Comparison of intravenous myocardial contrast echocardiography and low-dose dobutamine echocardiography for predicting left ventricular functional recovery following acute myocardial infarction.
Akinesia after acute myocardial infarction (AMI) may be reversible or irreversible. Distinguishing these 2 entities early after AMI is difficult, but clinically important. Previous studies have shown that myocardial contrast echocardiography (MCE) and low-dose dobutamine echocardiography (DE) may both be useful in this setting. However, there are few data regarding the relative and combined value of these techniques. The aim of this study was to compare the utility of real-time intravenous MCE and low-dose DE in the early prediction of functional recovery of akinetic myocardium after AMI. Thirty-seven patients were studied 3 +/- 2 days after an AMI. Each subject underwent real-time MCE using an intravenous infusion of perflutren microbubbles. Immediately after this, low-dose DE was performed. Contrast opacification and wall motion were determined by experienced observers blinded to clinical data. Repeat echocardiograms were obtained 51 +/- 19 days later and wall motion at rest was scored by an observer blinded to clinical data. Normal contrast opacification predicted functional recovery with a positive predictive value of 63%, a negative predictive value of 73%, and an accuracy of 66%. Residual contractility during low-dose DE had a positive predictive value of 82%, a negative predictive value of 72%, and a predictive accuracy of 76%. When the 2 tests were concordant (64%), they had a positive predictive value of 81%, a negative predictive value of 85%, and a predictive accuracy of 83%. Low-dose DE was superior to intravenous MCE in the prediction of functional recovery of akinetic myocardium after AMI, but the combination of both maximizes predictive accuracy.


Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.
Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.


Comparative Lipid Peroxidation and Apoptosis in Embryo-Larval Zebrafish Exposed to 3 Azole Fungicides, Tebuconazole, Propiconazole, and Myclobutanil, at Environmentally Relevant Concentrations.
Azole fungicides have entered the aquatic environment through agricultural and residential runoff. In the present study, we compared the off-target toxicity of tebuconazole, propiconazole, and myclobutanil using embryo-larval zebrafish as a model. The aim of the present study was to investigate the relative toxicity of tebuconazole, propiconazole, and myclobutanil using multiple-level endpoints such as behavioral endpoints and enzymatic and molecular biomarkers associated with their mode of action. Zebrafish embryos were exposed to azoles at environmentally relevant and high concentrations, 0.3, 1.0, and 1000 µg/L, starting at 5 h postfertilization (hpf) up to 48 hpf, as well as 5 d postfertilization (dpf). Relative mRNA expressions of cytochrome P450 family 51 lanosterol-14α-demethylase, glutathione S-transferase, caspase 9, phosphoprotein p53, and BCL2-associated X protein were measured to assess toxicity attributable to fungicides at the mRNA level, whereas caspase 3/7 (apoptosis) and 3,4-methylenedioxyamphetamine (lipid peroxidation) levels were measured at the enzymatic level. Furthermore, mitochondrial dysfunction was measure through the Mito Stress test using the Seahorse XFe24 at 48 hpf. In addition, light to dark movement behavior was monitored at 5 dpf using Danio Vision® to understand adverse effects at the organismal level. There was no significant difference in the light to dark behavior with exposure to azoles compared to controls. The molecular biomarkers indicated that propiconazole and myclobutanil induced lipid peroxidation, oxidative stress, and potentially apoptosis at environmentally relevant concentrations (0.3 and 1 µg/L). The results from the mitochondrial respiration assay indicated a slight decrease in spare respiratory capacity with an acute exposure (48 hpf) to all 3 azoles at 1000 µg/L. Based on the present results, propiconazole and myclobutanil are acutely toxic compared to tebuconazole in aquatic organisms at environmentally relevant concentrations. Environ Toxicol Chem 2019;38:1455-1466. © 2019 SETAC.


Associations between Electronic Media Use and Involvement in Violence, Alcohol and Drug Use among United States High School Students.
We identified associations between time spent watching television and time spent playing video or computer games or using computers and involvement in interpersonal violence, alcohol and drug use in a nationally representative sample of United States high school students. We analyzed data from the 2007 national Youth Risk Behavior Survey. Exposure variables were time spent watching television and time spent playing computer or video games or using computers (hereafter denoted as "computer/video game use") on an average school day; outcome variables included multiple measures assessing involvement in violence and alcohol or drug use. Chi-square tests were used to identify statistically significant associations between each exposure variable and each of the outcome variables. We used logistic regression to obtain crude odds ratios for outcome variables with a significant chi-square p-value and to obtain adjusted odds ratios controlling for sex, race, and grade in school. Overall, 35.4% (95% CI=33.1%-37.7%) of students reported frequent television (TV) use and 24.9% (95% CI=22.9%-27.0%) reported frequent computer/video game use. A number of risk behaviors, including involvement in physical fights and initiation of alcohol use before age 13, were significantly associated with frequent TV use or frequent computer/video game use, even after controlling for sex, race/ethnicity and grade. Findings highlight the need for additional research to better understand the mechanisms by which electronic media exposure and health-risk behaviors are associated and for the development of strategies that seek to understand how the content and context (e.g., watching with peers, having computer in common area) of media use influence risk behaviors among youth.


BMI does not accurately predict overweight in Asian Indians in northern India.
Asian Indians are at high risk for the development of atherosclerosis and related complications, possibly initiated by higher body fat (BF). The present study attempted to establish appropriate cut-off levels of the BMI for defining overweight, considering percentage BF in healthy Asian Indians in northern India as the standard. A total of 123 healthy volunteers (eighty-six males aged 18--75 years and thirty-seven females aged 20--69 years) participated in the study. Clinical examination and anthropometric measurements were performed, and percentage BF was calculated. BMI for males was 21.4 (sd 3.7) kg/m(2) and for females was 23.3 (sd 5.5) kg/m(2). Percentage BF was 21.3 (sd 7.6) in males and 35.4 (sd 5.0) in females. A comparison of BF data among Caucasians, Blacks, Polynesians and Asian ethnic groups (e.g. immigrant Chinese) revealed conspicuous differences. Receiver operating characteristic (ROC) curve analysis showed a low sensitivity and negative predictive value of the conventional cut-off value of the BMI (25 kg/m(2)) in identifying subjects with overweight as compared to the cut-off value based on percentage BF (males >25, females >30). This observation is particularly obvious in females, resulting in substantial misclassification. Based on the ROC curve, a lower cut-off value of the BMI (21.5 kg/m(2) for males and 19.0 kg/m(2) for females) displayed the optimal sensitivity and specificity, and less misclassification in identification of subjects with high percentage BF. Furthermore, a novel obesity variable, BF:BMI, was tested and should prove useful for interethnic comparison of body composition. In the northern Indian population, the conventional cut-off level of the BMI underestimates overweight and obesity when percentage BF is used as the standard to define overweight. These preliminary findings, if confirmed in a larger number of subjects and with the use of instruments having a higher accuracy of BF assessment, would be crucial for planning and the prevention and treatment of various obesity-related metabolic diseases in the Asian Indian population.


Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family.
Although the p53 tumor suppressor has been extensively studied, many critical questions remain unanswered about the biological functions of p53 homologs, p73 and p63. Accumulating evidence suggests that both p73 and p63 play important roles in regulation of apoptosis, cell differentiation, and therapeutic drug sensitivity. Gastric epithelial cells were cocultured with Helicobacter pylori, and the roles of p63 and p73 proteins were assessed by luciferase reporter, real-time polymerase chain reaction, immunoblotting, and cell survival assays. Short hairpin RNA and dominant-negative mutants were used to inhibit activity of p73 and p63 isoforms. Human and murine gastric tissues were analyzed by immunohistochemistry with p73 and p63 antibodies and modified Steiner's silver method. Interaction of H pylori with gastric epithelial cells leads to robust up-regulation of p73 protein in vitro and in vivo in human gastritis specimens and H pylori-infected mice. The p73 increase resulted in up-regulation of pro-apoptotic genes, NOXA, PUMA, and FAS receptor in gastric epithelial cells. Down-regulation of p73 activity suppressed cell death and Fas receptor induced by H pylori. Bacterial virulence factors within the cag pathogenicity island, c-Abl tyrosine kinase, and interaction with p63 isoforms control the activity of p73. Our findings implicate p73 in H pylori-induced apoptosis and more generally suggest that the p53 family may play a role in the epithelial cell response to H pylori infection.


The neuropsychiatric sequelae of mercury poisoning. The Mad Hatter's disease revisited.
The detailed effects of mercury poisoning on cognitive function, brain anatomy and regional brain function are largely unknown. We report the case of a 38-year-old man who was exposed to toxic levels of inorganic mercury. Four years after exposure, the patient was assessed using magnetic resonance imaging (MRI), single-photon emission computerised tomography (SPECT) and detailed neuropsychological evaluation. The patient developed a myriad of physical and psychiatric complaints, including stomatitis, muscle spasm, tremor, skin rash and the psychiatric syndrome known as 'erythism' (Mad Hatter's disease). Neuropsychological evaluation revealed marked and significant deficits of attention concentration, particularly when under time pressure. The MRI scan was unremarkable; however, SPECT revealed hypermetabolism of the posterior cingulate Mercury poisoning appeared to result in a dysregulation of posterior cingulate cortex, which was associated with attention/concentration deficits and marked anxiety/agitation.


