Advances in basic and clinical immunology in 2009.
In 2009, reports on basic and clinical immunology had an increased focus on human disease mechanisms and management. The molecular pathogenesis of familial angioedema associated with estrogen was further explored to find possible factors affecting severity, including polymorphisms in enzymes and receptors related to bradykinin pathways. A placebo-controlled clinical trial of C1 esterase inhibitor concentrate in patients with hereditary angioedema demonstrated the safety of its use and its efficacy to reduce the duration of angioedema attacks. The interaction of innate immunity and adaptive responses was further examined in several reports, establishing the significant role of Toll-like receptor stimulation for the development of optimal specific antibody responses. The 2009 update of the classification of primary immunodeficiencies introduced more than 15 new genetic defects related to the immune response, including of dedicator of cytokinesis 8 (DOCK8) mutations, which are responsible for the autosomal recessive form of the hyper-IgE syndrome. Other reports expanded the clinical spectrum of disease and improved the characterization of conditions such as warts, hypogammaglobulinemia, and myelokathexis syndrome or the occurrence of mucormycosis and Serratia species infections in patients with chronic granulomatous disease. The frequent presentation of gastrointestinal disorders in patients with humoral immunodeficiencies was recognized, and recommendations for management were reviewed. Clinical research focused on severe combined immunodeficiency included the development and implementation of a state-wide newborn screening program for this condition, a desired goal considering the significant reduction of mortality rate when the diagnosis is made early before opportunistic infections occur.


Serial grouping of 2D-image regions with object-based attention in humans.
After an initial stage of local analysis within the retina and early visual pathways, the human visual system creates a structured representation of the visual scene by co-selecting image elements that are part of behaviorally relevant objects. The mechanisms underlying this perceptual organization process are only partially understood. We here investigate the time-course of perceptual grouping of two-dimensional image-regions by measuring the reaction times of human participants and report that it is associated with the gradual spread of object-based attention. Attention spreads fastest over large and homogeneous areas and is slowed down at locations that require small-scale processing. We find that the time-course of the object-based selection process is well explained by a 'growth-cone' model, which selects surface elements in an incremental, scale-dependent manner. We discuss how the visual cortical hierarchy can implement this scale-dependent spread of object-based attention, leveraging the different receptive field sizes in distinct cortical areas.


The type III secretion chaperone LcrH co-operates with YopD to establish a negative, regulatory loop for control of Yop synthesis in Yersinia pseudotuberculosis.
The enteropathogen Yersinia pseudotuberculosis is a model system used to study the molecular mechanisms by which Gram-negative pathogens secrete and subsequently translocate antihost effector proteins into target eukaryotic cells by a common type III secretion system (TTSS). In this process, YopD (Yersinia outer protein D) is essential to establish regulatory control of Yop synthesis and the ensuing translocation process. YopD function depends upon the non-secreted TTSS chaperone LcrH (low-calcium response H), which is required for presecretory stabilization of YopD. However, as a new role for TTSS chaperones in virulence gene regulation has been proposed recently, we undertook a detailed analysis of LcrH. A lcrH null mutant constitutively produced Yops, even when this strain was engineered to produce wild-type levels of YopD. Furthermore, the YopD-LcrH interaction was necessary to regain the negative regulation of virulence associated genes yops). This finding was used to investigate the biological significance of several LcrH mutants with varied YopD binding potential. Mutated LcrH alleles were introduced in trans into a lcrH null mutant to assess their impact on yop regulation and the subsequent translocation of YopE, a Rho-GTPase activating protein, across the plasma membrane of eukaryotic cells. Two mutants, LcrHK20E, E30G, I31V, M99V, D136G and LcrHE30G lost all regulatory control, even though YopD binding and secretion and the subsequent translocation of YopE was indistinguishable from wild type. Moreover, these regulatory deficient mutants showed a reduced ability to bind YscY in the two-hybrid assay. Collectively, these findings confirm that LcrH plays an active role in yop regulation that might be mediated via an interaction with the Ysc secretion apparatus. This chaperone-substrate interaction presents an innovative means to establish a regulatory hierarchy in Yersinia infections. It also raises the question as to whether or not LcrH is a true chaperone involved in stabilization and secretion of YopD or a regulatory protein responsible for co-ordinating synthesis of Yersinia virulence determinants. We suggest that LcrH can exhibit both of these activities.


Effect of chronic ethanol treatment on the gamma-aminobutyric acid-mediated enhancement of [3H]flunitrazepam binding in rat cortex and hippocampus.
The mechanism by which ethanol affects the gamma-aminobutyric acid (GABA)/benzodiazepine complex is not clear. It is known that ethanol enhances the Cl- influx mediated by the GABAA receptor complex, and although chronic ethanol administration does not change the KD or Bmax for [3H]flunitrazepam binding, some reports have suggested that it could modify the modulation of benzodiazepine binding produced by GABA. In the present work, we studied the effect of chronic ethanol treatment on the modulation by GABA of [3H]flunitrazepam binding, using light microscopic autoradiography. This technique allows the measurement of densities of benzodiazepine receptors in different brain areas, the visual cortex and hippocampus, which appear to constitute the anatomical support for the behavioral and physiological responses affected by ethanol. We found enhancement of benzodiazepine binding by GABA at concentrations of greater than 10(-6) M for the various cortical and hippocampal areas studied from both control and ethanol-treated animals; this enhancement peaked at 10(-4) M GABA but decreased at 10(-3) M GABA. We found a clear effect of ethanol treatment on the modulatory properties of GABAA receptor, in both cortex and hippocampus, although only in cortex were the differences statistically significant between control and ethanol-treated animals.


Concomitant septic arthritis and tophaceous gout of the knee managed with intermittent closed joint irrigation combined with negative pressure therapy: a case study and literature review.
Tophaceous gout complicated by septic arthritis presents a management dilemma which can often require multiple surgical debridements. There is little published in the literature regarding treatment of these concomitant conditions. We postulate that biofilm may play a role increasing the difficulty of sterilising a tophaceous joint. The use of topical negative pressure therapy that targets biofilm has been well established for a range of wounds. A new device that incorporates both intermittent negative pressure therapy and wound irrigation was introduced in 2012. This case report describes the use of this topical negative device with the instillation option in the management of severe septic arthritis with concomitant gout and suggests directions for further research.


Whole-grain foods do not affect insulin sensitivity or markers of lipid peroxidation and inflammation in healthy, moderately overweight subjects.
High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes, but the mechanisms remain unclear. Our study aimed to evaluate the effects of a diet rich in whole grains compared with a diet containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and inflammation. In a randomized crossover study, 22 women and 8 men (BMI 28 +/- 2) were given either whole-grain or refined-grain products (3 bread slices, 2 crisp bread slices, 1 portion muesli, and 1 portion pasta) to include in their habitual daily diet for two 6-wk periods. Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic clamp tests. 8-Iso-prostaglandin F(2alpha) (8-iso PGF(2alpha)), an F(2)-isoprostane, was measured in the urine as a marker of lipid peroxidation, and highly sensitive C-reactive protein and IL-6 were analyzed in plasma as markers of inflammation. Peripheral insulin sensitivity [mg glucose . kg body wt(-1) . min(-1) per unit plasma insulin (mU/L) x 100] did not improve when subjects consumed whole-grain products (6.8 +/- 3.0 at baseline and 6.5 +/- 2.7 after 6 wk) or refined products (6.4 +/- 2.9 and 6.9 +/- 3.2, respectively) and there were no differences between the 2 periods. Whole-grain consumption also did not affect 8-iso-PGF(2alpha) in urine, IL-6 and C-reactive protein in plasma, blood pressure, or serum lipid concentrations. In conclusion, substitution of whole grains (mainly based on milled wheat) for refined-grain products in the habitual daily diet of healthy moderately overweight adults for 6-wk did not affect insulin sensitivity or markers of lipid peroxidation and inflammation.


Lifetime Job Demands and Later Life Disability.
Occupational characteristics may improve or harm health later in life. Previous research, largely based on limited exposure periods, reached mixed conclusions. We use Health and Retirement Study data linked to the Department of Labor's O*Net job classification system to examine the relationship between lifetime exposure to occupational demands and disability later in life. We consistently find an association between non-routine cognitive demands and lower rates of Social Security Disability Insurance (SSDI) receipt and work-limiting health conditions. Routine manual demands are associated with moderately worse health and increased SSDI receipt in most lifetime specifications. These results are robust to various specifications of occupational demand measures and controlling for transitions between jobs of different levels of occupational intensity. We show that failure to account for job characteristic exposure early in a worker's tenure obscures the relationship between physical job demands and disability later in life. While characteristics of jobs worked at ages 30 and 55 are both predictive of later-life health outcomes, early-life job characteristics frequently dominate in models containing early and late exposures.


