carriers is observed as the dominant loss mechanism. Site-selective excitation by variation of pump wavelength uncovers an energy transfer from P3HT coils to aggregates with a 1/e transfer time of 3 ps and reveals a factor of 2 more efficient polaron formation using aggregated RR-P3HT compared to disordered RRa-P3HT. Therefore, we find that polymer structural order rather than excess energy is the key criterion for free charge generation in hybrid P3HT/Si solar cells.


Effect of ascariasis and respiratory diseases on growth rates in swine.
Growth rates, measures of ascarid burden, and the levels of anteroventral pneumonia and atrophic rhinitis at slaughter were determined for 352 hogs born between March 8 and March 28, 1987 on 15 farms located in Prince Edward Island. Regression analyses were used to determine associations between average daily gain (ADG) and independent variables controlling for sex, farm, and litters nested within farm. The regression model accounted for 75.4% of the variation in ADG. The number of intestinal ascarids at slaughter did not affect ADG. However, the "life-time burden" (a composite measure based on fecal egg counts and duration of infection) was associated with ADG (p less than 0.05) in a quadratic manner. Although heavy ascarid burdens decreased the growth rate of swine, the magnitude of the effect was minimal. The maximum improvement one could expect from reducing the ascarid burden on heavily infected farms would be less than 1%. Severe atrophic rhinitis and the presence of anteroventral pneumonia each had a detrimental effect on ADG (p less than 0.001). The corresponding reductions in mean ADG were 7.7% and 2.8% respectively. There was significant interaction between the effects of atrophic rhinitis and anteroventral pneumonia on ADG (p less than 0.05). Hogs with both anteroventral pneumonia and severe atrophic rhinitis had a 17.6% lower ADG than hogs with neither disease. There is much greater potential for improvement in ADG through control of respiratory diseases than through control of ascariasis.


Effect of 6-thioguanine on Chlamydia trachomatis growth in wild-type and hypoxanthine-guanine phosphoribosyltransferase-deficient cells.
Chlamydiae have evolved a biphasic life cycle to facilitate their survival in two discontinuous habitats. The unique growth cycle is represented by two alternating forms of the organism, the elementary body and the reticulate body. Chlamydiae have an absolute nutritional dependency on the host cell to provide ribonucleoside triphosphates and other essential intermediates of metabolism. This report describes the pleiotropic effects of the purine antimetabolite 6-thioguanine on chlamydial replication. In order to display cytotoxicity, 6-thioguanine must first be converted to the nucleotide level by the host cell enzyme hypoxanthine-guanine phosphoribosyltransferase. Our results show that 6-thioguanine is an effective inhibitor of chlamydial growth with either wild-type or hypoxanthine-guanine phosphoribosyltransferase-deficient cell lines as the host. Interestingly, the mechanism of 6-thioguanine-induced inhibition of chlamydial growth is different depending on which cell line is used. With wild-type cells as the host, the cytotoxic effects of 6-thioguanine on chlamydial growth are relatively fast and irreversible. Under these circumstances, cytotoxicity likely results from the combined effect of starving chlamydiae for purine ribonucleotides and incorporation of host-derived 6-thioguanine-containing nucleotides into chlamydial nucleic acids. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine must be present at the start of the chlamydial infection cycle to be effective and the growth inhibition is reversible upon removal of the antimetabolite. These findings suggest that in hypoxanthine-guanine phosphoribosyltransferase-deficient cells, the free base 6-thioguanine may inhibit the differentiation of elementary bodies to reticulate bodies. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine was used as a selective agent in culture to isolate a Chlamydia trachomatis isolate resistant to the effects of the drug. This drug resistant C. trachomatis isolate was completely resistant to 6-thioguanine in hypoxanthine-guanine phosphoribosyltransferase-deficient cells; however, it displayed wildtype sensitivity to 6-thioguanine when cultured in wild-type host cells.


Facile synthesis of novel MoS₂@SnO₂ hetero-nanoflowers and enhanced photocatalysis and field-emission properties.
A novel hierarchical MoS2@SnO2 hetero-nanoflower was successfully synthesized by a facile, two-step hydrothermal method without using any additives or surfactants. One possible growth mechanism of the hetero-nanostructure was presented in detail based on OH(-) ion-dependent experimental facts. Due to the formation of the p-n junctions and the increased specific surface area in the composites, an outstanding photocatalytic activity of the as-prepared sample was obtained by monitoring the photodegradation of methylene blue (MB). According to the data, after irradiation for 100 min, the remaining MB in solution is about 26% for MoS2 nanoflowers and 9.5% for MoS2@SnO2 hetero-nanoflowers. Moreover, an excellent field-emission performance was obtained from MoS2@SnO2 hetero-nanoflower relative to the pure MoS2 with the turn-on field decreasing from 4.2 V μm(-1) to 3.4 V μm(-1) and the threshold field decreasing from 6.2 V μm(-1) to 5.2 V μm(-1), which is mainly attributed to the increased field-emission points and MoS2-SnO2 heterojunction.


Patient-centred tuberculosis treatment delivery under programmatic conditions in Tanzania: a cohort study.
Directly observed therapy (DOT) remains the cornerstone of the global tuberculosis (TB) control strategy. Tanzania, one of the 22 high-burden countries regarding TB, changed the first-line treatment regimen to contain rifampicin-containing fixed-dose combination for the full 6 months of treatment. As daily health facility-based DOT for this long period is not feasible for the patient, nor for the health system, Tanzania introduced patient centred treatment (PCT). PCT allows patients to choose for daily DOT at a health facility or at their home by a supporter of choice. The introduction of fixed dose combinations in the intensive and continuation phase made PCT feasible by eliminating the risk of selective drug taking by patients and reducing the number of tablets to be taken. The approach was tested in three districts with the objective to assess the effect of this strategy on TB treatment outcomes Cohort analysis comparing patients treated under the PCT strategy (registered April-September 2006) with patients treated under health-facility-based DOT (registered April-September 2005). The primary outcome was the cure rate. Differences were assessed by calculating the risk ratios. Associations between characteristics of the supporters and treatment outcomes in the group of patients opting for home-based DOT were assessed through logistic regression. In the PCT cohort there were 1208 patients and 1417 were included in the historic cohort. There was no significant difference in cure rates between the cohorts (risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.96-1.16). In the PCT cohort, significantly more patients had successful treatment (cure or treatment completed; RR: 1.10; 95%CI: 1.01-1.15). There were no characteristics of supporters that were associated with treatment outcome. The PCT approach showed similar cure rates and better treatment success rates compared to daily health-facility DOT. The results indicate that there are no specific prerequisites for the supporter chosen by the patient. The programmatic setting of the study lends strong support for scaling-up of TB treatment observation outside the health facility.