Impact of Co-Designed Game Learning on Cultural Safety in Colombian Medical Education: Protocol for a Randomized Controlled Trial.
Cultural safety encourages practitioners to examine how their own culture shapes their clinical practice and to respect their patients' worldviews. Lack of cultural safety in health care is linked to stigma and discrimination toward culturally diverse patients. Training in cultural safety poses considerable challenges. It is an unappealing subject for medical students and requires behavioral changes in their clinical practice. Game jams-collaborative workshops to create and play games-have recently shown effectiveness and engaging potential in university-level education. The trial aims to determine if medical students' participation in a game jam to design an educational game on cultural safety is more effective than a standard lesson on cultural safety in terms of change in the students' self-reported intended patient-oriented behavior. A parallel-group, 2-arm randomized controlled trial with a 1:1 allocation ratio will randomize 340 medical students and 60 medical interns (n=400) at the Faculty of Medicine at La Sabana University, Colombia (170 students and 30 medical interns to each arm). The intervention group will participate in an 8-hour game jam comprising (1) a preliminary lecture on cultural safety and game design, (2) a game building session where groups of students will create educational games about cultural safety, and (3) a play-test session in which students will play and learn from each other's games. The control group will receive a standard lesson, including a 2-hour lecture on cultural safety, followed by a 6-hour workshop to create posters about cultural safety. Web-based self-administered 30-item Likert-type questionnaires will assess cultural safety self-reported intended behavior before, immediately after, and 6 months after the intervention. An intention-to-treat approach will use a t-test with 95% CIs to determine the significance of the effect of the intervention, including within- and between-group comparisons. The qualitative most significant change technique will explore the impact of the intervention on the clinical experience of the students. Study enrollment began in July 2019. A total of 531 students completed the baseline survey and were randomized. Data collection is expected to be complete by July 2020, and results are expected in October 2020. The study was approved by the institutional review board of the Faculty of Medicine at McGill University (May 31, 2017) and by the Subcommittee for Research of the Faculty of Medicine at La Sabana University (approval number 445). The research will develop participatory methods in game-based learning co-design that might be relevant to other subjects. Ultimately, it should foster improved cultural safety skills for medical students, improve the quality of health services for diverse cultural groups, and contribute to enhanced population health. Game learning may provide an innovative solution to a long-standing and neglected problem in medical education, helping to meet the educational expectations and needs of millennial medical students. ISRCTN Registry ISRCTN14261595; http://www.controlled-trials.com/ISRCTN14261595.


Acute cardiovascular effects of dimethylsulfoxide.
Dimethylsulfoxide (DMSO) has been advocated as a central nervous system (CNS) protectant against ischemia and trauma. The present study was performed to evaluate acute cardiovascular effects of DMSO which might complicate the clinical treatment of CNS compromised patients. Intravenously administered DMSO in doses which reportedly provide CNS protection, 2 g/kg, were infused in 6 dogs; hemodynamic variables were measured and compared to infusion of equal volumes of 0.9% sodium chloride. Immediately after infusion, DMSO caused increases in cardiac index, heart rate, pulmonary capillary wedge pressures (WP), and pulmonary arterial (systolic, mean, and diastolic) pressures which were significantly greater than changes induced by saline. DMSO decreased systematic diastolic pressure and systemic vascular resistance at the end of infusion. Most DMSO induced changes returned toward pre-infusion values 10 min after the end of infusion. These results suggest transient DMSO effects different from equal volumes of saline, possibly due to hyperosmotic expansion of plasma volume. A decrease in systemic vascular resistances was also observed. Although neither CNS production, intracranial pressure or blood flow were studied, these data suggest that DMSO used for CNS protection would not have adverse acute hemodynamic consequences. This may be particularly relevant in traumatized, hypovolemic patients.


Predictive biomarkers for dasatinib treatment in melanoma.
Dasatinib has anti-proliferative and anti-invasive effects in melanoma cell lines. However clinical trials have shown modest activity for dasatinib in metastatic melanoma. Although dasatinib targets SRC kinase, neither expression nor phosphorylation of SRC appears to predict response to dasatinib. Identification of predictive biomarkers for dasatinib may facilitate selection of melanoma patients who are more likely to respond to dasatinib. We correlated the anti-proliferative effects of dasatinib in 8 melanoma cell lines with expression of a previously identified 6-gene biomarker panel. We examined the relationship between response to dasatinib and expression of each gene at both the mRNA and protein level. Dasatinib inhibited growth in 3 of the 8 cell lines tested. mRNA expression of the panel of 6 biomarkers did not correlate with response, whilst elevated protein expression of ANXA1, CAV-1 and EphA2 correlated significantly with response to dasatinib in the panel of cell lines. Expression of ANXA1, CAV-1 and EphA2 were analysed in 124 melanoma samples by immunohistochemistry. ANXA1 protein was detected in 81 % (97/120) of tumours, CAV-1 in 44 % (54/122) of tumours and EphA2 in 74 % (90/121) of tumours. Thirty one % (35/113) of tumours tested expressed all three markers and 19 % (21/112) had moderate or strong expression of ANXA1, CAV-1 and EphA2. Seventeen percent (19/112) of melanoma samples were positive for SRC kinase expression, combined with high expression of ANXA1, CAV-1 and EphA2. This subgroup may represent a population of melanoma patients who would be more likely to derive clinical benefit from dasatinib treatment.


Effects of the Dietary Protein and Carbohydrate Ratio on Gut Microbiomes in Dogs of Different Body Conditions.
Obesity has become a health epidemic in both humans and pets. A dysbiotic gut microbiota has been associated with obesity and other metabolic disorders. High-protein, low-carbohydrate (HPLC) diets have been recommended for body weight loss, but little is known about their effects on the canine gut microbiome. Sixty-three obese and lean Labrador retrievers and Beagles (mean age, 5.72 years) were fed a common baseline diet for 4 weeks in phase 1, followed by 4 weeks of a treatment diet, specifically, the HPLC diet (49.4% protein, 10.9% carbohydrate) or a low-protein, high-carbohydrate (LPHC) diet (25.5% protein, 38.8% carbohydrate) in phase 2. 16S rRNA gene profiling revealed that dietary protein and carbohydrate ratios have significant impacts on gut microbial compositions. This effect appeared to be more evident in obese dogs than in lean dogs but was independent of breed. Consumption of either diet increased the bacterial evenness, but not the richness, of the gut compared to that after consumption of the baseline diet. Macronutrient composition affected taxon abundances, mainly within the predominant phyla, Firmicutes and Bacteroidetes The LPHC diet appeared to favor the growth of Bacteroides uniformis and Clostridium butyricum, while the HPLC diet increased the abundances of Clostridium hiranonis, Clostridium perfringens, and Ruminococcus gnavus and enriched microbial gene networks associated with weight maintenance. In addition, we observed a decrease in the Bacteroidetes to Firmicutes ratio and an increase in the Bacteroides to Prevotella ratio in the HPLC diet-fed dogs compared to these ratios in dogs fed other diets. Finally, analysis of the effect of diet on the predicted microbial gene network was performed using phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). More than 50% of dogs are either overweight or obese in the United States. A dysbiotic gut microbiota is associated with obesity and other metabolic problems in humans. HPLC diets have been promoted as an effective weight loss strategy for many years, and potential effects were reported for both humans and dogs. In this study, we explored the influence of the protein and carbohydrate ratio on the gut microbiome in dogs with different body conditions. We demonstrated significant dietary effects on the gut microbiome, with greater changes in obese dogs than in lean dogs. The HPLC diet-fed dogs showed greater abundances of Firmicutes but fewer numbers of Bacteroidetes than other dogs. This knowledge will enable us to use prebiotics, probiotics, and other nutritional interventions to modulate the gut microbiota and to provide an alternative therapy for canine obesity.


[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development].
A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product.


The salvador-warts-hippo pathway is required for epithelial proliferation and axis specification in Drosophila.
In Drosophila, the body axes are specified during oogenesis through interactions between the germline and the overlying somatic follicle cells [1-5]. A Gurken/TGF-alpha signal from the oocyte to the adjacent follicle cells assigns them a posterior identity [6, 7]. These posterior cells then signal back to the oocyte, thereby inducing the repolarization of the microtubule cytoskeleton, the migration of the oocyte nucleus, and the localization of the axis specifying mRNAs [8-10]. However, little is known about the signaling pathways within or from the follicle cells responsible for these patterning events. We show that the Salvador Warts Hippo (SWH) tumor-suppressor pathway is required in the follicle cells in order to induce their Gurken- and Notch-dependent differentiation and to limit their proliferation. The SWH pathway is also required in the follicle cells to induce axis specification in the oocyte, by inducing the migration of the oocyte nucleus, the reorganization of the cytoskeleton, and the localization of the mRNAs that specify the anterior-posterior and dorsal-ventral axes of the embryo. This work highlights a novel connection between cell proliferation, cell growth, and axis specification in egg chambers.


