Working toward decreasing infant mortality in developing countries through change in the medical curriculum.
High infant and maternal mortality rates are one of the biggest health issues in Pakistan. Although these rates are given high priority at the national level (Millennium Development Goals 4 and 5, respectively), there has been no significant decrease in them so far. We hypothesize that this lack of success is because the undergraduate curriculum in Pakistan does not match local needs. Currently, the Pakistani medical curriculum deals with issues in maternal and child morbidity and mortality according to Western textbooks. Moreover, these are taught disjointedly through various departments. We undertook curriculum revision to sensitize medical students to maternal and infant mortality issues important in the Pakistani context and educate them about ways to reduce the same through an integrated teaching approach. The major determinants of infant mortality in underdeveloped countries were identified through a literature review covering international research produced over the last 10 years and the Pakistan Demographic Health Survey 2006-07. An interdisciplinary maternal and child health module team was created by the Medical Education Department at Shifa College of Medicine. The curriculum was developed based on the role of identified determinants in infant and maternal mortality. It was delivered by an integrated team without any subject boundaries. Students' knowledge, skills, and attitudes were assessed by multiple modalities and the module itself by student feedback using questionnaires and focus group discussions. Assessment and feedback demonstrated that the students had developed a thorough understanding of the complexity of factors that contribute to infant mortality. Students also demonstrated knowledge and skill in counseling, antenatal care, and care of newborns and infants. A carefully designed integrated curriculum can help sensitize undergraduate medical students and equip them to identify and address complex issues related to maternal and infant mortality in underdeveloped countries.


Preliminary evidence from a prospective DTI study suggests a posterior-to-anterior pattern of recovery in college athletes with sports-related concussion.
We compared the integrity of white matter (WM) microstructure to the course of recovery in athletes who sustained one sports-related concussion (SRC), assessing individual longitudinal changes in WM fiber tracts following SRC using pre- and post-injury measurements. Baseline diffusion tensor imaging (DTI) scans and neuropsychological tests were collected on 53 varsity contact-sport college athletes. Participants (n = 13) who subsequently sustained an SRC underwent DTI scans and neuropsychological testing at 2 days, 2 weeks, and 2 months following injury. Relying on tract-based spatial statistics (TBSS) analyses, we found that radial diffusivity (RD) and mean diffusivity (MD) were significantly increased at 2 days post-injury compared to the same-subject baseline (corrected p < 0.02). These alterations were visible in anterior/posterior WM regions spanning both hemispheres, demonstrating a diffuse pattern of injury after concussion. Implicated WM fiber tracts at 2 days include the following: right superior/inferior longitudinal fasciculus; right/left inferior fronto-occipital fasciculus; right corticospinal tract; right acoustic radiation; right/left anterior thalamic radiations; right/left uncinate fasciculus; and forceps major/minor. At 2 weeks post-injury, persistently elevated RD and MD were observed solely in prefrontal portions of WM fiber tracts (using same-subject contrasts). No significant differences were found for FA in any of the post-injury comparisons to baseline. Plots of individual subject RD and MD in prefrontal WM demonstrated homogenous increases from baseline to just after SRC; thereafter, trajectories became more variable. Most subjects' diffusivity values remained elevated at 2 months post-injury relative to their own baseline. Over the 2-month period after SRC, recovery of WM fiber tracts appeared to follow a posterior-to-anterior trend, paralleling the posterior-anterior pattern of WM maturation previously identified in the normal population. These results suggest greater vulnerability of prefrontal regions to SRC, underline the importance of an individualized approach to concussion management, and show promise for using RD and MD for imaging-based diagnosis of SRC.


Spectral mapping, a technique for classifying biological activity profiles of chemical compounds.
A mathematical technique is described that separates potency from spectral information in biological activity spectra. The technique is a preliminary step in the classification of chemical compounds and in the structuring of pharmacological assays. The method is illustrated using previously reported results on 40 neuroleptics in 12 assays on rats. Principal component analysis and cluster analysis are shown to provide complementing information.


Polymer microgels: reactors for semiconductor, metal, and magnetic nanoparticles.
We report a strategy for the production of materials with structural hierarchy. The approach employs polymer microgels as templates for the synthesis of semiconductor, metal, or magnetic nanoparticles (NPs). We show that NPs with predetermined dimensions and size-dependent properties can be synthesized by using a very delicate balance between the reaction conditions, the composition and the structure of microgel templates, and the concentration of NPs in the microgel. Postheat treatment of microgels doped with semiconductor nanoparticles reduces NP polydispersity and allows control of their photoluminescence. Microgel templates are particularly beneficial in the synthesis of polymer microspheres heavily loaded with monodisperse superparamagnetic Fe(3)O(4) NPs. Hybrid submicrometer-size microgels have promising potential applications in photonics, catalysis, and separation technologies.


Conservative Intervention Strategies for Adult Cancer-Related Lymphedema: A Systematic Review and Network Meta-Analysis.
The comparative effectiveness of available management options for cancer-related secondary lymphedema is unknown. CINAHL®, Embase®, and MEDLINE® were searched for randomized trials comparing conservative treatment strategies. A network meta-analysis was conducted for lymphedema volume, along with pairwise meta-analyses for remaining outcomes. Evidence certainty was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Overall, 36 studies with a total of 1,651 participants were included. Compared to standard care, conservative treatments did not significantly reduce lymphedema volume. There was low to very low certainty evidence of benefit for several treatments on secondary outcomes. There is insufficient evidence to suggest important differences between standard care and conservative treatment strategies for reducing lymphedema volume and improving lymphedema-related symptoms. //onf.ons.org/supplementary-material-conservative-intervention-strategies-adult-cancer-related-lymphedema.


Fixed-dose-rate gemcitabine: a viable first-line treatment option for advanced pancreatic and biliary tract cancer.
We have already reported on fixed-dose-rate gemcitabine (FDR-Gem) in advanced, inoperable pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) in the context of a formal phase II study; building on that experience, we have now expanded the study to reach a cumulative accrual of 106 patients. One hundred six patients (PDAC/BTC, 75/31) were treated with weekly FDR-Gem (1,000 mg/m(2) infused at 10 mg/m(2) per minute). Patient characteristics included: male-to-female ratio, 0.83; median age, 63 years (range, 28-82); metastatic disease in 66% of patients; and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1 in 81% of patients. The median and total number of treatment weeks delivered were 8 (range, 2-22) and 1,154, respectively. Thirteen percent of patients achieved an objective response, 42% experienced a positive clinical benefit response, and 54% achieved a >50% reduction in serum cancer antigen (CA)19.9 levels. The median progression-free survival (PFS) and overall survival (OS) times for the entire population were 4.4 months (95% confidence interval [CI], 3.5-5.1 months) and 7.7 months (95% CI, 6.3-8.8 months), respectively, with 20% of patients alive at 1 year. On multivariate analysis, a CA19.9 reduction >50% and baseline ECOG PS score of 0 were the only independent predictors of PFS and OS, respectively. Treatment was well tolerated, with grade 3-4 neutropenia in 47 of 1,154 treatment weeks (4.1%), and grade 3 anemia and thrombocytopenia in 8 of 1,154 (0.7%) and 16 of 1,154 (1.4%) treatment weeks, respectively. Currently available evidence, including this updated analysis, supports the use of FDR-Gem as a first-line option in advanced PDAC, and possibly in BTC, patients and prompts the continued evaluation of this approach in combination regimens.


Bond dissociation energies of organic molecules.
In this Account we have compiled a list of reliable bond energies that are based on a set of critically evaluated experiments. A brief description of the three most important experimental techniques for measuring bond energies is provided. We demonstrate how these experimental data can be applied to yield the heats of formation of organic radicals and the bond enthalpies of more than 100 representative organic molecules.


Kosmotoga pacifica sp. nov., a thermophilic chemoorganoheterotrophic bacterium isolated from an East Pacific hydrothermal sediment.
A novel strictly anaerobic thermophilic heterotrophic bacterium, strain SLHLJ1(T), was isolated from a Pacific hydrothermal sediment. Cells were Gram-negative coccobacilli (approximately 1.0 × 0.6 μm) with a toga. It grew at temperatures between 33 and 78 °C (optimum 70 °C). Elemental sulphur and L-cystine stimulated its growth. It contained C16:0, C16:1 ω11c, C18:0 and C18:1 ω9c as major fatty acids (>5%), 3 phospholipids and 2 glycolipids as polar lipids. Its DNA G+C content was 43.7 mol%. Phylogenetic analyses based on 16S rRNA gene sequences placed strain SLHLJ1(T) within the family Thermotogaceae. The novel isolate was most closely related to Kosmotoga arenicorallina (97.93 % 16S rRNA gene sequence similarity), K. olearia (92.43%) and K. shengliensis (92.17 %). On the basis of phenotypic, chemotaxonomic and phylogenetic comparisons with its closest relatives, we propose its assignment to a novel species of the genus Kosmotoga. The name Kosmotoga pacifica sp. nov. is proposed with strain SLHLJ1(T) (=DSM 26965(T) = JCM 19180(T) = UBOCC 3254(T)) as the type species.


Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome.
KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K(+) ion channel proteins. KCNQ1 associates with a regulatory subunit, KCNE1, to produce the cardiac repolarizing current, I(Ks). Loss-of-function mutations in the human KCNQ1 gene have been linked to Jervell and Lange-Nielsen Syndrome (JLNS), a disorder characterized by profound bilateral deafness and a cardiac phenotype. To generate a mouse model for JLNS, we created a line of transgenic mice that have a targeted disruption in the Kcnq1 gene. Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and exhibit a shaker/waltzer phenotype. Histological analysis of the inner ear structures of Kcnq1(-/-) mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph. ECGs recorded from Kcnq1(-/-) mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. Together, these data suggest that Kcnq1(-/-) mice are a potentially valuable animal model of JLNS.


