Detection of putative loci affecting conformational type traits in an elite population of United States Holsteins using microsatellite markers.
Quantitative trait loci affecting conformational type traits were studied in seven large grandsire families of US Holsteins using the granddaughter design and 16 microsatellite markers on 10 chromosomes. The most significant marker effect was marker BM203 (chromosome 27) for dairy form in a single grandsire family. A multivariate analysis for dairy form and milk yield was also conducted, and the result was highly significant, indicating that a segregating quantitative trait locus or loci affecting dairy form and milk yield could exist near BM203 on chromosome 27. Marker BM1258 (chromosome 23) had a significant effect on udder depth. A multivariate analysis on udder depth and somatic cell score was conducted for markers 513 and BM1258, and both markers showed significant effects on these two traits, indicating that one or several quantitative trait loci affecting udder depth and mastitis might exist on chromosome 23. Marker BM4204 (chromosome 9) had a significant effect on foot angle and on the composite index of traits pertaining to feet and legs, indicating that one or several quantitative trait loci affecting traits pertaining to feet and legs might exist on chromosome 9. Selection on these markers could increase genetic progress within these families.


Timing of transmission and the evolution of virulence of an insect virus.
We used the nuclear polyhedrosis virus of the gypsy moth, Lymantria dispar, to investigate whether the timing of transmission influences the evolution of virulence. In theory, early transmission should favour rapid replication and increase virulence, while late transmission should favour slower replication and reduce virulence. We tested this prediction by subjecting one set of 10 virus lineages to early transmission (Early viruses) and another set to late transmission (Late viruses). Each lineage of virus underwent nine cycles of transmission. Virulence assays on these lineages indicated that viruses transmitted early were significantly more lethal than those transmitted late. Increased exploitation of the host appears to come at a cost, however. While Early viruses initially produced more progeny, Late viruses were ultimately more productive over the entire duration of the infection. These results illustrate fitness trade-offs associated with the evolution of virulence and indicate that milder viruses can obtain a numerical advantage when mild and harmful strains tend to infect separate hosts.


The effect of ceramic restoration shade and thickness on the polymerization of light- and dual-cure resin cements.
Inadequately polymerized resin cements may negatively affect the clinical performance of cemented all-ceramic restorations. The purpose of this in vitro study was to evaluate the effect of ceramic thickness and shade on the microhardness of various light-cured (LC) and dual-cured (DC) resin cements. The amount of light transmission through the restoration was also evaluated to correlate the results. Three different brands of resin cements (Appeal/Ivoclar; Calibra/Dentsply; Nexus 2/Kerr) were used in LC and DC forms to prepare disk-shaped samples (0.5-mm thickness × 5-mm diameter) (n=15). Study group samples were light-cured for 40 seconds (Flashlite 1401/Discus Dental) through four shades (ETC1, ETC2, ETC3, ETC4) and four thicknesses (1 mm, 2 mm, 3 mm, 4 mm) of all-ceramic ingot discs (IPS Empress Esthetic/Ivoclar). Control samples were directly cured without the presence of ceramic. The light transmission through various shades and thicknesses of ceramics was measured using a hand-held radiometer (Demetron, Kerr). Vickers microhardness measurements were performed (Micromet/Buehler) at 24 hours following dark storage in 37°C water. Correlation between ceramic shade, thickness, and light intensity readings (mW/cm2) with respect to microhardness was statistically evaluated using analysis of variance (p=0.05). Ceramic thickness of 3 mm and/or above significantly decreased the microhardness values in all LC and DC groups (p<0.0001). Ceramic shade had a significant effect only on Calibra in both LC and DC groups (p<0.0001). Microhardness values of LC groups were significantly lower than DC groups (p<0.0001). Control groups had significantly higher hardness values in all cement groups (p<0.0001). There was a significant correlation between the amount of light transmitted and hardness (p=0.000). The ceramic thickness has a more intense effect on polymerization compared to the ceramic shade. Overlying ceramic thickness of 3 mm and above was found to adversely affect the polymerization of LC and DC resin cements and therefore a 3-mm thickness was considered the critical threshold.


Age differential between outcomes of carotid angioplasty and stent placement and carotid endarterectomy in general practice.
Data derived from prospective randomized clinical trials suggest differential comparative benefit between carotid angioplasty and stent (CAS) placement and carotid endarterectomy (CEA) in various age strata. We sought to investigate the impact of age on outcomes of CAS and CEA in general practice. We analyzed the data from the Nationwide Inpatient Sample (NIS), which is representative of all admissions in the United States from 2005 to 2008. The primary end point was occurrence of stroke, cardiac complications, or death during the postprocedural period. Outcomes of interest were compared between patients aged ≥70 years and <70 years, undergoing CEA and CAS. Multivariate logistic regression was performed to determine the effect of age on occurrence of postoperative stroke, cardiac complications, or death. Covariates included in the logistic regression were patient's age, gender, comorbid conditions, including hypertension, diabetes mellitus (DM), chronic lung disease, coronary artery disease (CAD), congestive heart failure (CHF), and renal failure; symptom status (symptomatic vs asymptomatic status), and hospital characteristics. Of the total 495,331 estimated patients who received treatment for CAD during the study period, 88% underwent CEA and the remaining 12% underwent CAS. Of the total procedures, 41% of the procedures were performed in patients aged <70 years compared to the remaining 59% that were performed among patients aged ≥70 years. For patients undergoing CAS, age ≥70 years was an important predictor of postoperative stroke (P = .0025; odds ratio [OR], 1.7; 95% confidence interval [CI], 1.2-2.5) and cardiac complications postprocedure (P = .045; OR, 1.3; 95% CI, 1.0-1.6). For patients undergoing CEA, age ≥70 years was associated with higher cardiac complications (P < .001; OR, 1.5; 95% CI, 1.3-1.7) and higher postoperative mortality risk (P = .0008; OR, 1.4; 95% CI, 1.1-1.8) compared to patients aged <70 years. The increased risk of composite end point (postoperative stroke/cardiac complications/mortality) among patients aged ≥70 years was a significant factor for patients undergoing either CAS or CEA (OR of 1.3 for both procedures). Our analysis suggests that most CAS and CEAs are performed in patients aged ≥70 years in general practice, and higher rates of postoperative complications are observed among these patients regardless of procedure choice.


Constant contour integration in peripheral vision for stimuli with good Gestalt properties.
The visual system integrates discrete but aligned local stimuli to form percept of global contours. Previous experiments using "snake" contours showed that contour integration was mainly present in foveal vision but absent or greatly weakened in peripheral vision. In this study, we demonstrated that, for contour stimuli such as circles and ellipses, which bore good Gestalt properties, contour integration for shape detection and discrimination was nearly constant from the fovea to up to 35 degrees visual periphery! Contour integration was impaired by local orientation and position jitters of contour elements, indicating that the same local contour linking mechanisms revealed with snake contour stimuli also played critical roles in integration of our good Gestalt stimuli. Contour integration was also unaffected by global position jittering up to 20% of the contour size and by dramatic shape jittering, which excluded non-contour integration processes such as detection of various local cues and template matching as alternative mechanisms for uncompromised peripheral perception of good Gestalt stimuli. Peripheral contour integration also presented an interesting upper-lower visual field symmetry after asymmetries of contrast sensitivity and shape discrimination were discounted. The constant peripheral performance might benefit from easy detection of good Gestalt stimuli, which popped out from background noise, from a boost of local contour linking by top-down influences and/or from multielement contour linking by long-range interactions.


Cortisol stress response predicts 9-year risky driving convictions in male first-time driving-while-impaired offenders.
With driving while impaired by alcohol (DWI) representing a persistent burden on global health, better understanding and prevention of recidivism following a first-time DWI conviction are needed. Progress towards these goals is challenged by the marked heterogeneity in offender characteristics and a traffic safety literature that relies on subjective self-report measures and cross-sectional study designs. The present study tested the hypothesis that an objective neurobiological marker of behavioural maladjustment, the cortisol stress response (CSR), predicts future DWI and other traffic convictions over a 9-year follow-up period. One hundred thirty-two male first-time DWI offenders and 31 non-offender comparators were recruited and assessed at intake for their substance use, psychosocial and psychological characteristics and CSR. Traffic conviction data were obtained from provincial driving records. Survival analysis estimated the association between CSR and risk of a traffic conviction over time. In support of our hypothesis, blunted CSR predicted traffic convictions during the follow-up duration. This effect generalized to both DWI offenders and non-DWI drivers. While CSR was lower in DWI offenders compared to non-offenders, it did not specifically predict recidivism in DWI offenders. Modelling results indicated that blunted CSR, along with DWI offender group membership, experience seeking and drug use frequency, may demarcate a high-risk driver phenotype. CSR is a neurobiological marker of a driver phenotype with elevated generalized driving risk. For drivers with characteristics consistent with this phenotype, expanding the focus of intervention to address multiple forms of risky driving may be necessary to curb their overall threat to traffic safety.