13 C dynamic nuclear polarization using isotopically enriched 4-oxo-TEMPO free radicals.
The nitroxide-based free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) is a widely used polarizing agent in NMR signal amplification via dissolution dynamic nuclear polarization (DNP). In this study, we have thoroughly investigated the effects of 15 N and/or 2 H isotopic labeling of 4-oxo-TEMPO free radical on 13 C DNP of 3 M [1-13 C] sodium acetate samples in 1 : 1 v/v glycerol : water at 3.35 T and 1.2 K. Four variants of this free radical were used for 13 C DNP: 4-oxo-TEMPO, 4-oxo-TEMPO-15 N, 4-oxo-TEMPO-d16 and 4-oxo-TEMPO-15 N,d16 . Our results indicate that, despite the striking differences seen in the electron spin resonance (ESR) spectral features, the 13 C DNP efficiency of these 15 N and/or 2 H-enriched 4-oxo-TEMPO free radicals are relatively the same compared with 13 C DNP performance of the regular 4-oxo-TEMPO. Furthermore, when fully deuterated glassing solvents were used, the 13 C DNP signals of these samples all doubled in the same manner, and the 13 C polarization buildup was faster by a factor of 2 for all samples. The data here suggest that the hyperfine coupling contributions of these isotopically enriched 4-oxo-TEMPO free radicals have negligible effects on the 13 C DNP efficiency at 3.35 T and 1.2 K. These results are discussed in light of the spin temperature model of DNP. Copyright © 2016 John Wiley & Sons, Ltd.


CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection.
Unlike Alzheimer's and most other neurodegenerative diseases, Transmissible Spongiform Encephalopathies (TSEs) are all caused by actively replicating infectious particles of viral size and density. Different strain-specific TSE agents cause CJD, kuru, scrapie and BSE, and all behave as latent viruses that evade adaptive immune responses and can persist for years in lymphoreticular tissues. A foreign viral structure with a nucleic acid genome best explains these TSE strains and their endemic and epidemic spread in susceptible species. Nevertheless, it is widely believed that host prion protein (PrP), without any genetic material, encodes all these strains. We developed rapid infectivity assays that allowed us to reproducibly isolate infectious particles where >85% of the starting titer separated from the majority of host components, including PrP. Remarkably, digestion of all forms of PrP did not reduce brain particle titers. To ask if TSE agents, as other viruses, require nucleic acids, we exposed high titer FU-CJD and 22L scrapie particles to potent nucleases. Both agent-strains were propagated in GT1 neuronal cells to avoid interference by complex degenerative brain changes that can impede nuclease digestions. After exposure to nucleases that are active in sarkosyl, infectivity of both agents was reproducibly reduced by ≥99%. No gold-stained host proteins or any form of PrP were visibly altered by these nucleases. In contrast, co-purifying protected mitochondrial DNA and circular SPHINX DNAs were destroyed. These findings demonstrate that TSE agents require protected genetic material to infect their hosts, and should reopen investigation of essential agent nucleic acids. J. Cell. Biochem. 117: 1947-1958, 2016. © 2016 Wiley Periodicals, Inc.


Conduction in bundles of demyelinated nerve fibers: computer simulation.
This study presents a model of action potential propagation in bundles of myelinated nerve fibers. The model combines the single-cable formulation of Goldman and Albus (1967) with a basic representation of the ephaptic interaction among the fibers. We analyze first the behavior of the conduction velocity (CV) under the change of the various conductance parameters and temperature. The main parameter influencing the CV is the fast sodium conductance, and the dependence of CV on the temperature is linear up to 30 degrees C. The increase of myelin thickness above its normal value (5 microm) gives a slight increase in CV. The CV of the single fiber decreases monotonically with the disruption of myelin, but the breakdown is abrupt. There is always conduction until the thickness is larger than 2% of its original value, at which with at this point a sharp transition of CV to zero occurs. Also, the increase of temperature can block conduction. At 5% of the original thickness there is still spike propagation, but an increase of 2 degrees C causes conduction block. These results are consistent with clinical observations. Computer simulations are performed to show how the CV is affected by local damage to the myelin sheath, temperature alterations, and increased ephaptic coupling (i.e., coupling of electrical origin due to the electric neutrality of all the nerve) in the case of fiber bundles. The ephaptic interaction is included in the model. Synchronous impulse transmission and the formation of "condensed" pulse states are found. Electric impulses with a delay of 0.5 ms are presented to the system, and the numerical results show that, for increasing coupling, the impulses tend to adjust their speed and become synchronized. Other interesting phenomena are that spurious spikes are likely to be generated when ephaptic interaction is raised and that damaged axons suffering conduction block can be brought into conduction by the normal functioning fibers surrounding them. This is seen also in the case of a large number of fibers (N=500). When all the fibers are stimulated simultaneously, the conduction velocity is found to be strongly dependent on the level of ephaptic coupling and a sensible reduction is observed with respect to the propagation along an isolated axon even for low coupling level. As in the case of three fibers, spikes tend to lock and form collective impulses that propagate slowly in the nerve. On the other hand, if only 10% of fibers are stimulated by an external input, the conduction velocity is only 2% less than that along a single axon. We found a threshold value for the ephaptic coupling such that for lower values it is impossible to recruit the damaged fibers into conduction, for values of the coupling equal to this threshold only one fiber can be restored by the nondamaged fibers, and for values larger than the threshold an increasing number of fibers can return to normal functioning. We get values of the ephaptic coupling such that 25% of axons can be damaged without change of the collective conduction.


Profile of Dermatophytosis in a Tertiary Care Center.
The incidence of dermatophytosis is increasing over the last few years and there are many cases which are recurrent and chronic. The aim was to study the host and pathogen factors in dermatophytosis, to identify the species responsible, and to study the histopathological features of chronic dermatophytosis. It was a descriptive study conducted in the Department of Dermatology for a period of 1 year and all patients who were clinically diagnosed as dermatophytosis were included. Isolated hair, and nail involvement were excluded from the study. Epidemiological parameters and treatment history were analyzed, scrapings, and fungal culture were done in all patients. Histopathological examination was done in patients with chronic dermatophytosis who had applied topical steroids. Chronic dermatophytosis was seen in 68%; tinea corporis was the most common presentation; topical steroid application was seen in 63%; azoles were the most common antifungals used; varied morphologies such as follicular and nonfollicular papules, arciform lesions, pseudoimbricata were seen in steroid modified tinea. Trichophyton rubrum and Trichophyton mentagrophytes were the most common species isolated in culture, but rare species such as Trichophyton tonsurans, Trichophyton schoenleinii, Epidermophyton floccosum, and Microsporum audouinii were also isolated from chronic cases. Histopathology showed perifolliculitis in steroid modified tinea. Minimal inhibitory concentration was lowest for itraconazole in susceptibility studies. Chronicity in dermatophytosis is due to various factors such as topical steroid application, noncompliance, and change in predominant species.


Obliging children.
Children may sometimes undergo healthcare procedures that are not intended to improve their health status. Such interventions might include the use of young children as bone marrow donors or their enrolment in non-therapeutic research. One of the justifications used to legitimise these interventions is the premise that children have obligations to others; to their family in the case of related bone marrow transplantation, and to wider society in the case of non-therapeutic research. However, this 'obligation model' (the notion that children possess positive obligations to advance the health status of others) fails as a justificatory paradigm because it is based upon a confusion, identified by Hart, between two notions; that of 'being under an obligation to do something' and that of 'being obliged to do something'. Instead the 'obligation model' is a device employed to put a justificatory gloss upon a consequentialist decision-making process; removing the legitimising gloss allows for a more transparent look at the conflict between parental rights and an individual child's right to bodily integrity.


Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery surgery.
Platelet dysfunction is one of the major reasons of postoperative bleeding following coronary artery surgery. The aim of this study was to evaluate the effects of clopidogrel; a specific and potent irreversible inhibitor of platelet aggregation; on bleeding and use of blood and blood products after coronary artery bypass surgery (CABG). Preoperative patient characteristics and perioperative and postoperative data were collected prospectively in 1628 consecutive patients undergoing isolated CABG performed by the same surgical and anesthesia team. Of these, 48 were receiving clopidogrel preoperatively. Of the 1628 patients, 1456 underwent elective and 172 (10.6%) underwent non-elective operation. Thirty-six (2.5%) of the elective patients and 12 (7%) of the non-elective patients were using clopidogrel, preoperatively. Baseline characteristics, chest tube output, and the need for reexploration or for blood and blood product transfusion of clopidogrel recipients and non-recipients were compared. The clopidogrel group had higher prothrombin time level (12.6+/-1.6; 11.5+/-1.7 s, (P=0.013), however comparable aPTT level (32.6+/-4.5 vs. 31.4+/-4.5 s), and platelet count (275,000+/-98,000 vs. 280,000+/-72,000 dl(-1)). The need for reexploration or for blood and blood product transfusion, chest tube output, ICU length of stay (20.1+/-2.9 vs. 21.9+/-13.5 h; P=NS), and hospital length of stay (5.5+/-1.7 vs. 5.4+/-2.1 days; P=NS) were similar in clopidogrel recipients and non-recipients, respectively. Further analysis demonstrated no significant difference in use of homologous blood or fresh frozen plasma, amount of postoperative bleeding and reoperation rates for bleeding as well as length of intensive care unit and hospital stay between the clopidogrel and the control groups both in elective and non-elective patients. The results of this study suggest that preoperative use of clopidogrel is not associated with increased bleeding and need for surgical exploration as well as risk of blood and blood product transfusion after CABG.


Impaired conflict monitoring in Parkinson's disease patients during an oculomotor redirect task.
Fallibility is inherent in human cognition and so a system that will monitor performance is indispensable. While behavioral evidence for such a system derives from the finding that subjects slow down after trials that are likely to produce errors, the neural and behavioral characterization that enables such control is incomplete. Here, we report a specific role for dopamine/basal ganglia in response conflict by accessing deficits in performance monitoring in patients with Parkinson's disease. To characterize such a deficit, we used a modification of the oculomotor countermanding task to show that slowing down of responses that generate robust response conflict, and not post-error per se, is deficient in Parkinson's disease patients. Poor performance adjustment could be either due to impaired ability to slow RT subsequent to conflicts or due to impaired response conflict recognition. If the latter hypothesis was true, then PD subjects should show evidence of impaired error detection/correction, which was found to be the case. These results make a strong case for impaired performance monitoring in Parkinson's patients.


Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage.
We demonstrate here that the E2F1 induced by DNA damage can bind to and promote the apoptotic function of p53 via the cyclin A binding site of E2F1. This function of E2F1 does not require its DP-1 binding, DNA binding, or transcriptional activity and is independent of mdm2. All the cyclin A binding E2F family members can interact and cooperate with p53 to induce apoptosis. This suggests a novel role for E2F in regulating apoptosis in response to DNA damage. Cyclin A, but not cyclin E, prevents E2F1 from interacting and cooperating with p53 to induce apoptosis. However, in response to DNA damage, cyclin A levels decrease, with a concomitant increase in E2F1-p53 complex formation. These results suggest that the binding of E2F1 to p53 can specifically stimulate the apoptotic function of p53 in response to DNA damage.


Advanced Running Performance by Genetic Predisposition in Male Dummerstorf Marathon Mice (DUhTP) Reveals Higher Sterol Regulatory Element-Binding Protein (SREBP) Related mRNA Expression in the Liver and Higher Serum Levels of Progesterone.
Long-term-selected DUhTP mice represent a non-inbred model for inborn physical high-performance without previous training. Abundance of hepatic mRNA in 70-day male DUhTP and control mice was analyzed using the Affymetrix mouse array 430A 2.0. Differential expression analysis with PLIER corrected data was performed using AltAnalyze. Searching for over-representation in biochemical pathways revealed cholesterol metabolism being most prominently affected in DUhTP compared to unselected control mice. Furthermore, pathway analysis by AltAnalyze plus PathVisio indicated significant induction of glycolysis, fatty acid synthesis and cholesterol biosynthesis in the liver of DUhTP mice versus unselected control mice. In contrast, gluconeogenesis was partially inactivated as judged from the analysis of hepatic mRNA transcript abundance in DUhTP mice. Analysis of mRNA transcripts related to steroid hormone metabolism inferred elevated synthesis of progesterone and reduced levels of sex steroids. Abundance of steroid delta isomerase-5 mRNA (Hsd3b5, FC 4.97) was increased and steroid 17-alpha-monooxygenase mRNA (Cyp17a1, FC -11.6) was massively diminished in the liver of DUhTP mice. Assessment of steroid profiles by LC-MS revealed increased levels of progesterone and decreased levels of sex steroids in serum from DUhTP mice versus controls. Analysis of hepatic mRNA transcript abundance indicates that sterol regulatory element-binding protein-1 (SREBP-1) may play a major role in metabolic pathway activation in the marathon mouse model DUhTP. Thus, results from bioinformatics modeling of hepatic mRNA transcript abundance correlated with direct steroid analysis by mass spectrometry and further indicated functions of SREBP-1 and steroid hormones for endurance performance in DUhTP mice.


The World Veterinary Association and animal welfare.
The World Veterinary Association, as the global representative of the veterinary profession, recognises the global influences on animal welfare and the changing role of the veterinarian in response to the changing attitudes of the human population. While urban populations are now dictating animal welfare standards, many practices still have a cultural and even religious basis. Veterinarians recognise these influences, but base their recommendations for animal welfare on scientifically justified practices. Veterinarians work not only for urban clients with their companion animals, but also very importantly with rural clients who provide the source of animal-based foodstuffs and goods sought by an increasingly demanding human population. The controversial areas of intensive animal production and the transportation that is required to move large numbers of animals around the world require veterinary supervision to ensure that animal welfare is preserved. The development of animal welfare standards is an ongoing process, with the major international effort being led by the World Organisation for Animal Health.


Electrotonic coupling between pyramidal cells: a direct demonstration in rat hippocampal slices.
Intracellular recordings from pairs of neurons in slices of rat hippocampus directly demonstrated electronic coupling between CA3 pyramidal cells. When two neurons were impaled simultaneously (as verified by subsequent double staining with horseradish peroxidase), current pulses injected into one cell caused voltage changes in other cells. These interactions were bidirectional. Fast prepotentials, historically thought to represent spike activity in dendrites, resulted from action potentials in other electronically coupled pyramidal cells. These data directly demonstrate electrotonic coupling between neurons in the mammalian brain and indicate that some fast prepotentials are coupling potentials. Coupling between pyramidal cells could mediate synchronization of normal rhythmic activity and of burst discharges during seizures.


Efficient cleavage of single and clustered AP site lesions within mono-nucleosome templates by CHO-K1 nuclear extract contrasts with retardation of incision by purified APE1.
Clustered DNA damage is a unique characteristic of radiation-induced DNA damage and the formation of these sites poses a serious challenge to the cell's repair machinery. Within a cell DNA is compacted, with nucleosomes being the first order of higher level structure. However, few data are reported on the efficiency of clustered-lesion processing within nucleosomal DNA templates. Here, we show retardation of cleavage of a single AP site by purified APE1 when contained in nucleosomal DNA, compared to cleavage of an AP site in non-nucleosomal DNA. This retardation seen in nucleosomal DNA was alleviated by incubation with CHO-K1 nuclear extract. When clustered DNA damage sites containing bistranded AP sites were present in nucleosomal DNA, efficient cleavage of the AP sites was observed after treatment with nuclear extract. The resultant DSB formation led to DNA dissociating from the histone core and nucleosomal dispersion. Clustered damaged sites containing bistranded AP site/8-oxoG residues showed no retardation of cleavage of the AP site but retardation of 8-oxoG excision, compared to isolated lesions, thus DSB formation was not seen. An increased understanding of processing of clustered DNA damage in a nucleosomal environment may lead to new strategies to enhance the cytotoxic effects of radiotherapeutics.


Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: an individual patient based meta-analysis of two controlled trials.
Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p=0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p=0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1-5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.


Global phylogenomic analysis disentangles the complex evolutionary history of DNA replication in archaea.
The archaeal machinery responsible for DNA replication is largely homologous to that of eukaryotes and is clearly distinct from its bacterial counterpart. Moreover, it shows high diversity in the various archaeal lineages, including different sets of components, heterogeneous taxonomic distribution, and a large number of additional copies that are sometimes highly divergent. This has made the evolutionary history of this cellular system particularly challenging to dissect. Here, we have carried out an exhaustive identification of homologs of all major replication components in over 140 complete archaeal genomes. Phylogenomic analysis allowed assigning them to either a conserved and probably essential core of replication components that were mainly vertically inherited, or to a variable and highly divergent shell of extra copies that have likely arisen from integrative elements. This suggests that replication proteins are frequently exchanged between extrachromosomal elements and cellular genomes. Our study allowed clarifying the history that shaped this key cellular process (ancestral components, horizontal gene transfers, and gene losses), providing important evolutionary and functional information. Finally, our precise identification of core components permitted to show that the phylogenetic signal carried by DNA replication is highly consistent with that harbored by two other key informational machineries (translation and transcription), strengthening the existence of a robust organismal tree for the Archaea.


A stepped-wedge evaluation of an initiative to spread the collaborative care model for depression in primary care.
Scale-up and spread of evidence-based practices is one of the most important challenges facing health care. We tested whether a statewide initiative, Depression Improvement Across Minnesota-Offering a New Direction (DIAMOND), to implement the collaborative care model for depression in 75 primary care clinics resulted in patient outcome improvements corresponding to those reported in randomized controlled trials. Health plans provided a new monthly payment to participating clinics after a 6-month intensive training program with ongoing data submission, networking, and consultation. Implementation was staggered, with 5 sequences of 10 to 40 clinics every 6 months. Payers provided weekly contact information for members from participating clinics who were filling antidepressant prescriptions, and we conducted baseline and 6-month surveys of 1,578 patients about their care and outcomes. There were 466 patients in DIAMOND clinics who received usual care before implementation (UCB), 559 who received usual care in DIAMOND clinics after implementation (UCA), 245 who received DIAMOND care after implementation (DCA), and 308 who received usual care in comparison clinics (UC). Patients who received DIAMOND care after implementation reported more collaborative care depression services than the 3 comparison groups (10.9 vs 6.4-6.7, on a scale of 0 of 14, where higher numbers indicate more services; P <.001) and more satisfaction with their care (4.0 vs 3.4 on a scale 1 to 5, in which higher scores indicate higher satisfaction; P ≤.001). Depression remission rates, however, were not significantly different among the 4 groups (36.4% DCA vs 35.8% UCB, 35.0% UCA, 33.9% UC; P = .94). Despite the incentive of a supporting payment change and intensive training and support for clinics volunteering to participate, no difference in depression outcomes was documented. Specific unmeasured actions present in trials but not present in these clinics may be critical for successful outcome improvement.


