tbuckley/cabot-search huggingface dataset:
Dynorphin Acts as a Neuromodulator to Inhibit Itch in the Dorsal Horn of the Spinal Cord
Authors: Adam P. Kardon, Erika Polgár, Junichi Hachisuka, Lindsey M. Snyder, Darren Cameron, Sinead Savage, Xiaoyun Cai, Sergei Karnup, Christopher R. Fan, Gregory M. Hemenway, Carcha S. Bernard, Erica S. Schwartz, Hiroshi Nagase, Christoph Schwarzer, Masahiko Watanabe, Takahiro Furuta, Takeshi Kaneko, H. Richard Koerber, Andrew J. Todd, Sarah E. Ross
Journal: Neuron (2014)

Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5(-/-) mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
Transvascular intracardiac applications of a miniaturized phased-array ultrasonic endoscope. Initial experience with intracardiac imaging in piglets.
Authors: L M Valdes-Cruz, E Sideris, D J Sahn, A Murillo-Olivas, O Knudson, R Omoto, S Kyo, R Gulde
Journal: Circulation (1991)

Recent advances in miniaturization of phased-array and mechanical ultrasound devices have resulted in exploration of alternative approaches to cardiac and vascular imaging in the form of transesophageal or intravascular imaging. Preliminary efforts in adapting phased-array endoscopes designed for transesophageal use to a transvascular approach have used full-sized phased-array devices introduced directly into the right atrium in open-chested animals. The purpose of this study was to assess the feasibility of using a custom-made, very small phased-array endoscope for intracardiac imaging introduced intravascularly through a jugular venous approach in young piglets.Experimental atrial septal defects created in four piglets (3-4 weeks old) had been closed with a buttoned atrial septal defect closure device consisting of an occluder in the left atrium and a counteroccluder in the right atrium. Five to 15 days after atrial septal defect closure, the piglets were returned to the experimental laboratory, where a 6.3-mm, 17-element, 5-MHz phased-array probe mounted on a 4-mm endoscope was introduced through a cutdown incision of the external jugular vein and advanced to the right atrium. From the right atrium all four cardiac chambers, their inflows and outflows, and all four valves were well imaged with minimal superior and inferior rotation. High-resolution imaging of the atrial septum defined with anatomical accuracy, later verified by autopsy, the exact placement of both the occluder and counteroccluder in the left and right sides of the atrial septal defects and the absence of any shunting across the atrial septum in any of the four animals.Our efforts indicate that transvascular passage of small phased-array probes can be easily accomplished and is a promising technique for detailed visualization of cardiac structures. This approach may provide an alternative to transesophageal echocardiography, particularly for guiding interventional procedures such as placement of transcatheter closure devices in pediatric patients.
Cortical Control of Whisker Movement
Authors: Carl C.H. Petersen
Journal: Annual Review of Neuroscience (2014)

Facial muscles drive whisker movements, which are important for active tactile sensory perception in mice and rats. These whisker muscles are innervated by cholinergic motor neurons located in the lateral facial nucleus. The whisker motor neurons receive synaptic inputs from premotor neurons, which are located within the brain stem, the midbrain, and the neocortex. Complex, distributed neural circuits therefore regulate whisker movement during behavior. This review focuses specifically on cortical whisker motor control. The whisker primary motor cortex (M1) strongly innervates brain stem reticular nuclei containing whisker premotor neurons, which might form a central pattern generator for rhythmic whisker protraction. In a parallel analogous pathway, the whisker primary somatosensory cortex (S1) strongly projects to the brain stem spinal trigeminal interpolaris nucleus, which contains whisker premotor neurons innervating muscles for whisker retraction. These anatomical pathways may play important functional roles, since stimulation of M1 drives exploratory rhythmic whisking, whereas stimulation of S1 drives whisker retraction.
Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway
Authors: Lana McClements, Anita Yakkundi, Angelos Papaspyropoulos, Hannah Harrison, Matthew P. Ablett, Puthen V. Jithesh, Hayley D. McKeen, Rachel Bennett, Christopher Donley, Adrien Kissenpfennig, Stuart McIntosh, Helen O. McCarthy, Eric O'Neill, Robert B. Clarke, Tracy Robson
Journal: Clinical Cancer Research (2013)

FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC).Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence.AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESA(+)/CD44(+)/CD24(-) or aldehyde dehydrogenase (ALDH)(+) cell subpopulations in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01-mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy-induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling.AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial.
Non-publication and delayed publication of randomized trials on vaccines: survey
Authors: L. Manzoli, M. E. Flacco, M. D'Addario, L. Capasso, C. De Vito, C. Marzuillo, P. Villari, J. P. A. Ioannidis
Journal: BMJ (2014)

<b>Objective</b> To evaluate the extent of non-publication or delayed publication of registered randomized trials on vaccines, and to investigate potential determinants of delay to publication. <b>Design</b> Survey. <b>Data sources</b> Trials registry websites, Scopus, PubMed, Google. <b>Study selection</b> Randomized controlled trials evaluating the safety or the efficacy or immunogenicity of human papillomavirus (HPV), pandemic A/H1N1 2009 influenza, and meningococcal, pneumococcal, and rotavirus vaccines that were registered in ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, Clinical Study Register, or Indian, Australian-New Zealand, and Chinese trial registries in 2006-12. Electronic databases were searched up to February 2014 to identify published manuscripts containing trial results. These were reviewed and classified as positive, mixed, or negative. We also reviewed the results available in ClinicalTrials.gov. <b>Main outcome measures</b> Publication status of trial results and time from completion to publication in peer reviewed journals. <b>Data synthesis</b> Cox proportional hazards regression was used to evaluate potential predictors of publication delay. <b>Results</b> We analysed 384 trials (85% sponsored by industry). Of 355 trials (404 758 participants) that were completed, 176 (n=151 379) had been published in peer reviewed journals. Another 42 trials (total sample 62 765) remained unpublished but reported results in ClinicalTrials.gov. The proportion of trials published 12, 24, 36, and 48 months after completion was 12%, 29%, 53%, and 73%, respectively. Including results posted in ClinicalTrials.gov, 48 months after study completion results were available for 82% of the trials and 90% of the participants. Delay to publication between non-industry and industry sponsored trials did not differ, but non-industry sponsored trials were 4.42-fold (P=0.008) more likely to report negative or mixed findings. Negative results were reported by only 2% of the published trials. <b>Conclusions</b> Most vaccine trials are published eventually or the results posted in ClinicalTrials.gov, but delays to publication of several years are common. Actions should focus on the timely dissemination of data from vaccine trials to the public.
Noradrenaline as a Vasoconstrictor in Local Anaesthesia for Thoracoplasty
Authors: H. E. Bell
Journal: Thorax (1955)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
Effective multimodality treatment for advanced epidermoid carcinoma of the female genital tract.
Authors: J Kalra, E Cortes, S Chen, B Krumholz, J J Rovinsky, L Molho, V Seltzer, P Papantoniou, J Y Lee
Journal: Journal of Clinical Oncology (1985)

Fifteen patients with advanced or recurrent squamous-cell carcinoma of the cervix, vulva, vagina, and urethra were treated with simultaneous combination chemotherapy (5-fluorouracil infusion and mitomycin C) and radiotherapy (3,000 rad for a period of three weeks). Three to four weeks after completion of radiotherapy, 13 of 15 patients achieved partial or complete tumor shrinkage. Nine of 15 patients are alive, eight of whom (at a median follow-up time of 24 months) have no evidence of disease. The longest survival time was 45 + months. There was minimal toxicity associated with this therapy. The results of this pilot study suggest that the simultaneous administration of radiation and chemotherapy is an effective method of treatment of advanced female genital tract carcinoma.
Influence of dietary factors on colorectal cancer survival
Authors: X Dray
Journal: Gut (2003)