Patterns and persistence of larval retention and connectivity in a marine fish metapopulation.
Connectivity, the demographic linking of local populations through the dispersal of individuals, is one of the most poorly understood processes in population dynamics, yet has profound implications for conservation and harvest strategies. For marine species with pelagic larvae, direct estimation of connectivity remains logistically challenging and has mostly been limited to single snapshots in time. Here, we document seasonal and interannual patterns of larval dispersal in a metapopulation of the coral reef fish Amphiprion polymnus. A 3-year record of larval trajectories within and among nine discrete local populations from an area of approximately 35 km was established by determining the natal origin of settled juveniles through DNA parentage analysis. We found that spatial patterns of both self-recruitment and connectivity were remarkably consistent over time, with a low level of self-recruitment at the scale of individual sites. Connectivity among sites was common and multidirectional in all years and was not significantly influenced by seasonal variability of predominant surface current directions. However, approximately 75% of the sampled juveniles could not be assigned to parents within the study area, indicating high levels of immigrations from sources outside the study area. The data support predictions that the magnitude and temporal stability of larval connectivity decreases significantly with increasing distance between subpopulations, but increases with the size of subpopulations. Given the considerable effort needed to directly measure larval exchange, the consistent patterns suggest snapshot parentage analyses can provide useful dispersal estimates to inform spatial management decisions.


Noisy metabolism can promote microbial cross-feeding.
Cross-feeding, the exchange of nutrients between organisms, is ubiquitous in microbial communities. Despite its importance in natural and engineered microbial systems, our understanding of how inter-species cross-feeding arises is incomplete, with existing theories limited to specific scenarios. Here, we introduce a novel theory for the emergence of such cross-feeding, which we term noise-averaging cooperation (NAC). NAC is based on the idea that, due to their small size, bacteria are prone to noisy regulation of metabolism which limits their growth rate. To compensate, related bacteria can share metabolites with each other to 'average out' noise and improve their collective growth. According to the Black Queen Hypothesis, this metabolite sharing among kin, a form of 'leakage', then allows for the evolution of metabolic interdependencies among species including de novo speciation via gene deletions. We first characterize NAC in a simple ecological model of cell metabolism, showing that metabolite leakage can in principle substantially increase growth rate in a community context. Next, we develop a generalized framework for estimating the potential benefits of NAC among real bacteria. Using single-cell protein abundance data, we predict that bacteria suffer from substantial noise-driven growth inefficiencies, and may therefore benefit from NAC. We then discuss potential evolutionary pathways for the emergence of NAC. Finally, we review existing evidence for NAC and outline potential experimental approaches to detect NAC in microbial communities.


A clinical and follow-up study of right and left bundle branch block.
The experience with bundle branch block at the USAF School of Aerospace Medicine was reviewed. The clinical and follow-up status was evaluated in 394 subjects with right bundle branch block (RBBB) and 125 subjects with left bundle branch block (LBBB). The majority of subjects were asymptomatic at the time of bundle branch block diagnosis. The subjects were divided into subfroups based on electrocardiographic (EEG) findings to determine if any one subfroup was at higher risk for initial or follow-up morbidity of cardiobascular disease or follow-up mortality. At initial diagnosis and clinical evaluation, 94% of RBBB and 89% of LBBB subjects had no evidence of cardiobascular disease. In the RBBB group, 3 and 2% had cornary heart disease and hypertension, respectively; in LBBB subjects, 9 and 7% had cornary heart disease and hypertension, respectively. No one ECG subfroup in either the RBBB or LBBB group had a higher incidence of cardiobascular disease. Complete follow-up information was available in 94% of the RBBB subgroup subjects and 91% of the LBBB group. In the follow-up period, new cases of coronary heart disease and hypertension occurred in 6% of the RBBB group and 5 and 8%, respectively, in the LBBB group. Fourteen (4%) RBBB and nine (8%) LBBB subjects died during the follow-up period. No differences for follow-up groups. Progressive electrical dysfunction in the form of complete heart block occurred in one subject each absence, and degree of associated cardiobascular disease. Furthermore, within the age limits of the present aeromedical implications of bundle block are discussed.


Broadened phase-matching bandwidth in waveguide-frequency-doubling devices.
Second harmonic generation in optical planar waveguides is the most promising mechanism for frequency doubling of laser emission since light can be highly confined to the nonlinear waveguide medium. However, this advantage is achievable only by precise phase matching between the fundamental wave and the doubled frequency wave, which is hard to control at the fabrication stage. Two tasks are addressed: a basic design for the layer thicknesses of a two-layer waveguide to achieve phase matching, and second, a multi-layer-waveguide design to achieve broadened phase matching bandwidth.


Different answers to different audiences: effects of social context on the accuracy-informativeness trade-off.
Research on conversational exchanges shows that people attempt to optimise their responses' relevance when they definitely know the correct answer (e.g., "What time is it?"). However, such certainty is often unavailable while speakers may still be under social pressure to provide an answer. We investigated how social context influences the informativeness level when answering questions under uncertainty. In three experiments, participants answered difficult general-knowledge questions placed in different social contexts (formal vs. informal). Participants generated their answers, then they were presented with a given context, and decided on the number of alternative responses they wanted to provide (single, with one alternative vs. plural, with several alternatives) and whether the answer should be reported or withheld (report option). Participants reported more answers in the informal context. In the formal context, single answers were preferred, and they were more frequently reported. We conclude that social context influences the level of informativeness in a conversation, affecting achievable accuracy. Our results also show the joint influence of the confidence and the social context on willingness to share information.


Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection.
Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontaneously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, particularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly influences the outcome of infection. We have therefore investigated the influence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequilibrium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispecific CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-alpha/ribavirin therapy, although the latter influenced the pattern of viral antigens to which patients responded. This is the first disease in which an association of HLA genotype with clinical outcome has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates.


Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia.
Among activating class III receptor tyrosine kinase (Flt3) mutations, internal tandem duplications of Flt3 (Flt3-ITD) are detected in about 25% of patients with acute myeloid leukemia (AML). In contrast, mutations within the tyrosine kinase domain of Flt3 (Flt3-TKD mutations) are less frequent (approximately 7%), and there are only limited data on the frequency of recently demonstrated activating Flt3 point mutation at codon 592 (Flt3-V592A mutation). We evaluated a new approach for rapid screening of Flt3-TKD and Flt3-V592A mutations using the fluorescence resonance energy transfer (FRET) principle in a group of 122 patients. Based on individual Flt3-TKD mutations, we designed patient-specific primers to perform a highly sensitive polymerase chain reaction (PCR) assay for rapid detection of minimal residual disease (MRD). We also used a model system with MonoMac-6 cells carrying the Flt3-V592A mutation to establish a mutation-specific real-time PCR approach also for this molecular aberration. We identified 9 cases (8%) of Flt3-TKD mutations (5 cases of mutation D835Y, 3 cases of mutation D835H, and 1 case of mutation Del836), and no cases of Flt3-V592A mutation. Screening for Flt3-TKD mutations with fluorescent probes is equivalent to conventional screening using standard PCR followed by EcoRV restriction. We present a real-time PCR protocol that can be used for MRD analyses based on individual Flt3-TKD mutations. Examples of MRD analyses are presented for all 3 subtypes of Flt3-TKD mutation identified in this study. In summary, we demonstrate new methodological approaches for rapid screening of Flt3 point mutations and for detection of MRD based on patient-specific Flt3-TKD mutations.


Functional and Prognostic Implications of the Main Pulmonary Artery Diameter to Aorta Diameter Ratio from Chest Computed Tomography in Korean COPD Patients.
The ratio of the diameter of the main pulmonary artery (mPA) to the diameter of the aorta (Ao) on chest computed tomography is associated with diverse clinical conditions. Herein, we determined the functional and prognostic implications of the mPA/Ao ratio in Korean chronic obstructive pulmonary disease (COPD) patients. The study population comprised 226 chronic obstructive pulmonary disease patients from the Korean Obstructive Lung Disease cohort who underwent chest computed tomography. We analyzed the relationships between the clinical characteristics, including pulmonary function, echocardiography findings, St. George's Respiratory Questionnaire, 6-minute walking (6MW) distance, and exacerbation with the mPA, Ao, and mPA/Ao ratio. The mean age was 65.8 years, and 219 (96.9%) patients were male. The mean FEV1% predicted and FEV1/FVC ratio were 61.2% and 47.3%, respectively. The mean mPA and Ao were 23.7 and 36.4 mm, respectively, and the mPA/Ao ratio was 0.66. The mPA/Ao ratio correlated negatively with the 6MW distance (G = -0.133, P = 0.025) and positively with the right ventricular pressure (G = 0.323, P = 0.001). After adjustment for potential confounders, the mPA/Ao ratio was significantly associated with 6MW distance (β = -107.7, P = 0.017). Moreover, an mPA/Ao ratio >0.8 was a significant predictor of exacerbation at the 1-year (odds ratio 2.12, 95% confidence interval 1.27-3.52) and 3-year follow-ups (odds ratio 2.04, 95% confidence interval 1.42-2.90). The mPA/Ao ratio is an independent predictor of exercise capacity and an mPA/Ao ratio >0.8 is a significant risk factor of COPD exacerbation.


Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents.
Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2086 MDS patients diagnosed in 2004-13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle after 2005. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. Thirty-two percent of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR = 1.29, 95% CI = 1.06-1.57; p = .01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients.


A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury.
We determine the efficacy of prophylactic phenytoin in preventing early posttraumatic seizures in children with moderate to severe blunt head injury. Children younger than 16 years and experiencing moderate to severe blunt head injury were randomized to receive phenytoin or placebo within 60 minutes of presentation at 3 pediatric trauma centers. The primary endpoint was posttraumatic seizures within 48 hours; secondary endpoints were survival and neurologic outcome 30 days after injury. A Bayesian decision-theoretic clinical trial design was used to determine the probability of remaining posttraumatic seizure free for each treatment group. One hundred two patients were enrolled, with a median age of 6.1 years. Sixty-eight percent were boys. The 2 treatment groups were well matched. During the 48-hour observation period, 3 (7%) of 46 patients given phenytoin and 3 (5%) of 56 patients given placebo experienced a posttraumatic seizure. There were no significant differences between the treatment groups in survival or neurologic outcome after 30 days. According to these results, the probability that phenytoin has the originally hypothesized effect of reducing the rate of early posttraumatic seizures by 12.5% is 0.0053. The probability that phenytoin has any prophylactic efficacy is 0.383. The median effect size in this trial was -0.015 (seizure rate increased by 1.5% in the phenytoin group), 95% probability interval -0.127 to 0.091 (12.7% higher rate of posttraumatic seizures to a 9.1% lower rate of posttraumatic seizures with phenytoin). The rate of early posttraumatic seizures in children may be much lower than previously reported. Phenytoin did not substantially reduce that rate.


Using mid-level cadres as substitutes for internationally mobile health professionals in Africa. A desk review.
BACKGROUND: Substitute health workers are cadres who take on some of the functions and roles normally reserved for internationally recognized health professionals such as doctors, pharmacists and nurses but who usually receive shorter pre-service training and possess lower qualifications. METHODS: A desk review is conducted on the education, regulation, scopes of practice, specialization, nomenclature, retention and cost-effectiveness of substitute health workers in terms of their utilization in countries such as Tanzania, Malawi, Mozambique, Zambia, Ghana etc., using curricula, evaluations and key-informant questionnaires. RESULTS: The cost-effectiveness of using substitutes and their relative retention within countries and in rural communities underlies their advantages to African health systems. Some studies comparing clinical officers and doctors show minimal differences in outcomes to patients. Specialized substitutes provide services in disciplines such as surgery, ophthalmology, orthopedics, radiology, dermatology, anesthesiology and dentistry, demonstrating a general bias of use for clinical services. CONCLUSIONS: The findings raise interest in expanding the use of substitute cadres, as the demands of expanding access to services such as antiretroviral treatment requires substantial human resources capacity. Understanding the roles and conditions under which such cadres best function, and managing the skepticism and professional turf protection that restricts their potential, will assist in effective utilization of substitutes.


Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors.
In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated marrow neoangiogenesis. We have tested simultaneous inhibition of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations for 50% of the colony formation/survival (IC50) for BIBF1000 were <100 nmol/L for 3 of 11, <or=500 nmol/L for 6 of 11, and <1,000 nmol/L for 10 of 11 leukemic cell lines, with one cell line being resistant in the dose range <1,000 nmol/L. BIBF1120 was less effective with 4 of 11 leukemic cell lines being resistant within the dose range <1,000 nmol/L. Testing of myeloid 32D cells transfected with empty vector, wild-type Flt3, or Flt3 carrying an internal tandem duplication mutation revealed higher resistance for the internal tandem duplication mutant. These effects of the compounds were associated with inhibition of tyrosine phosphorylation and the mitogen-activated protein kinase pathway. Furthermore, both compounds induced apoptosis in the sensitive cell lines. In Mono-Mac1 cells, the compounds had a direct proapoptotic effect that was increasing the proapoptotic effect of 1-beta-D-arabinofuranosylcytosine. The data provide a rationale for clinical evaluation of these tyrosine kinase inhibitors in AML.


The Genome of the Saprophytic Fungus Verticillium tricorpus Reveals a Complex Effector Repertoire Resembling That of Its Pathogenic Relatives.
Vascular wilts caused by Verticillium spp. are destructive plant diseases affecting hundreds of hosts. Only a few Verticillium spp. are causal agents of vascular wilt diseases, of which V. dahliae is the most notorious pathogen, and several V. dahliae genomes are available. In contrast, V. tricorpus is mainly known as a saprophyte and causal agent of opportunistic infections. Based on a hybrid approach that combines second and third generation sequencing, a near-gapless V. tricorpus genome assembly was obtained. With comparative genomics, we sought to identify genomic features in V. dahliae that confer the ability to cause vascular wilt disease. Unexpectedly, both species encode similar effector repertoires and share a genomic structure with genes encoding secreted proteins clustered in genomic islands. Intriguingly, V. tricorpus contains significantly fewer repetitive elements and an extended spectrum of secreted carbohydrate- active enzymes when compared with V. dahliae. In conclusion, we highlight the technical advances of a hybrid sequencing and assembly approach and show that the saprophyte V. tricorpus shares many hallmark features with the pathogen V. dahliae.


320-row CT coronary angiography predicts freedom from revascularisation and acts as a gatekeeper to defer invasive angiography in stable coronary artery disease: a fractional flow reserve-correlated study.
To determine the accuracy of 320-row multidetector coronary computed tomography angiography (M320-CCTA) to detect functional stenoses using fractional flow reserve (FFR) as the reference standard and to predict revascularisation in stable coronary artery disease. One hundred and fifteen patients (230 vessels) underwent M320-CCTA and FFR assessment and were followed for 18 months. Diameter stenosis on invasive angiography (ICA) and M320-CCTA were assessed by consensus by two observers and significant stenosis was defined as ≥50%. FFR ≤0.8 indicated functionally significant stenoses. M320-CCTA had 94% sensitivity and 94% negative predictive value (NPV) for FFR ≤0.8. Overall accuracy was 70%, specificity 54% and positive predictive value 65%. On receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for CCTA to predict FFR ≤0.8 was 0.74 which was comparable with ICA. The absence of a significant stenosis on M320-CCTA was associated with a 6% revascularisation rate. M320-CCTA predicted revascularisation with an AUC of 0.71 which was comparable with ICA. M320-CCTA has excellent sensitivity and NPV for functional stenoses and therefore may act as an effective gatekeeper to defer ICA and revascularisation. Like ICA, M320-CCTA lacks specificity for functional stenoses and only has moderate accuracy to predict the need for revascularisation. • Important information about the heart is provided by 320-row multidetector CT coronary angiography (M320-CCTA). • M320-CCTA accurately detects and excludes functional stenoses determined by fractional flow reserve (FFR). • Non-significant stenoses on M320-CCTA associated with fewer cardiac events and less revascularisation. • M320-CCTA may act as a gatekeeper for invasive angiography and inappropriate revascularisation. • Like ICA, M320-CCTA only has moderate accuracy to predict vessels requiring revascularisation.


Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.
Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. 106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients. Ardian.


A lipocalin protein, Neural Lazarillo, is key to social interactions that promote termite soldier differentiation.
Social communication among castes is a crucial component of insect societies. However, the genes involved in soldier determination through the regulation of inter-individual interactions are largely unknown. In an incipient colony of the damp-wood termite Zootermopsis nevadensis, the first larva to develop into a third instar always differentiates into a soldier via frequent trophallactic feeding from the reproductives. Here, by performing RNA-seq analysis of third instar larvae, a homologue of Neural Lazarillo (named ZnNLaz1) was found to be the most differentially expressed gene in these soldier-destined larvae, compared with worker-destined larvae. This gene encodes a lipocalin protein related to the transport of small hydrophobic molecules. RNAi-induced knockdown of ZnNLaz1 significantly inhibited trophallactic interactions with the queen and decreased the soldier differentiation rates. This protein is localized in the gut, particularly in the internal wall, of soldier-destined larvae, suggesting that it is involved in the integration of social signals from the queen through frequent trophallactic behaviours. Based on molecular phylogenetic analysis, we suggest that a novel function of termite NLaz1 has contributed to social evolution from the cockroach ancestors of termites. These results indicated that a high larval NLaz1 expression is crucial for soldier determination through social communication in termites.