Comparison of RNA isolation procedures for analysis of adult murine brain and spinal cord astrocytes.
Molecular analyses of cell populations and single cells have been instrumental in the advancement of our understanding of the physiology and pathologic processes of the nervous system. However, the limitation of these methods is the dependence on a gentle, efficient and specific enrichment procedure for the target cell population. In particular, this has been challenging for tightly interconnected cells, for example central nervous system (CNS) endogenous cells such as astrocytes. Here we adopted one of the most common methods of cell extraction, namely, enzymatic tissue digestion followed by fluorescence-activated cell sorting (FACS) of individual cells. We evaluated different enzymatic/mechanical tissue dissociation procedures and analyzed different astrocyte lineage transgenic models. Furthermore, we compared the cell extraction efficiency from spinal cord vs. brain. Enzymatic digestion of CNS tissue of Glast-CreERT2x tdTomatofl/fl or Aldh1l1-CreERT2x tdTomatofl/fl followed by FACS resulted in highly purified astrocytes. Automated tissue digestion strongly improved the isolated cell numbers. Aldh1l1-CreERT2 identified more astrocytes than Glast-CreERT2; isolation from brain yields higher numbers than from spinal cord. We compared the efficiency and purity of the enzymatic dissociation/FACS approach with a more modern procedure consisting of tissue homogenization followed by translating ribosome affinity purification (TRAP). We found that both methods result in highly enriched astrocytic RNA. However, only TRAP isolation resulted in reliably detectable RNA concentrations from spinal cord tissue on a single animal level. Depending on the aim of the study both methods have advantages and disadvantages but both are acceptable for astrocytic RNA analysis.


Recombinant expression of human microsomal epoxide hydrolase protects V79 Chinese hamster cells from styrene oxide- but not from ethylene oxide-induced DNA strand breaks.
Styrene 7,8-oxide and ethylene oxide are widely used genotoxic bulk chemicals, which have been associated with potential carcinogenic hazard for occupationally exposed workers. Both epoxides alkylate DNA preferentially at the N-7 position of guanine and consequently produce single-strand breaks and alkali labile sites in the DNA of exposed cells. In order to study the role of human microsomal epoxide hydrolase (hmEH) in protecting cells against genotoxicity of styrene 7,8-oxide and ethylene oxide, we expressed the cDNA of hmEH in V79 Chinese hamster cells. We obtained a number of cell clones that expressed functionally active epoxide hydrolase. Among these, the clone 92hmEH-V79 revealed an especially high enzymatic mEH activity toward styrene 7,8-oxide (10 nmol converted per mg of protein per min, measured in the 9,000 x g supernatant of the cell homogenate), that was 100 times higher than that determined in mock-transfected cells and within the range of mEH activity in human liver. Styrene 7,8-oxide-induced DNA single-strand breaks/alkali labile sites (dose range 10 microM to 1 mM styrene 7,8-oxide) measured by the alkaline elution technique were significantly lower in the 92hmEH-V79 cells as compared to the mock-transfected cells. The protection against styrene 7,8-oxide genotoxicity in 92hmEH-V79 cells could be abolished by addition of valpromide, a selective inhibitor of microsomal epoxide hydrolase. These results clearly show that the metabolism of styrene 7,8-oxide by hmEH in 92hmEH-V79 cells was responsible for the protection against styrene 7,8-oxide genotoxicity. On the other hand, no protective effect of epoxide hydrolase expression could be observed on ethylene oxide-induced DNA damage with the recombinant cell line over a dose range of 0.5-2.5 mM ethylene oxide. This selectivity of the protective effect on epoxide genotoxicity thus appears to be an important factor that must be taken into account for the prediction of the genotoxic risk of epoxides themselves or compounds that can be metabolically activated to epoxides.


Deductive sort and climbing sort: new methods for non-dominated sorting.
In recent years an increasing number of real-world many-dimensional optimisation problems have been identified across the spectrum of research fields. Many popular evolutionary algorithms use non-dominance as a measure for selecting solutions for future generations. The process of sorting populations into non-dominated fronts is usually the controlling order of computational complexity and can be expensive for large populations or for a high number of objectives. This paper presents two novel methods for non-dominated sorting: deductive sort and climbing sort. The two new methods are compared to the fast non-dominated sort of NSGA-II and the non-dominated rank sort of the omni-optimizer. The results demonstrate the improved efficiencies of the deductive sort and the reductions in comparisons that can be made when applying inferred dominance relationships defined in this paper.


Gas in the wound: what does it mean?
Gas-forming infections on the surgical service are usually due to anaerobic microorganisms such as clostridia, peptostreptococci or bacteroides, or to one of the aerobic coliforms. Factors that predispose to the development of gas infections include lower extremity vascular disease and diabetes mellitus. Early treatment based on the inital Gram-stain study as well as the clinical presentation is helpful in reducing tissue losses and increasing overall survival. Treatment for nonclostridial gas infections includes prompt adequate surgical debridement and appropriate parenteral antibiotics. When available, hyperbaric oxygen should be added to the treatment plan in all extensive clostridial infections.


First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study.
This phase II study assessed the safety and efficacy of oxaliplatin and capecitabine in patients with advanced oesophageal cancer. Fifty-one eligible patients received oxaliplatin 130 mg m(-2) intravenously on day 1 and capecitabine 1000 mg m(-2) orally twice daily on days 1 to 14 in a 21-day treatment cycle as first-line treatment for advanced oesophageal cancer. Grade 3 neutropenia was seen in one patient and anaemia in another patient. No grade 4 haematological toxicities were observed. Grade 4 non-haematological toxicity (lethargy) occurred in one patient (2%). Grade 3 non-haematological toxicity was seen in 14 (27%) patients (vomiting and polyneuropathy (8%); nausea (6%); lethargy and hand-foot syndrome (4%); and anorexia, diarrhoea, and hyperbilirubinaemia (each in one patient)). In 22% of the patients, toxicity was the reason for stopping the treatment. The overall response rate was 39%. The median overall survival was 8 months; the 1-year survival rate was 26%. In the quality of life (QoL) analysis, the emotional well-being improved during treatment, but the physical functioning scores declined. The fatigue score on the symptom scales increased. Overall, the global QoL score did not change during treatment. In conclusion, the activity of oxaliplatin and capecitabine is comparable with other chemotherapy regimens in advanced oesophageal cancer with a low frequency of grade 3/4 toxicity. Because this treatment can be given on an outpatient basis, it is probably less toxic than cisplatin-based therapy and preserves QoL during treatment, it is a viable treatment option in patients with advanced oesophageal cancer.


Conserved Tetramer Junction in the Kinetochore Ndc80 Complex.
The heterotetrameric Ndc80 complex establishes connectivity along the principal longitudinal axis of a kinetochore. Its two heterodimeric subcomplexes, each with a globular end and a coiled-coil shaft, connect end-to-end to create a ∼600 Å long rod spanning the gap from centromere-proximal structures to spindle microtubules. Neither subcomplex has a known function on its own, but the heterotetrameric organization and the characteristics of the junction are conserved from yeast to man. We have determined crystal structures of two shortened ("dwarf") Ndc80 complexes that contain the full tetramer junction and both globular ends. The junction connects two α-helical coiled coils through regions of four-chain and three-chain overlap. The complexity of its structure depends on interactions among conserved amino-acid residues, suggesting a binding site for additional cellular factor(s) not yet identified.


A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans.
An essential stage of neural development involves the assembly of neural circuits via formation of inter-neuronal connections. Early steps in neural circuit formation, including cell migration, axon guidance, and the localization of synaptic components, are well described. However, upon reaching their target region, most neurites still contact many potential partners. In order to assemble functional circuits, it is critical that within this group of cells, neurons identify and form connections only with their appropriate partners, a process we call synaptic partner recognition (SPR). To understand how SPR is mediated, we previously developed a genetically encoded fluorescent trans-synaptic marker called NLG-1 GRASP, which labels synaptic contacts between individual neurons of interest in dense cellular environments in the genetic model organism Caenorhabditis elegans. Here, we describe the first use of NLG-1 GRASP technology, to identify SPR genes that function in this critical process. The NLG-1 GRASP system allows us to assess synaptogenesis between PHB sensory neurons and AVA interneurons instantly in live animals, making genetic analysis feasible. Additionally, we employ a behavioral assay to specifically test PHB sensory circuit function. Utilizing this approach, we reveal a new role for the secreted UNC-6/Netrin ligand and its transmembrane receptor UNC-40/Deleted in colorectal cancer (DCC) in SPR. Synapses between PHB and AVA are severely reduced in unc-6 and unc-40 animals despite normal axon guidance and subcellular localization of synaptic components. Additionally, behavioral defects indicate a complete disruption of PHB circuit function in unc-40 mutants. Our data indicate that UNC-40 and UNC-6 function in PHB and AVA, respectively, to specify SPR. Strikingly, overexpression of UNC-6 in postsynaptic neurons is sufficient to promote increased PHB-AVA synaptogenesis and to potentiate the behavioral response beyond wild-type levels. Furthermore, an artificially membrane-tethered UNC-6 expressed in the postsynaptic neurons promotes SPR, consistent with a short-range signal between adjacent synaptic partners. These results indicate that the conserved UNC-6/Netrin-UNC-40/DCC ligand-receptor pair has a previously unknown function, acting in a juxtacrine manner to specify recognition of individual postsynaptic neurons. Furthermore, they illustrate the potential of this new approach, combining NLG-1 GRASP and behavioral analysis, in gene discovery and characterization.


Comparative spring mechanics in mantis shrimp.
Elastic mechanisms are fundamental to fast and efficient movements. Mantis shrimp power their fast raptorial appendages using a conserved network of exoskeletal springs, linkages and latches. Their appendages are fantastically diverse, ranging from spears to hammers. We measured the spring mechanics of 12 mantis shrimp species from five different families exhibiting hammer-shaped, spear-shaped and undifferentiated appendages. Across species, spring force and work increase with size of the appendage and spring constant is not correlated with size. Species that hammer their prey exhibit significantly greater spring resilience compared with species that impale evasive prey ('spearers'); mixed statistical results show that species that hammer prey also produce greater work relative to size during spring loading compared with spearers. Disabling part of the spring mechanism, the 'saddle', significantly decreases spring force and work in three smasher species; cross-species analyses show a greater effect of cutting the saddle on the spring force and spring constant in species without hammers compared with species with hammers. Overall, the study shows a more potent spring mechanism in the faster and more powerful hammering species compared with spearing species while also highlighting the challenges of reconciling within-species and cross-species mechanical analyses when different processes may be acting at these two different levels of analysis. The observed mechanical variation in spring mechanics provides insights into the evolutionary history, morphological components and mechanical behavior, which were not discernible in prior single-species studies. The results also suggest that, even with a conserved spring mechanism, spring behavior, potency and component structures can be varied within a clade with implications for the behavioral functions of power-amplified devices.