<b>Background:</b> Diet has been identified as a major determinant of colorectal cancer (CRC) but little is known of its influence on CRC survival. <b>Aims:</b> To study the influence of dietary factors on survival in patients who had undergone potentially curative CRC surgery. <b>Patients:</b> Among 171 patients included in a case control study of CRC aetiological factors, 10 year survival data on 148 patients who underwent resection of the tumour for potential cure were obtained from a Registry of Digestive Tumours. <b>Methods:</b> Tertiles of food and nutrient intakes were entered into Cox proportional hazards survival models, controlling for age, sex, tumour stage, and tumour location. <b>Results:</b> Only five year survival was influenced by the pre-diagnosis diet. High energy intake, as a result of high carbohydrate, protein, and lipid intake, was strongly related to increased survival. Five year relative risk of death for the highest versus the two lowest tertiles of energy intake was 0.18 (95% confidence interval 0.07; 0.44). This effect was similar in both sexes, for the colon and for the rectum. It was stronger in patients with N+/M+ tumours (relative risk 0.06) than in those with less advanced tumours (relative risk 0.37; stage-energy interaction term non-significant). No specific food or nutrient could be identified as having prognostic significance. <b>Conclusions:</b> Whether high energy intake selects less severe tumoral clones or modifies antitumoral immunity remains unclear. Larger series need to be investigated before conducting intervention studies but our findings should prompt nutritional follow up in CRC patients.
Familial Hyperproinsulinemia Associated With NIDDM: A case study
Authors: Hiroshi Oohashi, Hisako Ohgawara, Kishio Nanjo, Yoshimasa Tasaka, Qiu-Ping Cao, Shu Jin Chan, Arthur H Rubenstein, Donald F Steiner, Yasue Omori
Journal: Diabetes Care (1993)

OBJECTIVE To report studies on an elderly patient with moderate NIDDM associated with marked fasting hyperinsulinemia. RESEARCH DESIGN AND METHODS The propositus and several family members were studied by a combination of clinical, biochemical, and molecular genetic approaches to define the underlying genetic defect. RESULTS Fasting levels of contrainsulin hormones were normal, and resistance to exogenous insulin was absent. Gel filtration and reverse-phase high-performance liquid chromatography revealed elevated amounts of a structurally abnormal proinsulin intermediate (AC proinsulin). A study of the family of the propositus showed rhe same abnormality in 4 of 5 members in 3 successive generations. Genetic analysis revealed a point mutation affecting residue 65 of human proinsulin (Arg→His) in one allele of the insulin gene in the propositus, a defect similar to that described previously in 3 other apparently unrelated lineages. CONCLUSIONS This family exhibits a clear-cut relationship between increasing age and metabolic decompensation in all the hyperproinsulinemic members, suggesting that (inherited) metabolic stress and age both contribute to development of diabetes mellitus.
Association of Interferon‐ and Transforming Growth Factor β–Regulated Genes and Macrophage Activation With Systemic Sclerosis–Related Progressive Lung Fibrosis
Authors: Romy B. Christmann, Percival Sampaio‐Barros, Giuseppina Stifano, Claudia L. Borges, Carlos R. de Carvalho, Ronaldo Kairalla, Edwin R. Parra, Avrum Spira, Robert Simms, Vera L. Capellozzi, Robert Lafyatis
Journal: Arthritis & Rheumatology (2013)

Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease.Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein.Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor β (TGFβ)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins.These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFβ- and IFN-regulated genes.
Hospital-Level Compliance With Asthma Care Quality Measures at Children's Hospitals and Subsequent Asthma-Related Outcomes
Authors: Rustin B. Morse, Matthew Hall, Evan S. Fieldston, Gerd McGwire, Melanie Anspacher, Marion R. Sills, Kristi Williams, Naomi Oyemwense, Keith J. Mann, Harold K. Simon, Samir S. Shah
Journal: JAMA (2011)