Myocardial injury after non-cardiac surgery: diagnosis and management.
Myocardial injury after non-cardiac surgery (MINS) is due to myocardial ischaemia (i.e. supply-demand mismatch or thrombus) and is associated with an increased risk of mortality and major vascular complications at 30 days and up to 2 years after non-cardiac surgery. The diagnostic criteria for MINS includes an elevated post-operative troponin measurement judged as resulting from myocardial ischaemia (i.e. no evidence of a non-ischaemic aetiology), during or within 30 days after non-cardiac surgery, and without the requirement of an ischaemic feature (e.g. ischaemic symptom, ischaemic electrocardiography finding). For patients with MINS who are not at high risk of bleeding, physicians should consider initiating dabigatran 110 mg twice daily and low-dose aspirin. Physicians should also consider initiating statin therapy in patients with MINS. Most MINS patients should only be referred to cardiac catheterization if they demonstrate recurrent instability (e.g. cardiac ischaemia, heart failure). Patients ≥65 years of age or with known atherosclerotic disease should have troponin measurements on days 1, 2, and 3 after surgery while the patient is in hospital to avoid missing >90% of MINS and the opportunity to initiate secondary prophylactic measures and follow-up.


Genome of alkaliphilic Bacillus pseudofirmus OF4 reveals adaptations that support the ability to grow in an external pH range from 7.5 to 11.4.
Bacillus pseudofirmus OF4 is an extreme but facultative alkaliphile that grows non-fermentatively in a pH range from 7.5 to above 11.4 and can withstand large sudden increases in external pH. It is a model organism for studies of bioenergetics at high pH, at which energy demands are higher than at neutral pH because both cytoplasmic pH homeostasis and ATP synthesis require more energy. The alkaliphile also tolerates a cytoplasmic pH > 9.0 at external pH values at which the pH homeostasis capacity is exceeded, and manages other stresses that are exacerbated at alkaline pH, e.g. sodium, oxidative and cell wall stresses. The genome of B. pseudofirmus OF4 includes two plasmids that are lost from some mutants without viability loss. The plasmids may provide a reservoir of mobile elements that promote adaptive chromosomal rearrangements under particular environmental conditions. The genome also reveals a more acidic pI profile for proteins exposed on the outer surface than found in neutralophiles. A large array of transporters and regulatory genes are predicted to protect the alkaliphile from its overlapping stresses. In addition, unanticipated metabolic versatility was observed, which could ensure requisite energy for alkaliphily under diverse conditions.


Nanoimprinted polymer lasers with threshold below 100 W/cm2 using mixed-order distributed feedback resonators.
Organic semiconductor lasers were fabricated by UV-nanoimprint lithography with thresholds as low as 57 W/cm(2) under 4 ns pulsed operation. The nanoimprinted lasers employed mixed-order distributed feedback resonators, with second-order gratings surrounded by first-order gratings, combined with a light-emitting conjugated polymer. They were pumped by InGaN LEDs to produce green-emitting lasers, with thresholds of 208 W/cm(2) (102 nJ/pulse). These hybrid lasers incorporate a scalable UV-nanoimprint lithography process, compatible with high-performance LEDs, therefore we have demonstrated a coherent, compact, low-cost light source.


Incorporating clinical trial data into daily cancer care.
The objective of clinical trials is to determine the effectiveness and safety of specific interventions. Regulatory agencies, clinicians, and patients depend on clinical trials because they provide the most reliable information about treatment outcomes. The ability to predict how a patient may respond to a given treatment and what potential types, degree, and frequency of adverse events could occur is invaluable. Although data from clinical trials can determine effective treatment options for patients, it is the explanation of what to expect from treatment and how it may affect quality of life that will determine which option a patient chooses. Translating clinical trial data into "real life" can be challenging for the oncology advanced practitioner (AP) because primary and secondary endpoints may differ among clinical trials. This variability can produce confusion when comparing, contrasting, and translating clinical evidence into clinical practice. This article reviews clinical trial endpoints and surrogate markers and describes how findings can influence decision-making and patient care. With social media increasing patients' awareness and encouraging active participation in their own care, it is imperative that APs be able to articulate clinical trial outcomes along with their strengths, limitations, and life impact.


Nitric oxide: a new biomarker of Doxorubicin toxicity in children?
Doxorubicin (DOX) has been used in the treatment of childhood cancers, but its usage is limited because of cardiotoxicity. There are many studies on the role of nitric oxide (NO) in several cardiac diseases. However, to the authors' knowledge, no studies have investigated the plasma levels of total nitrite, a stable product of NO, in children that received DOX. The authors determined plasma total nitrite levels in 29 children who received DOX and investigated the correlations between these and other clinical and laboratory findings. All patients were in remission during the study period. Plasma total nitrite levels and cardiac functions were determined prospectively. The mean cumulative DOX dose was 310.0 ± 90.9 mg/m(2). In echocardiographic evaluation, 3 patients (10.3%) had a pathological value for ejection fraction (EF) and/or fractional shortening (FS), whereas 11 patients (37.9%) had a threshold value. Total nitrite levels were higher in patients than in matched controls (75.24 ± 39.4 vs 43.14 ± 10.58 μmol/L, respectively, P < .001). It was also found to be higher in patients who had a pathological/threshold value of EF and FS than in patients who had a physiological value of EF and FS (92.35 ± 50.36 vs 59.26 ± 13.56 μmol/L, respectively, P = .038). A negative correlation was found between FS and plasma total nitrite level (r = -.42, P = .023). The authors speculate that increased NO may be a sign of subclinical cardiotoxicity of DOX.


Mitochondrial Hep27 is a c-Myb target gene that inhibits Mdm2 and stabilizes p53.
The ever-expanding knowledge of the role of p53 in cellular metabolism, apoptosis, and cell cycle control has led to increasing interest in defining the stress response pathways that regulate Mdm2. In an effort to identify novel Mdm2 binding partners, we performed a large-scale immunoprecipitation of Mdm2 in the osteosarcoma U2OS cell line. One significant binding protein identified was Hep27, a member of the short-chain alcohol dehydrogenase/reductase (SDR) family of enzymes. Here, we demonstrate that the Hep27 preprotein contains an N-terminal mitochondrial targeting signal that is cleaved following mitochondrial import, resulting in mitochondrial matrix accumulation of mature Hep27. A fraction of the mitochondrial Hep27 translocates to the nucleus, where it binds to Mdm2 in the central domain, resulting in the attenuation of Mdm2-mediated p53 degradation. In addition, Hep27 is regulated at the transcriptional level by the proto-oncogene c-Myb and is required for c-Myb-induced p53 stabilization. Breast cancer gene expression analysis correlated estrogen receptor (ER) status with Hep27 expression and p53 function, providing a potential in vivo link between estrogen receptor signaling and p53 activity. Our data demonstrate a unique c-Myb-Hep27-Mdm2-p53 mitochondria-to-nucleus signaling pathway that may have functional significance for ER-positive breast cancers.


Physiology of Pseudomonas aeruginosa in biofilms as revealed by transcriptome analysis.
Transcriptome analysis was applied to characterize the physiological activities of Pseudomonas aeruginosa grown for three days in drip-flow biofilm reactors. Conventional applications of transcriptional profiling often compare two paired data sets that differ in a single experimentally controlled variable. In contrast this study obtained the transcriptome of a single biofilm state, ranked transcript signals to make the priorities of the population manifest, and compared rankings for a priori identified physiological marker genes between the biofilm and published data sets. Biofilms tolerated exposure to antibiotics, harbored steep oxygen concentration gradients, and exhibited stratified and heterogeneous spatial patterns of protein synthetic activity. Transcriptional profiling was performed and the signal intensity of each transcript was ranked to gain insight into the physiological state of the biofilm population. Similar rankings were obtained from data sets published in the GEO database http://www.ncbi.nlm.nih.gov/geo. By comparing the rank of genes selected as markers for particular physiological activities between the biofilm and comparator data sets, it was possible to infer qualitative features of the physiological state of the biofilm bacteria. These biofilms appeared, from their transcriptome, to be glucose nourished, iron replete, oxygen limited, and growing slowly or exhibiting stationary phase character. Genes associated with elaboration of type IV pili were strongly expressed in the biofilm. The biofilm population did not indicate oxidative stress, homoserine lactone mediated quorum sensing, or activation of efflux pumps. Using correlations with transcript ranks, the average specific growth rate of biofilm cells was estimated to be 0.08 h(-1). Collectively these data underscore the oxygen-limited, slow-growing nature of the biofilm population and are consistent with antimicrobial tolerance due to low metabolic activity.


Model based and empirical spectral analysis for the diagnosis of breast cancer.
We explored the use of both empirical (Partial Least Squares, PLS) and Monte Carlo model based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from freshly excised breast tissues and for the diagnosis of breast cancer. Features extracted using both approaches, i.e. principal components (PCs) obtained from empirical analysis or tissue properties obtained from model based analysis, displayed statistically significant difference between malignant and non-malignant tissues, and can be used to discriminate breast malignancy with comparable sensitivity and specificity of up to 90%. The PC scores of a subset of PCs also displayed significant correlation with the tissue properties extracted from the model based analysis, suggesting both approaches likely probe the same sources of contrast in the tissue spectra that discriminate between malignant and non-malignant breast tissues but in different ways.