Mindfulness-based stress reduction for chronic pain conditions: variation in treatment outcomes and role of home meditation practice.
This study compared changes in bodily pain, health-related quality of life (HRQoL), and psychological symptoms during an 8-week mindfulness-based stress reduction (MBSR) program among groups of participants with different chronic pain conditions. From 1997-2003, a longitudinal investigation of chronic pain patients (n=133) was nested within a larger prospective cohort study of heterogeneous patients participating in MBSR at a university-based Integrative Medicine center. Measures included the Short-Form 36 Health Survey and Symptom Checklist-90-Revised. Paired t tests were used to compare pre-post changes on outcome measures. Differences in treatment effect sizes were compared as a function of chronic pain condition. Correlations were examined between outcome parameters and home meditation practice. Outcomes differed in significance and magnitude across common chronic pain conditions. Diagnostic subgroups of patients with arthritis, back/neck pain, or two or more comorbid pain conditions demonstrated a significant change in pain intensity and functional limitations due to pain following MBSR. Participants with arthritis showed the largest treatment effects for HRQoL and psychological distress. Patients with chronic headache/migraine experienced the smallest improvement in pain and HRQoL. Patients with fibromyalgia had the smallest improvement in psychological distress. Greater home meditation practice was associated with improvement on several outcome measures, including overall psychological distress, somatization symptoms, and self-rated health, but not pain and other quality of life scales. MBSR treatment effects on pain, HRQoL and psychological well-being vary as a function of chronic pain condition and compliance with home meditation practice.


Healthcare workers' attitudes towards working during pandemic influenza: a multi method study.
Healthcare workers (HCWs) will be key players in any response to pandemic influenza, and will be in the front line of exposure to infection. Responding effectively to a pandemic relies on the majority of medical, nursing, laboratory and hotel services staff continuing to work normally. Planning assumes that during a pandemic normal healthcare service levels will be provided, although it anticipates that as caseloads increase only essential care will be provided. The ability of the NHS to provide expected service levels is entirely dependent upon HCWs continuing to work as normal. This study is designed as a two-phase multi-method study, incorporating focus groups and a questionnaire survey. In phase one, qualitative methods will be used to collect the views of a purposive sample of HCWs, to determine the range of factors associated with their responses to the prospect of working through pandemic influenza. In phase two, the findings from the focus groups, combined with the available literature, will be used to inform the design of a survey to determine the generalisability of these factors, enabling the estimation of the likely proportion of HCWs affected by each factor, and how likely it is that they would be willing and/or able to continue to work during an influenza pandemic. There are potentially greater than normal health risks for some healthcare workers working during a pandemic, and these workers may be concerned about infecting family members/friends. HCWs will be as liable as other workers to care for sick family members and friends. It is vital to have information about how motivated HCWs will be to continue to work during such a crisis, and what factors might influence their decision to work/not to work. Through the identification and subsequent management of these factors it may be possible to implement strategies that will alleviate the concerns and fears of HCWs and remove potential barriers to working.


A risk assessment study on work-related musculoskeletal disorders among dentists in Bhopal, India.
Work-related musculoskeletal disorders (WMSDs) are responsible for morbidity in many working populations, which are of multifactorial in origin and of global concern due to industrialization. Dentists as one of the health-care professionals are prone to develop these WMSDs. The study aims to determine the prevalence of WMSDs among dentists in Bhopal region and explores the various risk factors for the development of MSDs and WMSDs. This proposed study is a cross-sectional study conducted among dentists of two randomly selected dental colleges of Bhopal, India. A structured questionnaire was used to collect the demographic information, occupational history, risk factors, and ergonomic awareness with job task details. Prevalidated standardized tools such as quick exposure check list, rapid entire body assessment score sheet, and Nordic Musculoskeletal Questionnaire were also used. Data were entered in MS-Excel and analyzed through SPSS version 18. More than 92% of the participants reported pain and discomfort in at least one part of their body. The major affected body part is neck, followed by the lower back and wrist. More than half of the orthodontists and oral surgeons reported that their MSDs are work-related origin. Pearson's correlation test indicated that there is a positive correlation between the current exposure and risk (r = 0.613). Multivariate regression analysis found that younger participants, male (OR = 4.1), involved physical activity (OR = 1.04), dentists not taught about ergonomics in their dental school (OR = 1.69) or never attended any workshops (OR = 1.38), who reported task involving sustained muscle contraction (OR = 1.12) or task with repetitive movements (OR = 1.11) are the major risk factors for the development of MSDs among the dentists. This risk assessment study found that there is a high prevalence of MSDs and WMSDs among dentists. Ergonomic awareness and health promotion need to be integrated with the professional practice for dentists.


Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer.
Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-XL and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidyl-inositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumin-induced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspase-dependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.


Relationships among family participation, team support, and intensity of early intervention services.
In America, children with disabilities and their families may receive early intervention (EI) services under the Individuals with Disabilities Education Improvement Act (IDEA). The IDEA mandates that decisions on service delivery are based on the needs of the child and family. It is unclear how decisions on intensity of services are made in EI. The purpose of this study was to determine whether parent participation and team support are determinants of the recommendation for intensity of service at the initial Individualized Family Service Planning (IFSP) meeting. The participants were 63 parents of children 2-33 months of age and 74 professionals. The first author observed all IFSP meetings and completed the Parent Participation Measure. Following the meeting, parents completed a demographic form, the Ages and Stages Questionnaire, and the Family Needs Survey. The recommended intensity of service was recorded. Parent participation and team support were not significant determinants of intensity of EI service after controlling for child development and family needs (R2 = 0.145, p = .14). The recommended intensity of service was 240 min per month for 57% of the families suggesting that factors other than parent participation and team support influenced the decision on intensity of service.


Beneficial effects of yoga lifestyle on reversibility of ischaemic heart disease: caring heart project of International Board of Yoga.
Yoga based lifestyle modifications have been earlier shown to be beneficial in coronary artery disease in a small number of patients. We evaluated the role of lifestyle modification based on Yoga techniques, stress management and dietary modifications in retardation of coronary artery disease. This prospective, controlled, open trial included angiographically proven coronary artery disease patients (71 patients in study group and 42 patients in control group). They were assessed clinically, by biochemical parameters, stress myocardial perfusion and function studies and coronary angiography and on psychological parameters. The study group patients were given a family based Yoga Programme which included, control of risk factors, dietary modifications and stress management for a period of one year. The patients were assessed at baseline, at frequent intervals and at the end of one year. At the end of one year of yoga training, statistical significant changes (P<0.05) were found in serum total cholesterol (reduction by 23.3% in study group patients as compared to 4.4% in controls); serum LDL cholesterol (reduction of 26% in study group patients as compared to 2.6% in the control group), regression of disease (43.7% of study group patients v/s 31% control group on MPI and 70.4% of study group v/s 28% of control group on angiography) arrest of progression (46.5% study group v/s 33.3% control group on MPI) and progression (9.9% of study group vs 35.7% of controls on MPI, 29.6% of study group v/s 60.0% of controls on angiography). At the end of the study improvement in anxiety scores was concordant with the improvement seen in the MPI. No untoward effects of the therapy were observed. Yoga based lifestyle modifications help in regression of coronary lesions and in improving myocardial perfusion. This is translated into clinical benefits and symptomatic improvement.


Post-kala-azar dermal leishmaniasis.
Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL); it is characterised by a macular, maculopapular, and nodular rash in a patient who has recovered from VL and who is otherwise well. The rash usually starts around the mouth from where it spreads to other parts of the body depending on severity. It is mainly seen in Sudan and India where it follows treated VL in 50% and 5-10% of cases, respectively. Thus, it is largely restricted to areas where Leishmania donovani is the causative parasite. The interval at which PKDL follows VL is 0-6 months in Sudan and 2-3 years in India. PKDL probably has an important role in interepidemic periods of VL, acting as a reservoir for parasites. There is increasing evidence that the pathogenesis is largely immunologically mediated; high concentrations of interleukin 10 in the peripheral blood of VL patients predict the development of PKDL. During VL, interferon gamma is not produced by peripheral blood mononuclear cells (PBMC). After treatment of VL, PBMC start producing interferon gamma, which coincides with the appearance of PKDL lesions due to interferon-gamma-producing cells causing skin inflammation as a reaction to persisting parasites in the skin. Diagnosis is mainly clinical, but parasites can be seen by microscopy in smears with limited sensitivity. PCR and monoclonal antibodies may detect parasites in more than 80% of cases. Serological tests and the leishmanin skin test are of limited value. Treatment is always needed in Indian PKDL; in Sudan most cases will self cure but severe and chronic cases are treated. Sodium stibogluconate is given at 20 mg/kg for 2 months in Sudan and for 4 months in India. Liposomal amphotericine B seems effective; newer compounds such as miltefosine that can be administered orally or topically are of major potential interest. Although research has brought many new insights in pathogenesis and management of PKDL, several issues in particular in relation to control remain unsolved and deserve urgent attention.


Effect of water storage on the flexural properties of E-glass and silica fiber acrylic resin composite.
The aim of this study was to determine the effect of water on the flexural properties of fiber-reinforced denture base polymers. Continuous woven silanized electrical glass, or E-glass, fibers and woven silica fibers were used to reinforce heat-cured and autopolymerized denture base polymers. Fibers were oriented at a 45-degree angle to the long axis of the test specimens. Control specimens were unreinforced. Dry test specimens and those stored in water for up to 48 weeks were tested with a three-point loading apparatus. The surfaces of the fibers of the test specimens stored dry or 48 weeks in water were analyzed with a scanning electron microscope to evaluate the degree of adhesion between fibers and polymer matrix. The ultimate transverse strength of unreinforced and reinforced denture base polymers decreased during 48 weeks' storage in water (P < 0.05, one-way analysis of variance, n = 5), and most of this reduction occurred during the first 4 weeks of storage in water. The flexural modulus of the unreinforced test specimens decreased significantly (P < 0.001), whereas there was less, if any, change in the flexural modulus of the fiber-reinforced test specimens. Scanning electron microscopic examination revealed no differences in adhesion of E-glass fibers to the polymer matrix when the specimens stored in water were compared with those stored by. Reduced adhesion between the silica fibers and matrix was observed after 48 weeks' storage in water. The results of this study suggest that the ultimate transverse strength of the E-glass fiber-reinforced test specimens decreased 14% and that of the silica fiber-reinforced test specimens decreased 36% after 48 weeks of storage in water.


Control of the Cutaneous Circulation by the Central Nervous System.
The central nervous system (CNS), via its control of sympathetic outflow, regulates blood flow to the acral cutaneous beds (containing arteriovenous anastomoses) as part of the homeostatic thermoregulatory process, as part of the febrile response, and as part of cognitive-emotional processes associated with purposeful interactions with the external environment, including those initiated by salient or threatening events (we go pale with fright). Inputs to the CNS for the thermoregulatory process include cutaneous sensory neurons, and neurons in the preoptic area sensitive to the temperature of the blood in the internal carotid artery. Inputs for cognitive-emotional control from the exteroceptive sense organs (touch, vision, sound, smell, etc.) are integrated in forebrain centers including the amygdala. Psychoactive drugs have major effects on the acral cutaneous circulation. Interoceptors, chemoreceptors more than baroreceptors, also influence cutaneous sympathetic outflow. A major advance has been the discovery of a lower brainstem control center in the rostral medullary raphé, regulating outflow to both brown adipose tissue (BAT) and to the acral cutaneous beds. Neurons in the medullary raphé, via their descending axonal projections, increase the discharge of spinal sympathetic preganglionic neurons controlling the cutaneous vasculature, utilizing glutamate, and serotonin as neurotransmitters. Present evidence suggests that both thermoregulatory and cognitive-emotional control of the cutaneous beds from preoptic, hypothalamic, and forebrain centers is channeled via the medullary raphé. Future studies will no doubt further unravel the details of neurotransmitter pathways connecting these rostral control centers with the medullary raphé, and those operative within the raphé itself. © 2016 American Physiological Society. Compr Physiol 6:1161-1197, 2016.


Efficient coding of spatial information in the primate retina.
Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (~30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.


Benefits of costing in the clinical laboratory.
This paper urges the benefits of applying more widely a method for pathology laboratory costing originally devised for a clinical chemistry department, and illustrates these with examples drawn from costing studies in three clinical laboratories. Heads of pathology departments, laboratory managers, administrators and clinicians require different kinds of costing information, each of which can be obtained by the costing procedure outlined. The method also yields valuable and sometimes surprising insights into the workings of a pathology service. Cost comparisons between different laboratories can now become more informative. Flaws in the concept of the "cost per test" are discussed and the value of this concept is questioned; for most purposes the cost per request has greater application.


Human antibodies reactive with beta-amyloid protein in Alzheimer's disease.
Four human B cell lines established by Epstein-Barr viral transformation of B cells from a patient with a clinical diagnosis of Alzheimer's disease (AD) were found to secrete antibodies that react with plaques and cerebrovascular blood vessels in AD brain in a staining profile characteristic of beta-amyloid protein (beta-AP) in AD brain. Two of these antibodies were shown to be reactive with a rare plaque in a normal brain. In these studies, immunofluorescence and avidin-biotin complex immunoperoxidase methodology were used to determine antibody reaction, and thioflavine S was used to double label amyloid and neurofibrillary tangles. The four antibodies also reacted with neurons in normal and AD brain. Absorption studies, dot immunoblots, and enzyme-linked immunosorbent assays with beta-amyloid peptides 1-28 (beta-A1-28) and 1-40 (beta-A1-40) indicate the major determinant of the reactive epitope is located in the region of amino acids 1-28 of beta-AP. However, inhibition studies demonstrate a significant contribution to the antigenic determinant by the 29-40 region of the beta-A1-40. These antibodies represent the first human autoantibodies against beta-AP. The pathological significance of these autoantibodies is discussed.


Direct investigation of intracellular presence of gold nanoparticles via photothermal heterodyne imaging.
Nanotechnology as well as advanced microscopy can play a fundamental role in understanding biological mechanisms. Here we present a study that combines a new type of nanomaterial with a new type of microscopy and highlights the potential for gathering novel information about cell membrane penetration and cytosol local viscosity. On the material side, we used gold nanoparticles that have an ordered stripe-like arrangement of domains. These "striped" nanoparticles are able to penetrate cell membranes directly without porating them. On the microscopy side, we used photothermal heterodyne imaging which allows detection of individual nanometer-sized gold particles in complex media. We showed that we can probe cytosolic presence as well as dynamics of these nanoparticles even at very low concentrations. We used the fluctuations of the photothermal signal from particles diffusing in the detection volume to estimate local cytosol viscosity which is about 20 times larger than that of water. This work opens new perspectives for mapping local diffusion properties of nano-objects inside living cells.


Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice.
Insulin signalling pathways regulate pancreatic beta cell function. Conditional gene targeting using the Cre/loxP system has demonstrated that mice lacking insulin receptor substrate 2 (IRS2) in the beta cell have reduced beta cell mass. However, these studies have been complicated by hypothalamic deletion when the RIPCre (B6.Cg-tg(Ins2-cre)25Mgn/J) transgenic mouse (expressing Cre recombinase under the control of the rat insulin II promoter) is used to delete floxed alleles in insulin-expressing cells. These features have led to marked insulin resistance making the beta cell-autonomous role of IRS2 difficult to determine. To establish the effect of deleting Irs2 only in the pancreas, we generated PIrs2KO mice in which Cre recombinase expression was driven by the promoter of the pancreatic and duodenal homeobox factor 1 (Pdx1, also known as Ipf1) gene. In vivo glucose homeostasis was examined in PIrs2KO mice using glucose tolerance and glucose-stimulated insulin secretion tests. Endocrine cell mass was determined by morphometric analysis. Islet function was examined in static cultures and by performing calcium imaging in Fluo3am-loaded beta cells. Islet gene expression was determined by RT-PCR. The PIrs2KO mice displayed glucose intolerance and impaired glucose-stimulated insulin secretion in vivo. Pancreatic insulin and glucagon content and beta and alpha cell mass were reduced. Glucose-stimulated insulin secretion and calcium mobilisation were attenuated in PIrs2KO islets. Expression of the Glut2 gene (also known as Slc2a2) was also reduced in PIrs2KO mice. These studies suggest that IRS2-dependent signalling in pancreatic islets is required not only for the maintenance of normal beta and alpha cell mass but is also involved in the regulation of insulin secretion.


MicroRNA Dysregulation in Cystic Fibrosis.
The cystic fibrosis lung is a complex milieu comprising multiple factors that coordinate its physiology. MicroRNAs are regulatory factors involved in most biological processes and it is becoming increasingly clear that they play a key role in the development and manifestations of CF lung disease. These small noncoding RNAs act posttranscriptionally to inhibit protein production. Their involvement in the pathogenesis of CF lung disease stems from the fact that their expression is altered in vivo in the CF lung due to intrinsic and extrinsic factors; to date defective chloride ion conductance, endoplasmic reticulum stress, inflammation, and infection have been implicated in altering endogenous miRNA expression in this setting. Here, the current state-of-the-art and biological consequences of altered microRNA expression in cystic fibrosis are reviewed.


Functional results after surgical treatment for congenital knee dislocation.
Congenital knee dislocation (CDK) is a rare congenital deformity, which often requires surgery for treatment. Little objective data exist characterizing the outcome of patients who require operative treatment for this condition. The purposes of this study were to objectively evaluate the functional, clinical, and gait outcomes of patients who underwent surgical treatment of CDK; and compare the results of outcome between 2 surgical approaches for this condition: quadricepsplasty and femoral shortening. We performed a retrospective review of all patients (7) treated surgically for CDK. Patients were evaluated at an average follow-up of 12+6 years. Each patient underwent a clinical examination, functional evaluation using the Lysholm Knee Questionnaire and Pediatric Outcomes Data Collection Instrument, and a 3-dimensional gait evaluation. The results of the total group were compared with normal controls. Additionally, results of the patients treated with quadricepsplasty were compared with patients treated with femoral shortening. Total knee range of motion for the entire group averaged 112 degrees, with 8 of the 9 knees having flexion>90 degrees. Seven of the 9 knees were found to have some degree of instability on examination, yet none of the patients reported using any form of brace for ambulation. Functional evaluation showed good knee specific and overall function, comparable to normal controls. There were no differences in clinical or functional outcomes between the 2 surgical approaches. Gait analysis revealed a stiff-knee gait pattern to the congenital knee dislocation group, as compared with normal controls, and subtle differences in knee function between the surgical approaches. The function of patients after surgical treatment for CDK seems to be quite good compared with normal controls. Good knee specific and overall function scores are reported with limitations seen only in higher demand activities. Despite instability of the knee noticed on clinical examination, patients ambulate without braces and have a functional knee range of motion. Little difference in outcome was seen between the 2 surgical approaches used to treat this condition. Therapeutic Study, Level III.