Identification of cis elements involved in Commelina yellow mottle virus promoter activity.
Commelina yellow mottle virus (CoYMV) is a double-stranded DNA virus that infects a monocot host. A promoter fragment isolated from CoYMV is a strong promoter when assayed after transient introduction into monocot and dicot suspension cells and is highly active in vascular cells of flowers, leaves, stems and roots of stably transformed tobacco plants. Here it is reported that in stably transformed maize calli and transgenic tobacco leaves the CoYMV and CaMV 35S promoters exhibit similar amounts of activity. Deletion of the sequences located distal to nucleotide -230 relative to the start of transcription has no significant effect on promoter strength or tissue specificity. The region between -230 and -200 shares sequence similarity with the as-1 promoter element of the CaMV 35S promoter. Deletion of this as-1-like motif decreases promoter activity in maize suspension cells by 85%. Analysis of deletions affecting the -200 to -52 region indicates that sequences located between -159 and -84 are required for activity in vascular tissues. In addition, this region exhibits properties of a vascular tissue-specific enhancer since it confers vascular expression in an orientation-independent manner when fused to promoters that are not normally active in vascular tissues.


Integrating spread dynamics and economics of timber production to manage Chinese tallow invasions in southern U.S. forestlands.
Economic costs associated with the invasion of nonnative species are of global concern. We estimated expected costs of Chinese tallow (Triadica sebifera (L.) Small) invasions related to timber production in southern U.S. forestlands under different management strategies. Expected costs were confined to the value of timber production losses plus costs for search and control. We simulated management strategies including (1) no control (NC), and control beginning as soon as the percentage of invaded forest land exceeded (2) 60 (Low Control), (3) 25 (Medium Control), or (4) 0 (High Control) using a spatially-explicit, stochastic, bioeconomic model. With NC, simulated invasions spread northward and westward into Arkansas and along the Gulf of Mexico to occupy ≈1.2 million hectares within 20 years, with associated expected total costs increasing exponentially to ≈$300 million. With LC, MC, and HC, invaded areas reached ≈275, 34, and 2 thousand hectares after 20 years, respectively, with associated expected costs reaching ≈$400, $230, and $200 million. Complete eradication would not be cost-effective; the minimum expected total cost was achieved when control began as soon as the percentage of invaded land exceeded 5%. These results suggest the importance of early detection and control of Chinese tallow, and emphasize the importance of integrating spread dynamics and economics to manage invasive species.


Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation.
T-lymphocyte trafficking is targeted to specific organs by selective molecular interactions depending on their differentiation and functional properties. Specific chemokine receptors have been associated with organ-specific trafficking of memory and effector T-cells, as well as the recirculation of naïve T-cells to secondary lymphoid organs. In addition to the acquisition of tissue-selective integrins and chemokine receptors, an additional level of specificity for T-cell trafficking into the tissue is provided by specific recognition of antigen displayed by the endothelium involving the TCRs (T-cell antigen receptors) and co-stimulatory receptors. Activation of PI3K (phosphoinositide 3-kinase) is a robust signalling event shared by most chemokine receptors as well as the TCR and co-stimulatory receptors, contributing to several aspects of T-lymphocyte homing as well as actin reorganization and other components of the general migratory machinery. Accordingly, inhibition of PI3K has been considered seriously as a potential therapeutic strategy by which to combat various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases, as well as to prevent transplant rejection. However, there is substantial evidence for PI3K-independent mechanisms that facilitate T-lymphocyte migration. In this regard, several other signalling-pathway components, including small GTPases, PLC (phospholipase C) and PKC (protein kinase C) isoforms, have also been implicated in T-lymphocyte migration in response to chemokine stimulation. The present review will therefore examine the PI3K-dependent and -independent signal-transduction pathways involved in T-cell migration during distinct modes of T-cell trafficking in response to either chemokines or the TCR and co-stimulatory molecules.


Maryland dental hygienists' knowledge, opinions and practices regarding dental caries prevention and early detection.
The purpose of this study was to assess Maryland dental hygienists' knowledge, practices and opinions regarding dental caries prevention and early detection. A 30 item survey was mailed to 1,258 Maryland dental hygienists. Two follow-up mailings and email reminders were sent. The response rate was 43% (n=540). Nearly all respondents were female (98%), and 58% practiced in solo settings. Knowledge and certainty of knowledge were moderate: sealants are needed regardless of topical fluoride use (55% certain, 40% less certain), newly erupted permanent molars are the best candidates for sealants (54%, 36%) and professionally applied fluorides are desirable in areas without fluoridated water (55%, 36%). Fewer were certain that incipient lesions can be remineralized before cavitation (23%, 69%), and dilute, frequently administered fluorides are more effective in caries prevention than concentrated, less frequently administered fluorides (6%, 24%). Opinions regarding effectiveness of protocols for 2 age groups from 6 months to 6 years, the challenges of early childhood caries (ECC), prevention practices regarding sealant and topical fluoride applications varied widely. Eighty-nine percent reported routinely assessing dental caries risk factors of child patients and 90% were interested in continuing education courses. There were no significant differences between different types of practice settings, year of graduation, race/ethnicity or gender. Knowledge of recommended guidelines for fluoride and sealant application support clinical decision-making and self-care counseling. Misinformation and lack of understanding of current research and recommendations identify a need for educational interventions in undergraduate dental hygiene programs and through continuing education for practicing hygienists.


Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1.
Interleukin-1 (IL-1) is a major regulator of inflammation and immunity. IL-1 induces T lymphocyte growth by acting as a second signal (together with antigen) in enhancing the production of interleukin-2 (IL-2). An IL-1-responsive element in the promoter region of the human IL-2 gene was similar to the binding site for the transcription factor AP-1. IL-1 enhanced expression of c-jun messenger RNA, whereas the antigenic signal enhanced messenger RNA expression of c-fos. Thus, the two components of the AP-1 factor are independently regulated and the AP-1 factor may serve as a nuclear mediator for the many actions of IL-1 on cells.