Model-based derivation, analysis and control of unstable microaerobic steady-states--considering Rhodospirillum rubrum as an example.
Microaerobic (oxygen-limited) conditions are critical for inducing many important microbial processes in industrial or environmental applications. At very low oxygen concentrations, however, the process performance often suffers from technical limitations. Available dissolved oxygen measurement techniques are not sensitive enough and thus control techniques, that can reliable handle these conditions, are lacking. Recently, we proposed a microaerobic process control strategy, which overcomes these restrictions and allows to assess different degrees of oxygen limitation in bioreactor batch cultivations. Here, we focus on the design of a control strategy for the automation of oxygen-limited continuous cultures using the microaerobic formation of photosynthetic membranes (PM) in Rhodospirillum rubrum as model phenomenon. We draw upon R. rubrum since the considered phenomenon depends on the optimal availability of mixed-carbon sources, hence on boundary conditions which make the process performance challenging. Empirically assessing these specific microaerobic conditions is scarcely practicable as such a process reacts highly sensitive to changes in the substrate composition and the oxygen availability in the culture broth. Therefore, we propose a model-based process control strategy which allows to stabilize steady-states of cultures grown under these conditions. As designing the appropriate strategy requires a detailed knowledge of the system behavior, we begin by deriving and validating an unstructured process model. This model is used to optimize the experimental conditions, and identify properties of the system which are critical for process performance. The derived model facilitates the good process performance via the proposed optimal control strategy. In summary the presented model-based control strategy allows to access and maintain microaerobic steady-states of interest and to precisely and efficiently transfer the culture from one stable microaerobic steady-state into another. Therefore, the presented approach is a valuable tool to study regulatory mechanisms of microaerobic phenomena in response to oxygen limitation alone. Biotechnol. Bioeng. 2014;111: 734-747. © 2013 Wiley Periodicals, Inc.


Full-color active-matrix organic light-emitting diode display on human skin based on a large-area MoS2 backplane.
Electronic applications are continuously developing and taking new forms. Foldable, rollable, and wearable displays are applicable for human health care monitoring or robotics, and their operation relies on organic light-emitting diodes (OLEDs). Yet, the development of semiconducting materials with high mechanical flexibility has remained a challenge and restricted their use in unusual format electronics. This study presents a wearable full-color OLED display using a two-dimensional (2D) material-based backplane transistor. The 18-by-18 thin-film transistor array was fabricated on a thin MoS2 film that was transferred to Al2O3 (30 nm)/polyethylene terephthalate (6 μm). Red, green, and blue OLED pixels were deposited on the device surface. This 2D material offered excellent mechanical and electrical properties and proved to be capable of driving circuits for the control of OLED pixels. The ultrathin device substrate allowed for integration of the display on an unusual substrate, namely, a human hand.


Cytological diagnosis of malignant mesothelioma--improvement by additional analysis of hyaluronic acid in pleural effusions.
Cytology allows the diagnosis of malignant mesothelioma (MM) from effusions with high specificity but low sensitivity. Conversely, elevated levels of hyaluronic acid (HA) in effusions are sensitive indicators of MM, although specificity is insufficient. We studied whether the cytological diagnosis of MM could be improved by HA analysis. HA was analysed in patients with histologically confirmed MM (n=162), adenocarcinoma or other malignant tumours (n=100) and in 90 patients with benign pleural diseases. In 77 out of 162 effusions, all, and in 33 some, cytological criteria of MM were satisfied. The cut-off value of HA showing maximum diagnostic reliability (86%) regarding MM was 30 mg/l (sensitivity 87%, specificity 86%). A HA value of 100 mg/l yielded 39 and 98%, respectively. Seventy three out of 77 patients with cytological findings indicative of MM showed HA levels greater than 30 mg/l as well as 27 of 33 patients with suspicious lesions. These 100 patients were correctly recognised as having MM. The addition of HA analysis to cytology, requiring all or some criteria of MM as positive, increased sensitivity for MM from 48 to 71-91%, whereas specificity only slightly decreased to 94-96%. We conclude that the combined cytological and HA analysis of pleural effusions had the potential to improve the diagnosis of MM.


Mediterranean diet and life expectancy; beyond olive oil, fruits, and vegetables.
The recent relevant evidence of the effects of the Mediterranean diet (MedDiet) and lifestyle on health (2015 and first months of 2016). Large observational prospective epidemiological studies with adequate control of confounding and two large randomized trials support the benefits of the Mediterranean dietary pattern to increase life expectancy, reduce the risk of major chronic disease, and improve quality of life and well-being. Recently, 19 new studies from large prospective studies showed - with nearly perfect consistency - strong benefits of the MedDiet to reduce the risk of myocardial infarction, stroke, total mortality, heart failure, and disability. Interestingly, two large and well conducted cohorts reported significant cardiovascular benefits after using repeated measurements of diet during a long follow-up period. In addition, Prevención con Dieta Mediterránea, the largest randomized trial with MedDiet, recently reported benefits of this dietary pattern to prevent cognitive decline and breast cancer. In the era of evidence-based medicine, the MedDiet represents the gold standard in preventive medicine, probably because of the harmonic combination of many elements with antioxidant and anti-inflammatory properties, which overwhelm any single nutrient or food item. The whole seems more important than the sum of its parts.


Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers.
Despite the recent popularity of e-cigarettes, to date only limited data is available on their safety for both users and secondhand smokers. The present study reports a comprehensive inner and outer exposure assessment of e-cigarette emissions in terms of particulate matter (PM), particle number concentrations (PNC), volatile organic compounds (VOC), polycyclic aromatic hydrocarbons (PAH), carbonyls, and metals. In six vaping sessions nine volunteers consumed e-cigarettes with and without nicotine in a thoroughly ventilated room for two hours. We analyzed the levels of e-cigarette pollutants in indoor air and monitored effects on FeNO release and urinary metabolite profile of the subjects. For comparison, the components of the e-cigarette solutions (liquids) were additionally analyzed. During the vaping sessions substantial amounts of 1,2-propanediol, glycerine and nicotine were found in the gas-phase, as well as high concentrations of PM2.5 (mean 197 μg/m(3)). The concentration of putative carcinogenic PAH in indoor air increased by 20% to 147 ng/m(3), and aluminum showed a 2.4-fold increase. PNC ranged from 48,620 to 88,386 particles/cm(3) (median), with peaks at diameters 24-36 nm. FeNO increased in 7 of 9 individuals. The nicotine content of the liquids varied and was 1.2-fold higher than claimed by the manufacturer. Our data confirm that e-cigarettes are not emission-free and their pollutants could be of health concern for users and secondhand smokers. In particular, ultrafine particles formed from supersaturated 1,2-propanediol vapor can be deposited in the lung, and aerosolized nicotine seems capable of increasing the release of the inflammatory signaling molecule NO upon inhalation. In view of consumer safety, e-cigarettes and nicotine liquids should be officially regulated and labeled with appropriate warnings of potential health effects, particularly of toxicity risk in children.


Evidence of Signs and Symptoms of Craniomandibular Disorders in Fibromyalgia Patients.
The purpose of this study is to highlight the evidence of signs and symptoms of craniomandibular disorders (CMD) in patients suffering from fibromyalgia. The study has been carried out from May 2011 to May 2015, recruiting a sample of fibromyalgia patients at the Department of Neurophysiopathology at the hospital Policlinico in Bari. Among the 150 examined patients, 60 of them have been diagnosed to suffer from fibromyalgia and 27 accepted to be investigated with a gnathologic examination at the Dental School at the University of Bari. 24 patients (88.9%) were women and 3 (11.1%) men; from 26 to 66 years old (average age, 39). 14 patients (51.9%) were affected by primary fibromyalgia, the remaining 13 (48.1%) by secondary fibromyalgia, mainly associated with hypothyroidism (29.6%). VAS average score was about 8 ± 1.85. The frequency of pain was daily in 15 patients (55.6%); twice a week in 10 patients (37.03%) and a few times a month in 2 patients (7.4%). 11 patients (40.7%) attributed the onset of fibromyalgia to a specific instigating event. In addition, from the gnathologic anamnesis, 11 patients (40,7%) reported a painful symptom in the head-neck region, especially in the frontal region, in the neck, in the masseter muscle and ATM. VAS average score was 3.4 ± 2.8, significantly lower than the one referring to the fibromyalgia pain. The gnathological examination found CMD signs and symptoms in 18 patients (66.7%). Concerning the prevalence of CMD, in type I fibromyalgia, myofascial pain was more frequent (5 patients), whereas in type II fibromyalgia, what was more frequent was a dislocation with reduction (3 patients). Based on clinic experience, we can affirm that some patients with CMD report pain in other regions. It is difficult to distinguish the CMD forms directly correlated to fibromyalgia from those engendered by parafunctional activities; hence the need is to resolve the fibromyalgia syndrome adopting a multidisciplinary approach.