Developmentally regulated biosynthesis of carbohydrate and storage polysaccharide during differentiation and tissue cyst formation in Toxoplasma gondii.
Toxoplasma gondii belongs to the Apicomplexa phylum, which comprises protozoan parasites of medical and veterinary significance, responsible for a wide variety of diseases in human and animals, including malaria, toxoplasmosis, coccidiosis and cryptosporidiosis. During infection in the intermediate host, T. gondii undergoes stage conversion between the rapidly replicating tachyzoite that is responsible for acute toxoplasmosis and the dormant or slowly dividing encysted bradyzoite. The tachyzoite-bradyzoite interconversion is central to the pathogenic process and is associated with the life-threatening recrudescence of infection observed in immunocompromised patients such as those suffering from AIDS. In chronic infections, the bradyzoites are located within tissue cysts found predominantly in brain and muscles. The tissue cyst is enclosed by a wall containing specific lectin binding sugars while the bradyzoites have accumulated large amounts of the storage polysaccharide of glucose, amylopectin. Our recent findings have identified several genes and proteins associated with amylopectin synthesis or degradation and glucose metabolism, including different isoforms of certain glycolytic enzymes, which are stage-specifically expressed during tachyzoite-bradyzoite interconversion. Here, we will discuss how the genes and enzymes involved in carbohydrate metabolisms are used as molecular and biochemical tools for the elucidation of molecular mechanisms controlling T. gondii stage interconversion and cyst formation.


Does Mindfulness-Based Cognitive Therapy for Migraine Reduce Migraine-Related Disability in People with Episodic and Chronic Migraine? A Phase 2b Pilot Randomized Clinical Trial.
The current Phase 2b study aimed to evaluate the efficacy of mindfulness-based cognitive therapy for migraine (MBCT-M) to reduce migraine-related disability in people with migraine. Mindfulness-based interventions represent a promising avenue to investigate effects in people with migraine. MBCT teaches mindfulness meditation and cognitive-behavioral skills and directly applies these skills to address disease-related cognitions. Participants with migraine (6-30 headache days/month) were recruited from neurology office referrals and local and online advertisements in the broader New York City area. During the 30-day baseline period, all participants completed a daily headache diary. Participants who met inclusion and exclusion criteria were randomized in a parallel design, stratified by chronic migraine status, to receive either 8 weekly individual MBCT-M sessions or 8 weeks of waitlist/treatment as usual (WL/TAU). All participants completed surveys including primary outcome evaluations at Months 0, 1, 2, and 4. All participants completed a headache diary during the 30-day posttreatment evaluation period. Primary outcomes were the change from Month 0 to Month 4 in the headache disability inventory (HDI) and the Migraine Disability Assessment (MIDAS) (total score ≥ 21 indicating severe disability); secondary outcomes (headache days/30 days, average headache attack pain intensity, and attack-level migraine-related disability [Migraine Disability Index (MIDI)]) were derived from the daily headache diary. Sixty participants were randomized to receive MBCT-M (n = 31) or WL/TAU (n = 29). Participants (M age = 40.1, SD = 11.7) were predominantly White (n = 49/60; 81.7%) and Non-Hispanic (N = 50/60; 83.3%) women (n = 55/60; 91.7%) with a graduate degree (n = 35/60; 55.0%) who were working full-time (n = 38/60; 63.3%). At baseline, the average HDI score (51.4, SD = 19.0) indicated a moderate level of disability and the majority of participants (50/60, 83.3%) fell in the "Severe Disability" range in the MIDAS. Participants recorded an average of 16.0 (SD = 5.9) headache days/30 days, with an average headache attack pain intensity of 1.7 on a 4-point scale (SD = 0.3), indicating moderate intensity. Average levels of daily disability reported on the MIDI were 3.1/10 (SD = 1.8). For the HDI, mean scores decreased more from Month 0 to Month 4 in the MBCT-M group (-14.3) than the waitlist/treatment as an usual group (-0.2; P < .001). For the MIDAS, the group*month interaction was not significant when accounting for the divided alpha, P = .027; across all participants in both groups, the estimated proportion of participants falling in the "Severe Disability" category fell significantly from 88.3% at Month 0 to 66.7% at Month 4, P < .001. For diary-reported headache days/30 days an average headache attack pain intensity, neither the group*month interaction (Ps = .773 and .888, respectively) nor the time effect (Ps = .059 and .428, respectively) was significant. Mean MIDI scores decreased in the MBCT-M group (-0.6/10), whereas they increased in the waitlist/treatment as an usual group (+0.3/10), P = .007. MBCT-M demonstrated efficacy to reduce headache-related disability and attack-level migraine-related disability. MBCT-M is a promising emerging treatment for addressing migraine-related disability.


Radiation Dosimetry of a Graphite Moderated Radium-Beryllium Source.
The Brookhaven National Laboratory Sigma Pile is a radium-beryllium neutron source imbedded in a cube of graphite blocks. The pile is approximately 2.13 m on four sides and is 3.07 m high. Thermoluminescent dosimeters were used to determine the neutron and gamma-ray dose rates in the pile. Gamma-ray dose rate measurements have also been made in the air outside of the pile, while the radium-beryllium neutron source was being withdrawn from the pile. The Monte Carlo code has been used to calculate the coupled neutron-photon transport. Measured dose rates at various locations agreed with the calculated values within 5% to 15%.


A central region in the minor capsid protein of papillomaviruses facilitates viral genome tethering and membrane penetration for mitotic nuclear entry.
Incoming papillomaviruses (PVs) depend on mitotic nuclear envelope breakdown to gain initial access to the nucleus for viral transcription and replication. In our previous work, we hypothesized that the minor capsid protein L2 of PVs tethers the incoming vDNA to mitotic chromosomes to direct them into the nascent nuclei. To re-evaluate how dynamic L2 recruitment to cellular chromosomes occurs specifically during prometaphase, we developed a quantitative, microscopy-based assay for measuring the degree of chromosome recruitment of L2-EGFP. Analyzing various HPV16 L2 truncation-mutants revealed a central chromosome-binding region (CBR) of 147 amino acids that confers binding to mitotic chromosomes. Specific mutations of conserved motifs (IVAL286AAAA, RR302/5AA, and RTR313EEE) within the CBR interfered with chromosomal binding. Moreover, assembly-competent HPV16 containing the chromosome-binding deficient L2(RTR313EEE) or L2(IVAL286AAAA) were inhibited for infection despite their ability to be transported to intracellular compartments. Since vDNA and L2 were not associated with mitotic chromosomes either, the infectivity was likely impaired by a defect in tethering of the vDNA to mitotic chromosomes. However, L2 mutations that abrogated chromatin association also compromised translocation of L2 across membranes of intracellular organelles. Thus, chromatin recruitment of L2 may in itself be a requirement for successful penetration of the limiting membrane thereby linking both processes mechanistically. Furthermore, we demonstrate that the association of L2 with mitotic chromosomes is conserved among the alpha, beta, gamma, and iota genera of Papillomaviridae. However, different binding patterns point to a certain variance amongst the different genera. Overall, our data suggest a common strategy among various PVs, in which a central region of L2 mediates tethering of vDNA to mitotic chromosomes during cell division thereby coordinating membrane translocation and delivery to daughter nuclei.


Significance of distal polyps detected with flexible sigmoidoscopy in asymptomatic patients.
Colorectal cancer is a frequent cause of death from cancer. To reduce the mortality associated with this disease, regular flexible sigmoidoscopy is recommended. However, the significance of diminutive polyps (adenomatous or hyperplastic) detected during flexible sigmoidoscopy remains controversial, as does the appropriate endoscope length (35 vs 60 cm) for colorectal cancer screening. One hundred one consecutive patients with no history of colonic disease, gastrointestinal tract symptoms, or positive results of fecal occult blood testing underwent flexible sigmoidoscopy as part of a colorectal cancer screening program. All patients with distal polyps detected during flexible sigmoidoscopy underwent colonoscopy. More than 25% of these asymptomatic, predominantly male subjects had colonic neoplasms or polyps detected. Fifty percent more lesions could be detected with a 60-cm sigmoidoscope than with a 35-cm sigmoidoscope, and detection of any distal polyp, whether adenomatous or hyperplastic, was associated with at least one proximal colon adenoma in 20% of patients. "Extended flexible sigmoidoscopy" for colorectal cancer screening was well tolerated by patients, as evidenced by insertion to the hepatic flexure in 25% of patients, and provided significantly more information than could be obtained with a 35-cm sigmoidoscope. Colorectal cancer screening should be performed with a 60-cm flexible sigmoidoscope, and distal colonic polyps or neoplasms will be detected in 25% of asymptomatic patients.


Photoantimicrobials and PACT: what's in an abbreviation?
The use of a separate nomenclature for the application of photosensitisers to the oncological and infectious disease fields represents a sensible approach. There is commonality, of course, in that both utilise light activation and act via the local generation of reactive oxygen species, but the difference in cellular targets is so great that different designs are required to achieve proper selectivity for a clinical end use, whether in human or veterinary medicine. The following represents a personal view, and perhaps a clarification of terms, in what might be considered a major etymological dichotomy existing within photodynamic research, on the 20th anniversary of "PACT".


Diagnosing early Lyme disease.
The diagnostic value of clinical, culture, and serologic findings was studied prospectively in 41 patients with early Lyme disease. Fifteen patients had erythema chronicum migrans alone, and 26 had clinical evidence of disseminated infection, most commonly affecting the brain or meninges, other skin sites, lymph nodes, or joints. Of 40 blood cultures, only one, from a patient with disseminated infection, yielded spirochetes. One of 10 patients tested with localized infection had an elevated IgM response to the Lyme spirochete (200 units or greater) during acute disease. Two to three weeks after beginning antibiotic therapy, four of the 10 patients had elevated specific IgM or IgG responses (200 units or greater). Of the 22 patients tested with disseminated disease, 10 initially had elevated levels of specific IgM or IgG, and 12 had such responses by convalescence. Because of the low yield of cultures and the delay in the specific antibody response, recognition of the clinical picture remains very important in diagnosing early Lyme disease.


Lumbar spinous process-splitting laminectomy for lumbar canal stenosis. Technical note.
In conventional laminectomy for lumbar canal stenosis (LCS), intraoperative damage of posterior supporting structures can lead to irreversible atrophy of paraspinal muscles. In 2001, the authors developed a new procedure for lumbar laminectomy, the lumbar spinous process-splitting laminectomy (LSPSL). In this new procedure, the spinous process is split longitudinally in the middle and then divided at its base from the posterior arch, leaving the bilateral paraspinal muscles attached to the lateral aspects. Ample working space for laminectomy is obtained by retracting the split spinous process laterally together with its attached paraspinal muscles. After successfully decompressing nerve tissues, each half of the split spinous process is reapproximated using a strong suture. Thus, the supra- and interspinous ligaments are preserved, as is the spinous process, and damage to the paraspinal muscles is minimal. Eighteen patients with LCS underwent surgery in which this new technique was used. Twenty patients in whom conventional laminectomy was undertaken were chosen as controls. At 2 years, the clinical outcomes (as determined using the Japanese Orthopaedic Association [JOA] scores and recovery rate) and the rate of measured magnetic resonance imaging-documented paravertebral muscle atrophy were evaluated and compared between the two groups. The mean JOA score recovery rates were 67.6 and 59.2%, respectively, for patients treated with LSPSL and conventional laminectomy; the mean rates of paravertebral muscle atrophy were 5.3 and 23.9%, respectively (p = 0.0005). Preservation of posterior supporting structures and satisfactory recovery rate after 2 years indicated that this technique can be a useful alternative to conventional decompression surgery for lumbar canal stenosis.


Vascular component analysis of hyperoxic and hypercapnic BOLD contrast.
Hyperoxia or hypercapnia provides a useful experimental tool to systematically alter the blood oxygenation level dependent (BOLD) contrast. Typical applications include calibrated functional magnetic resonance imaging (fMRI), BOLD sensitivity mapping, vessel size imaging or cerebrovascular reactivity mapping. This article describes a novel biophysical model of hyperoxic and hypercapnic BOLD contrast, which accounts for the magnetic susceptibility effects of molecular oxygen that is dissolved in blood and tissue, in addition to the well-established effects caused by the paramagnetic properties of deoxyhaemoglobin. Furthermore, the concept of vascular component analysis (VCA) is introduced and is shown to provide a computationally efficient tool for investigating the vascular specificity of hyperoxic and hypercapnic BOLD contrast. A theoretical investigation of gradient and spin echo BOLD contrast based on computer simulations was performed to compare three different conditions (hypercapnia induced by breathing 6% CO2, hyperoxia induced by breathing 100% O2, and simultaneous hypercapnia and hyperoxia induced by breathing carbogen, i.e. 5% CO2 in 95% CO2) with baseline (breathing air). Simulations were carried out for different levels of metabolic oxygen extraction fraction (OEF) ranging from 0 to 0.5. The key findings can be summarised as follows: (i) for hyperoxia the susceptibility of dissolved O2 may lead to a significant arterial BOLD contrast; (ii) under normoxic conditions the susceptibility of dissolved O2 is negligible; (iii) an almost complete loss of BOLD sensitivity may occur at lower OEF values in all parts of the vascular tree, whereas hyperoxic BOLD sensitivity is largely maintained; (iv) under hyperoxic conditions, a transition from positive to negative BOLD contrast occurs with decreasing OEF values. These findings have important implications for experimental applications of hyperoxic and hypercapnic BOLD contrast and may enable new clinical applications in ischemic stroke and other forms of acquired brain injury.


Quantification of GC-biased gene conversion in the human genome.
Much evidence indicates that GC-biased gene conversion (gBGC) has a major impact on the evolution of mammalian genomes. However, a detailed quantification of the process is still lacking. The strength of gBGC can be measured from the analysis of derived allele frequency spectra (DAF), but this approach is sensitive to a number of confounding factors. In particular, we show by simulations that the inference is pervasively affected by polymorphism polarization errors and by spatial heterogeneity in gBGC strength. We propose a new general method to quantify gBGC from DAF spectra, incorporating polarization errors, taking spatial heterogeneity into account, and jointly estimating mutation bias. Applying it to human polymorphism data from the 1000 Genomes Project, we show that the strength of gBGC does not differ between hypermutable CpG sites and non-CpG sites, suggesting that in humans gBGC is not caused by the base-excision repair machinery. Genome-wide, the intensity of gBGC is in the nearly neutral area. However, given that recombination occurs primarily within recombination hotspots, 1%-2% of the human genome is subject to strong gBGC. On average, gBGC is stronger in African than in non-African populations, reflecting differences in effective population sizes. However, due to more heterogeneous recombination landscapes, the fraction of the genome affected by strong gBGC is larger in non-African than in African populations. Given that the location of recombination hotspots evolves very rapidly, our analysis predicts that, in the long term, a large fraction of the genome is affected by short episodes of strong gBGC.


Dual regulatory roles of the extended N terminus for activation of the tomato MI-1.2 resistance protein.
Plant resistance (R) proteins mediate race-specific immunity and initiate host defenses that are often accompanied by a localized cell-death response. Most R proteins belong to the nucleotide binding-leucine-rich repeat (NB-LRR) protein family, as they carry a central NB-ARC domain fused to an LRR domain. The coiled-coil (CC) domain at the N terminus of some solanaceous NB-LRR proteins is extended with a solanaceae domain (SD). Tomato Mi-1.2, which confers resistance against nematodes, white flies, psyllids, and aphids, encodes a typical SD-CNL protein. Here, we analyzed the role of the extended N terminus for Mi-1.2 activation. Removal of the first part of the N terminus (Nt1) induced Mi-1.2-mediated cell death that could be suppressed by overexpression of the second half of the N-terminal region. Yet, autoactivating NB-ARC-LRR mutants require in trans coexpression of the N-terminal region to induce cell death, indicating that the N terminus functions both as a negative and as a positive regulator. Based on secondary structure predictions, we could link both activities to three distinct subdomains, a typical CC domain and two novel, structurally-conserved helical subdomains called SD1 and SD2. A negative regulatory function could be assigned to the SD1, whereas SD2 and the CC together function as positive regulators of Mi-1.2-mediated cell death.


A recurrence of benign multicystic peritoneal mesothelioma treated through laparoscopic excision: a case report and review of the literature.
Benign multicystic peritoneal mesothelioma is a rare cystic tumor with approximately 140 cases reported to date. It is found mainly in women of reproductive age and is commonly attached to the serosal surface of pelvic viscera. The pathogenesis is uncertain and debate regarding its neoplastic or reactive nature exists. The presenting symptoms are often nonspecific and most commonly include vague lower abdominal pain and fullness. Imaging studies are used to identify the lesion, but histologic studies with the aid of immunohistochemical techniques are needed for definitive diagnosis as the differential diagnosis is quite extensive. Surgical resection is the primary form of treatment, and follow-up is important due to the high rate of recurrence and the rare possibility of malignant transformation. Here, we present a case of a 50-year-old female with a recurrence of benign multicystic peritoneal mesothelioma treated through laparoscopic excision and also a review of the literature.


All-hazards preparedness in an era of bioterrorism funding.
All-hazards preparedness was evaluated in North Carolina's 85 local health departments (LHDs). In regional meetings, data were collected from LHD teams from North Carolina's LHDs using an instrument constructed from Centers for Disease Control and Prevention's preparedness indicators and from the Local Public Health Preparedness and Response Capacity Inventory. Levels of preparedness differ widely by disaster types. LHDs reported higher levels of preparedness for natural disasters, outbreaks, and bioterrorist events than for chemical, radiation, or mass trauma disasters. LHDs face challenges to achieving all-hazards preparedness since preparation for one type of disaster does not lead to preparedness for all types of disasters. LHDs in this survey were more prepared for disasters for which they were funded (bioterrorism) and for events they faced regularly (natural disasters, outbreaks) than they were for other types of disasters.


Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance.
Celiac disease, and, more generally, gluten intolerance, is a growing problem worldwide, but especially in North America and Europe, where an estimated 5% of the population now suffers from it. Symptoms include nausea, diarrhea, skin rashes, macrocytic anemia and depression. It is a multifactorial disease associated with numerous nutritional deficiencies as well as reproductive issues and increased risk to thyroid disease, kidney failure and cancer. Here, we propose that glyphosate, the active ingredient in the herbicide, Roundup(®), is the most important causal factor in this epidemic. Fish exposed to glyphosate develop digestive problems that are reminiscent of celiac disease. Celiac disease is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on gut bacteria. Characteristics of celiac disease point to impairment in many cytochrome P450 enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in iron, cobalt, molybdenum, copper and other rare metals associated with celiac disease can be attributed to glyphosate's strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine and selenomethionine associated with celiac disease match glyphosate's known depletion of these amino acids. Celiac disease patients have an increased risk to non-Hodgkin's lymphoma, which has also been implicated in glyphosate exposure. Reproductive issues associated with celiac disease, such as infertility, miscarriages, and birth defects, can also be explained by glyphosate. Glyphosate residues in wheat and other crops are likely increasing recently due to the growing practice of crop desiccation just prior to the harvest. We argue that the practice of "ripening" sugar cane with glyphosate may explain the recent surge in kidney failure among agricultural workers in Central America. We conclude with a plea to governments to reconsider policies regarding the safety of glyphosate residues in foods.