Ruptured anterior paraclinoid aneurysms.
The purpose of this study was to evaluate cases of subarachnoid hemorrhage (SAH) from ruptured anterior (dorsal) paraclinoid aneurysms. Anterior paraclinoid aneurysms are defined as aneurysms arising from the anterolateral wall of the proximal internal carotid artery without any relationship to an arterial branch. Between 1991 and 2008, a total of 159 patients with 169 paraclinoid aneurysms were treated at the Shinshu University Hospital and its affiliated hospitals. A retrospective analysis was carried out using charts, operation records, operation videos, and neuroimagings. Twenty six patients had anterior paraclinoid aneurysm. Six patients presented with SAH. Three aneurysms were saccular and the others were blister-like aneurysms based on operative findings. Neck laceration or premature rupture frequently happened during the clipping surgery even though the aneurysm was saccular type. The treatment of a ruptured anterior paraclinoid aneurysm is quite difficult. Trapping and bypass would be recommended for such fragile aneurysms.


Evaluation of New Drugs for Asthma and COPD: Endpoints, Biomarkers and Clinical Trial Design.
There remains a considerable need to develop novel therapies for patients with asthma and chronic obstructive pulmonary disease (COPD). The greatest challenge at the moment is measuring the effects of novel anti-inflammatory drugs, as these drugs often cause only small effects on lung function. Measurements that demonstrate the pharmacological and clinical effects of these drugs are needed. Furthermore, we now recognise that only subgroups of patients are likely to respond to these novel drugs, so using biomarkers to determine the clinical phenotype most suitable for such therapies is important. An endotype is a subtype of a (clinical) condition defined by a distinct pathophysiological mechanism. An endotype-driven approach may be more helpful in drug development, enabling drugs to be targeted specifically towards specific biological mechanisms rather than clinical characteristics. This requires the development of biomarkers to define endotypes and/or to measure drug effects. This newer approach should continue alongside efforts to optimise the measurement of clinical endpoints, including patient-reported outcome measurements, required by drug regulatory authorities.


Local auxin biosynthesis modulates gradient-directed planar polarity in Arabidopsis.
The coordination of cell polarity within the plane of a single tissue layer (planar polarity) is a crucial task during development of multicellular organisms. Mechanisms underlying establishment of planar polarity, however, differ substantially between plants and animals. In Arabidopsis thaliana, planar polarity of root-hair positioning along epidermal cells is coordinated towards maximum concentration of an auxin gradient in the root tip. This gradient has been hypothesized to be sink-driven and computational modelling suggests that auxin efflux carrier activity may be sufficient to generate the gradient in the absence of auxin biosynthesis in the root. Here, we demonstrate that the Raf-like kinase CONSTITUTIVE TRIPLE RESPONSE1 (CTR1; Refs 8, 9) acts as a concentration-dependent repressor of a biosynthesis-dependent auxin gradient that modulates planar polarity in the root tip. We analysed auxin biosynthesis and concentration gradients in a variety of root-hair-position mutants affected in CTR1 activity, auxin biosynthesis and transport. Our results reveal that planar polarity relies on influx- and efflux-carrier-mediated auxin redistribution from a local biosynthesis maximum. Thus, a local source of auxin biosynthesis contributes to gradient homeostasis during long-range coordination of cellular morphogenesis.


Field study on effects of a heat exchanger on broiler performance, energy use, and calculated carbon dioxide emission at commercial broiler farms, and the experiences of farmers using a heat exchanger.
In broiler houses, ventilation removes moisture and maintains ambient temperature and air quality. During cold weather conditions, ventilation can result in undesirable heat loss from the house. Extra input of energy for heating the building is needed then, resulting in extra CO(2) emissions when fossil fuels are used for this purpose. In such a situation, an air-to-air heat exchanger (HE) might be valuable because it recovers heat by prewarming fresh supply air with warm inside air. The aim of this study was to analyze effects of on-farm use of an HE on broiler performance, energy use, and CO(2) emission by comparing production cycles with and without an HE, and to inventory the experiences of farmers using an HE. Data were collected of production cycles finished with (102) or without (149) an HE on 25 farms. Data on mortality, feed intake, water intake, and BW gain were obtained to analyze broiler performance. When available, gas and electricity use were obtained to analyze energy use and to calculate CO(2) emission. Farmers were interviewed about their experiences regarding the HE. The use of an HE tended to increase daily weight gain (56 vs. 55, SEM 0.3 g/d; P = 0.07), but did not affect other performance variables. Based on 13 farms, gas use was reduced by 38% (P < 0.01) after installing an HE. Based on 3 farms only, an HE did not affect electricity use, total energy use, or calculated CO(2) emission. It appeared that farmers were satisfied with the HE because they experienced an increase in job satisfaction, an improvement of climate conditions and litter quality in the broiler house, and a more uniform temperature and broiler distribution in the house. We concluded that the use of an HE reduced gas use and has the ability to improve broiler weight gain but had no effect on other broiler performance variables. Effects on CO(2) emission were unclear. Farmers appeared to be positive about using an HE, because it improved broiler house climate and job satisfaction.


Upper Paleolithic cultural diversity in the Iranian Zagros Mountains and the expansion of modern humans into Eurasia.
This paper aims to understand the cultural diversity among the first modern human populations in the Iranian Zagros and the implications of this diversity for evolutionary and ecological models of human dispersal through Eurasia. We use quantitative data and technotypological attributes combined with physiogeographic information to assess if the Zagros Upper Paleolithic (UP) developed locally from the Middle Paleolithic (MP), as well as to contextualize the variation in lithics from four UP sites of Warwasi, Yafteh, Pasangar, and Ghār-e Boof. Our results demonstrate (1) that the Zagros UP industries are intrusive to the region, and (2) that there is significant cultural diversity in the early UP across different Zagros habitat areas, and that this diversity clusters in at least three groups. We interpret this variation as parallel developments after the initial occupation of the region shaped by the relative geotopographical isolation of different areas of the Zagros, which would have favored different ecological adaptations. The greater similarity of lithic traditions and modes of production observed in the later phases of the UP across all sites indicates a marked increase in inter-group contact throughout the West-Central Zagros mountain chain. Based on the chronological and geographical patterns of Zagros UP variability, we propose a model of an initial colonization phase leading to the emergence of distinct local traditions, followed by a long phase of limited contact among these first UP groups. This has important implications for the origins of biological and cultural diversity in the early phases of modern human colonization of Eurasia. We suggest that the mountainous arc that extends from Anatolia to the Southern Zagros preserves the archaeological record of different population trajectories. Among them, by 40 ka, some would have been transient, whereas others would have left no living descendants. However, some would have led to longer term local traditions, including groups who share ancestry with modern Europeans and modern East/Southeast Asians.


Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies.
We have analyzed the factors associated with engraftment in 216 recipients of T-cell depleted allogeneic HLA identical sibling marrow transplants using Campath 1 monoclonal antihuman lymphocyte (CD52) antibodies. The patient population consisted of 168 patients with hematologic malignancies, 26 with severe aplastic anemia (SAA), and 22 with hemoglobinopathies, half of whom received marrow treated in vitro with Campath-1M (IgM) and half received marrow with Campath-1G (IgG2b isotype). Patients with durable engraftment had fast hematopoietic recovery: SAA patients reached ANC > 0.5 x 10(6)/L on Day 14; those with leukemia attained ANC > 0.5 x 10(6)/L on Days 18, 17, and 15 for ANLL, ALL and CML respectively, while patients with thalasemia reached ANC > 0.5 x 10(6)/L on Day 21. Overall, 24 patients (17 with leukemia, 4 with SAA, and 3 with thalassemia) suffered graft failure: 10 patients (all grafted with Campath-1M) rejected their grafts, while 14 others (9 grafted with Campath-1M, and 5 with 1G isotype) never engrafted (p = 0.009). Multivariate analysis revealed that neither pretransplant protocol, nor stage of disease or type of antibody used, donor sex and ABO match had any impact on engraftment. The variables favorably associated with engraftment were older age (p = 0.030, RR = 1.016) and CFU-GM number (p = 0.013, RR = 1.001). Patients with ANLL or SAA had a better chance to engraft (p = 0.027, RR = 1.400; and p = 0.003, RR = 2.677, respectively) compared to patients with thalassemia (p = 0.001, RR = 0.551). A higher concentration of Campath-1 antibody in vitro and in vivo adversely affected engraftment. Our data show that satisfactory engraftment can be achieved in patients transplanted with Campath-1 treated marrow allografts. However, despite the measures undertaken to prevent rejection, graft failure still poses a problem. Further pretransplant immunosuppression and perhaps more selective T-cell depletion may reduce the increased graft failure in these patients.


An enhanced hTERT promoter-driven CRISPR/Cas9 system selectively inhibits the progression of bladder cancer cells.
The current therapies for treating tumors are lacking in efficacy and specificity. Synthetic biology principles may bring some new possible methods for curing cancer. Here we present a synthetic logic circuit based on the CRISPR/Cas9 system. The CRISPR/Cas9 technology has been applied in many biological fields, including cancer research. In this study, the expression of Cas9 nuclease was controlled indirectly by an enhanced hTERT promoter using the GAL4/upstream activating sequence (UAS) binding system. Cas9 was driven by 5XUAS, single guide RNA (sgRNA) was used to target mutant or wild-type HRAS, and the fusion gene GAL4-P65 was driven by the enhanced hTERT promoter. The system was tested in bladder cancer cells (T24 and 5637) and the results showed that the enhanced hTERT promoter could drive the expression of GAL4-P65 in these bladder cancer cell lines. Then all these devices were packed into lentivirus and the results of quantitative real-time PCR showed that the mRNA expression level of HRAS was selectively inhibited in the T24 and 5637 cells. The results of functional experiments suggested that the proliferation, cell migration and invasion were selectively suppressed, and that the apoptosis rate was increased in bladder cancer cells but not in human foreskin fibroblasts (HFF). In conclusion, we successfully constructed an enhanced hTERT promoter-driven CRISPR/Cas9 system and data showed that it could selectively suppress the progression of bladder cancer cells.