A novel signaling pathway from rod photoreceptors to ganglion cells in mammalian retina.
Current understanding suggests that mammalian rod photoreceptors connect only to an ON-type bipolar cell. This rod-specific bipolar cell excites the All amacrine cell, which makes connections to cone-specific bipolar cells of both ON and OFF type; these, in turn, synapse with ganglion cells. Recent work on rabbit retina has shown that rod signals can also reach ganglion cells without passing through the rod bipolar cell. This route was thought to be provided by electrical gap junctions, through which rods signal directly to cones and thence to cone bipolar cells. Here, we show that the mouse retina also provides a rod pathway bypassing the rod bipolar cell, suggesting that this is a common feature in mammals. However, this alternative pathway does not require cone photoreceptors; it is perfectly intact in a transgenic mouse whose retina lacks cones. Instead, the results can be explained if rods connect directly to OFF bipolar cells.


Comparative Evaluation of Colour Stability and Surface Hardness of Methacrylate Based Flowable and Packable Composite -In vitro Study.
With the advent of new technology in material sciences in recent years, the quality of composite resin restorations has improved; however, discolouration and wear of composite resin materials remains to be a major problem in long-term clinical studies. The aim of the present study was to compare the colour stability and surface hardness of methacrylate based flowable nano composite with methacrylate based packable nano composite. The difference in colour stability and microhardness of the three composites: G aenial Universal Flo (GC India), Filtek Z350XT (3MESPE) and Tetric N Ceram (Ivoclar Vivadent) were evaluated. Forty eight disc shaped specimens were made out of three different resin composite materials which were subdivided into two groups of Colour Stability (CS) and Vicker's Hardness (VH). For colour stability, specimens were immersed in staining solution consisting instant coffee for 72 hours, and then specimens were rinsed thoroughly under tap water and subjected to 10 strokes of brushing with a soft-grade toothbrush. The colour measurements were obtained using spectrophotometer and the process was repeated every 72 hours for three weeks. VH was evaluated using microhardness tester (Zwick/Roell Vicker's Microhardness Tester). Vicker's Hardness Numbers (VHN) were determined from indentations made under 10 N load for 15 seconds by the arithmetic mean of three indentation values randomly performed. One-way ANOVA and Tukey's post-hoc analysis were applied. Statistically significant difference was found in comparison of colour stability at different time interval in study groups (p<0.001). Filtek Z350XT group showed least discolouration followed by Tetric N Ceram group and highest colour change in G aenial Universal Flo group after immersion for 21 days. Mean microhardness value of Filtek Z350XT (101.62) group was found to be significantly different from Tetric N Ceram group (63.74) (p<0.001*) and G aenial Universal Flo group (56.75) (p<0.001*). Greatest CS and VH was seen in Filtek Z350XT followed by Tetric N Ceram and least values were seen in G aenial Universal Flo.


Milk drinking and mortality: findings from the Japan collaborative cohort study.
Findings regarding the association between milk consumption and all-cause mortality reported by studies carried out in Western populations have been inconsistent. However, no studies have been conducted in Japan on this issue. The present study aimed to investigate the association of milk drinking with all-cause, cardiovascular, and cancer mortality in Japan. The data were obtained from the Japan Collaborative Cohort (JACC) study. A total of 94 980 Japanese adults aged 40-79 years who had no history of cancer, stroke, or chronic cardiovascular diseases were followed between 1988 and 2009. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of mortalities were assessed using a Cox proportional hazard regression model and taking the lowest milk consumption group as the reference. During a median of 19 years of follow-up, there were 21 775 deaths (28.8% and 35.3% from cardiovascular diseases and cancer, respectively). Drinking milk 1-2 times a month was associated with lower all-cause mortality in men compared to those who never drank milk (multivariable-adjusted HR 0.92; 95% CI, 0.85-0.99). In women, those who drank 3-4 times a week also had a lower mortality risk compared with those who never drank milk (HR 0.91; 95% CI 0.85-0.98). Inverse associations between drinking milk and mortality from cardiovascular diseases and cancer were found only in men. Drinking milk at least 1-2 times a month was associated with lower all-cause mortality in men compared to never drinking milk. An inverse association was also found between drinking milk and mortality from both cardiovascular diseases and cancer. However, lower all-cause mortality in women was found only in those who drank milk 3-4 times/week.


Medicare program; hospital inpatient prospective payment systems for acute care hospitals and the long-term care hospital prospective payment system and fiscal year 2015 rates; quality reporting requirements for specific providers; reasonable compensation equivalents for physician services in excluded hospitals and certain teaching hospitals; provider administrative appeals and judicial review; enforcement provisions for organ transplant centers; and electronic health record (EHR) incentive program. Final rule.
We are revising the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals to implement changes arising from our continuing experience with these systems. Some of these changes implement certain statutory provisions contained in the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 (collectively known as the Affordable Care Act), the Protecting Access to Medicare Act of 2014, and other legislation. These changes are applicable to discharges occurring on or after October 1, 2014, unless otherwise specified in this final rule. We also are updating the rate-of-increase limits for certain hospitals excluded from the IPPS that are paid on a reasonable cost basis subject to these limits. The updated rate-of-increase limits are effective for cost reporting periods beginning on or after October 1, 2014. We also are updating the payment policies and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long-term care hospitals (LTCHs) and implementing certain statutory changes to the LTCH PPS under the Affordable Care Act and the Pathway for Sustainable Growth Rate (SGR) Reform Act of 2013 and the Protecting Access to Medicare Act of 2014. In addition, we discuss our proposals on the interruption of stay policy for LTCHs and on retiring the "5 percent" payment adjustment for collocated LTCHs. While many of the statutory mandates of the Pathway for SGR Reform Act apply to discharges occurring on or after October 1, 2014, others will not begin to apply until 2016 and beyond. In addition, we are making a number of changes relating to direct graduate medical education (GME) and indirect medical education (IME) payments. We are establishing new requirements or revising requirements for quality reporting by specific providers (acute care hospitals, PPS-exempt cancer hospitals, and LTCHs) that are participating in Medicare. We are updating policies relating to the Hospital Value-Based Purchasing (VBP) Program, the Hospital Readmissions Reduction Program, and the Hospital-Acquired Condition (HAC) Reduction Program. In addition, we are making technical corrections to the regulations governing provider administrative appeals and judicial review; updating the reasonable compensation equivalent (RCE) limits, and revising the methodology for determining such limits, for services furnished by physicians to certain teaching hospitals and hospitals excluded from the IPPS; making regulatory revisions to broaden the specified uses of Medicare Advantage (MA) risk adjustment data and to specify the conditions for release of such risk adjustment data to entities outside of CMS; and making changes to the enforcement procedures for organ transplant centers. We are aligning the reporting and submission timelines for clinical quality measures for the Medicare HER Incentive Program for eligible hospitals and critical access hospitals (CAHs) with the reporting and submission timelines for the Hospital IQR Program. In addition, we provide guidance and clarification of certain policies for eligible hospitals and CAHs such as our policy for reporting zero denominators on clinical quality measures and our policy for case threshold exemptions. In this document, we are finalizing two interim final rules with comment period relating to criteria for disproportionate share hospital uncompensated care payments and extensions of temporary changes to the payment adjustment for low-volume hospitals and of the Medicare-Dependent, Small Rural Hospital (MDH) Program.


Standard care impact on effects of highly active antiretroviral therapy adherence interventions: A meta-analysis of randomized controlled trials.
Poor adherence to medication limits the effectiveness of treatment for human immunodeficiency virus. Systematic reviews can identify practical and effective interventions. Meta-analyses that control for variability in standard care provided to control groups may produce more accurate estimates of intervention effects. To examine whether viral load and adherence success rates could be accurately explained by the active content of highly active antiretroviral therapy (HAART) adherence interventions when controlling for variability in care delivered to controls, databases were searched for randomized controlled trials of HAART adherence interventions published from 1996 to January 2009. A total of 1342 records were retrieved, and 52 articles were examined in detail. Directly observed therapy and interventions targeting specific patient groups (ie, psychiatric or addicted patients, patients <18 years) were excluded, yielding a final sample of 31 trials. Two coders independently retrieved study details. Authors were contacted to complete missing data. Twenty studies were included in the analyses. The content of adherence care provided to control and intervention groups predicted viral load and adherence success rates in both conditions (P < .001 for all comparisons), with an estimated impact of optimal adherence care of 55 percentage points. After controlling for variability in care provided to controls, the capacity of the interventions accurately predicted viral load and adherence effect sizes (R(2) = 0.78, P = .02; R(2) = 0.28, P < .01). Although interventions were generally beneficial, their effectiveness reduced noticeably with increasing levels of standard care. Intervention and control patients were exposed to effective adherence care. Future meta-analyses of (behavior change) interventions should control for variability in care delivered to active controls. Clinical practice may be best served by implementing current best practice.