A sequence-ready map of the human chromosome 1q telomere.
A 260-kb half-YAC clone derived from human chromosome 1q was mapped at high resolution using cosmid subclone fingerprint analysis and was integrated with overlapping clones from the telomeric end of a separately derived 1q44 BAC contig to create a sequence-ready map extending to the molecular telomere of 1q. Analysis of 100 kb of sample sequences from across the 260-kb region encompassed by the half-YAC revealed the presence of EST sequence matches corresponding to 12 separate Unigene clusters and to 12 separate unclustered EST sequences. Low-copy subtelomeric repeats typical of many human telomere regions are present within the distal-most 30 kb of 1q. The previously isolated and radiation hybrid-mapped markers Bda84F03, 1QTEL019, and WI11861 localized at distances approximately 32, 88, and 99 kb, respectively, from the 1q terminus. This sequence-ready map permits high-resolution integration of genetic maps with the DNA sequences directly adjacent to the tip of human chromosome 1q and will enable telomeric closure of the human chromosome 1q DNA reference sequence by connecting the molecular 1q telomere to an internal BAC contig.


A rapid RT-LAMP assay for the detection of all four lineages of Peste des Petits Ruminants Virus.
Peste des petits ruminants (PPR) is a viral disease of small ruminants that is caused by the PPR virus (PPRV) and is a significant burden on subsistence farmers across the developing world. Loop-mediated isothermal amplification (LAMP) provides cost-effective, rapid, specific and sensitive detection of nucleic acid and has been demonstrated to have field application for a range of viruses. We describe the development of a novel PPRV RT-LAMP assay utilising carefully-selected primers (targeting the N-gene) allowing for the detection of all known PPRV lineages in < 20 min. The assay was evaluated in comparison with a "gold standard" real-time RT-PCR assay using more than 200 samples, comprising samples from recent PPRV outbreaks, experimentally-infected goats, well-characterised cell culture isolates and samples collected from uninfected animals. The RT-LAMP assay demonstrated 100% diagnostic specificity and greater than 97% diagnostic sensitivity in comparison with the real-time RT-PCR assay. The limit of detection was between 0.3 and 0.8 log10 TCID50 ml-1 equating to a CT value of 31.52 to 33.48. In experimentally-infected animals, the RT-LAMP could detect PPRV as early as 4 days post infection (dpi) - before clinical signs were observed at 7 dpi. The RT-LAMP assay can support the global PPR eradication campaign.


High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats.
A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.


A systematic review of selected interventions for worksite health promotion. The assessment of health risks with feedback.
Many health behaviors and physiologic indicators can be used to estimate one's likelihood of illness or premature death. Methods have been developed to assess this risk, most notably the use of a health-risk assessment or biometric screening tool. This report provides recommendations on the effectiveness of interventions that use an Assessment of Health Risks with Feedback (AHRF) when used alone or as part of a broader worksite health promotion program to improve the health of employees. The Guide to Community Preventive Services' methods for systematic reviews were used to evaluate the effectiveness of AHRF when used alone and when used in combination with other intervention components. Effectiveness was assessed on the basis of changes in health behaviors and physiologic estimates, but was also informed by changes in risk estimates, healthcare service use, and worker productivity. The review team identified strong evidence of effectiveness of AHRF when used with health education with or without other intervention components for five outcomes. There is sufficient evidence of effectiveness for four additional outcomes assessed. There is insufficient evidence to determine effectiveness for others such as changes in body composition and fruit and vegetable intake. The team also found insufficient evidence to determine the effectiveness of AHRF when implemented alone. The results of these reviews indicate that AHRF is useful as a gateway intervention to a broader worksite health promotion program that includes health education lasting > or =1 hour or repeating multiple times during 1 year, and that may include an array of health promotion activities. These reviews form the basis of the recommendations by the Task Force on Community Preventive Services presented elsewhere in this supplement.


A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene® MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma.
Background: Two sequential single-dose crossover dose-ranging studies were performed to evaluate the clinical efficacy and safety profile of epinephrine hydrofluroalkane (HFA) metered-dose inhaler (MDI) formulation at various doses in subjects with asthma. Methods: In these multicenter, multiarm, double-blinded, or evaluator-blinded studies, subjects were randomized to receive the epinephrine HFA (Primatene® MIST HFA) MDI medication at doses ranging from 90 to 440 μg/dose, as well as to a placebo (PLA) control and an active control of epinephrine CFC (chlorofluorocarbon) MDI (Primatene® MIST CFC) at 220 μg/inhalation. Results: Spirometry testing for FEV1 (Forced Expiratory Volume in one second) demonstrated statistically significant improvements over PLA for epinephrine HFA MDI at all doses above 125 μg, as the amount out of the actuator (i.e., mouthpiece). The efficacy results for epinephrine HFA MDI in the dose range of 125-250 μg were also comparable to epinephrine CFC MDI (220 μg/inh). Safety assessments demonstrated minimal safety concerns for all treatment groups. No notable safety differences were observed between the studied doses of epinephrine HFA MDI and the active control formulation of epinephrine CFC MDI. Conclusion: The findings indicate that epinephrine HFA MDI provided clinically significant bronchodilator efficacy with minimal safety concerns in a dose range of 125-250 μg. These findings confirmed the optimal treatment doses of 125-250 μg that were appropriate for use in longer term 12 and 26 week chronic dosing studies of epinephrine HFA MDI for patients with intermittent or mild to moderate persistent asthma. Clinical trials registration number: NCT01025648.


The influence of flexed-knee gait on the energy cost of walking in children.
There is an understanding that walking with flexed knees contributes to the increased energy cost of walking found in children with neurological conditions. To determine the influence of flexed-knee gait on energy cost of walking in a group of children without neurological abnormality, the gait patterns of 10 normal children were studied using a Vicon system and standard marker set. A telemetric system (Cosmed K2) was then used to measure the oxygen cost of walking of the same children. The tests were repeated restricting the subjects' knee extension bilaterally, using hinged braces, set to 0, 15, 30, and 45 degrees of flexion. Although the braces themselves caused a significant increase in O2 cost (mL/kg/m) (P < 0.05), due to a decrease in walking speed, no further significant increase in oxygen cost was demonstrated regardless of the degree of knee flexion imposed, despite a significant increase in measured hip flexion and ankle dorsiflexion at the 45 degrees of knee flexion setting (P < 0.05). We propose that moderate flexed-knee gait does not of itself cause an increase in the energy cost of walking and that other factors present in the physically disabled child are likely to be implicated.


Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy.
A mushroom extract, Agaricus blazei Murill Kyowa (ABMK), has been reported to possess antimutagenic and antitumor effects. Here, we investigate the beneficial effects of ABMK consumption on immunological status and qualities of life in cancer patients undergoing chemotherapy. One hundred cervical, ovarian, and endometrial cancer patients were treated either with carboplatin (300 mg / m(2)) plus VP16 (etoposide, 100 mg / m(2)) or with carboplatin (300 mg / m(2)) plus taxol (175 mg / m(2)) every 3 weeks for at least three cycles with or without oral consumption of ABMK. We observed that natural killer cell activity was significantly higher in ABMK-treated group (ANOVA, n = 39, P < 0.002) as compared with nontreated placebo group (n = 61). However, no significant difference in lymphokine-activated killer and monocyte activities was observed in a manner similar to the count of specific immune cell populations between ABMK-treated and nontreated groups. However, chemotherapy-associated side effects such as appetite, alopecia, emotional stability, and general weakness were all improved by ABMK treatment. Taken together, this suggests that ABMK treatment might be beneficial for gynecological cancer patients undergoing chemotherapy.


Excitation failure in eccentric contraction-induced injury of mouse soleus muscle.
1. Histological evidence suggests that the force deficit associated with eccentric contraction-induced muscle injury is due to structural damage to contractile elements within the muscle fibre. Alternatively, the force deficit could be explained by an inability to activate the contractile proteins. It was the objective of this study to investigate the latter possibility. 2. Mouse soleus muscles were isolated, placed in an oxygenated Krebs-Ringer buffer at 37 degrees C, and baseline measurements were made. The muscle then performed one of three contraction protocols: (1) twenty eccentric (n = 10 muscles); (2) ten eccentric (n = 12); or (3) twenty isometric (n = 10) contractions. At the end of the injury protocol, measurements were made during performance of a passive stretch, twitch and tetanus. Next, force was recorded during exposure of the muscle to buffer containing 50 mM caffeine. 3. Decrements in maximal isometric tetanic force (P0) observed for muscles in the twenty eccentric, ten eccentric, and twenty isometric contraction protocols were 42.6 +/- 4.2, 20.0 +/- 2.3 and 3.9 +/- 2.4%, respectively. However, the caffeine-elicited forces in muscles from the three protocols were not different when corrected for initial differences in P0 (64.9 +/- 1.3, 64.2 +/- 2.1 and 68.9 +/- 2.5% of pre-injury P0). The peak caffeine-elicited force was 118.4 +/- 8.6% of post-injury P0 for the muscles in the twenty eccentric contraction protocol, which was significantly different from that observed for the other protocols (71.8-80.2% post-injury P0). These findings indicate that the force deficit in this muscle injury model results from a failure of the excitation process at some step prior to calcium (Ca2+) release by the sarcoplasmic reticulum. 4. In an attempt to locate the site of failure, intracellular measurements were made in injured muscles to test whether injury to the sarcolemma might have resulted in a shift of the resting membrane potential of the muscle fibre. However, microelectrode measurements of resting membrane potential for muscles in the twenty eccentric contraction protocol (-74.4 +/- 0.6 mV) were not different from muscles in the twenty isometric contraction protocol (-73.4 +/- 1.0 mV). These data suggest that membrane resting conductances were normal and are compatible with the idea that the ability of the injured fibres to conduct action potentials was probably not impaired.


Agricultural Animals as Biomedical Models: Occupational Health and Safety Considerations.
The use of agricultural animals in biomedical research is increasing. Their overall size and metabolic rate, organ size, longer gestation period, and other physiological similarities make them good candidates for animal models of human disease. There are a number of special considerations for use of traditional farm animals for biomedical research. Differences in physical plant infrastructure, handling equipment, training of personnel, and potential zoonoses are some of the important considerations when traditional farm animals are used in biomedical research. This article provides an overview of some of the special considerations for using traditional agricultural animals in biomedical research. With the growing need for improved translational research, it is reasonable to predict significant growth in these animal models.


Semen characteristics and artificial insemination in rockhopper penguins (Eudyptes chrysocome chrysocome).
This work was performed as part of a multi-year study to determine the cause of the low fertility in captive rockhopper penguins (Eudyptes chrysocome chrysocome) and attempt to increase the fertility through artificial insemination (AI). Semen collection and characterization was performed on 14 male rockhopper penguins. The samples were evaluated for volume, sperm concentration, and sperm quality (motility, forward motility, viability, and morphology). There was a large variation between individuals and between collections for each individual. Mean volume of ejaculate was 0.24 ml. Mean concentration was 47.09 × 10(6) sperm/ml. Mean number of sperm per collection was 6.57 × 10(6). The mean motility was 49.4%. Mean forward motility was 1.7. Mean percentage of living sperm was 88.9%. Mean percentage of sperm with normal morphology was 69.4%. AI was performed on a total of 10 females using pooled semen samples. The birds were also allowed to naturally mate. Ten eggs were laid and three fertile eggs were produced, one of them hatched but died within 24 hr. Paternity testing was performed using 12 microsatellite loci, but unfortunately due to insufficient variability, the paternity of the chick and two embryos could not be determined.


Rapid turnover of effectors in grass powdery mildew (Blumeria graminis).
Grass powdery mildew (Blumeria graminis, Ascomycota) is a major pathogen of cereal crops and has become a model organism for obligate biotrophic fungal pathogens of plants. The sequenced genomes of two formae speciales (ff.spp.), B.g. hordei and B.g. tritici (pathogens of barley and wheat), were found to be enriched in candidate effector genes (CEGs). Similar to other filamentous pathogens, CEGs in B. graminis are under positive selection. Additionally, effectors are more likely to have presence-absence polymorphisms than other genes among different strains. Here we identified effectors in the genomes of three additional host-specific lineages of B. graminis (B.g. poae, B.g. avenae and B.g. infecting Lolium) which diverged between 24 and 5 million years ago (Mya). We found that most CEGs in B. graminis are clustered in families and that most families are present in both reference genomes (B.g. hordei and B.g. tritici) and in the genomes of all three newly annotated lineages. We identified conserved protein domains including a novel lipid binding domain. The phylogenetic analysis showed that frequent gene duplications and losses shaped the diversity of the effector repertoires of the different lineages through their evolutionary history. We observed several lineage-specific expansions where large clades of CEGs originated in only one lineage from a single gene through repeated gene duplications. When we applied a birth-death model we found that the turnover rate (the rate at which genes are deleted and duplicated) of CEG families is much higher than for non-CEG families. The analysis of genomic context revealed that the immediate surroundings of CEGs are enriched in transposable elements (TE) which could play a role in the duplication and deletion of CEGs. The CEG repertoires of related pathogens diverged dramatically in short evolutionary times because of rapid turnover and of positive selection fixing non-synonymous mutations. While signatures of positive selection on effector sequences are the expected outcome of the evolutionary "arms race" between pathogen and plant immune system, it is more difficult to infer the mechanisms and evolutionary forces that maintained an extreme turnover rate in CEG families of B. graminis for several millions of years.


Solubilization of single-wall carbon nanotubes by supramolecular encapsulation of helical amylose.
We have developed a simple, efficient process for solubilization of single-wall carbon nanotubes (SWNTs) with amylose in aqueous DMSO. This process requires two important conditions, presonication of SWNTs and subsequent amylose treatment in an optimum mixture of DMSO/H2O. The former step separates SWNT bundles, and the latter step provides a maximum cooperative interaction of SWNTs with amylose, leading to the immediate and complete solubilization. The best solvent condition for this is around 10-20% DMSO, in which amylose assumes a random conformation or an interrupted helix. This indicates that the amylose helix is not the prerequisite for encapsulation of SWNTs. The SEM and AFM images of the encapsulated SWNTs manifest loosely twisted ribbons wrapping around SWNTs, which are locally intertwined as a multiple twist, but no clumps of the host amylose are seen on SWNT capsules.


Financing the delivery of vaccines to children and adolescents: challenges to the current system.
Recent increases in the number and costs of vaccines routinely recommended for children and adolescents have raised concerns about the ability of the current vaccine financing and delivery systems to maintain access to recommended vaccines without financial barriers. Here we review the current state of US financing for vaccine delivery to children and adolescents and identify challenges that should be addressed to ensure future access to routinely recommended vaccines without financial barriers. Challenges were considered from the perspectives of vaccine providers; state and local governments; insurers, employers, and other health care purchasers; vaccine manufacturers; and consumers.


Visual motion perception deficits due to cerebellar lesions are paralleled by specific changes in cerebro-cortical activity.
Recent anatomical studies have revealed strong cerebellar projections into parietal and prefrontal cortex. These findings suggest that the cerebellum might not only play a functional role in motor control but also cognitive domains, an idea also supported by neuropsychological testing of patients with cerebellar lesions that has revealed specific deficits. The goal of the present study was to test whether or not cognitive impairments after cerebellar damage are resulting from changes in cerebro-cortical signal processing. The detection of global visual motion embedded in noise, a faculty compromised after cerebellar lesions, was chosen as a model system. Using magnetoencephalography, cortical responses were recorded in a group of patients with cerebellar lesions (n = 8) and controls (n = 13) who observed visual motion of varied coherence, i.e., motion strength, presented in the peripheral visual field during controlled stationary fixation. Corroborating earlier results, the patients showed a significant impairment in global motion discrimination despite normal fixation behavior. This deficit was paralleled by qualitative differences in responses recorded from parieto-temporal cortex, including a reduced responsiveness to coherent visual motion and a striking loss of bilateral representations of motion coherence. Moreover, the perceptual thresholds correlated with the cortical representation of motion strength on single subject basis. These results demonstrate that visual motion processing in cerebral cortex critically depends on an intact cerebellum and establish a correlation between cortical activity and impaired visual perception resulting from cerebellar damage.


All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45-74 years, 1984-1988. The Strong Heart Study.
Community mortality surveillance for 1984-1988 was conducted by researchers of the Strong Heart Study, which examined the incidence, prevalence, and risk factors of cardiovascular disease in three American Indian populations, aged 45-74 years, in Arizona, Oklahoma, and South/North Dakota. All-cause and cardiovascular disease mortality rates were determined through the use of death certificate data. Cardiovascular disease deaths were confirmed by independent systematic review of medical records. In all three populations, men had higher all-cause and cardiovascular disease mortality rates than did women. Oklahoma exhibited slightly lower 5-year, age-adjusted, all-cause mortality (96/1,000) than did Arizona (107/1,000) and South/North Dakota (114/1,000). The leading cause of death among both sexes in Oklahoma and in South/North Dakota was cardiovascular disease. Diabetes mellitus led among Arizona women. The other major causes of death were cancer, liver disease including cirrhosis, and injury. When compared with the rates in each state, average annual all-cause mortality rates were higher for the American Indian populations in almost every age group. The all-cause annual mortality rates in the three Indian populations were close to rates in the US black population and higher than the rates of the entire US population and of US whites. This trend was amplified in the 45- to 64-year age group. Only in the 65- to 74-year age group did mortality rates in the Indian population approach those of the US population. Cardiovascular disease mortality rates were close to the US averages in Arizona and Oklahoma, but they were more than two times higher in South/North Dakota among those between 45 and 64 years of age. Thus, American Indians in Arizona, Oklahoma, and South/North Dakota exhibit high all-cause mortality rates. In particular, the South/North Dakota population cardiovascular disease death rate appears to present a potential target for community-based programs to intervene on known risk factors to promote healthy lifestyles.


Obesity is a risk factor for musculoskeletal pain in adolescents: findings from a population-based cohort.
Obesity is a risk factor for fibromyalgia in adults, but whether a similar relationship exists in children is uncertain. This study examined whether obesity is associated with reporting of musculoskeletal pain, including chronic regional pain (CRP) and chronic widespread pain (CWP), in adolescents, in a population-based setting. A pain questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children at age 17, asking about site, duration, and pain intensity, from which participants with different types of musculoskeletal pain were identified. Relationships between obesity and pain were examined by calculating odds ratios stratified by gender and adjusted for socioeconomic status as reflected by level of maternal education. A total of 3376 participants (1424 boys) with complete data were identified, mean age 17.8; 44.7% of participants reported any pain within the last month lasting 1day or longer; 16.3% reported lower back pain, 9.6% shoulder pain, 9.4% upper back pain, 8.9% neck pain, 8.7% knee pain, 6.8% ankle/foot pain, 4.7% CRP, and 4.3% CWP; 7.0% of participants were obese. Obesity was associated with increased odds of any pain (odds ratio [OR] 1.33, P=.04), CRP (OR 2.04, P=.005), and knee pain (OR 1.87, P=.001), but not CWP (OR 1.10, P=.5). Compared with non obese participants, those with any pain, knee pain, and CRP reported more severe average pain (P<.01). Obese adolescents were more likely to report musculoskeletal pain, including knee pain and CRP. Moreover, obese adolescents with knee pain and CRP had relatively high pain scores, suggesting a more severe phenotype with worse prognosis.


Transplantation of marrow-derived cardiac stem cells carried in fibrin improves cardiac function after myocardial infarction.
The high death rate of the transplanted stem cells in the infarcted heart and the low efficiency of differentiation toward cardiomyocytes influence the outcome of stem cell transplantation for treatment of myocardial infarction (MI). Fibrin glue (FG) has been extensively used as a cell implantation matrix to increase cell survival. However, mechanisms of the effects of FG for stem cell transplantation to improve cardiac function are unclear. We have isolated c-kit+/Sca-1+ marrow-derived cardiac stem cells (MCSCs) from rat bone marrow; the cells expressed weakly early cardiac transcription factor Nkx2.5, GATA-4, Mef2C, and Tbx5. Effects of FG on survival, proliferation, and migration of MCSCs were examined in vitro. Cytoprotective effects of FG were assessed by exposure of MCSCs to anoxia. Efficacy of MCSC transplantation in FG was evaluated in the female rat MI model. The MCSCs survived well and proliferated in FG, and they may migrate out from the edge of FG in the wound and nature state. Acridine orange/ethidium bromide staining and lactate dehydrogenase analysis showed that MCSCs in FG were more resistant to anoxia as compared with MCSCs alone. In a rat MI model, cardiac function was improved and scar area was obviously reduced in group of MCSCs in FG compared with group of MCSCs and FG alone, respectively. Y chromosome fluorescence in situ hybridization showed that there were more survived MCSCs in group of MCSCs in FG than those in group of MCSCs alone, and most Y chromosome positive cells expressed cardiac troponin T (cTnT) and connexin-43 (Cx-43). Cx-43 was located between Y chromosome positive cells and recipient cardiomyocytes. Microvessel density in the peri-infarct regions and infarct regions significantly increased in group of MCSCs in FG. These results suggest that FG provide a suitable microenvironment for survival and proliferation of MCSCs and protect cells from apoptosis and necrosis caused by anoxia. MCSCs could differentiate into cardiomyocytes after being transplanted in the border of the infarcted myocardium and form connections with native cardiomyocytes. FG is helpful for MCSC transplantation to repair myocardium and improve cardiac function through promoting the survival, migration, and cardiomyogenic differentiation of MCSCs and inducing angiogenesis.


Interactive model of therapeutic response in panic disorder: moclobemide, a case in point.
It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments (interaction between treatment and baseline score). Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks, but not for the frequency of situational panic attacks or measures of agoraphobia. This report presents similar analyses of data from a study using moclobemide. Patients (N = 452) with panic disorder were randomized to placebo or a fixed dose of moclobemide (75, 150, 300, 600, or 900 mg/day). They were treated double-blindly and evaluated at baseline and 1, 2, 3, 4, 6, and 8 weeks later. The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary, and fear and avoidance ratings based on the patient's main phobia using baseline (pre) and end-point (post) values for all randomized patients. Adjoining dose groups were combined. Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes. Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms. This study replicates the authors' earlier findings, except for situational panic attacks, which probably were not reliably identified. Antidepressants selectively suppress panic attacks, especially unexpected attacks, but not agoraphobia. The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinically separable biologic and cognitive components that respond differentially to treatment. Antidepressants benefit primarily patients with many unexpected panic attacks. Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means (analysis of covariance).


Genetic differentiation of eastern wolves in Algonquin Park despite bridging gene flow between coyotes and grey wolves.
Distinguishing genetically differentiated populations within hybrid zones and determining the mechanisms by which introgression occurs are crucial for setting effective conservation policy. Extensive hybridization among grey wolves (Canis lupus), eastern wolves (C. lycaon) and coyotes (C. latrans) in eastern North America has blurred species distinctions, creating a Canis hybrid swarm. Using complementary genetic markers, we tested the hypotheses that eastern wolves have acted as a conduit of sex-biased gene flow between grey wolves and coyotes, and that eastern wolves in Algonquin Provincial Park (APP) have differentiated following a history of introgression. Mitochondrial, Y chromosome and autosomal microsatellite genetic data provided genotypes for 217 canids from three geographic regions in Ontario, Canada: northeastern Ontario, APP and southern Ontario. Coyote mitochondrial DNA (mtDNA) haplotypes were common across regions but coyote-specific Y chromosome haplotypes were absent; grey wolf mtDNA was absent from southern regions, whereas grey wolf Y chromosome haplotypes were present in all three regions. Genetic structuring analyses revealed three distinct clusters within a genetic cline, suggesting some gene flow among species. In APP, however, 78.4% of all breeders and 11 of 15 known breeding pairs had assignment probability of Q0.8 to the Algonquin cluster, and the proportion of eastern wolf Y chromosome haplotypes in APP breeding males was higher than expected from random mating within the park (P<0.02). The data indicate that Algonquin wolves remain genetically distinct despite providing a sex-biased genetic bridge between coyotes and grey wolves. We speculate that ongoing hybridization within the park is limited by pre-mating reproductive barriers.


Quantitative dose-response curves from subcellular lipid multilayer microarrays.
The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate.


In vitro Results of Scanning Technique on Assessing Cement Thickness and Interfacial Nanoleakage of Luted CAD/CAM-Fabricated Fiber Posts.
Fiber posts are broadly used due to their good esthetics and elasticity close to that of dentin, which allows for uniform stress distribution within a root and lowers the possibility of nonrestorable root fractures. The study assessed the layer of cement thickness and interfacial nanoleakage of luted fiber posts which were fabricated with CAD/CAM technology following direct scanning of the post space (DS) method, scanning of a polyether impression of the post space (IS), and scanning of a plaster model of the post space (MS). Ninety premolars were chosen randomly and were assigned to three groups according to the scanning technique. Posts were computer designed and milled from experimental fiber-reinforced composite blocks. The mean and standard deviation values of cement thickness, respectively, were: DS 172 ± 39 = m; IS 199 ± 55 = m, and MS MPa 272 ± 81 = m. The fiber posts fabricated following DS technique demonstrated superior performance compared to posts fabricated upon IS and MS, in terms of the post retention. The cement thickness did not differ between DS and IS, whereas in MS group, the cement layer was significantly thicker than in the remaining two groups. The scanning technique did not influence the sealing ability, as all groups showed comparable nanoleakage. Fiber posts fabricated following DS technique demonstrated superior performance. Furthermore, scanning technique did not influence the sealing ability, as all groups showed comparable nanoleakage.


Improving Alkaline Hydrogen Oxidation through Dynamic Lattice Hydrogen Migration in Pd@Pt Core-Shell Electrocatalysts.
Tracking the trajectory of hydrogen intermediates during hydrogen electro-catalysis is beneficial for designing synergetic multi-component catalysts with division of chemical labor. Herein, we demonstrate a novel dynamic lattice hydrogen (LH) migration mechanism that leads to two orders of magnitude increase in the alkaline hydrogen oxidation reaction (HOR) activity on Pd@Pt over pure Pd, even ~31.8 times mass activity enhancement than commercial Pt. Specifically, the polarization-driven electrochemical hydrogenation process from Pd@Pt to PdHx@Pt by incorporating LH allows more surface vacancy Pt sites to increase the surface H coverage. The inverse dehydrogenation process makes PdHx as an H reservoir, providing LH migrates to the surface of Pt and participates in the HOR. Meanwhile, the formation of PdHx induces electronic effect, lowering the energy barrier of rate-determining Volmer step, thus resulting in the HOR kinetics on Pd@Pt being proportional to the LH concentration in the in situ formed PdHx@Pt. Moreover, this dynamic catalysis mechanism would open up the catalysts scope for hydrogen electro-catalysis.


Does human relaxin-2 affect peripheral blood mononuclear cells to increase inflammatory mediators in pathologic bone loss?
This study was designed to test the hypothesis that relaxin stimulates bone resorption by regulating the production of several mediators that stimulate osteoclast formation. The levels of mediators were measured in response to differing relaxin concentrations in supernatants from peripheral blood mononuclear cells (PBMCs), MCF-7 breast cancer cells, and normal human osteoblasts. Although all cell types expressed mRNA for the relaxin receptor (LGR7), only PBMCs responded to relaxin at physiologic levels by increasing tumor necrosis factor-alpha and interleukin-1beta secretion. The findings indicate that PBMCs should be studied in relation to the effect of relaxin on inflammation and bone destruction caused by osteoclasts.