Distribution of voltage-gated sodium channel alpha-subunit and beta-subunit mRNAs in human hippocampal formation, cortex, and cerebellum.
The distribution of mRNAs encoding voltage-gated sodium channel alpha subunits (I, II, III, and VI) and beta subunits (beta1 and beta2) was studied in selected regions of the human brain by Northern blot and in situ hybridisation experiments. Northern blot analysis showed that all regions studied exhibited heterogenous expression of sodium channel transcripts. In situ hybridisation experiments confirmed these findings and revealed a predominantly neuronal distribution. In the parahippocampal gyrus, subtypes II and VI and the beta-subunit mRNAs exhibited robust expression in the granule cells of the dentate gyrus and pyramidal cell layer of the hippocampus. Subtypes I and III showed moderate expression in granule cells and low expression in the pyramidal cell layer. Distinct expression patterns were also observed in the cortical layers of the middle frontal gyrus and in the entorhinal cortex. In particular, all subtypes exhibited higher levels of expression in cortical layers III, V, and VI compared with layers I and II. All subtypes were expressed in the granular layer of the cerebellum, whereas specific expression of subtypes I, VI, beta1, and beta2 mRNAs was observed in Purkinje cells. Subtypes I, VI, and beta1 mRNAs were expressed, at varying levels, in the pyramidal cells of the deep cerebellar nuclei. These data indicate that, as in rat, human brain sodium channel mRNAs have a distinct regional distribution, with individual cell types expressing different compliments of sodium channels. The differential distribution of sodium channel subtypes suggest that they have distinct roles that are likely to be of paramount importance in maintaining the functional heterogeneity of central nervous system neurons.


Cardiologists' awareness and perceptions of guidelines for chronic heart failure. The ADDress your Heart survey.
Several surveys show that patients with chronic heart failure (CHF) are sub-optimally managed and treatment guidelines are not implemented in clinical practice. To investigate awareness and perceptions of the 2005 European Society of Cardiology (ESC) guidelines for CHF. 467 cardiologists from seven European countries completed an on-line interview using a validated, semi-structured questionnaire including questions about awareness and relevance of CHF guidelines. To assess agreement with ESC guidelines, three fictitious patient cases were presented and respondents' management choices compared with those of an expert panel based on the guidelines. Awareness of CHF guidelines was high, with 98% aware of any guideline and 65% aware of ESC guidelines. ESC guidelines were considered relevant (51%) or very relevant (38%) for guiding treatment decisions. Up to 92% of respondents perceived that they adhered to the ESC guidelines. For the patient cases, <or=25% made treatment recommendations that completely matched those formulated by the expert panel. Respondents considered patient compliance (52%) and guideline complexity (46%) major barriers to implementation. Cardiologists reported high awareness of and a positive attitude towards ESC CHF guidelines. Provision of guidelines in a concise and accessible format is perceived as a key factor to improve implementation.


Current results of studies of immunophenotype-, age- and leukocyte-based therapy for children with acute lymphoblastic leukemia. The Pediatric Oncology Group.
From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.


The dddP gene of Roseovarius nubinhibens encodes a novel lyase that cleaves dimethylsulfoniopropionate into acrylate plus dimethyl sulfide.
The cloned dddP gene of the marine bacterium Roseovarius nubinhibens allows Escherichia coli to form the volatile dimethyl sulfide (DMS) from dimethylsulfoniopropionate (DMSP), an abundant anti-stress compatible solute made by many marine plankton and macroalgae. Using purified DddP, we show here that this enzyme is a DMSP lyase that cleaves DMSP to DMS plus acrylate. DddP forms a functional homodimeric enzyme, has a pH optimum of 6.0 and was a K(m) of approximately 14 mM for the DMSP substrate. DddP belongs to the M24B family of peptidases, some members of which have metal cofactors. However, the metal chelators EDTA and bipyridyl did not affect DddP activity in vitro and the as-isolated enzyme did not contain metal ions. Thus, DddP resembles those members of the M24B family, such as creatinase, which also act on a non-peptide substrate and have no metal cofactor. Site-directed mutagenesis of the active-site region of DddP completely abolished its activity. Another enzyme, termed DddL, which occurs in other alphaproteobacteria, had also been shown to generate DMS plus acrylate from DMSP. However, DddL and DddP have no sequence similarity to each other, so DddP represents a second, wholly different class of DMSP lyase.


pKa tuning in quadrupolar-type two-photon ratiometric fluorescent membrane probes.
Two bolaamphiphilic quadrupoles built from a fluorene core conjugated with azine endgroups were designed and successfully used to stain GUV membranes. Their quadrupolar character induces both a shift of the pKa values close to the physiological pH and large two-photon absorption responses (i.e. over 1000 GM for acidic forms). As such they hold promise as ratiometric two-photon pH probes for monitoring slight variations of pH near cell membranes using two-photon excitation in the NIR region.


Effectiveness of clinical pharmacist intervention on health-related quality of life in chronic obstructive pulmonary disorder patients - a randomized controlled study.
Chronic obstructive pulmonary disease (COPD), a preventable and treatable disease, has been described as '10% medication and 90% education'. Extreme physician scarcity limits the implementation of quality healthcare delivery in India. We conducted this study to evaluate the effectiveness of clinical pharmacist intervention on health-related quality of life (HRQoL) in patients with COPD in an Indian tertiary care hospital. An open-labelled randomized controlled study was conducted over a 3-year period, at Kasturba Medical College Hospital, Manipal, India, after obtaining institutional ethics clearance (IEC 88/2012). The study was registered with the Indian clinical trial registry (CTRI/2014/08/004848). Patients were randomly assigned to two groups (intervention group [IG] and control group [CG]) by envelope method. St. George's Respiratory Questionnaire (SGRQ) was used to assess the HRQoL. The pharmacist intervention laid emphasis on (i) importance of medication compliance, (ii) need for smoking cessation, (iii) simple exercise, (iv) proper use of inhaler devices and (v) need for timely follow-up by pulmonary medicine department. SGRQ assessment was repeated at 6, 12, 18 and 24 months. Of 328 patients with COPD screened during the study period (March 2012 to June 2013), 260 (79%) were recruited. Of these, 202 (78%) patients completed follow-up (98 in CG and 104 in IG). Both groups were matched for baseline, sociodemographics and clinical characteristics. SGRQ scores and its subscales (symptoms, activity and impact) improved significantly after the pharmacist intervention in IG at follow-up (P < 0·001). Our randomized controlled study shows that pharmacist intervention improved the HRQoL of patients with COPD in India. The generalizability of our results requires exploration even within other settings in India. Nonetheless, our results provide support for a greater involvement of pharmacists in the care of patients with COPD.


Genetical control of B-cell responses. III. Requirement for functional mitogenicity of the antigen in thymus-independent specific responses.
Spleen cells from C3H/HeJ mice fail to respond with polyclonal antibody synthesis to mitogenic concentrations of lipopolysaccharide (LPS) which are optimal for activating spleen cells from a high-responder strain (B10.5M). This unresponsiveness is selective for LPS, since C3H/HeJ cells respond as normals to another B-cell mitogen, purified protein derivative of tuberculin. Spleen cells from low-responder mice also fail to mount a specific anti-NNP plaque-forming cell (PFC) response, when challenged in vitro by NNP-LPS. However, C3H/HeJ cells develop normal responses to another thymus-independent hapten conjugate, DNP-AECM-Ficoll. C3H/HeJ mice fail to mount a specific anti-LPS antibody response, when challenged in vivo with doses of soluble LPS which are fully immunogenic for the high-responder strain. However, C3H/HeJ mice develop normal direct and indirect PFC responses to LPS, when challenged with a thymus-dependent form of the immunogen. These results are interpreted as indicating as absolute requirement for functional mitogenicity of the antigen, in the induction of specific thymus-independent antibody responses.


Diagnostic precision of sentinel lymph node biopsy in penile cancer.
Sentinel lymph node biopsy (SLNB) was designed as a minimally invasive method for evaluation of nodal involvement in patients with penile cancer and nonpalpable lymph nodes. Nevertheless, SLNB is not used in a regular basis due to the lack of studies that adequately characterize the performance of this procedure. The purpose of this study was to evaluate the diagnostic performance of SLNB in patients with infiltrative penile carcinoma without palpable inguinal lymph nodes in a Colombian population. This is a retrospective observational study of 89 patients diagnosed with infiltrative penile squamous cell carcinoma with nonpalpable inguinal lymph nodes. These patients underwent partial or complete penectomy, along with SLNB, between 2008 and 2017. Those individuals with a positive SLNB underwent inguinal lymphadenectomy, while those with a negative SLNB were followed on a quarterly basis with a physical examination and imaging to assess relapse. Statistical analysis was done using the STATA 14 software. A contingency table was made to calculate sensitivity, specificity, positive predictive value, negative predictive value, and exactitude, each one with its own confidence interval (CI) of 95%. There was an average follow-up of 31.4 months, and all 89 patients were evaluated; most primary tumors were T2 (55%), followed by T1 (37%), all of which were subclassified as T1b and T3 (8%). Tumours were most frequently located in the glans (43%). All patients were classified as cN0 and underwent SLNB. Sixty-one patients (69%) tested negative in the SLNB, four of whom (6%) presented with lymph node relapse. On the other hand, 28 patients (31%) tested positive in the SLNB and consequently underwent inguinal lymphadenectomy, seven of whom had negative lymph nodeinvolvement (25% false positives). According to the results, the sensitivity was 84% (95% CI, 65.3-93.6) and the specificity was 89% (95% CI, 79.4-94.7), with a false-negative rate of 6.5%. The SLNB using radiotracer can be a useful method for lymph node staging in patients with penile cancer and nonpalpable lymph nodes when performed in experienced centers.