Preoperative blood transfusions for sickle cell disease.
Sickle cell disease is one of the most common inherited diseases in the world, and causes haemolytic anaemia, vaso-occlusive crises and dysfunction in virtually any organ system in the body. Surgical procedures are often required. Blood transfusion regimes can be used preoperatively in an attempt to increase transport of oxygen around the body and dilute the sickled red blood cells, thus reducing the risk of vaso-occlusion. To assess the relative risks and benefits of preoperative blood transfusion regimes in patients with sickle cell disease undergoing surgery of any type in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: January 2001 All randomised or quasi-randomised controlled trials comparing preoperative blood transfusion regimes to different regimes or no transfusion in patients with sickle cell disease undergoing surgery. Both reviewers independently assessed trial quality and extracted data from the study included. Only one trial met the inclusion criteria for the review. The trial compared an aggressive transfusion regime (decreasing sickle haemoglobin to less than 30%) to a conservative transfusion regime (increasing haemoglobin to 10 g/dl) in 604 elective operations in patients with sickle cell disease. The conservative regime was found to be as effective as the aggressive regime in preventing perioperative complications, and was associated with less transfusion related adverse events. No randomised controlled trials were found for transfusion compared to no transfusion. While in general conservative therapy appears to be as effective as aggressive in preparation for surgery in sickle cell patients, further research is needed to examine the optimal regime for different surgical types, and to address whether preoperative transfusion is needed in all surgical situations.


Genetic connectivity between north and south Mid-Atlantic Ridge chemosynthetic bivalves and their symbionts.
Transform faults are geological structures that interrupt the continuity of mid-ocean ridges and can act as dispersal barriers for hydrothermal vent organisms. In the equatorial Atlantic Ocean, it has been hypothesized that long transform faults impede gene flow between the northern and the southern Mid-Atlantic Ridge (MAR) and disconnect a northern from a southern biogeographic province. To test if there is a barrier effect in the equatorial Atlantic, we examined phylogenetic relationships of chemosynthetic bivalves and their bacterial symbionts from the recently discovered southern MAR hydrothermal vents at 5°S and 9°S. We examined Bathymodiolus spp. mussels and Abyssogena southwardae clams using the mitochondrial cytochrome c oxidase subunit I (COI) gene as a phylogenetic marker for the hosts and the bacterial 16S rRNA gene as a marker for the symbionts. Bathymodiolus spp. from the two southern sites were genetically divergent from the northern MAR species B. azoricus and B. puteoserpentis but all four host lineages form a monophyletic group indicating that they radiated after divergence from their northern Atlantic sister group, the B. boomerang species complex. This suggests dispersal of Bathymodiolus species from north to south across the equatorial belt. 16S rRNA genealogies of chemoautotrophic and methanotrophic symbionts of Bathymodiolus spp. were inconsistent and did not match the host COI genealogy indicating disconnected biogeography patterns. The vesicomyid clam Abyssogena southwardae from 5°S shared an identical COI haplotype with A. southwardae from the Logatchev vent field on the northern MAR and their symbionts shared identical 16S phylotypes, suggesting gene flow across the Equator. Our results indicate genetic connectivity between the northern and southern MAR and suggest that a strict dispersal barrier does not exist.


Adrenarche results from development of a 3beta-hydroxysteroid dehydrogenase-deficient adrenal reticularis.
Adrenarche is the increased adrenal production of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs during the prepubertal period. To date, the exact mechanism initiating adrenarche is unknown, although many factors have been postulated. In the present study, we examined the hypothesis that alterations in intra-adrenal expression of 3beta-hydroxysteroid dehydrogenase (3betaHSD) or 21-hydroxylase (CYP21) within the inner reticularis zone leads to the increased production of 19-carbon (C19) steroids. After conversion of cholesterol to pregnenolone, 17alpha-hydroxylase/17,20-lyase (CYP17) can metabolize pregnenolone through to DHEA. The enzyme 3betaHSD competes for substrate with CYP17 and effectively removes steroid precursor from the pathway leading to DHEA. On the other hand, deficiency in CYP21 expression is known to cause excessive production of adrenal C19 steroids, suggesting that CYP21 could play a role in adrenarche. Thus, a decrease in 3betaHSD or CYP21 expression would allow substrate to flow toward the synthesis of DHEA. To determine whether adrenarche results from a decreased expression of 3betaHSD or CYP21 in the reticularis, immunohistochemical localization of 3betaHSD and CYP21 was performed, and staining intensities compared using adrenal glands from children ages 4 months to 4 yr (n = 12), ages 5-7 yr (n = 9), ages 8-13 yr (n = 9), and adults ages 25-56 yr (n = 8). There were no differences in the zonal expression of CYP21. No difference in 3betaHSD staining was observed between the glomerulosa and fasciculata from any age group. However, children age 8 yr and older show a significant decrease in 3betaHSD expression in reticularis as compared with the fasciculata. No significant difference was noted for 3betaHSD levels between the fasciculata and reticularis for children age 7 yr or younger. The level of 3betaHSD expression in the reticularis continued to decrease in the adult adrenals examined. These findings suggest that as children mature there is a decreased level of 3betaHSD in the adrenal reticularis that may contribute to the increased production of DHEA and DHEAS seen during adrenarche.


Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction.
The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of different substances for subureteric injection in the management of vesicoureteric reflux in children.
Endoscopic techniques are becoming increasingly accepted for treatment of vesicoureteric reflux as alternatives to open surgical reimplantation. However, there is some debate about the ideal injectable material. Since we have accumulated experience with several substances, an opportunity existed to compare them. From 1991 to 2003, 101 children with vesicoureteric reflux were treated by endoscopic subureteric injection either once (74) or twice (27) by either of two pediatric urologists. There were a total of 165 ureteral injections, 83 with polytetrafluoroethylene (Teflon), 73 with polydimethylsiloxane (Macroplastique), and 9 with collagen. Each child was evaluated pre-operatively and 3 months post-operatively with a nuclear cystogram and renal ultrasonography. The polytetrafluoroethylene and polydimethylsiloxane groups were not significantly different with respect to sex, age, indication for surgery, severity of reflux or prior surgeries. The collagen group overall did very poorly with only 3 of 9 refluxing ureters cured. The other two substances had much more success with 61% of ureters in the polytetrafluoroethylene group cured on first injection and 75% with polydimethylsiloxane, plus another 19% and 11% cured on second attempt, respectively (total 80% and 86%). Subureteric injections of polytetrafluoroethylene and polydimethylsiloxane are very effective at curing vesicoureteric reflux in children with little morbidity. When comparing individual cases, ureters, and all grades of reflux, polytetrafluoroethylene and polydimethylsiloxane have similar success rates. Collagen injections were less successful, and patients with neurogenic bladders had poor results.


Identification of single- and multiple-class specific signature genes from gene expression profiles by group marker index.
Informative genes from microarray data can be used to construct prediction model and investigate biological mechanisms. Differentially expressed genes, the main targets of most gene selection methods, can be classified as single- and multiple-class specific signature genes. Here, we present a novel gene selection algorithm based on a Group Marker Index (GMI), which is intuitive, of low-computational complexity, and efficient in identification of both types of genes. Most gene selection methods identify only single-class specific signature genes and cannot identify multiple-class specific signature genes easily. Our algorithm can detect de novo certain conditions of multiple-class specificity of a gene and makes use of a novel non-parametric indicator to assess the discrimination ability between classes. Our method is effective even when the sample size is small as well as when the class sizes are significantly different. To compare the effectiveness and robustness we formulate an intuitive template-based method and use four well-known datasets. We demonstrate that our algorithm outperforms the template-based method in difficult cases with unbalanced distribution. Moreover, the multiple-class specific genes are good biomarkers and play important roles in biological pathways. Our literature survey supports that the proposed method identifies unique multiple-class specific marker genes (not reported earlier to be related to cancer) in the Central Nervous System data. It also discovers unique biomarkers indicating the intrinsic difference between subtypes of lung cancer. We also associate the pathway information with the multiple-class specific signature genes and cross-reference to published studies. We find that the identified genes participate in the pathways directly involved in cancer development in leukemia data. Our method gives a promising way to find genes that can involve in pathways of multiple diseases and hence opens up the possibility of using an existing drug on other diseases as well as designing a single drug for multiple diseases.


MUMMALS: multiple sequence alignment improved by using hidden Markov models with local structural information.
We have developed MUMMALS, a program to construct multiple protein sequence alignment using probabilistic consistency. MUMMALS improves alignment quality by using pairwise alignment hidden Markov models (HMMs) with multiple match states that describe local structural information without exploiting explicit structure predictions. Parameters for such models have been estimated from a large library of structure-based alignments. We show that (i) on remote homologs, MUMMALS achieves statistically best accuracy among several leading aligners, such as ProbCons, MAFFT and MUSCLE, albeit the average improvement is small, in the order of several percent; (ii) a large collection (>10 000) of automatically computed pairwise structure alignments of divergent protein domains is superior to smaller but carefully curated datasets for estimation of alignment parameters and performance tests; (iii) reference-independent evaluation of alignment quality using sequence alignment-dependent structure superpositions correlates well with reference-dependent evaluation that compares sequence-based alignments to structure-based reference alignments.