Understanding and evaluating new models of Child and Adolescent Mental Health Services in South-East England: a study protocol for an observational mixed-methods study.
Increased demand for Child and Adolescent Mental Health Services (CAMHS), alongside concerns that services should be better commissioned to meet the needs of the most vulnerable, has contributed to a requirement to transform services to improve accessibility, quality of care and health outcomes. Following the submission of government-mandated transformation plans for CAMHS, services in England are changing in how, where and by whom they are delivered. This protocol describes the research methods to be applied to understand CAMHS transformations and evaluate the impact on the use of mental health services, patient care, satisfaction, health outcomes and health resource utilisation costs. A mixed-methods approach will be taken in an observational retrospective study of CAMHS provided by a large National Health Service (NHS) mental health trust in South-East England (Oxford Health NHS Foundation Trust). Quantitative research will include descriptive analysis of routinely collected data, with difference-in-differences analysis supplemented with propensity score matching performed to assess the impact of CAMHS transformations from 2015 onwards. An economic evaluation will be conducted from a healthcare perspective to provide commissioners with indications of value for money. Qualitative research will include observations of services and interviews with key stakeholders including CAMHS staff, service users and guardians, to help identify mechanisms leading to changes in service delivery, as well as barriers and enabling factors in this phase of transformation. This project has been registered with NHS Oxford Health Foundation Trust as a service evaluation. Informed consent will be sought from all stakeholders partaking in interviews according to good clinical practice. A local data sharing protocol will govern the transfer of quantitative data. Study findings will be published in professional journals for NHS managers and peer-reviewed scientific journals. They will be discussed in seminars targeting CAMHS providers, managers and commissioners and presented at scientific conferences.


Contact dermatitis to Vicks VapoRub.
Vicks VapoRub (VVR) is a commonly used inhalant ointment that helps relieve symptoms of upper respiratory tract infections. It contains several plant substances, including turpentine oil, eucalyptus oil, and cedar leaf oil, which can potentially irritate or sensitize the skin, as well as camphor, menthol, nutmeg oil, and thymol. Although many reports describe allergic contact dermatitis (ACD) to the various constituents in VVR ointment, there are no cases of VVR directly causing ACD. We present a case of a patient who developed an ACD secondary to application of her VVR.


Fractures of the thoracolumbar spine sustained by soldiers in vehicles attacked by improvised explosive devices.
Retrospective analysis. To analyze the types of orthopedic spine fractures sustained by North Atlantic Treaty Organization soldiers when vehicles are attacked by improvised explosive devices (IEDs), with specific focus on the flexion-distraction type thoracolumbar fracture (Chance fracture). Operation Enduring Freedom is the North Atlantic Treaty Organization's effort in Afghanistan. IED attacks on armored vehicles are common and account for high proportion of soldiers' deaths and injuries. Retrospective record review was accomplished on soldiers admitted to a military hospital with orthopedic spine fractures after IED attacks on vehicles from January 1, 2008 to May 15, 2008. Thoracolumbar fractures were classified using the McAfee classification system. Twelve male patients with 16 thoracolumbar fractures were identified (3 patients with multiple fractures). The 16 thoracolumbar fractures included 6 flexion-distraction fractures in 5 patients (38%, 6/16: two T12, two L1, one L3, and one L4), 7 compression fractures in 5 patients (44%, 5/16; one T7, one T8, two L1, one L2, one L3, and one L4), and 3 burst fractures (19%, 3/16; two L1 and one L2). The incidence of flexion-distraction thoracolumbar (Chance) fractures has been reported to be between 1.0% and 2.5% in most spine fracture series. In this small study, Chance fractures represented 38% of all tho-racolumbar fractures sustained after IED attack on armored vehicles. The blast pattern associated with IED explosion may be responsible for the high rate of these injuries in vehicle occupants.


Sparseness and expansion in sensory representations.
In several sensory pathways, input stimuli project to sparsely active downstream populations that have more neurons than incoming axons. Here, we address the computational benefits of expansion and sparseness for clustered inputs, where different clusters represent behaviorally distinct stimuli and intracluster variability represents sensory or neuronal noise. Through analytical calculations and numerical simulations, we show that expansion implemented by feed-forward random synaptic weights amplifies variability in the incoming stimuli, and this noise enhancement increases with sparseness of the expanded representation. In addition, the low dimensionality of the input layer generates overlaps between the induced representations of different stimuli, limiting the benefit of expansion. Highly sparse expansive representations obtained through synapses that encode the clustered structure of the input reduce both intrastimulus variability and the excess overlaps between stimuli, enhancing the ability of downstream neurons to perform classification and recognition tasks. Implications for olfactory, cerebellar, and visual processing are discussed.


Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth.
Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic-based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs affected the viability of breast cancer cell lines and osteoclast precursors, but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor-associated bone destruction. In addition, BMMPIs are superior in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate. We demonstrated MMP-2-selective inhibition in the bone microenvironment using specific and broad-spectrum MMP probes. Furthermore, compared with zoledronate, BMMPI-treated mice had significantly lower levels of TGFβ signaling and MMP-generated type I collagen carboxy-terminal fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates. Mol Cancer Ther; 16(3); 494-505. ©2017 AACR.


TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.
It has long been postulated that protein tyrosine phosphatases may act as tumor suppressors because of their ability to counteract the oncogenic actions of protein tyrosine kinases. Here we report the cloning and characterization of a novel human protein tyrosine phosphatase, TEP1. TEP1 contains the protein tyrosine phosphatase signature motif, and we show that it possesses an intrinsic protein tyrosine phosphatase activity. TEP1 also shares extensive homology with tensin, a cytoskeletal protein localized to focal adhesions, and with auxilin, a protein involved in synaptic vesicle transport. Immunofluorescence studies show that TEP1 is a cytoplasmic protein. The abundance of TEP1 transcription is altered in many transformed cells. In the transforming growth factor beta-sensitive cells, TEP1 expression is rapidly down-regulated by transforming growth factor beta, a cytokine shown to be involved in regulating cell adhesion and cell motility. We have also mapped the gene encoding TEP1 to chromosome 10q23, a locus that is frequently deleted in a variety of human cancers. TEP1 protein is identical to the protein encoded by the candidate tumor suppressor gene PTEN/MMAC1. Our functional studies of the TEP1 protein suggest that its tumor suppressor function may associate with its intrinsic protein tyrosine phosphatase activity and its cytoplasmic localization.


Genetic map-guided genome assembly reveals a virulence-governing minichromosome in the lentil anthracnose pathogen Colletotrichum lentis.
Colletotrichum lentis causes anthracnose, which is a serious disease on lentil and can account for up to 70% crop loss. Two pathogenic races, 0 and 1, have been described in the C. lentis population from lentil. To unravel the genetic control of virulence, an isolate of the virulent race 0 was sequenced at 1481-fold genomic coverage. The 56.10-Mb genome assembly consists of 50 scaffolds with N50 scaffold length of 4.89 Mb. A total of 11 436 protein-coding gene models was predicted in the genome with 237 coding candidate effectors, 43 secondary metabolite biosynthetic enzymes and 229 carbohydrate-active enzymes (CAZymes), suggesting a contraction of the virulence gene repertoire in C. lentis. Scaffolds were assigned to 10 core and two minichromosomes using a population (race 0 × race 1, n = 94 progeny isolates) sequencing-based, high-density (14 312 single nucleotide polymorphisms) genetic map. Composite interval mapping revealed a single quantitative trait locus (QTL), qClVIR-11, located on minichromosome 11, explaining 85% of the variability in virulence of the C. lentis population. The QTL covers a physical distance of 0.84 Mb with 98 genes, including seven candidate effector and two secondary metabolite genes. Taken together, the study provides genetic and physical evidence for the existence of a minichromosome controlling the C. lentis virulence on lentil.


Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.
To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.


Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission.
Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.


Day of injury assessment of sport-related concussion.
To conduct a critical review of the literature on instruments currently used in the assessment of sport-related concussion on the day of injury. Computerised searches of the literature posted to MEDLINE, PubMed, CINAHL, PsychInfo and Cochrane Library from 1 January 1982 through 21 August 2012. Key words and medical embedded subheadings (MeSH) terms relevant to sport-related concussion were applied, which identified 577 articles. In addition to MeSH term and key word criteria, a study was included in the analysis if the article: (1) was published in English, (2) represented original research, (3) pertained to sport-related concussion (ie, not non-sports traumatic brain injury), (4) included assessment or diagnostic data collected within 24 h of the injury event and (5) involved human research. A total of 41 studies qualified for review. All articles were examined to determine if the study met the additional requirements for inclusion. A standardised method was used to document critical elements of the study design, population, tests employed and key findings. A large number of studies were analysed that reported data from testing conducted within 24 h of injury. These studies collectively demonstrated that a number of instruments are capable of measuring the acute effects of concussion across several domains, such as symptoms, cognition and balance. Relating to specific assessment domains are compiled in separate tables and an interpretive summary of the findings is provided. Several well-validated tests are appropriate for use in the assessment of acute concussion in the competitive sporting environment. These tests provide important data on the symptoms and functional impairments that clinicians can incorporate into their diagnostic formulation, but they should not solely be used to diagnose concussion.


Comparison of combined therapies in treatment of secondary failure to glyburide.
To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.


A 13-Bit, 12-ps Resolution Vernier Time-to-Digital Converter Based on Dual Delay-Rings for SPAD Image Sensor.
A three-dimensional (3D) image sensor based on Single-Photon Avalanche Diode (SPAD) requires a time-to-digital converter (TDC) with a wide dynamic range and fine resolution for precise depth calculation. In this paper, we propose a novel high-performance TDC for a SPAD image sensor. In our design, we first present a pulse-width self-restricted (PWSR) delay element that is capable of providing a steady delay to improve the time precision. Meanwhile, we employ the proposed PWSR delay element to construct a pair of 16-stages vernier delay-rings to effectively enlarge the dynamic range. Moreover, we propose a compact and fast arbiter using a fully symmetric topology to enhance the robustness of the TDC. To validate the performance of the proposed TDC, a prototype 13-bit TDC has been fabricated in the standard 0.18-µm complementary metal-oxide-semiconductor (CMOS) process. The core area is about 200 µm × 180 µm and the total power consumption is nearly 1.6 mW. The proposed TDC achieves a dynamic range of 92.1 ns and a time precision of 11.25 ps. The measured worst integral nonlinearity (INL) and differential nonlinearity (DNL) are respectively 0.65 least-significant-bit (LSB) and 0.38 LSB, and both of them are less than 1 LSB. The experimental results indicate that the proposed TDC is suitable for SPAD-based 3D imaging applications.


Frequent multidrug-resistant Acinetobacter baumannii contamination of gloves, gowns, and hands of healthcare workers.
Multidrug-resistant (MDR) gram-negative bacilli are important nosocomial pathogens. To determine the incidence of transmission of MDR Acinetobacter baumannii and Pseudomonas aeruginosa from patients to healthcare workers (HCWs) during routine patient care. Prospective cohort study. Medical and surgical intensive care units. Methods. We observed HCWs who entered the rooms of patients colonized with MDR A. baumannii or colonized with both MDR A. baumannii and MDR P. aeruginosa. We examined their hands before room entry, their disposable gloves and/or gowns upon completion of patient care, and their hands after removal of gloves and/or gowns and before hand hygiene. Sixty-five interactions occurred with patients colonized with MDR A. baumannii and 134 with patients colonized with both MDR A. baumannii and MDR P. aeruginosa. Of 199 interactions between HCWs and patients colonized with MDR A. baumannii, 77 (38.7% [95% confidence interval {CI}, 31.9%-45.5%]) resulted in HCW contamination of gloves and/or gowns, and 9 (4.5% [95% CI, 1.6%-7.4%]) resulted in contamination of HCW hands after glove removal before hand hygiene. Of 134 interactions with patients colonized with MDR P. aeruginosa, 11 (8.2% [95% CI, 3.6%-12.9%]) resulted in HCW contamination of gloves and/or gowns, and 1 resulted in HCW contamination of hands. Independent risk factors for contamination with MDR A. baumannii were manipulation of wound dressing (adjusted odds ratio [aOR], 25.9 [95% CI, 3.1-208.8]), manipulation of artificial airway (aOR, 2.1 [95% CI, 1.1-4.0]), time in room longer than 5 minutes (aOR, 4.3 [95% CI, 2.0-9.1]), being a physician or nurse practitioner (aOR, 7.4 [95% CI, 1.6-35.2]), and being a nurse (aOR, 2.3 [95% CI, 1.1-4.8]). Gowns, gloves, and unwashed hands of HCWs were frequently contaminated with MDR A. baumannii. MDR A. baumannii appears to be more easily transmitted than MDR P. aeruginosa and perhaps more easily transmitted than previously studied methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus. This ease of transmission may help explain the emergence of MDR A. baumannii.


Intravenous Bone Marrow Stem Cell Grafts Preferentially Migrate to Spleen and Abrogate Chronic Inflammation in Stroke.
Adult stem cell therapy is an experimental stroke treatment. Here, we assessed homing and anti-inflammatory effects of bone marrow stromal cells (hBMSCs) in chronic stroke. At 60 days post stroke, adult Sprague-Dawley rats received intravenous hBMSCs (4×10(6) labeled or nonlabeled cells) or vehicle (saline). A sham surgery group served as additional control. In vivo imaging was conducted between 1 hour and 11 days post transplantation, followed by histological examination. Labeled hBMSCs migrated to spleen which emitted significantly higher fluorescent signal across all time points, especially during the first hour, and were modestly detected in the head region at the 12 hours and 11 days, compared with nonlabeled hBMSCs and vehicle-infused stroke animals, or sham (P<0.05). At 11 days post transplantation, ex vivo imaging confirmed preferential hBMSC migration to the spleen over the brain. Hematoxylin and eosin staining revealed significant 15% and 30% reductions in striatal infarct and peri-infarct area, and a trend of rescue against neuronal loss in the hippocampus. Unbiased stereology showed significant 75% and 60% decrements in major histocompatibility complex II-activated inflammatory cells in gray and white matter, and a 43% diminution in tumor necrosis factor-α cell density in the spleen of transplanted stroke animals compared with vehicle-infused stroke animals (P<0.05). Human antigen immunostaining revealed 0.03% hBMSCs survived in spleen and only 0.0007% in brain. MSC migration to spleen, but not brain, inversely correlated with reduced infarct, peri-infarct, and inflammation. hBMSC transplantation is therapeutic in chronic stroke possibly by abrogating the inflammation-plagued secondary cell death.


Placental site trophoblastic tumor in a patient with brain and lung metastases.
Placental site trophoblastic tumor is a rare neoplasm that arises from intermediate trophoblasts and shows diversity of biological behaviors, resulting in the absence of consistency in treatment modalities. A case of placental site trophoblastic tumor that extended to the cervix, with primary manifestation of amenorrhea and yellow foul-smelling vaginal discharge, is presented. Total abdominal hysterectomy was performed initially, and serial measurements of human chorionic gonadotropin levels were obtained. She was admitted with metastases to brain and lung 1.5 years after surgery. Combination chemotherapy (etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine) and radiotherapy were administered. There was no significant response to chemoradiotherapy. Despite changing chemotherapy regimen, she is still alive with progressive disease.


Pregnancy and Family Planning in Multiple Sclerosis.
This article provides practical guidance on successful management of women with multiple sclerosis (MS) through pregnancy and the postpartum period. Recent studies indicate that most women diagnosed with MS today can have children, breast-feed, and resume beta interferons or glatiramer acetate per their preferences without incurring an increased risk of relapses during the postpartum period. More than 40% of women with mild MS do not require any treatment before conception or in the postpartum period. Women with highly active MS can now become well-controlled before, throughout, and after pregnancy via highly effective treatments. Unfortunately, pregnancy does not protect against relapses following the cessation of fingolimod or natalizumab, and some women experience severe rebound relapses during pregnancy. Accidental first-trimester exposure to teriflunomide or fingolimod increases the risk of fetal harm. Most women with MS can have normal pregnancies and breast-feed without incurring harm. Clinicians should avoid prescribing medications with known teratogenic potential (teriflunomide, fingolimod), known risk of severe rebound relapses (fingolimod, natalizumab), or unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of childbearing age who desire pregnancy or are not on reliable birth control. If a treatment needs to be resumed during breast-feeding, clinicians should opt for glatiramer acetate, interferon beta, natalizumab, or rituximab/ocrelizumab, as biologically plausible risks to the infant are exceedingly low.


Vocal imitation and individual recognition of finch calls.
American goldfinch females recognize individual males by their individually distinctive flight calls. Goldfinches and other cardueline finch species are also capable of learning new flight calls by imitation during pair and flock formation. Vocal imitation can occur between members of different species as well as between members of the same species. Learning of new flight calls differs in several respects from typical passerine song learning.


Viral-bacterial interactions in the respiratory tract.
In the respiratory tract, viruses and bacteria can interact on multiple levels. It is well known that respiratory viruses, particularly influenza viruses, increase the susceptibility to secondary bacterial infections. Numerous mechanisms, including compromised physical and immunological barriers, and changes in the microenvironment have hereby been shown to contribute to the development of secondary bacterial infections. In contrast, our understanding of how bacteria shape a response to subsequent viral infection is still limited. There is emerging evidence that persistent infection (or colonization) of the lower respiratory tract (LRT) with potential pathogenic bacteria, as observed in diseases like chronic obstructive pulmonary disease or cystic fibrosis, modulates subsequent viral infections by increasing viral entry receptors and modulating the inflammatory response. Moreover, recent studies suggest that even healthy lungs are not, as had long been assumed, sterile. The composition of the lung microbiome may thus modulate responses to viral infections. Here we summarize the current knowledge on the co-pathogenesis between viruses and bacteria in LRT infections.


Antidiabetic activity of Embelia ribes, embelin and its derivatives: A systematic review and meta-analysis.
Embelia ribes (ER) has been documented in Ayurveda for treating various diseases, including diabetes mellitus (DM). The present systematic review and meta-analysis evaluated the efficacy and safety of ER and its active bio-marker, embelin and its derivatives in the treatment of DM. Literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, ScienceDirect, Scifinder, and Google Scholar. Using Review Manager, meta-analysis of ER/embelin/derivatives of embelin versus diabetic control was performed with inverse-variance model, providing mean differences (MDs) and 95% confidence intervals (CIs). Heterogeneity was determined by I2 statistic. A total of 13 studies were included in the systematic review and meta-analysis, and were conducted in experimental rats. ER and embelin significantly (P≤0.01) resorted blood glucose (MD, -231.30; CI, -256.79, -205.82; and MD, -154.70; CI, -168.65, -140.74) and glycosylated haemoglobin (MD, -6.36; CI, -8.33, -4.39; and MD,-4.68; CI, -7.76, -1.60), respectively. Meta-analysis findings also reported considerable restoration of insulin, lipid profile, haemodynamic parameters, serum and oxidative stress markers. The derivatives of embelin, 6-bromoembelin and vilangin, also improved diabetic condition. In addition, treatments also ameliorated body weight changes due to diabetes. The present systematic review and meta-analysis supports scientific evidence for the antidiabetic activity of ER/embelin/derivatives of embelin. However, further research is warranted in clinical trials to validate the present findings.


Interactions of Valeriana officinalis L. and Passiflora incarnata L. in a patient treated with lorazepam.
There is an increasing interest in the health risks related to the use of herbal remedies. Although most consumers think that phytomedicines are safe and without side effects, interactions between complementary alternative and conventional medicines are being described. The aim of this clinical case report is to highlight the importance of the safe use of herbal remedies by providing a clinical interaction study between pharmaceutical medicines and herbal medicinal products. The case of a patient self-medicated with Valeriana officinalis L. and Passiflora incarnata L. while he was on lorazepam treatment is described. Handshaking, dizziness, throbbing and muscular fatigue were reported within the 32 h before clinical diagnosis. The analysis of family medical history ruled out essential tremor, Parkinson's disease, Wilson's disease and other symptom-related pathologies. His medical history revealed a generalized anxiety disorder and medicinal plant consumption but no neurological disorder. Appropriate physical examination was carried out. An additive or synergistic effect is suspected to have produced these symptoms. The active principles of Valerian and passionflower might increase the inhibitory activity of benzodiazepines binding to the GABA receptors, causing severe secondary effects. Due to the increase in herbal product self-medication, the use of herbal remedies should be registered while taking the personal clinical history. Multidisciplinary teams should be created to raise studies on medicinal plants with impact on medical praxis.


Efficient conditional and promoter-specific in vivo expression of cDNAs of choice by taking advantage of recombinase-mediated cassette exchange using FlEx gene traps.
Recombinase-mediated cassette exchange (RMCE) exploits the possibility to unidirectionally exchange any genetic material flanked by heterotypic recombinase recognition sites (RRS) with target sites in the genome. Due to a limited number of available pre-fabricated target sites, RMCE in mouse embryonic stem (ES) cells has not been tapped to its full potential to date. Here, we introduce a universal system, which allows the targeted insertion of any given transcriptional unit into 85 742 previously annotated retroviral conditional gene trap insertions, representing 7013 independent genes in mouse ES cells, by RMCE. This system can be used to express any given cDNA under the control of endogenous trapped promoters in vivo, as well as for the generation of transposon 'launch pads' for chromosomal region-specific 'Sleeping Beauty' insertional mutagenesis. Moreover, transcription of the gene-of-interest is only activated upon Cre-recombinase activity, a feature that adds conditionality to this expression system, which is demonstrated in vivo. The use of the RMCE system presented in this work requires one single-cloning step followed by one overnight gateway clonase reaction and subsequent cassette exchange in ES cells with efficiencies of 40% in average.


New smokers and quitters. Transitions in smoking status in a national population.
Few studies have examined individual transitions in smoking status in national populations. A representative sample of 21,970 men and women aged 15-64 were questioned regarding current smoking status and smoking status 12 months ago. 1.56% of respondents had started to smoke and 1.58% had quit smoking. Becoming a smoker was significantly associated with younger age and lower social economic status (SES). Among women, many new smokers were between the age of 30 and 34, presumably due to relapse after pregnancy. High SES smokers quit at a younger age then lower SES groups. To reduce smoking prevalence in the Netherlands, more attention should be given to women aged 30-34 years and to people from the lower SES groups, especially those under the age of 45.


Behavioral adaptation and late-life disability: a new spectrum for assessing public health impacts.
To inform public health efforts to promote independent functioning among older adults, we have provided new national estimates of late-life disability that explicitly recognize behavioral adaptations. We analyzed the 2011 National Health and Aging Trends Study, a study of Medicare enrollees aged 65 years and older (n = 8077). For 7 mobility and self-care activities we identified 5 hierarchical stages--fully able, successful accommodation with devices, activity reduction, difficulty despite accommodations, and receipt of help--and explored disparities and associations with quality of life measures. Among older adults, 31% were fully able to complete self-care and mobility activities. The remaining groups successfully accommodated with devices (25%), reduced their activities (6%), reported difficulty despite accommodations (18%), or received help (21%). With successive stages, physical and cognitive capacity decreased and symptoms and multimorbidity increased. Successful accommodation was associated with maintaining participation in valued activities and high well-being, but substantial disparities by race, ethnicity, and income existed. Increased public health attention to behavioral adaptations to functional change can promote independence for older adults and may enhance quality of life.


The heterocellular heart: identities, interactions, and implications for cardiology.
The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as the prototypical cell type of the heart, non-myocytes such as endothelial cells, fibroblasts, or immune cells are coming more into focus. The rise of single-cell sequencing technologies enables identification of ever more subtle differences and has reignited the question of what defines a cell's identity. Here we provide an overview of the major cardiac cell types, describe their roles in homeostasis, and outline recent findings on non-canonical functions that may be of relevance for cardiology. We highlight modes of biochemical and biophysical interactions between different cardiac cell types and discuss the potential implications of the heterocellular nature of the heart for basic research and therapeutic interventions.


Patient acceptance and clinical impact of Bravo monitoring in patients with previous failed catheter-based studies.
Standard pH monitoring is performed over 24 h with a naso-oesophageal catheter (C-pH). Limitations include naso-pharyngeal discomfort, nausea and social embarrassment resulting in reduced reflux-provoking activities. Recently a catheter-free pH-monitoring technique has become available. The tolerability and diagnostic yield of this system in patients who failed standard monitoring remain unknown. To examine the tolerability and diagnostic outcome of catheter-free pH-monitoring technique in patients who failed standard monitoring. Patients referred for C-pH and catheter-free pH monitoring completed a tolerability questionnaire. Acid exposure in the distal oesophagus and symptom index (SI) were reviewed. Over 4 years, 883/1751 (50%) of patients with typical reflux symptoms referred for C-pH were diagnosed with gastro-oesophageal reflux disease (GERD) based on a pathological percentage time acid exposure (%time pH <4);134 (8%) patients failed C-pH and, of these, 129 successfully completed 2-day catheter-free pH monitoring. Ninety-eight (76%) of these patients had a pathological percentage pH <4 on either day compared with 49/102 (49%) of contemporaneous C-pH patients (P < 0.01). There was no difference in SI for heartburn (35% vs. 42%; P = 0.49). The questionnaire demonstrated a preference for catheter-free pH monitoring (96%) with less restriction in activities of daily living, naso-pharyngeal discomfort, dysphagia and chest pain. Tolerance and satisfaction with catheter-free pH monitoring are high in patients who had previously failed C-pH; catheter-free pH monitoring assists the definitive diagnosis of GERD in this group.


Catalytic and spectroscopic analysis of blue copper-containing nitrite reductase mutants altered in the environment of the type 2 copper centre: implications for substrate interaction.
The blue dissimilatory nitrite reductase (NiR) from Alcaligenes xylosoxidans is a trimer containing two types of Cu centre, three type 1 electron transfer centres and three type 2 centres. The latter have been implicated in the binding and reduction of nitrite. The Cu ion of the type 2 centre of the oxidized enzyme is ligated by three His residues, and additionally has a co-ordinated water molecule that is also hydrogen-bonded to the carboxyl of Asp(92) [Dodd, Van Beeumen, Eady and Hasnain (1998), J. Mol. Biol. 282, 369-382]. Two mutations of this residue have been made, one to a glutamic acid residue and a second to an asparagine residue; the effects of both mutations on the spectroscopic and catalytic properties of the enzyme have been analysed. EPR spectroscopy revealed that both mutants retained intact type 1 Cu centres with g( parallel)=2.12 (A( parallel)=0 mT) and g( perpendicular)=2.30 (A( perpendicular)=6.4 mT), which was consistent with their blue colour, but differed in their activities and in the spectroscopic properties of the type 2 centres. The D92E mutant had an altered geometry of its type 2 centre such that nitrite was no longer capable of binding to elicit changes in the EPR parameters of this centre. Accordingly, this mutation resulted in a form of NiR that had very low enzyme activity with the artificial electron donors reduced Methyl Viologen and sodium dithionite. As isolated, the EPR spectrum of the Asp(92)-->Asn (D92N) mutant showed no characteristic type 2 hyperfine lines. However, oxidation with iridium hexachloride partly restored a type 2 EPR signal, suggesting that type 2 copper is present in the enzyme but in a reduced, EPR-silent form. Like the Asp(92)-->Glu mutant, D92N had very low enzyme activities with either Methyl Viologen or dithionite. Remarkably, when the physiological electron donor reduced azurin I was used, both mutant proteins exhibited restoration of enzyme activity. The degree of restoration differed for the two mutants, with the D92N derivative exhibiting approx. 60% of the activity seen for the wild-type NiR. These findings suggest that on formation of an electron transfer complex with azurin, a conformational change in NiR occurs that returns the catalytic Cu centre to a functionally active state capable of binding and reducing nitrite.


Corticomotor plasticity induced by tongue-task training in humans: a longitudinal fMRI study.
Corticomotor pathways may undergo neuroplastic changes in response to acquisition of new motor skills. Little is known about the motor control strategies for learning new tongue tasks. The aim of this study was to investigate the longitudinal effect of novel tongue-task training on corticomotor neuroplasticity. Thirteen healthy, right-handed men, aged 24-35 years (mean age ± SD: 27.3 ± 0.3 years), performed a training task consisting of standardized tongue protrusion onto a force transducer. The tongue task consisted of a relax-protrude-hold-relax cycle with 1.0 N as the target at the hold phase lasting for 1.5 s. Subjects repeated this task for 1 h. Functional magnetic resonance imaging was carried out before the tongue-task training (baseline), 1-h after the training, and one-day and one-week follow-up. During scanning, the subjects performed tongue protrusion in blocks interspersed with rest. A region-of-interest (ROI) approach and an explorative search were implemented for the analysis of corticomotor activity across conditions. All subjects completed the tongue-task training (mean success rate 43.0 ± 13.2%). In the baseline condition, tongue protrusion resulted in bilateral activity in regions most typically associated with a motor task including medial frontal gyrus (supplementary motor area [SMA]), precentral gyrus (tongue motor cortex), putamen, thalamus, and cerebellum. The ROI analysis revealed increased activity in the precentral gyrus already 1 h post-training. One day after the training, increased activity was observed in the precentral gyrus, SMA, putamen, and cerebellum. No increase was found 1 week after training. Correlation analyses between changes in success rates and changes in the numbers of voxels showed robust associations for left Area 4a in primary motor cortex 1 h, 1 day, and 1 week after the tongue-task training and for the left Area 4p in primary motor cortex and the left lateral premotor cortex 1 day after the training. In the unrestricted analysis, increased activity was found in the parahippocampal gyrus 1 h after the tongue-task training and remained for a week. Decreased activity was found in right post-central and middle frontal gyri 1 h and 1 week post-training. The results verified the involvement of specific corticomotor areas in response to tongue protrusion. Short-term tongue-task training was associated with longer-lasting (up to 1 week) changes in motor-related brain activity. The results suggested that primary motor areas are involved in the early and late stages, while other motor areas mainly are engaged in the later stage of corticomotor neuroplasticity of the tongue.


"Hairy baskets" associated with degenerative Purkinje cell changes in essential tremor.
Essential tremor (ET) is one of the most common neurologic diseases. Increased numbers of torpedoes and Purkinje cell (PC) loss have been documented in the brains of patients with ET. We recently observed a dense and tangled appearance ("hairiness") of the basket cell axonal plexuses that surround PC soma in Bielschowsky preparations of cerebellar cortex in ET brains. Here, we assessed basket cell "hairiness" in 37 ET (32 cerebellar ET; 5 Lewy body variant ET), 21 nondisease control, and 48 disease control brains using a semiquantitative scale. In 8 cerebellar ET cases (25%), there were high basket scores (rating = 3), whereas no Lewy body variant ET, 1 nondisease control (4.8%), and 2 diseased controls (4.2%) had high basket scores (p = 0.001). The hairy basket scores correlated with numbers of torpedoes (p < 0.001) and inversely with numbers of PCs (p = 0.06). Axonal plexus density obtained by image analysis of basket cell processes traced from digitized images was higher in ET than in nondiseased control cases (p = 0.016). Closely spaced sites of synaptic contact between basket cell processes and PCs were identified by electron microscopy in ET cases. These data indicate that structural changes are not restricted to PCs in ET, and that other neurons within their functional network may be involved in its pathogenesis.


All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers.
Alzheimer's disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor-peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn(2+), a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca(2+) leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism.


Noninvasive Estimation of Aortic Stiffness Through Different Approaches.
Aortic pulse wave velocity is a worldwide accepted index to evaluate aortic stiffness and can be assessed noninvasively by several methods. This study sought to determine if commonly used noninvasive devices can all accurately estimate aortic pulse wave velocity. Pulse wave velocity was estimated in 102 patients (aged 65±13 years) undergoing diagnostic coronary angiography with 7 noninvasive devices and compared with invasive aortic pulse wave velocity. Devices evaluating carotid-femoral pulse wave velocity (Complior Analyse, PulsePen ET, PulsePen ETT, and SphygmoCor) showed a strong agreement between each other ( r>0.83) and with invasive aortic pulse wave velocity. The mean difference ±SD with the invasive pulse wave velocity was -0.73±2.83 m/s ( r=0.64) for Complior-Analyse: 0.20±2.54 m/s ( r=0.71) for PulsePen-ETT: -0.04±2.33 m/s ( r=0.78) for PulsePen ET; and -0.61±2.57 m/s ( r=0.70) for SphygmoCor. The finger-toe pulse wave velocity, evaluated by pOpmètre, showed only a weak relationship with invasive aortic recording (mean difference ±SD =-0.44±4.44 m/s; r=0.41), and with noninvasive carotid-femoral pulse wave velocity measurements ( r<0.33). Pulse wave velocity estimated through a proprietary algorithm by BPLab (v.5.03 and v.6.02) and Mobil-O-Graph showed a weaker agreement with invasive pulse wave velocity compared with carotid-femoral pulse wave velocity (mean difference ±SD =-0.71±3.55 m/s, r=0.23; 1.04±2.27 m/s, r=0.77; and -1.01±2.54 m/s, r=0.71, respectively), revealing a negative proportional bias at Bland-Altman plot. Aortic pulse wave velocity values provided by BPLab and Mobil-O-Graph were entirely dependent on age-squared and peripheral systolic blood pressure (cumulative r2=0.98 and 0.99, respectively). Thus, among the methods evaluated, only those assessing carotid-femoral pulse wave velocity (Complior Analyse, PulsePen ETT, PulsePen ET, and SphygmoCor) appear to be reliable approaches for estimation of aortic stiffness.