Physical activity, alcohol consumption, BMI and smoking status before and after prostate cancer diagnosis in the ProtecT trial: opportunities for lifestyle modification.
Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0-9), 40.7% had increased their activity by a median of 22 U week(-1) (IQR 15-35) 9 months later, and there was weak evidence that men were more active after diagnosis than before (p = 0.07). Men categorised as "working" occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03-3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as "managerial or professional." Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29-4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake (p = 0.03) and the proportion of current smokers (p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes.


NOTCH1 expression predicts patient prognosis in esophageal squamous cell cancer.
The prognosis of patients with esophageal cancer remains poor, and the classification of tumor node metastasis has proven insufficient to predict patient prognosis. Therefore, novel predictive markers of esophageal cancer prognosis are needed. Notch receptors and their ligands have been reported to be upregulated in cervical, lung, colon, renal, and pancreatic cancers, but NOTCH1 expression has not been studied in esophageal cancer. Expression of NOTCH1 was quantified by real-time reverse transcription-polymerase chain reaction in 55 primary esophageal squamous cell carcinomas (ESCCs) and their paired normal esophageal mucosa. We then examined the correlations between NOTCH1 expression, clinicopathological factors, and prognosis in patients with ESCC. The probability of overall survival was significantly lower for patients with high NOTCH1 expression (p = 0.0028; log-rank test). Overexpression of NOTCH1 was identified as a significant and independent prognostic factor (p = 0.0061) in patients who had undergone surgical treatment for ESCCs. The hazard ratio for predicting early death was 4.298 (95% confidence interval 1.515-12.195) for high versus low NOTCH1 expression. Our data indicate that NOTCH1 may be a candidate molecular prognostic marker and a molecular target for the development of an effective therapeutic intervention for patients with ESCC.


Diagnostic Performance of Breast MRI in the Evaluation of Contralateral Breast in Patients with Diagnosed Breast Cancer.
The purpose of our study was to evaluate the diagnostic performance of breast magnetic resonance imaging (MRI) in the evaluation of contralateral breast in patients with diagnosed breast cancer. A secondary objective was to determine accuracy of breast MRI in diagnosing multi-focal and multicentric lesions in the ipsilateral breast. Using a non-probability convenience sampling technique, patients with histopathologically diagnosed breast cancer with MRI of breast performed to exclude additional lesions were included. MRI findings were correlated with histopathology. In addition, follow-up imaging with mammography and ultrasound was also assessed for establishing stability of negative findings and for the detected of benign lesions. Out of 157 MRI breast conducted during the period of 2008 to 2013, 49 were performed for patients with diagnosed breast cancer. The sample comprised of all females with mean age 50.7 ± 11.0 years. The patient follow-up imaging was available for a period of 2-5 years. The sensitivity, specificity, and positive and negative predictive values of MRI in the detection of multifocal/multicenteric lesions was 85.7%, 88.8%, 60% and 96.6% respectively and for the detection of lesions in the contralateral breast were 100%, 97%, 83.3% and 100% respectively. Our study highlights the diagnostic performance and the added value of MRI in the detection of multifocal /multicenteric and contralateral malignant lesions. In patients with diagnosed breast cancer having dense breast parenchyma and with infiltrating lobular carcinoma as the index lesion MRI is particularly useful with excellent negative predictive value in the exclusion of additional malignant foci in the ipsilateral and contralateral breasts.


The DELLA-CONSTANS Transcription Factor Cascade Integrates Gibberellic Acid and Photoperiod Signaling to Regulate Flowering.
Gibberellin (GA) and photoperiod pathways have recently been demonstrated to collaboratively modulate flowering under long days (LDs). However, the molecular mechanisms underlying this collaboration remain largely unclear. In this study, we found that GA-induced expression of FLOWERING LOCUS T (FT) under LDs was dependent on CONSTANS (CO), a critical transcription factor positively involved in photoperiod signaling. Mechanistic investigation revealed that DELLA proteins, a group of crucial repressors in GA signaling, physically interacted with CO. The DELLA-CO interactions repressed the transcriptional function of CO protein. Genetic analysis demonstrated that CO acts downstream of DELLA proteins to regulate flowering. Disruption of CO rescued the earlier flowering phenotype of the gai-t6 rga-t2 rgl1-1 rgl2-1 mutant (dellap), while a gain-of-function mutation in GA INSENSITIVE (GAI, a member of the DELLA gene) repressed the earlier flowering phenotype of CO-overexpressing plants. In addition, the accumulation of DELLA proteins and mRNAs was rhythmic, and REPRESSOR OF GA1-3 protein was noticeably decreased in the long-day afternoon, a time when CO protein is abundant. Collectively, these results demonstrate that the DELLA-CO cascade inhibits CO/FT-mediated flowering under LDs, which thus provide evidence to directly integrate GA and photoperiod signaling to synergistically modulate flowering under LDs.


Health profile differences for menthol and non-menthol smokers: findings from the National Health Interview Survey.
Although the adverse effects of smoking are well known, limited information exists about the overall health profiles of menthol smokers when compared to their non-menthol smoking counterparts. Using a well-known nationally representative survey, this study examines differences between self-reported health characteristics for menthol and non-menthol smokers. Cross-sectional data from the 2005 National Health Interview Survey and its cancer control supplement were used to analyze responses for current and former smokers (n = 12,004) independently. All analyses were conducted using SAS version 9.2 and SAS callable SUDAAN version 9.0.3. Multiple logistic regression analysis was used to model menthol smoking. After controlling for sex, age and race, we found that in current smokers the mean number of cigarettes smoked per day is significantly lower for menthol smokers when compared to non-menthol smokers [odds ratio (OR): 0.99; 95% confidence interval (CI): 0.98, 1.00]. Also, we found that former menthol smokers had higher body mass indices (BMIs) (OR: 1.01; 95% CI: 1.00, 1.02) and were more likely to have visited the emergency room due to asthma (OR: 2.30, 95% CI: 1.04, 5.09). Overall, current menthol and non-menthol smokers have similar health profiles. However, menthol smokers reported smoking fewer cigarettes per day than their non-menthol counterparts. While these findings are supportive of other published data, future studies may need to tease out the health-related significance of smoking fewer menthol cigarettes per day but having similar health outcomes to those who smoke more non-menthol cigarettes per day. Additionally, our findings suggest that there may be some differences between the former menthol and non-menthol smoker.


First Report of Root-Knot Nematode Meloidogyne arenaria Infesting Roots of Anubias barteri in Guangdong, China.
Anubias spp. are very popular aquatic plants that are native to Africa. Anubias barteri is a broadleaf Anubias and is a popular choice for aquariums because of its robust size. In China, broadleaf Anubias is usually planted in sand, with sponges around the rhizome, in small plastic baskets in aquatic plant nurseries. In December 2010, a survey of phytoparasitic nematodes was conducted in the nurseries in Guangzhou, Guangdong Province. Many second-stage juveniles of a Meloidogyne sp. were detected from the roots of A. barteri, but no root galls were found. To identify these juveniles, molecular identification was performed with PCR. The DNA sequence between CO II and l-rRNA of the mitochondrial gene of single juveniles was amplified with universal primers of Meloidogyne, #C2F3 (5'-GGTCAATGTTCAGAAATTTGTGG-3') and #1108 (5'-TACCTTTGACCAATCACGCT-3') (3). The amplified fragments were approximately 1.1 kb long and could not be digested with restrictive enzyme HinfI. The specific fragments were then sequenced. The blast search result revealed that the DNA sequence (GenBank Accession No. JQ446377) had 99 to 100% identity with submitted sequences of Meloidogyne arenaria (GenBank Accession Nos. EU364879, GQ266686, and AY635610). The other extracted juveniles were inoculated into sterile, potted, water spinach (Ipomoea aquatica) in the greenhouse to obtain more nematodes. After 40 days, root galls and female egg masses were clearly observed, and biochemical, molecular, and morphological identifications were conducted. Isoenzyme phenotype (esterase and malate dehydrogenase (MDH) patterns) and the perineal pattern of several gravid females were the same as M. arenaria (1,2), and PCR amplification of single juveniles produced identical fragments as previously found. Single egg masses were collected and juveniles were hatched out and inoculated onto 10 nematode-free plants of A. barteri in a greenhouse. After 40 days, roots of A. barteri exhibited inconspicuous small galls, and the same identification procedures were conducted as mentioned previously. Isoenzyme phenotypes, perineal patterns of adult females, and amplified fragments of single juveniles were identical to those of M. arenaria. M. arenaria is one of the most important root-knot nematodes and causes great losses in many crops around the world (2). To our knowledge, this is the first record of M. arenaria parasitizing aquatic plants of broadleaf Anubias in China and elsewhere, and A. barteri is a new host of M. arenaria. The economic importance of this nematode to A. barteri production is currently unknown. However, because A. barteri is a commercial aquatic plant, more attention should be given by producers to prevent this nematode from becoming an important pathogen. In addition, this finding is very helpful for relevant plant nematode quarantine work. References: (1) P. R. Esbenshade and A. C. Triantaphyllou. J. Nematol. 17:1, 1985. (2) R. N. Perry et al. Root-Knot Nematodes. CABI. Wallingford, UK, 2009. (3) T. O. Powers and T. S. Harris. J. Nematol. 25:1, 1993.