Polymyxin for treatment of ventilator-associated pneumonia in a setting of high carbapenem resistance.
To analyse the use of polymyxins for the treatment of ventilator-associated pneumonia (VAP) at a teaching hospital where carbapenem-resistant gram-negative bacteria are endemic. This was a historical cohort study of patients receiving polymyxins to treat VAP in ICUs at a public university hospital in southern Brazil between January 1, 2017 and January 31, 2018. During the study period, 179 cases of VAP were treated with polymyxins. Of the 179 patients, 158 (88.3%) were classified as having chronic critical illness. Death occurred in 145 cases (81.0%). Multivariate analysis showed that the factors independently associated with mortality were the presence of comorbidities (P<0.001) and the SOFA score of the day of polymyxin prescription (P<0.001). Being a burn patient was a protective factor for mortality (P<0.001). Analysis of the 14-day survival probability showed that mortality was higher among the patients who had sepsis or septic shock at the time of polymyxin prescription (P = 0.028 and P<0.001, respectively). Acinetobacter baumannii was identified as the etiological agent of VAP in 121 cases (67.6%). In our cohort, polymyxin consumption and the incidence density of VAP were quite high. In our study, comprised primarily of chronically critically ill patients, there was a high prevalence of VAP caused by multidrug-resistant bacteria, consistent with healthcare-associated infections in low- and middle-income countries. Presence of comorbidities and the SOFA score at the time of polymyxin prescription were predictors of mortality in this cohort. Despite aggressive antimicrobial treatment, mortality was high, stressing the need for antibiotic stewardship.


[Oral bioavailability and drug/carrier particulate systems].
The oral route remains the preferred route of administration to ensure patient satisfaction and compliance. However, new chemical entities may exhibit low bioavailability after oral administration because of poor stability within the gastrointestinal tract, poor solubility in gastrointestinal fluids, low mucosal permeability, and/or extensive first-pass metabolism. Consequently, these new drug substances cannot be further developed using conventional oral formulations. This issue is addressed by an innovative approach based on the entrapment of drug molecules in drug/carrier assembling systems. The carrier materials are lipids, naturally occurring polymers or synthetic polymers, which are considered as nontoxic and biocompatible materials. Drug entrapment is intended to protect drug substances against degradation by gastrointestinal fluids. Fine drug/carrier particle size ensures increased drug dissolution rates. Carriers and particle supramolecular organization can be designed to enhance drug absorption through the intestinal epithelium and lymphatic transport. Promising preclinical results have been obtained with model drugs like paclitaxel, insulin, calcitonin, or cyclosporin. Attention has focused on mucoadhesive carriers like chitosan that favor an intimate and extended contact between drugs and intestinal cells, thus enhancing absorption. Addition of ligands such as lectins improves intestinal drug absorption through specific binding of the carrier to intestinal cell carbohydrates. In conclusion, drug/carrier particulate systems are an attractive and exciting drug delivery strategy for highly potent drug substances unsuitable for oral use. Further evidence will determine whether this approach has marked therapeutic benefits over conventional drug formulations and is compatible with large-scale industrial production and stringent registration requirements. Producing highly effective particulate systems requiring low-complexity manufacturing processes is therefore an ongoing challenge.


Morphology of the lacrimal sac and nasolacrimal duct in adult human cadaver.
The lacrimal sac (LS) is a dilated structure that lies in the lacrimal fossa, and the nasolacrimal duct (NLD) is the continuation of LS from its neck up to the inferior meatus of the nose. A study of 50 specimens of formalin-fixed adult cadavers of both sexes of Indian origin was conducted. The morphological features like length and breadth of LS and NLD, along with the histology of LS has been observed. The mean length of LS and NLD on the right side was 10.5 mm (1.04) and 16 mm (2.6) respectively, whereas the mean breadth of the above structures, on the right side was 6 mm (0.63) and 5.66 mm (0.81) respectively. The mean length of LS and NLD on the left side was 10.57 mm (1.13) and 16.42 mm (2.29), whereas, the mean breadth of the same structure on the left side was 6.71 mm (0.95) and 5 mm (0.81) respectively. The sides did not show any significant statistical difference but when the correlation between the length and breadth of LS is considered, significance was observed in the lacrimal sac of the left side. No variations were observed in the gross structure of LS and NLD. Microscopic study showed the presence of elastic fibers in LS. The importance of LS and NLD is that the blockage of this lacrimal passage is the most common cause of epiphora (watering of the eye). The presence of elastic fibers in this study confirms the hypothesis that the sac elasticity may perform a dynamic role, in forceful evacuation of lacrimal fluid in reverse direction (Tab. 2, Fig. 3, Ref. 10). Full Text (Free, PDF) www.bmj.sk.


Species interactions drive the spread of ampicillin resistance in human-associated gut microbiota.
Slowing the spread of antimicrobial resistance is urgent if we are to continue treating infectious diseases successfully. There is increasing evidence microbial interactions between and within species are significant drivers of resistance. On one hand, cross-protection by resistant genotypes can shelter susceptible microbes from the adverse effects of antibiotics, reducing the advantage of resistance. On the other hand, antibiotic-mediated killing of susceptible genotypes can alleviate competition and allow resistant strains to thrive (competitive release). Here, by observing interactions both within and between species in microbial communities sampled from humans, we investigate the potential role for cross-protection and competitive release in driving the spread of ampicillin resistance in the ubiquitous gut commensal and opportunistic pathogen Escherichia coli. Using anaerobic gut microcosms comprising E.coli embedded within gut microbiota sampled from humans, we tested for cross-protection and competitive release both within and between species in response to the clinically important beta-lactam antibiotic ampicillin. While cross-protection gave an advantage to antibiotic-susceptible E.coli in standard laboratory conditions (well-mixed LB medium), competitive release instead drove the spread of antibiotic-resistant E.coli in gut microcosms (ampicillin boosted growth of resistant bacteria in the presence of susceptible strains). Competition between resistant strains and other members of the gut microbiota can restrict the spread of ampicillin resistance. If antibiotic therapy alleviates competition with resident microbes by killing susceptible strains, as here, microbiota-based interventions that restore competition could be a key for slowing the spread of resistance. Slowing the spread of global antibiotic resistance is an urgent task. In this paper, we ask how interactions between microbial species drive the spread of resistance. We show that antibiotic killing of susceptible microbes can free up resources for resistant microbes and allow them to thrive. Therefore, we should consider microbes in light of their social interactions to understand the spread of resistance.


Clinical Performance and Impact of Accelerate Pheno for Gram-negative Bacteremia in Hospitalized Children.
Accelerate Pheno provides rapid identification and antimicrobial susceptibility tests (ASTs) of pathogens that cause blood stream infections (BSIs). The study objective was to assess the accuracy of the Accelerate Pheno platform and its impact on antimicrobial modification in children with gram-negative BSIs. A retrospective review was conducted of patients at a children's hospital with gram-negative BSIs from November 2018 to November 2019. Proportion of agreement between Accelerate Pheno and standard of care (SOC) was determined for organism identification (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) and susceptibilities (MicroScan). Time from culture collection to Gram stain, identification and AST by the Accelerate Pheno method, and AST results by MicroScan were calculated. Antibiotic modifications and opportunities to optimize antimicrobial stewardship were recorded. Of 115 BSIs from 90 patients, 90 monomicrobial gram-negative BSIs with an organism included on the Accelerate Pheno panel were found. Compared with SOC, the organism was correctly identified in 90 patients (100%). Overall, 5 of 732 ASTs (0.7%) reported susceptible by Accelerate Pheno were resistant by SOC, and 8 of 109 (7.3%) reported resistant by Accelerate Pheno were susceptible by SOC. On the basis of the Accelerate Pheno AST results, antibiotic spectrum was increased in 10 of 11 instances to correct organism-drug mismatch and narrowed in 16 of 33 instances. Median times from culture collection to reporting of Gram stain, Accelerate Pheno identification, Accelerate Pheno AST, and SOC AST were 12.6, 14.6, 19.9, and 60.6 h, respectively. Median time to optimal therapy was 21.8 h for infections with actionable AST data. Accelerate Pheno was accurate and decreased time to optimal therapy by almost 40 h for children with gram-negative BSIs. Antibiotic spectrum was increased in multiple instances, but opportunities to decrease spectrum were underused.


Are we recording peak flows properly in young children?
Peak flow rate is used in young children to assess bronchodilator response and monitor asthma status at home. Frequently the best of only three peak flow manoeuvres is reported. The aim of this study was to assess if this was sufficient to give the maximum peak flow rate and to determine the reproducibility of the measurement. Thirty nine children aged between three and ten years were recruited. Peak expiratory flow rate (PEFR) was measured six times in each child at two minute intervals. Less than half (13 of 39) of the children made their maximum blow in the first three manoeuvres. The maximum peak flow from the second set of three blows was a median of 7% greater than that from the first three blows. The coefficient of variation of the measurement was 8.8% suggesting a change in PEFR greater than 17.6% is necessary to demonstrate a response to bronchodilator. We conclude three peak flow manoeuvres are insufficient in the majority of young children to demonstrate the maximum peak flow.


Synovial fluid chondroitin and keratan sulphate epitopes, glycosaminoglycans, and hyaluronan in arthritic and normal knees.
To determine concentrations of chondroitin sulphate (CS) and keratan sulphate (KS) epitopes, glycosaminoglycans (GAGs) and hyaluronan (HA) in knee synovial fluid (SF) from normal subjects and patients with osteoarthritis (OA) or rheumatoid arthritis (RA), to test whether these variables may be used as markers of the OA process. OA was subdivided into large joint OA (LJOA), nodal generalised OA (NGOA), and OA with calcium pyrophosphate crystal deposition (CPA). Clinical assessment of inflammation (0-6) was undertaken on OA and RA knees. Knee SF was examined by enzyme linked immunosorbent assay for: CS epitopes, using monoclonal antibodies 3-B-3 and 7-D-4; KS epitope using monoclonal antibody 5-D-4; and HA, using biotinylated HA binding region of cartilage proteoglycan. Total sulphated GAGs were measured by dye binding with 1:9 dimethylmethylene blue. Increased SF 3-B-3 concentrations and 3-B-3/GAG ratio were found in OA, compared with RA or normal knees, with higher 3-B-3 and 3-B-3/GAG in LJOA and NGOA than in CPA. SF 7-D-4 and 7-D-4/GAG were reduced in RA, compared with normal and OA; SF 5-D-4 was reduced in OA compared with normal. GAG and HA concentrations were decreased in both OA and RA. No correlations with radiographic scores were observed, but SF 7-D-4 was lower in 'inflamed' compared with 'non-inflamed' RA and OA knees. In patients with bilateral samples there were strong correlations between right and left knees for all SF variables. Changed concentrations of SF CS and KS can be detected in OA with a profile that differs from that seen in RA. Clinical subgrouping and local joint inflammation may influence these measures, supporting different pathogenesis within OA subgroups and requirement for careful patient characterisation in SF studies.