Categorical color constancy for real surfaces.
In everyday experience, perceived colors of objects remain approximately constant under changes in illumination. This constancy is helpful for identifying objects across viewing conditions. Studies on color constancy often employ monitor simulations of illumination and reflectance changes. Real scenes, however, have features that might be important for color constancy but that are in general not captured by monitor displays. Here, we investigate categorical color constancy employing real surfaces and real illuminants in a rich viewing context. Observers sorted 450 Munsell samples into the 11 basic color categories under a daylight and four filtered daylight illuminants. We additionally manipulated illuminant cues from the local surround. Color constancy as quantified both with a classification consistency index and a standard color constancy index was high in both cue conditions. Observers generally classified colors with the same precision across different illuminants as across repetitions for the daylight illuminant. Moreover, the pattern of classification consistency in terms of stimulus hue, value, and chroma was similar when comparing different observers for the daylight illuminant and when comparing individual observers across different illuminants. We conclude that color categorization is robust under illuminant changes as well as across observers, thus potentially serving both object identification and communication.


Hypokalemia following polyethylene glycol-based bowel preparation for colonoscopy in older hospitalized patients with significant comorbidities.
Polyethylene glycol-based bowel preparations (PEGBPs) are widely perceived as safe and effective alternatives to oral sodium phosphate for bowel cleansing prior to colonoscopy. Most studies supporting this belief involve young patients with few comorbidities. To characterize the incidence of electrolyte disturbances following PEGBPs administered prior to colonoscopy among elderly inpatients and hypothesize that PEGBP would be associated with hypokalemia in this setting. This retrospective chart review, conducted at 3 tertiary care teaching hospitals in Toronto, Canada, from 2005 to 2007, included 96 consecutive patients aged 65 or older who were admitted to the hospital and given PEGBP prior to their first inpatient colonoscopy. Patients were excluded if they received additional cathartics, underwent colonoscopy while admitted to a critical care unit, or were admitted for a complication arising from an outpatient colonoscopy. The primary outcome was hypokalemia (serum potassium < or =3.2 mEq/L) within 48 hours of PEGBP. Of 96 patients, 73 had serum electrolytes measured at baseline and within 48 hours following PEGBP administration. Hypokalemia was identified in 4 patients (5.5%) prior to PEGBP and in 15 patients (20.5%) after PEGBP (p < 0.001). The incidence of significant hypokalemia, defined as serum potassium < or =3.0 mEq/L, in this group was 9.6% (p = 0.008). We found consistent results among patients with and without concomitant diuretic treatment. Among older patients, administration of PEGBP is commonly complicated by the development of hypokalemia, which is occasionally severe. Monitoring of electrolytes may be necessary following colonoscopy, particularly in patients with cardiac or renal disease.


WNK kinases influence TRPV4 channel function and localization.
TRPV4, a renally expressed nonselective cation channel of the transient receptor potential (TRP) family, is gated by hypotonicity. Kinases of the WNK family influence expression and function of the thiazide-sensitive Na+-Cl- cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4. Along with TRPV4, WNK isoforms are highly expressed in the distal nephron. We show here that coexpression of WNK4 downregulates TRPV4 function in human embryonic kidney (HEK-293) cells and that this effect is mediated via decreased cell surface expression of TRPV4; total abundance of TRPV4 in whole cell lysates is unaffected. The effect of the related kinase WNK1 on TRPV4 function and surface expression was similar to that of WNK4. Disease-causing point mutations in WNK4 abrogate, but do not eliminate, the inhibitory effect on TRPV4 function. In contrast to wild-type WNK4, a kinase-dead WNK4 point mutant failed to influence TRPV4 trafficking; however, deletion of the entire WNK4 kinase domain did not blunt the effect of WNK4 on localization of TRPV4. Deletion of the extreme COOH-terminal putative coiled-coil domain of WNK4 abolished its effect. In immunoprecipitation experiments, we were unable to detect direct interaction between TRPV4 and either WNK kinase. In aggregate, these data indicate that TRPV4 is functionally regulated by WNK family kinases at the level of cell surface expression. Because TRPV4 and WNK kinases are coexpressed in the distal nephron in vivo and because there is a tendency toward hypercalcemia in TRPV4-/- mice, we speculate that this pathway may impact systemic Ca2+ balance. In addition, because WNK kinases and TRPV4 are activated by anisotonicity, they may comprise elements of an osmosensing or osmotically responsive signal transduction cascade in the distal nephron.


Epigenetic regulation of the ribosomal cistron seasonally modulates enrichment of H2A.Z and H2A.Zub in response to different environmental inputs in carp (Cyprinus carpio).
The specific deposition of histone variants into chromatin is an important epigenetic mechanism that contributes to gene regulation through chromatin architectural changes. The histone variant H2A.Z is essential in higher eukaryotes, and its incorporation within chromatin is a relevant process for gene expression and genome stability. However, the dual positive and negative roles of H2A.Z in gene regulation still remain unclear. We previously reported that acclimatization in common carp fish (Cyprinus carpio) involves cyclical seasonal gene reprogramming as an adaptation response to its natural environment, when rRNA synthesis and processing are profoundly affected. Epigenetic mechanisms primarily contribute to the transcriptional modulation of ribosomal genes concomitant with the acclimatization process, thus significantly regulating this process. The aim of this study was to describe the presence of several H2A.Z subtypes in carp, and assess the role of H2A.Z on the ribosomal cistron in summer- and winter-acclimatized carp. This paper reports for the first time about the transcriptional expression of four different H2A.Z subtypes belonging to the same organism. Remarkably, a novel H2A.Z.7 was found, which corresponds to a tissue-specific histone subtype that contains seven amino acid residues longer than the canonical H2A.Z. Moreover, H2A.Z enrichment through the ribosomal cistron was significantly higher during summer, when rRNA transcription and processing are highly active, than it was in winter. Similar patterns of H2A.Z enrichment are found in two seasonally active promoters for genes transcribed by RNA polymerase II, the L41 and Δ9-desaturase genes. Interestingly, ubiquitylated-H2A.Z (H2A.Zub) was strongly enriched on regulatory regions of the ribosomal cistron in summer-acclimatized carp. Additionally, H2A.Z was present in both heterochromatin and euchromatin states on ribosomal cistron and RNA polymerase II promoters. Our study revealed seasonally-dependent H2A.Z enrichment for active ribosomal cistron and RNA polymerase II promoters during the carp environmental adaptation. Moreover, seasonal H2A.Zub enrichment appears as a specific mechanism contributing to the regulation of chromatin architecture under natural conditions. The existence of several H2A.Z subtypes in carp suggests that the epigenetic regulation in this species constitutes a complex and finely tuned mechanism developed to cope with seasonal environmental changes that occur in its habitat.


A balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer.
Referred to as the "guardian of the genome", p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. As an overexpressed and tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. In this review we collect and communicate the chemical principles involved in small molecule drug design for misfolded proteins in anticancer therapy. While this approach has met with significant challenges including off-target mechanisms that induce cytotoxicity independent of p53 status, major technological advancements in gene sequencing capability and a shift towards personalized medicine holds significant promise for p53 reactivating compounds and could have widespread benefits for the field of cancer therapy.


Pretreatment anterior cingulate activity predicts antidepressant treatment response in major depressive episodes.
Major depressive disorder leads to substantial individual and socioeconomic costs. Despite the ongoing efforts to improve the treatment for this condition, a trial-and-error approach until an individually effective treatment is established still dominates clinical practice. Searching for clinically useful treatment response predictors is one of the most promising strategies to change this quandary therapeutic situation. This study evaluated the predictive value of a biological and a clinical predictor, as well as a combination of both. Pretreatment EEGs of 31 patients with a major depressive episode were analyzed with neuroelectric brain imaging technique to assess cerebral oscillations related to treatment response. Early improvement of symptoms served as a clinical predictor. Treatment response was assessed after 4 weeks of antidepressant treatment. Responders showed more slow-frequency power in the right anterior cingulate cortex compared to non-responders. Slow-frequency power in this region was found to predict response with good sensitivity (82 %) and specificity (100 %), while early improvement showed lower accuracy (73 % sensitivity and 65 % specificity). Combining both parameters did not further improve predictive accuracy. Pretreatment activity within the anterior cingulate cortex is related to antidepressive treatment response. Our results support the search for biological treatment response predictors using electric brain activity. This technique is advantageous due to its low individual and socioeconomic burden. The benefits of combining both, a clinically and a biologically based predictor, should be further evaluated using larger sample sizes.


Reproducibility and relative validity of a food frequency questionnaire developed for adults in Taizhou, China.
To evaluate the reproducibility and validity of a food frequency questionnaire (FFQ) developed to investigate the relationship between dietary factors and diseases in the adult Chinese population in East China. A total of 78 males and 129 females aged 30-75 years completed four inconsecutive 24-hour dietary recalls (24-HRs, served as a reference method) and two FFQs (FFQ1 and FFQ2) over a nine-month interval. The reproducibility of the FFQ was estimated with correlation coefficients, cross-classification, and weighted kappa statistic. The validity was assessed by comparing the data obtained from FFQ and 24-HRs. The median nutrient intakes assessed with FFQs were higher than the average of four 24-HRs. For the food groups, Spearman, Pearson, and intraclass correlation coefficients between FFQ1 and FFQ2 ranged from 0.23 to 0.61, 0.27 to 0.64, and 0.26 to 0.65, respectively. For total energy and nutrient intakes, the corresponding coefficients ranged from 0.25 to 0.61, 0.28 to 0.64, and 0.28 to 0.62, respectively. The correlations between FFQ1 and FFQ2 for most nutrients decreased after adjustment with total energy intake. More than 70% of the subjects were classified into the same and adjacent categories by both FFQs. For food groups, the crude, energy-adjusted, and de-attenuated Spearman correlation coefficients between FFQ2 and the 24-HRs ranged from 0.17 to 0.59, 0.10 to 0.57, and 0.11 to 0.64, respectively. For total energy and nutrient intakes, the corresponding coefficients ranged from 0.20 to 0.58, 0.08 to 0.54, and 0.09 to 0.56, respectively. More than 67% of the subjects were classified into the same and adjacent categories by both instruments. Both weighted kappa statistic and Bland-Altman Plots showed reasonably acceptable agreement between the FFQ2 and 24-HRs. The FFQ developed for adults in the Taizhou area is reasonably reliable and valid for assessment of most food and nutrient intakes.


Adolescent angst or true intent? Suicidal behavior, risk, and neurobiological mechanisms in depressed children and teenagers taking antidepressants.
Suicide is one of the major causes of morbidity and mortality amongst children and adolescents. In 2004 the Food and Drug Administration (FDA) issued a "black-box" warning for antidepressants in children and adolescents, stating that these drugs may increase suicidality, a term encompassing both suicidal thoughts and behavior, especially in the first few weeks of treatment. The warning was extended in 2007 to antidepressants prescribed to adults aged 25 and under. The evidence behind this decision stemmed from meta-analyses of antidepressant clinical trials that demonstrated a slight increase in suicidality in those receiving antidepressants versus those treated with a placebo. Due to methods of this pooled data compilation, the relationship between antidepressants and suicidality remains controversial. This report investigates a case where a 14 year old with major depressive disorder (MDD) developed suicidal ideation shortly after being prescribed a selective serotonin reuptake inhibitor (SSRI). Investigating the role antidepressants may play in suicidality suggests the need to explore the neurobiological mechanisms within the serotonin system. This case and its theoretical explanations attempt to bridge the gap between neurobiology and pharmacology in order to better delineate the etiology of this adverse effect.


Evaluation of partial-response maximum-likelihood detection for phase-change optical data storage.
We describe the application of partial-response (PR) maximum-likelihood (ML) detection in rewritable phase-change optical data storage. The input to this detector, which is simulated in software, is the actual signal (without any equalization), reproduced from reading of the recorded sequence on an optical disk. The detection algorithm involves the extraction of the impulse response from the readout signal, PR equalization, the adjustment of gain and recovery of clock, ML sequence estimation with the Viterbi algorithm, and analysis of PRML performance. With a laser wavelength of 0.69 microm and an objective lens with a numerical aperture of 0.6, three linear densities are examined: 0.35 and 0.31 microm/bit without modulation code and 0.2 microm/bit with the (1, 7) modulation code. The equalized signal exhibits good eye patterns, especially at the densities of 0.35 and 0.31 microm/bit. Analyses of noise and bit-error rate indicate that jitter, rather than noise, is the main obstacle to realizing ultrahigh density in phase-change media with PRML detection. We also briefly discuss the problem of the inherent nonlinear effect in phase-change readout.


Non-insulin-dependent diabetes: 10-year outcome in relation to initial response to diet and subsequent sulfonylurea therapy.
Thirty-eight non-insulin-dependent diabetic patients within 130% of desirable body weight were given a 100-g oral glucose tolerance test (OGTT) at diagnosis and after at least 1 mo of dietary treatment with energy and carbohydrate restriction. Thirteen "responders" showed an improvement in fasting blood glucose, glucose tolerance, and insulin secretion, with near-normalization of plasma, lactate, pyruvate, free fatty acids, glycerol, and ketone bodies. There were no significant changes in the 25 "non-responders." The responders were, at diagnosis, heavier than the non-responders (75.5 versus 64.3 kg, P less than 0.01). Twenty non-responders subsequently completed a prospective controlled study of glibenclamide, chlorpropamide, and placebo lasting for 16 mo with OGTTs at the end of each 4-mo treatment phase. The results showed that there were no significant differences between the metabolic effects of glibenclamide and chlorpropamide. On active treatment, insulin levels rose coincident with a fall in fasting blood glucose and an improvement in glucose tolerance and near-normalization of plasma lactate, pyruvate, free fatty acids, glycerol, and ketone bodies, all of which relapsed to initial values after placebo. Ten years after the initial study, 29 of the original patients were traced and reviewed and the outcome related to their earlier tests. Twenty-two percent of the responders and 70% of the non-responders were now on insulin (P less than 0.02); the initial insulin response to OGTT at the end of the diet treatment was significantly lower in those subsequently treated with insulin (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Different human TFIIIB activities direct RNA polymerase III transcription from TATA-containing and TATA-less promoters.
Transcription initiation at RNA polymerase III promoters requires transcription factor IIIB (TFIIIB), an activity that binds to RNA polymerase III promoters, generally through protein-protein contacts with DNA binding factors, and directly recruits RNA polymerase III. Saccharomyces cerevisiae TFIIIB is a complex of three subunits, TBP, the TFIIB-related factor BRF, and the more loosely associated polypeptide beta("). Although human homologs for two of the TFIIIB subunits, the TATA box-binding protein TBP and the TFIIB-related factor BRF, have been characterized, a human homolog of yeast B(") has not been described. Moreover, human BRF, unlike yeast BRF, is not universally required for RNA polymerase III transcription. In particular, it is not involved in transcription from the small nuclear RNA (snRNA)-type, TATA-containing, RNA polymerase III promoters. Here, we characterize two novel activities, a human homolog of yeast B("), which is required for transcription of both TATA-less and snRNA-type RNA polymerase III promoters, and a factor equally related to human BRF and TFIIB, designated BRFU, which is specifically required for transcription of snRNA-type RNA polymerase III promoters. Together, these results contribute to the definition of the basal RNA polymerase III transcription machinery and show that two types of TFIIIB activities, with specificities for different classes of RNA polymerase III promoters, have evolved in human cells.


The historical origin of the term "meningioma" and the rise of nationalistic neurosurgery.
The historical origin of the meningioma nomenclature unravels interesting social and political aspects about the development of neurosurgery in the late 19th century. The meningioma terminology itself was the subject of nationalistic pride and coincided with the advancement in the rise of medicine in Continental Europe as a professional social enterprise. Progress in naming and understanding these types of tumor was most evident in the nations that successively assumed global leadership in medicine and biomedical science throughout the 19th and 20th centuries, that is, France, Germany, and the United States. In this vignette, the authors delineate the uniqueness of the term "meningioma" as it developed within the historical framework of Continental European concepts of tumor genesis, disease states, and neurosurgery as an emerging discipline culminating in Cushing's Meningiomas text. During the intellectual apogee of the French Enlightenment, Antoine Louis published the first known scientific treatise on meningiomas. Like his father, Jean-Baptiste Louis, Antoine Louis was a renowned military surgeon whose accomplishments were honored with an admission to the Académie royale de chirurgie in 1749. His treatise, Sur les tumeurs fongueuses de la duremère, appeared in 1774. Following this era, growing economic depression affecting a frustrated bourgeoisie triggered a tumultuous revolutionary period that destroyed France's Ancien Régime and abolished its university and medical systems. The resulting anarchy was eventually quelled through legislation aiming to satisfy Napoleon's need for qualified military professionals, including physicians and surgeons. These laws laid the foundations for the subsequent flourishing of French medicine throughout the mid-19th century. Subsequent changes to the meningioma nomenclature were authored by intellectual giants of this postrevolutionary period, for example, by the Limogesborn pathologist Jean Cruveilhier known for the term "tumeurs cancéreuses de la duremère," and the work of histopathologists, such as Hermann Lebert, who were influenced by Pasteur's germ theory and by Bernard's experimental medicine. The final development of the meningioma nomenclature corresponded to the rise of American neurosurgery as a formal academic discipline. This historical period of growth is chronicled in Cushing's text Meningiomas, and it set the scientific stage for the modern developments in meningioma research and surgery that are conducted and employed today.


Geographical emergence of sulfadoxine-pyrimethamine drug resistance-associated P. falciparum and P. malariae alleles in co-existing Anopheles mosquito and asymptomatic human populations across Cameroon.
Malaria molecular surveillance remains critical in detecting and tracking emerging parasite resistance to anti-malarial drugs. The current study employed molecular techniques to determine Plasmodium species prevalence and characterize the genetic diversity of Plasmodium falciparum and Plasmodium malariae molecular markers of sulfadoxine-pyrimethamine resistance in humans and wild Anopheles mosquito populations in Cameroon. Anopheles mosquito collections and parasitological survey were conducted in villages to determine Plasmodium species infection, and genomic phenotyping of anti-folate resistance was accomplished by sequencing the dihydrofolate-reductase (dhfr) and dihydropteroate-synthase (dhps) genes of naturally circulating P. falciparum and P. malariae isolates. The malaria prevalence in Elende was 73.5% with the 5-15 years age group harboring significant P. falciparum (27%) and P. falciparum + P. malariae (19%) infections. The polymorphism breadth of the pyrimethamine-associated Pfdhfr marker revealed a near fixation (94%) of the triple-mutant -A16I51R59N108I164. The Pfdhps backbone mediating sulfadoxine resistance reveals a high frequency of the V431A436G437K540A581A613 alleles (20.8%). Similarly, the Pmdhfr N50K55L57R58S59S114F168I170 haplotype (78.4%) was predominantly detected in the asexual blood stage. In contrast, the Pmdhps- S436A437occured at 37.2% frequency. The combined quadruple N50K55L57R58S59S114F168I170_ S436G437K540A581A613 (31.9%) was the major circulating haplotype with similar frequency in humans and mosquitoes. This study highlights the increasing frequency of the P. malariae parasite mostly common in asymptomatic individuals with apparent P. falciparum infection. Interventions directed at reducing malaria transmission such as the scaling-up of SP are favoring the emergence and spread of multiple drug-resistant alleles between the human and mosquito host systems.