Cardiovascular effects and placental passage of dantrolene in the maternal-fetal sheep model.
Using the chronic maternal-fetal sheep preparation, nine pregnant ewes were studied to determine the effects of intravenous dantrolene sodium on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Two doses of dantrolene sodium were studied: 1.2 mg/kg and 2.4 mg/kg. After 2.4 mg/kg, maternal cardiac output increased 29% (P less than 0.05) after 1 min and returned to normal after 30 min. Maternal mean arterial pressure increased 13% after 1 min and remained significantly elevated (P less than 0.01) for 3 h. No significant changes (P greater than 0.05) were observed in maternal heart rate, uterine artery blood flow, or central venous pressure. Maternal arterial pH declined from 7.42 to 7.39 (P less than 0.01) after 1 min and returned to baseline values after 10 min. Fetal heart rate decreased 24% (P less than 0.01) after 3 min and returned to normal after 10 min; the mean fetal arterial pressure remained unchanged (P greater than 0.05). Fetal arterial pH declined from 7.29 to 7.27 (P less than 0.05) after 1 min and remained significantly decreased for 120 min. Similar changes of lesser magnitude and shorter duration were seen following the 1.2 mg/kg dose. Maternal levels of dantrolene were less than 3 micrograms/ml. Although an equilibrium between maternal and fetal plasma dantrolene concentrations was apparent at 5 min, the fetal levels of dantrolene were approximately 10% of the mother's. The results indicate that the administration of intravenous dantrolene at 1.2 mg/kg or 2.4 mg/kg has no clinically significant adverse effect on mother or fetus in the sheep model.


Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation.
The incidence of hepatocellular carcinoma (HCC) in the United States has increased 75% in the last decade. Liver transplantation is gaining acceptance for the treatment of early HCC, even in patients with adequate liver function. The objective of this study was to determine the long-term outcome of patients with early HCC who would have been candidates for transplantation but were treated instead with partial hepatectomy. From August 1989 to November 2001, 611 patients with HCC were evaluated at our institution and entered into a prospective database. There were 180 (29%) patients who underwent partial hepatectomy, of whom 36 (20%) satisfied the currently accepted criteria for transplantation: 2 or 3 lesions each </= 3 cm in size or a solitary tumor </= 5 cm. Survival was determined by Kaplan-Meier analysis. Median tumor size was 3.5 (range, 1.8-5) cm and the median number of lesions was 1 (range, 1-3). Patients had pathologically confirmed cirrhosis of the liver in 78% (28/36) of cases, and 86% had normal liver function (Child class A). Perioperative morbidity was 25%, the median length of hospital stay was 8 (range, 4-24) days, and there was 1 (2.8%) perioperative death. At a median follow-up of 35 months for survivors, the 1-, 3-, and 5-year overall survival was 85%, 74%, and 69%, respectively, with a median survival of 71 months. The 5-year disease-free survival was 48% with a median of 52 months. Partial hepatectomy in patients with early HCC who are otherwise eligible for transplantation can be performed with minimal morbidity and can achieve comparable 5-year survival to that reported for liver transplantation. Resection should be considered the standard therapy for patients with HCC who have adequate liver reserve.


Supporting cancer patients in illness management: usability evaluation of a mobile app.
Mobile phones and tablets currently represent a significant presence in people's everyday lives. They enable access to different information and services independent of current place and time. Such widespread connectivity offers significant potential in different app areas including health care. Our goal was to evaluate the usability of the Connect Mobile app. The mobile app enables mobile access to the Connect system, an online system that supports cancer patients in managing health-related issues. Along with symptom management, the system promotes better patient-provider communication, collaboration, and shared decision making. The Connect Mobile app enables access to the Connect system over both mobile phones and tablets. The study consisted of usability tests of a high fidelity prototype with 7 cancer patients where the objectives were to identify existing design and functionality issues and to provide patients with a real look-and-feel of the mobile system. In addition, we conducted semistructured interviews to obtain participants' feedback about app usefulness, identify the need for new system features and design requirements, and measure the acceptance of the mobile app and its features within everyday health management. The study revealed a total of 27 design issues (13 for mobile apps and 14 for tablet apps), which were mapped to source events (ie, errors, requests for help, participants' concurrent feedback, and moderator observation). We also applied usability heuristics to identify violations of usability principles. The majority of violations were related to enabling ease of input, screen readability, and glanceability (15 issues), as well as supporting an appropriate match between systems and the real world (7 issues) and consistent mapping of system functions and interactions (4 issues). Feedback from participants also showed the cancer patients' requirements for support systems and how these needs are influenced by different context-related factors, such as type of access terminal (eg, desktop computer, tablet, mobile phone) and phases of illness. Based on the observed results, we proposed design and functionality recommendations that can be used for the development of mobile apps for cancer patients to support their health management process. Understanding and addressing users' requirements is one of the main prerequisites for developing useful and effective technology-based health interventions. The results of this study outline different user requirements related to the design of the mobile patient support app for cancer patients. The results will be used in the iterative development of the Connect Mobile app and can also inform other developers and researchers in development, integration, and evaluation of mobile health apps and services that support cancer patients in managing their health-related issues.


Use of an expert panel to identify domains and indicators of delirium severity.
Our purpose was to create a content domain framework for delirium severity to inform item development for a new instrument to measure delirium severity. We used an established, multi-stage instrument development process during which expert panelists discussed best approaches to measure delirium severity and identified related content domains. We conducted this work as part of the Better ASsessment of ILlness (BASIL) study, a prospective, observational study aimed at developing and testing measures of delirium severity. Our interdisciplinary expert panel consisted of twelve national delirium experts and four expert members of the core research group. Over a one-month period, experts participated in two rounds of review. Experts recommended that the construct of delirium severity should reflect both the phenomena and the impact of delirium to create an accurate, patient-centered instrument useful to interdisciplinary clinicians and family caregivers. Final content domains were Cognitive, Level of consciousness, Inattention, Psychiatric-Behavioral, Emotional dysregulation, Psychomotor features, and Functional. Themes debated by experts included reconciling clinical geriatrics and psychiatric content, mapping symptoms to one specific domain, and accurate capture of unclear clinical presentations. We believe this work represents the first application of instrument development science to delirium. The identified content domains are inclusive of various, wide-ranging domains of delirium severity and are reflective of a consistent framework that relates delirium severity to potential clinical outcomes. Our content domain framework provides a foundation for development of delirium severity instruments that can help improve care and quality of life for patients with delirium.