Novel Multi-Parametric Sensor System for Comprehensive Multi-Wavelength Photoplethysmography Characterization.
Photoplethysmography (PPG) is widely used to assess cardiovascular health. However, its usage and standardization are limited by the impact of variable contact force and temperature, which influence the accuracy and reliability of the measurements. Although some studies have evaluated the impact of these phenomena on signal amplitude, there is still a lack of knowledge about how these perturbations can distort the signal morphology, especially for multi-wavelength PPG (MW-PPG) measurements. This work presents a modular multi-parametric sensor system that integrates continuous and real-time acquisition of MW-PPG, contact force, and temperature signals. The implemented design solution allows for a comprehensive characterization of the effects of the variations in these phenomena on the contour of the MW-PPG signal. Furthermore, a dynamic DC cancellation circuitry was implemented to improve measurement resolution and obtain high-quality raw multi-parametric data. The accuracy of the MW-PPG signal acquisition was assessed using a synthesized reference PPG optical signal. The performance of the contact force and temperature sensors was evaluated as well. To determine the overall quality of the multi-parametric measurement, an in vivo measurement on the index finger of a volunteer was performed. The results indicate a high precision and accuracy in the measurements, wherein the capacity of the system to obtain high-resolution and low-distortion MW-PPG signals is highlighted. These findings will contribute to developing new signal-processing approaches, advancing the accuracy and robustness of PPG-based systems, and bridging existing gaps in the literature.


Characterization of bacterial pathogens in rural and urban irrigation water.
The study aimed to compare the bacteriological quality of an urban and rural irrigation water source. Bacterial counts, characterization, identification and diversity of aerobic bacteria were determined. Escherichia coli isolated from both sites was subjected to antibiotic susceptibility testing, virulence gene (Stx1/Stx2 and eae) determination and (GTG)5 Rep-PCR fingerprinting. Low mean monthly counts for aerobic spore formers, anaerobic spore formers and Staphylococcus aureus were noted although occasional spikes were observed. The most prevalent bacterial species at both sites were Bacillus spp., E. coli and Enterobacter spp. In addition, E. coli and Bacillus spp. were most prevalent in winter and summer respectively. Resistance to at least one antibiotic was 84% (rural) and 83% (urban). Highest resistance at both sites was to cephalothin and ampicillin. Prevalence of E. coli possessing at least one virulence gene (Stx1/Stx2 and eae) was 15% (rural) and 42% (urban). All (rural) and 80% (urban) of E. coli possessing virulence genes showed antibiotic resistance. Complete genetic relatedness (100%) was shown by 47% of rural and 67% of urban E. coli isolates. Results from this study show that surface irrigation water sources regardless of geographical location and surrounding land-use practices can be reservoirs of similar bacterial pathogens.


Abnormally-fucosylated serum haptoglobins in patients with inflammatory joint disease.
The fucosylation of haptoglobins is altered in rheumatoid arthritis. In order to investigate the clinical usefulness of this finding, serum levels of abnormally-fucosylated haptoglobins (FHp) have been assessed in defined and matched groups of patients with different inflammatory joint diseases. FHp was elevated in 16/17 patients with active rheumatoid arthritis (RA); 1/20 patients with inactive rheumatoid arthritis; 1/11 patients with osteoarthritis; and 4/10 patients with seronegative polyarthritis. Raised FHp levels, therefore, are not disease-specific. There was no relationship between the duration of RA and the FHp level. The FHp expression in RA was also compared with other biochemical indices of disease activity. The degree of correlation between FHp and articular index, joint score and early-morning stiffness was very similar to that obtained for C reactive protein (CRP), and better than that obtained for erythrocyte sedimentation rate and haemoglobin. FHp, however, gives fewer false-positives than CRP in cases of inactive disease. until FHp can be measured more easily and cheaply, CRP estimation is still the biochemical test of choice in RA.


Enantioselectivity of odor perception in squirrel monkeys and humans.
With use of a conditioning paradigm, the ability of six squirrel monkeys to distinguish between 10 pairs of enantiomers, i.e., odorants that are identical except for chirality, was investigated. As a group, the animals were only able to discriminate between the optical isomers of alpha-pinene, carvone, limonene, and fenchone, whereas they failed to distinguish between the (+) and (-) forms of beta-citronellol, menthol, rose oxide, 2-butanol, alpha-terpineol, and camphor. With use of a triple forced-choice procedure, 10 human subjects were tested for their ability to discriminate between the same enantiomeric odor pairs in parallel and, with the exception of fenchone, showed a very similar pattern of performance compared with the squirrel monkeys. These findings support the assumption that human and nonhuman primates may share common principles of odor quality perception. Furthermore, the results suggest that, in both species, enantioselective molecular odor receptors may only exist for some, but not all volatile enantiomers and thus that chiral recognition of odorants is not a general phenomenon, but may be restricted to some substances.


The effects of benzopyrene and safrole on biphenyl 2-hydroxylase and other drug-metabolizing enzymes.
A study was made of the nature and specificity of the increase in biphenyl 2-hydroxylase activity after preincubation of liver microsomal preparations with various carcinogens in vitro. This enhancement of enzyme activity in vitro was investigated in mouse, hamster and rat, and although the rat appears to be atypical in the variation of the pattern of 2- and 4-hydroxylation with age, similar enhancements were detectable in each species examined. An increase in biphenyl 2-hydroxylase activity was apparent 2h after intraperitoneal administration of safrole or benzopyrene to mature Wistar albino rats and appeared to be similar in nature to that observed after preincubation of liver microsomal preparations with the same chemical in vitro. Investigation of other drug-metabolizing enzyme systems suggests that the enhancing effects of carcinogens in vitro are specific for biphenyl 2-hydroxylase. No correlation between the enhancement of biphenyl 2-hydroxylase and inhibtion of biphenyl 4-hydroxylase was apparent.


Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.
An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.


On the pattern of cohort fertility.
Abstract An examination of the patterns of cohort fertility rates in a number of populations revealed the existence of a common pattern showing how mean family sizes of the different age-at-marriage groups of a given marriage cohort are built up over the reproductive span. Standard schedules of fertility patterns are generated by the use of the Gompertz function which defines the distribution of cumulative fertility rates of a given marriage cohort by marriage duration by means of only three parameters. The generated system is tested with the historical series for England and Wales and Sweden and is found adequate to describe widely different childbearing patterns. Some of the demographic implications of the existence of common fertility patterns are examined and the usefulness of the generated system in projecting future fertility trends is briefly discussed.


Pulmonary sequestration of amiodarone and desethylamiodarone.
We hypothesized that one of the reasons for the particular susceptibility of the lung toward the adverse effects from the antiarrhythmic agent amiodarone (A) could be a high pulmonary accumulation of this drug. This hypothesis was tested using the isolated perfused lungs of Fischer 344 and Sprague-Dawley rats and New Zealand White rabbits. Uptake of a 3 microM starting concentration of a mixture of A and [14C]A by the lung occurred rapidly in each species, and only 25.6, 19 and 16.4% of the initial concentration remained in the perfusate at the end (60 min) of the experiment in Fischer 344, Sprague-Dawley rats and rabbits, respectively. No metabolism of A was detected by the high-performance liquid chromatography technique. Raising the initial concentration of A from 0.3 to 120 microM (n = 26) in the Fischer 344 rats apparently did not saturate the uptake process, and the tissue/medium ratio averaged 122.5. The uptake of desethylamiodarone (DEA), the main metabolite of A in vivo, was more extensive (tissue/medium ratio = 506) than that of the parent compound. DEA also was not metabolized by the isolated perfused lungs. Lung homogenate incubations fortified with cofactors did not metabolize A or DEA. We conclude that in the isolated perfused lungs: A is extensively taken up by the lungs of rats and rabbits; the uptake is not saturated by raising the concentrations over a 400-fold range; DEA is taken up more readily than A; and metabolism of neither compound is observed.


Characterization of phenolic substances and antioxidant properties of food soybeans grown in the North Dakota-Minnesota region.
Phenolic profiles and antioxidant properties of a total of 30 soybean samples, including 27 grown in the North Dakota-Minnesota region and three soybeans from the other regions, were investigated. The total phenolic content (TPC), total flavonoids content (TFC), phenolic acids, flavonols, anthocyanins, and isoflavones were quantified. Antioxidant properties of soybean extracts were assessed using 2-diphenyl-1-picryhydrazyl free radical scavenging activity (DPPH), ferric reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC) methods. Results showed that black soybean cultivars possessed significantly higher TPC, TFC, DPPH, FRAP, and ORAC values than all yellow soybean cultivars. However, black soybean cultivars did not exhibit significantly higher individual phenolic contents (except for anthocyanins), such as phenolic acids and isoflavones, than the yellow soybean cultivars. The isoflavone profiles of North Dakota soybean cultivars were similar to those of South Dakota, but average values of total isoflavone (TI) contents were higher than soybeans grown in the other states and Korea and Japan according to the U.S. Department of Agriculture-Iowa State University Database on the isoflavone contents of foods. Correlation assays showed that TPC, TI, total phenolic acids, daidzin, genistin, malonyldaidzin, daidzein, genistein, and trans-cinnamic acid significantly ( r = 0.73, 0.62, 0.49, 0.68, 0.59, 0.59, 0.56, 0.47, and 0.76, respectively, p < 0.0001) correlated with ORAC values of yellow soybeans. Both isoflavones and phenolic acids contributed to the ORAC values of yellow soybeans. These data suggest that some selected soybean cultivars may be used as high-quality food-grade soybeans for providing high phenolic phytochemicals and antioxidant activities.


[Gastrointestinal Epstein Barr virus positive diffuse large B cell lymphoma in elderly: report of five cases and review of literature].
EBV-positive diffuse large B-cell lymphoma (DLBCL) in elderly is a new entity included provisionally in the most recent WHO Classification of lymphoid neoplasms. It usually affects elderly patients and has a poor survival. The goal of this report was to evaluate clinical, endoscopic characteristics and survival of five patients with this entity and gastrointestinal afectation. From five cases, three cases had gastric infiltration, one ileon and one in cecum.


X2-VLM: All-In-One Pre-trained Model For Vision-Language Tasks.
Vision language pre-training aims to learn alignments between vision and language from a large amount of data. Most existing methods only learn image-text alignments. Some others utilize pre-trained object detectors to leverage vision language alignments at the object level. In this paper, we propose to learn multi-grained vision language alignments by a unified pre-training framework that learns multi-grained aligning and multi-grained localization simultaneously. Based on it, we present X2-VLM, an all-in-one model with a flexible modular architecture, in which we further unify image-text pre-training and video-text pre-training in one model. X2-VLM is able to learn unlimited visual concepts associated with diverse text descriptions. Experiment results show that X2-VLM performs the best on base and large scale for both image-text and video-text tasks, making a good trade-off between performance and model scale. Moreover, we show that the modular design of X2-VLM results in high transferability for it to be utilized in any language or domain. For example, by simply replacing the text encoder with XLM-R, X2-VLM outperforms state-of-the-art multilingual multi-modal pre-trained models without any multilingual pre-training. The code and pre-trained models are available athttps://github.com/zengyan-97/X2-VLM.


The future use of in vitro data in risk assessment to set human exposure standards: challenging problems and familiar solutions.
The vision of a National Research Council (NRC) committee (the Committee on Toxicity Testing and Assessment of Environmental Agents) for future toxicity testing involves the testing of human cells in in vitro assays for "toxicity pathways"--normal signaling pathways that when perturbed can lead to adverse effects. Risk assessments would eventually be conducted using mathematical models of toxicity pathways (TP models) to estimate exposures that will not cause biologically significant perturbations in these pathways. In this commentary we present our vision of how risk assessment to support exposure standards will be developed once a suitable suite of in vitro assays becomes available. Issues to be faced basing risk assessments on in vitro data are more complex than, but conceptually similar to, those faced currently when applying in vivo data. Absent some unforeseen technical breakthrough, in vitro data will be used in ways similar to current practices that involve applying uncertainty or safety factors to no observed adverse effect levels or benchmark doses. TP models are unlikely to contribute quantitatively to risk assessments for several reasons, including that the statistical variability inherent in such complex models severely limits their usefulness in estimating small changes in response, and that such models will likely continue to involve empirical modeling of dose responses. The vision of the committee predicts that chemicals will be tested more quickly and cheaply and that animal testing will be reduced or eliminated. Progress toward achieving these goals will be expedited if the issues raised herein are given careful consideration.


Compliance to consensus recommendations, surgeon's experience, and introduction of a quality assurance and management program: influence on therapy of early-stage ovarian carcinoma.
State-of-the-art surgical staging and adjuvant chemotherapy in early-stage ovarian carcinoma have an impact on patient's outcome, but compliance to guidelines and consensus recommendations is still poor. This article reports on our results before and after introduction of a quality assurance and management program in our clinic in 2001. Patients with ovarian carcinoma limited to the pelvis who underwent primary surgery in our hospital from 1997 to October 2007 were eligible for this study. Univariate and multivariate logistic regression analyses were performed to evaluate the impact of compliance with our management program and physician's experience in ovarian carcinoma surgery on achieving both standards of surgery and chemotherapy. In a total of 117 women, a significant impact on adherence to guideline-defined comprehensive surgical staging was found for poor Eastern Cooperative Oncology Group performance status (odds ratio [OR], 22.16; confidence interval [CI] 3.2-152.0; P = 0.002) and year of surgery before 2001 (OR, 47.60; CI, 9.20-245.22; P < 0.001). Tumor grading less than G3 (OR, 4.14; CI, 1.20-14.22; P = 0.02) was a statistically significant predictor for receiving standard adjuvant chemotherapy. Survival analyses showed a trend toward improved survival for patients having received guideline-adopted therapy, but event numbers were too low for adequate analyses. The introduction of a quality assurance program for treatment of ovarian carcinoma represents a major improvement of patient care. It led to a higher compliance with consensus recommendations and showed already a trend toward improved outcome. Further outcome research should focus on methods for implementation of guidelines in daily practice in institutions caring for patients with ovarian carcinoma.


[Pilot study of Experience Focused Counselling by nurses with people who hear voices: Evaluation of the implementation of the study protocol].
Pilot study of Experience Focused Counselling by nurses with people who hear voices: Evaluation of the implementation of the study protocol Abstract: Background: Hearing voices and the treatment and support of people who hear voices and are distressed by the experience are defined differently in psychiatry. In contrast to the medical approach to define and treat voices as symptoms of a disease, the EFC counselling approach developed with voice-hearers focuses on non-pathologizing acceptance and a constructive relationship to voices. Mental health nurses with their focus on everyday life are predestined for the dissemination and application of alternative therapeutic approaches in practice. Aim: The aim was to evaluate the study protocol as part of a pilot study regarding its suitability for a larger trial. Method: The multi centre pilot study had a single-blind randomised controlled design. The intervention consisted of EFC counselling by nurses with people who hear voices. The control group received Treatment As Usual (TAU). The suitability of the study design was evaluated in terms of recruitment, burden on study participants, suitability of assessment tools, the application of EFC counselling and the use of study nurses. Results: As planned 21 participants could be included in the study within fifteen months across the two study sites. Overall, the participants rated the study as not very burdensome and the intervention as helpful. The application of EFC by the nurses as well as the use of study nurses was assessed as good and suitable respectively. Discussion: The evaluation of the study protocol shows that with minor adjustments it is suitable for conducting a larger study.


Prognosis of stroke in the south of Greece: 1 year mortality, functional outcome and its determinants: the Arcadia Stroke Registry.
For Greece, data on incidence of stroke, type of stroke, and prognosis of stroke is limited. Recently, results on incidence of stroke were published. Here 1 year mortality, functional outcome after a first ever stroke, and determinants of the prognosis are described. A population based registry was established in the Arcadia area, located in eastern central Peloponessos in southern Greece. Between 1 November 1993 and 31 October 1995, 555 patients with a first ever stroke were identified using information from death certificates, hospital records, public health centres and general practitioners. Extensive information on cardiovascular risk factors and stroke characteristics was obtained. After 1 year a modified Rankin score was determined in all surviving patients. After 1 year of follow up, 204 (36.8%) patients died. The probability of survival 1 year after stroke was higher for cerebral infarction than for intracerebral haemorrhage; 67.8% (95% confidence interval (95% CI) 64-72) and 46.4% (35-57), respectively. Of the survivors, 68.9% had either no symptoms or symptoms that would not interfere with their capacity to look after themselves (Rankin score 0 to 2). Increasing age and low Glasgow coma scale score were the most powerful predictors of death within 1 year (p<0.01), whereas increasing age, atrial fibrillation, and low Glasgow coma scale score were the most important predictors of functional outcome 1 year after a stroke (p<0.01). One year mortality from stroke in Greece is similar to that of other industrialised countries. The most important factors that affect the prognosis of a patient with a first ever stroke are increasing age, stroke severity, and atrial fibrillation.


Local chemical composition of nanophase-separated polymer brushes.
Using scattering scanning nearfield infrared microscopy (s-SNIM), we have imaged the nanoscale phase separation of mixed polystyrene-poly(methyl methacrylate) (PS-PMMA) brushes and investigated changes in the top layer as a function of solvent exposure. We deduce that the top-layer of the mixed brushes is composed primarily of PMMA after exposure to acetone, while after exposure to toluene this changes to PS. Access to simultaneously measured topographic and chemical information allows direct correlation of the chemical morphology of the sample with topographic information. Our results demonstrate the potential of s-SNIM for chemical mapping based on distinct infrared absorption properties of polymers with a high spatial resolution of 80 nm × 80 nm.


Covariation between homeodomain transcription factors and the shape of their DNA binding sites.
Protein-DNA recognition is a critical component of gene regulatory processes but the underlying molecular mechanisms are not yet completely understood. Whereas the DNA binding preferences of transcription factors (TFs) are commonly described using nucleotide sequences, the 3D DNA structure is recognized by proteins and is crucial for achieving binding specificity. However, the ability to analyze DNA shape in a high-throughput manner made it only recently feasible to integrate structural information into studies of protein-DNA binding. Here we focused on the homeodomain family of TFs and analyzed the DNA shape of thousands of their DNA binding sites, investigating the covariation between the protein sequence and the sequence and shape of their DNA targets. We found distinct homeodomain regions that were more correlated with either the nucleotide sequence or the DNA shape of their preferred binding sites, demonstrating different readout mechanisms through which homeodomains attain DNA binding specificity. We identified specific homeodomain residues that likely play key roles in DNA recognition via shape readout. Finally, we showed that adding DNA shape information when characterizing binding sites improved the prediction accuracy of homeodomain binding specificities. Taken together, our findings indicate that DNA shape information can generally provide new mechanistic insights into TF binding.


Does caloric restriction alter IL-2 transcription?
Caloric restriction has been the subject of intensive research and is known to be the most efficacious means of increasing longevity and reducing pathology. Caloric restriction has been found to influence a wide variety of age-sensitive immunological parameters such as interleukin-2 (IL-2) gene expression, and overall, the immunological status of rodents fed a caloric restriction diet is superior to the immunological status of the non-restricted animals. IL-2 is a growth promoting cytokine that plays a critical role in immune function. The expression of IL-2 has been shown to decrease with age, and the decrease in IL-2 expression parallels the age-related decrease in immune function. The focus of this review article is to discuss the studies on the influence of caloric restriction on IL-2 expression and the recent findings on the mechanisms by which caloric restriction enhances IL-2 gene expression. A number of studies have demonstrated that caloric restriction alters the expression of the IL-2 gene at the level of transcription. The increase in IL-2 expression correlates with an increase in binding activity of the transcription factor NFAT which plays a predominant role in IL-2 transcription. In addition, preliminary results suggest that activation of the upstream signaling molecules, the mitogen-activated protein kinase (MAPK) signaling cascade, may play a role in the enhancement of IL-2 transcription.


A confocal microscopy image analysis method to measure adhesion and internalization of Pseudomonas aeruginosa multicellular structures into epithelial cells.
Formation of multicellular structures such as biofilms is an important feature in the physiopathology of many disease-causing bacteria. We recently reported that Pseudomonas aeruginosa adheres to epithelial cells rapidly forming early biofilm-like aggregates, which can then be internalized into cells. Conventional methods to measure adhesion/internalization, such as dilution plating for total cell-associated or antibiotic protected bacteria, do not distinguish between single and aggregated bacteria. We report a procedure that combining double bacteria labeling, confocal microscopy and image analysis allows identification and quantification of the number of adhered and internalized bacteria distinguishing between single and aggregated bacterial cells. A plugin for Fiji to automatically perform these procedures has been generated.


Does endocarditis require routine coagulation screening?
We report a case of probable iatrogenic vitamin K deficiency in the context of antibiotic treatment for endocarditis. The patient was initially admitted with breathlessness and treated for an exacerbation of chronic obstructive pulmonary disease. However, during this period the patient was further diagnosed with endocarditis following repeated temperature spikes. Following initiation of antibiotic treatment for endocarditis the patient was noted to become increasingly anaemic. The patient was noted to have prolonged prothrombin time despite no anticoagulants. Antibiotics have been reported to alter the gut flora causing vitamin K deficiency; thereby, resulting in coagulopathy. We give a brief overview and literature review regarding potential vitamin K deficiency in this clinical context.


A photoprotein in mouse embryonic stem cells measures Ca2+ mobilization in cells and in animals.
Exogenous expression of pharmacological targets in transformed cell lines has been the traditional platform for high throughput screening of small molecules. However, exogenous expression in these cells is limited by aberrant dosage, or its toxicity, the potential lack of interaction partners, and alterations to physiology due to transformation itself. Instead, primary cells or cells differentiated from precursors are more physiological, but less amenable to exogenous expression of reporter systems. To overcome this challenge, we stably expressed c-Photina, a Ca(2+)-sensitive photoprotein, driven by a ubiquitous promoter in a mouse embryonic stem (mES) cell line. The same embryonic stem cell line was also used to generate a transgenic mouse that expresses c-Photina in most tissues. We show here that these cells and mice provide an efficient source of primary cells, cells differentiated from mES cells, including cardiomyocytes, neurons, astrocytes, macrophages, endothelial cells, pancreatic islet cells, stably and robustly expressing c-Photina, and may be exploited for miniaturized high throughput screening. Moreover, we provide evidence that the transgenic mice may be suitable for ex-vivo bioimaging studies in both cells and tissues.


Gut microbial diversity in HIV infection post combined antiretroviral therapy: a key target for prevention of cardiovascular disease.
Although the HIV-infected population is living longer and getting older under current treatment regimens, significant challenges arise for health management as the infection is associated with various premature aging phenotypes, particularly increased incidence of cardiovascular diseases (CVDs). Here we review the current understanding of HIV-related gut dysbiosis in association with CVD and advances in clinical trials aiming to restore gut microbial diversity. Identification of a unique signature for gut dysbiosis in HIV infection between different cohorts remains challenging. However, low diversity of microbiota combined with the outgrowth of pathogenic bacterial species together with dysregulated metabolic pathways have been linked to compromised gut immunity, bacterial translocation and systemic inflammation, hence higher CVD risk among different cohorts. Data from recent clinical trials aiming to evaluate the tolerability and efficacy of probiotics in treated HIV+ patients are promising and support a significant increase in microbiota diversity and reduction of systemic inflammation. However, the impact of these microbial and immunological corrections on the prevalence of CVD in HIV+ patients remains unclear. Positive immunological outcomes following enrichment of the gut microbial diversity have been documented, and further trials are in progress to evaluate the range of patients, with different immunological backgrounds, who might benefit from these treatments.


Voice and Communication Training Program Improves Performance of University Students in Oral Presentations.
To investigate the effect of a voice and communication training program for oral presentations on higher education students. The proposed training program was based on the areas of social skills, voice projection techniques, and neurolinguistic programming. Thirty-eight students participated in the training with active learning methodologies at the university. Before and after the intervention, the participants recorded a short oral presentation on a topic of their choice. The recording was presented to the other participants and to a panel formed by three examiners (two articulation therapists and a psychologist), who evaluated the oral presentation performances. Moreover, each individual self-assessed their communication. The evaluation criteria covered the linguistic aspects, formal and non-formal, verbal and non-verbal communication, planning, and elaboration of the presentation. All participants improved their performance in oral presentations regarding verbal and para-verbal aspects, ability to keep the audience, emotional control, planning, objective, content, approach, organization, visual resource, form of presentation, language, and general elements (general presentation). The proposed training program is effective in improving the performance of university students in oral presentations.


Transsphenoidal microsurgical management of Cushing's disease. Report of 100 cases.
The development of transsphenoidal microsurgery and the refinement of endocrinological and radiological diagnostic procedures have afforded therapeutic options appropriate to the individual case in patients with hypercortisolism. The present series of 100 cases is derived from 104 patients with the diagnosis of Cushing's disease who underwent transsphenoidal pituitary exploration between 1974 and 1981. Excluding four patients in whom the pituitary gland was not exposed because of intraoperative technical difficulties, an overall cure rate of 78% was achieved. Among 71 patients with tumors confined to the sella turcica, 87% had correction of their hypercortisolism, 11% represented therapeutic failures, and one patient had tumor recurrence. In contrast, among 25 patients with extrasellar extension, correction of hypercortisolism was achieved in only 48%, 40% failed to respond, and 12% of the patients had recurrence. Four patients who failed to respond to total hypophysectomy have ectopic sources of adenocorticotropic hormone. The results indicate that transsphenoidal microsurgical exploration for a basophilic adenoma is the procedure of choice in adults and children with Cushing's disease. The diagnostic and surgical approach to these tumors, as well as pitfalls in the transsphenoidal treatment of Cushing's disease, are discussed.


The importance of community and culture for the recruitment, engagement, and retention of Chinese American immigrants in health interventions.
Chinese Americans experience cancer health disparities throughout the entire cancer continuum. Yet, they remain underrepresented in health research in part due to barriers in recruitment, engagement, and retention. This paper describes the strategies that we devised, by drawing upon our experiences with conducting two culturally sensitive cancer intervention studies, to help researchers improve their recruitment and retention rates of Chinese Americans in health research and address the gap in knowledge on intervention research with this population. The first study assessed the efficacy, adoption, and impact of an intervention, delivered by community health workers, to improve adherence to recommended stomach cancer prevention guidelines for at-risk Chinese Americans. The second study evaluated the feasibility and preliminary efficacy of a culturally adapted version of the Expressive Helping intervention for Chinese American cancer patients and survivors. Our main recruitment strategies revolved around building community relationships, developing culturally sensitive materials, and establishing good first impressions with participants. Our main engagement and retention strategies focused on attending to cultural sensitivity, fostering relationships, and using technology. Harnessing the community's inherent strengths and prioritizing cultural understanding is crucial for culturally sensitive health research with Chinese Americans.


Understanding cost-effectiveness in the ICU.
Health care delivery in the United States and abroad has undergone tremendous growth over the last several decades. Accompanying this growth in the diagnostic and therapeutic armamentarium, the costs of health care have escalated out of proportion to the rest of the economy. This exuberant growth has engendered careful scrutiny of the practice of medicine with regard to both its effectiveness and its efficiency. The intensive care unit (ICU) has not been exempt from the quest for increased efficiency of health care delivery. This movement demands that physicians understand not only the effectiveness but also the cost of their interventions. Cost-effectiveness and cost-utility analyses have become critical evaluative tools in medicine. Explicit articulation of comparative cost-effectiveness is helpful in making choices about allocating limited resources in the setting of increasing competition for these resources. This article provides a primer for understanding the methods and applications of cost-effectiveness and cost-utility analyses in the ICU.