Transitions between variant forms of primary biliary cirrhosis during long-term follow-up.
Conditions exhibiting features of two different autoimmune liver diseases are designated overlap syndromes. Variant forms display some, but not all, characteristics of a distinct autoimmune liver disease. We describe transitions over time between variant forms of PBC, i.e. AMA-negative PBC, autoimmune hepatitis (AIH)-PBC overlap and autoimmune cholangitis (AIC) in a large cohort of PBC patients in Sweden. We retrieved all patients with variant forms of PBC in six university hospitals in Sweden, covering 60% of the Swedish population. The diagnosis of PBC and its variants was based on laboratory findings and compatible histological features. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis of AIH. In a population of 800 patients with PBC, we identified 35 (5%) variant forms; 25 patients with AIH-PBC overlap, 8 with AIC and 2 with AMA-negative PBC at the time of our study. The initial diagnoses were PBC (3 patients), AIH (3), AIH-PBC overlap (16), AIC (8) and AMA-negative PBC with (1) or without (4) concomitant AIH. The median follow-up was 125 (41-360) months. Immunosuppression and ursodeoxycholic acid induced a complete or good regression of increased aminotransferases in about half of the patients who were given one or both of these treatments. Variant forms of PBC are seen in approximately 5% of PBC patients in Sweden. Transition between different forms may occur, emphasizing the value of repeat biopsies, but established overlapping AIH-PBC seems to be stable over time.


The evolutionary legacy of size-selective harvesting extends from genes to populations.
Size-selective harvesting is assumed to alter life histories of exploited fish populations, thereby negatively affecting population productivity, recovery, and yield. However, demonstrating that fisheries-induced phenotypic changes in the wild are at least partly genetically determined has proved notoriously difficult. Moreover, the population-level consequences of fisheries-induced evolution are still being controversially discussed. Using an experimental approach, we found that five generations of size-selective harvesting altered the life histories and behavior, but not the metabolic rate, of wild-origin zebrafish (Danio rerio). Fish adapted to high positively size selective fishing pressure invested more in reproduction, reached a smaller adult body size, and were less explorative and bold. Phenotypic changes seemed subtle but were accompanied by genetic changes in functional loci. Thus, our results provided unambiguous evidence for rapid, harvest-induced phenotypic and evolutionary change when harvesting is intensive and size selective. According to a life-history model, the observed life-history changes elevated population growth rate in harvested conditions, but slowed population recovery under a simulated moratorium. Hence, the evolutionary legacy of size-selective harvesting includes populations that are productive under exploited conditions, but selectively disadvantaged to cope with natural selection pressures that often favor large body size.


Efficient capture of high-quality data on outcomes of treatment for macular diseases: the fight retinal blindness! Project.
To describe the development of a web-based high-quality data collection tool to track the outcomes of treatment of macular disease in routine practice. Testing of a larger data collection tool established which fields a clinician would reliably fill out. The program, which was developed using freely available software, consists of modules interacting with a core system. The module for neovascular age-related macular degeneration is described here. Data for initial visits can be entered within 30 seconds, 15 seconds for follow-up visits. Fifteen centers from Australia, New Zealand, and Switzerland are currently contributing data. Finalized data from 2,052 eyes of 1,693 participants dating from January 2006 were analyzed. Median (25th and 75th percentiles) visual acuity at the index visit was 55 (41, 68) logarithm of the minimum angle of resolution letters with the following lesion types: minimally classic 17.2%, predominantly classic 24.6%, occult 52.0%, idiopathic polypoidal choroidal vasculopathy 1.2%, and retinal angiomatous proliferation 3.2%. This software tool will facilitate the collection of large amounts of data on the routine use of treatments of neovascular age-related macular degeneration. This will allow us to analyze important potentially modifiable variables, such as the effect of different treatment patterns on visual outcomes, and to evaluate new treatments as they are introduced into practice.


Evidence of land-sea transfer of the zoonotic pathogen Campylobacter to a wildlife marine sentinel species.
Environmental pollution often accompanies the expansion and urbanization of human populations where sewage and wastewaters commonly have an impact on the marine environments. Here, we explored the potential for faecal bacterial pathogens, of anthropic origin, to spread to marine wildlife in coastal areas. The common zoonotic bacterium Campylobacter was isolated from grey seals (Halichoerus grypus), an important sentinel species for environmental pollution, and compared to isolates from wild birds, agricultural sources and clinical samples to characterize possible transmission routes. Campylobacter jejuni was present in half of all grey seal pups sampled (24/50 dead and 46/90 live pups) in the breeding colony on the Isle of May (Scotland), where it was frequently associated with histological evidence of disease. Returning yearling animals (19/19) were negative for C. jejuni suggesting clearance of infection while away from the localized colony infection source. The genomes of 90 isolates from seals were sequenced and characterized using a whole-genome multilocus sequence typing (MLST) approach and compared to 192 published genomes from multiple sources using population genetic approaches and a probabilistic genetic attribution model to infer the source of infection from MLST data. The strong genotype-host association has enabled the application of source attribution models in epidemiological studies of human campylobacteriosis, and here assignment analyses consistently grouped seal isolates with those from human clinical samples. These findings are consistent with either a common infection source or direct transmission of human campylobacter to grey seals, raising concerns about the spread of human pathogens to wildlife marine sentinel species in coastal areas.


Debaryomyces hansenii (Candida famata), a rare human fungal pathogen often misidentified as Pichia guilliermondii (Candida guilliermondii).
Debaryomyces hansenii is a hemiascomycetous yeast commonly found in natural substrates and in various types of cheese. Pichia guilliermondii is widely distributed in nature and is a common constituent of the normal human microflora. Both species have been described in human infections but are extremely difficult to differentiate phenotypically. Thus, frequent errors in identification occur. The 62 clinical and environmental isolates sent between 2000 and 2007 to the French National Reference Center for Mycoses and Antifungals as D. hansenii or P. guilliermondii were analyzed by using the carbon assimilation pattern, the presence of pseudohyphae, and sequencing of the ITS and D1/D2 regions of the rRNA gene. The objective of this study was to assess using nucleotide sequences whether phenotypic identification was accurate and whether phenotypic characteristics could be used to differentiate the two species when sequencing was not available. We found that 58% of the isolates were misidentified and belong to seven different species: P. guilliermondii, P. caribbica, P. jadinii, D. hansenii, Candida palmioleophila, C. haemulonii type II, and Clavispora lusitaniae. In conclusion, D. hansenii may not be as common a human pathogen as previously thought. Sequencing of either ITS or D1/D2 regions is a good tool for differentiating the species more frequently confused with D. hansenii, keeping in mind that reliable databases should be used.


New developments in anthracycline-induced cardiotoxicity.
Anthracyclines are among the most effective anticancer drugs ever developed. Unfortunately, their clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, usually refractory to conventional therapy. The pathophysiology of anthracycline-induced cardiomyopathy remains controversial and incompletely understood. The current thinking is that anthracyclines are toxic per se but gain further cardiotoxicity after one-electron reduction with ROS overproduction or two-electron reduction with conversion to C-13 alcohol metabolites. ROS overproduction can probably be held responsible for anthracycline acute cardiotoxicity, but not for all the aspects of progressive cardiomyopathy. Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the progression of cardiotoxicity toward end-stage cardiomyopathy and congestive heart failure. In this review we also discuss recent developments in: a) the molecular mechanisms underlying anthracycline-induced cardiotoxicity; b) the role of cytosolic NADPH-dependent reductases in anthracycline metabolism; c) the influence of genetic polymorphisms on cardiotoxicity outcome; d) the perspectives on the most promising strategies for limiting or preventing anthracycline-induced cardiotoxicity, focusing on controversial aspects and on recent data regarding analogues of the natural compounds, tumor-targeted formulations and cardioprotective agents.


An experience with 156 patients attending a newly organized pain and palliative care clinic in a tertiary hospital.
Pain and palliative care clinic (PCC). The primary object of this study was to enumerate the demographic characteristics of patients attending a newly organized PCC. The secondary purpose was to detect symptom prevalence and frequency of different cancers in these patients. Prospective cross-sectional descriptive study. A prospective cross-sectional descriptive study was done on patients referred to the PCC of a tertiary hospital in North India. Comprehensive details of all patients were recorded systematically on the first visit on a proforma specially prepared for the newly established palliative care clinic. The descriptive statistics of palliative care data was presented in terms of frequencies and percentages (%) for categorical variables. The data collected at our PCC showed that out of 156 patients, 87 were males and 69 were females. Patients of all ages varying from 6 to 85 years were seen. Most patients (82.1%) lived with their families, and 28 (17.1%) patients lived alone and had no financial support. The most common primary diagnoses were head and neck cancers (38.5%), carcinoma cervix (15.4%), breast cancer (10.3%), colorectal cancer (6.4%), and lung cancer (4.5%). Frequency of seven most common symptoms was pain (100%), insomnia (64.1%), loss of appetite (34.6%), nausea (32.7%), vomiting (32.1%), constipation (31.4%) and sore mouth (28.8%). Population-based studies determine the actual magnitude of sufferers and suffering and show that palliative care services should be included as an essential component in a tertiary care hospital. The objective should be to reach out to the patient and help in improving the patent's quality of life in every way possible.