The effects of maternal depression, anxiety, and perceived stress during pregnancy on preterm birth: A systematic review.
Experiencing psychological distress such as depression, anxiety, and/or perceived stress during pregnancy may increase the risk for adverse birth outcomes, including preterm birth. Clarifying the association between exposure and outcome may improve the understanding of risk factors for prematurity and guide future clinical and research practices. The aims of the present review were to outline the evidence on the risk of preterm associated with antenatal depression, anxiety, and stress. Four electronic database searches were conducted to identify quantitative population-based, multi-centre, cohort studies and randomised-controlled trial studies focusing on the association between antenatal depression, anxiety, and stress, and preterm birth published in English between 1980 and 2013. Of 1469 electronically retrieved articles, 39 peer-reviewed studies met the final selection criteria and were included in this review following the PRISMA and MOOSE review guidelines. Information was extracted on study characteristics; depression, anxiety and perceived stress were examined as separate and combined exposures. There is strong evidence that antenatal distress during the pregnancy increases the likelihood of preterm birth. Complex paths of significant interactions between depression, anxiety and stress, risk factors and preterm birth were indicated in both direct and indirect ways. The effects of pregnancy distress were associated with spontaneous but not with medically indicated preterm birth. Health practitioners engaged in providing perinatal care to women, such as obstetricians, midwives, nurses, and mental health specialists need to provide appropriate support to women experiencing psychological distress in order to improve outcomes for both mothers and infants.


Hereditary Dopamine Transporter Deficiency Syndrome: Challenges in Diagnosis and Treatment.
Hereditary dopamine transporter deficiency syndrome (DTDS) is a neurotransmitter disorder caused by a defect in the neuronal uptake of dopamine. To date, 20 patients are reported in the literature, and we present 2 additional patients with DTDS harboring novel homozygous SLC6A3 gene mutations. Patient A is an 8-month-old male with neonatal-onset hypotonia, who developed orolingual dyskinetic movements and oculogyric crises after 4 months of age, with evolution to status dystonicus episodes. Patient B is a 4-year-old male who also had hypotonia since birth, with additional severe limb contractions and oculogyric crises after the age of 3 months, with a misdiagnosis of epileptic encephalopathy. Both patients had consanguineous parents and similar cerebrospinal fluid (CSF) neurotransmitter profiles with elevated homovanillic acid and increased the ratio of homovanillic acid to 5-hydroxyindoleacetic acid. Diagnostic delay is 4 months, and 3 years 9 months, respectively. Treatment response to levodopa is poor. Early infantile-onset progressive dystonia with oculogyric crises, hypotonia, developmental delay, and CSF neurotransmitter profile led to a diagnosis of DTDS in these two patients. Management of hyperkinetic movement disorder, status dystonicus, and feeding difficulties are challenging. Detailed phenotyping of individual patients along with treatment response should provide insight into dopamine homeostasis.


Major contributions of comparative endocrinology to the development and exploitation of the incretin concept.
An incretin is a factor released by the gut in response to nutrients that facilitates uptake of glucose by peripheral tissues. The incretin concept predates the discovery of insulin but it is now clear that incretins act by stimulating secretion of this hormone. As glucagon has insulin-releasing activity, it was speculated that intestinal glucagon-like immunoreactivity (enteroglucagon) was involved in the incretin effect but it was an achievement in the field of comparative endocrinology that led to the demonstration that the preproglucagon gene encodes the most potent incretin in the human. Characterization of cloned cDNAs encoding two preproglucagons from the Brockmann body of the anglerfish Lophius americanus demonstrated that the glucagon sequence is flanked by a 34 amino-acid-residue sequence with appreciable structural similarity to glucagon that was termed glucagon-like peptide (GLP). A 36 amino-acid-residue ortholog of anglerfish GLP was subsequently identified in human preproglucagon but this peptide had only weak insulin-releasing activity. However, alignment of GLP sequences from human and teleost fish showed that the human ortholog is extended from its N-terminus by a hexapeptide. Removal of this extension by an endogenous protease generates GLP-1-(7-36)amide, the potent and effective form of the incretin. More recently, comparative endocrinology has contributed to the exploitation of incretins as antidiabetic drugs. Exendin-4, a GLP-1 receptor agonist first isolated from the venom of the Gila monster Heloderma suspectum, is a clinically valuable, long-acting incretin and the skins of several species of frogs synthesize potent insulin-releasing peptides with therapeutic potential.


B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.
Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.


Riemann tensor of motion vision revisited.
This note shows that the Riemann-space interpretation of motion vision developed by Barth and Watson is neither necessary for their results, nor sufficient to handle an intrinsic coordinate problem. Recasting the Barth-Watson framework as a classical velocity-solver (as in computer vision) solves these problems.


Fabrication of single-chain nanoparticles through the dimerization of pendant anthracene groups via photochemical upconversion.
We report on the use of visible light as the driving force for the intramolecular dimerization of pendant anthracene groups on a methacrylic polymer to induce the formation of single-chain nanoparticles (SCNPs). Using a 532 nm green laser light source and platinum octaethylporphyrin as a sensitizer, we first demonstrated the use of TTA-UC to dimerize monomeric anthracene, and subsequently applied this concept to dilute poly((methyl methacrylate)-stat-(anthracenyl methacrylate)) samples. A combination of triple-detection size-exclusion chromatography, atomic force microscopy, and UV-visible spectroscopy confirmed the formation of the SCNPs. This report pioneers the use of TTA-UC to drive photochemical reactions in polymeric systems, and showcases the potential for TTA-UC in the development of nanoobjects.


The role of honey in healing of bedsores in cancer patients.
Honey was used to treat infected wounds as long as 2000 years before bacteria were discovered. It has been reported to have inhibitory action to around 50 species of bacteria and fungi (aspergillus, penicillium). Usually, Metronidazole powder is used in our palliative clinic for wound healing due to low cost & effectivity. Honey is cheap, easily available ingredient with high astringent activity. Objectives of the study were to find out the effectiveness of Honey in terms of rate of wound healing & pain control in bedsores of cancer patients. 40 cancer patients with bedsore wounds were randomly assigned (1:1 ratio i.e. 20 in each arm) for Study Arm (Honey plus Metronidazole powder) and Control Arm (only Metronidazole powder), attending Palliative clinic of our department in between July 2010 to September 2011.Washing of the wound with normal saline done daily before application of above medicaments. Change of posture & soft bed were encouraged in both groups. A pre designed interview proforma, standardised Bates Jensen Wound Assessment Tool and Visual Analogue Pain assessment scale were used to collect and assess data. There was significant difference in wound healing status (F value = 6.523; Critical Difference =14.03, P>0.05) from day 10 and pain reduction also (F value = 6.638 and Critical Difference = 1.667, P>0.05) from day 7 in study arm. Application of honey dressing provides a better wound healing, rapid pain relief in cancer patients with bedsores in palliative settings.


Multiple beneficial health effects of natural alkylglycerols from shark liver oil.
Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo biological activities including stimulation of hematopoiesis and immunological defences, sperm quality improvement, or anti-tumor and anti-metastasis activities. Several mechanisms are suggested for these multiple activities, resulting from incorporation of alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl- Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and mechanisms are probably involved in the multiple activities of natural alkyl-Gro.


Dezinamide for partial seizures: results of an n-of-1 design trial.
Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.


Computer Modeling of Diabetes and Its Transparency: A Report on the Eighth Mount Hood Challenge.
The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups' replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether). Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results.


Suaveolic acid: a potent phytotoxic substance of Hyptis suaveolens.
Hyptis suaveolens (Lamiaceae) is an exotic invasive plant in many countries. Earlier studies reported that the aqueous, methanol, and aqueous methanol extract of H. suaveolens and its residues have phytotoxic properties. However, to date, the phytotoxic substances of this plant have not been reported. Therefore, the objectives of this study were isolation and identification of phytotoxic substances of H. suaveolens. Aqueous methanol extract of this plant was purified by several chromatographic runs through bioassay guided fractionation using garden cress (Lepidium sativum) as a test plant. Final purification of a phytotoxic substance was achieved by reverse phase HPLC and characterized as 14α-hydroxy-13β-abiet-8-en-18-oic acid (suaveolic acid) by high-resolution ESI-MS, (1)H-,(13)C-NMR, CD, and specific rotation. Suaveolic acid inhibited the shoot growth of garden cress, lettuce (Lactuca sativa), Italian ryegrass (Lolium multiflorum), and barnyard grass (Echinochloa crus-galli) at concentrations greater than 30 µM. Root growth of all but lettuce was also inhibited at concentrations greater than 30 µM. The inhibitory activities were concentration dependent. Concentrations required for 50% growth inhibition of suaveolic acid for those test plant species were ranged from 76 to 1155 µM. Therefore, suaveolic acid is phytotoxic and may be responsible for the phytotoxicity of H. suaveolens plant extracts.