The Children's Asthma Care (CAC) measure set evaluates whether children admitted to hospitals with asthma receive relievers (CAC-1) and systemic corticosteroids (CAC-2) and whether they are discharged with a home management plan of care (CAC-3). It is the only Joint Commission core measure applicable to evaluate the quality of care for hospitalized children.To evaluate longitudinal trends in CAC measure compliance and to determine if an association exists between compliance and outcomes.Cross-sectional study using administrative data and CAC compliance data for 30 US children's hospitals. A total of 37,267 children admitted with asthma between January 1, 2008, and September 30, 2010, with follow-up through December 31, 2010, accounted for 45,499 hospital admissions. Hospital-level CAC measure compliance data were obtained from the National Association of Children's Hospitals and Related Institutions. Readmission and postdischarge emergency department (ED) utilization data were obtained from the Pediatric Health Information System.Children's Asthma Care measure compliance trends; postdischarge ED utilization and asthma-related readmission rates at 7, 30, and 90 days.The minimum quarterly CAC-1 and CAC-2 measure compliance rates reported by any hospital were 97.1% and 89.5%, respectively. Individual hospital CAC-2 compliance exceeded 95% for 97.9% of the quarters. Lack of variability in CAC-1 and CAC-2 compliance precluded examination of their association with the specified outcomes. Mean CAC-3 compliance was 40.6% (95% CI, 34.1%-47.1%) and 72.9% (95% CI, 68.8%-76.9%) for the initial and final 3 quarters of the study, respectively. The mean 7-, 30-, and 90-day postdischarge ED utilization rates were 1.5% (95% CI, 1.3%-1.6%), 4.3% (95% CI, 4.0%-4.5%), and 11.1% (95% CI, 10.5%-11.7%) and the mean quarterly 7-, 30-, and 90-day readmission rates were 1.4% (95% CI, 1.2%-1.6%), 3.1% (95% CI, 2.8%-3.3%), and 7.6% (95% CI, 7.2%-8.1%). There was no significant association between overall CAC-3 compliance (odds ratio [OR] for 5% improvement in compliance) and postdischarge ED utilization rates at 7 days (OR, 1.00; 95% CI, 0.98-1.02), 30 days (OR, 0.97; 95% CI, 0.90-1.04), and 90 days (OR, 0.96; 95% CI, 0.77-1.18). In addition, there was no significant association between overall CAC-3 compliance (OR for 5% improvement in compliance) and readmission rates at 7 days (OR, 1.00; 95% CI, 0.99-1.02), 30 days (OR, 0.99; 95% CI, 0.96-1.02), and 90 days (OR, 1.01; 95% CI, 0.90-1.12).Among children admitted to pediatric hospitals for asthma, there was high hospital-level compliance with CAC-1 and CAC-2 quality measures and moderate compliance with the CAC-3 measure but no association between CAC-3 compliance and subsequent ED visits and asthma-related readmissions.
An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection
Authors: Andrew J. Vickers, Cathee Till, Catherine M. Tangen, Hans Lilja, Ian M. Thompson
Journal: JNCI Journal of the National Cancer Institute (2011)

The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE).To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied. PSA cut points with a comparable specificity to PSA velocity cut points had a higher sensitivity (23% vs 19%), particularly for high-grade (41% vs 25%) and clinically significant (32% vs 22%) disease. These findings were robust to the method of calculating PSA velocity.We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.
A Phase I Study of the Combination of Intravenous Reovirus Type 3 Dearing and Gemcitabine in Patients with Advanced Cancer
Authors: Martijn P. Lolkema, Hendrik-Tobias Arkenau, Kevin Harrington, Patricia Roxburgh, Rosemary Morrison, Victoria Roulstone, Katie Twigger, Matt Coffey, Karl Mettinger, George Gill, T.R. Jeffry Evans, Johann S. de Bono
Journal: Clinical Cancer Research (2010)

This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 10(10) TCID(50). Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay.Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response.Reovirus at the dose of 1 × 10(10) TCID(50) can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule.