tbuckley/cabot-search huggingface dataset:
A Novel Mutation in<i>ELOVL4</i>Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia
Authors: Kokoro Ozaki, Hiroshi Doi, Jun Mitsui, Nozomu Sato, Yoichiro Iikuni, Takamasa Majima, Kiyomi Yamane, Takashi Irioka, Hiroyuki Ishiura, Koichiro Doi, Shinichi Morishita, Miwa Higashi, Teruhiko Sekiguchi, Kazuo Koyama, Naohisa Ueda, Yoshiharu Miura, Satoko Miyatake, Naomichi Matsumoto, Takanori Yokota, Fumiaki Tanaka, Shoji Tsuji, Hidehiro Mizusawa, Kinya Ishikawa
Journal: JAMA Neurology (2015)

IMPORTANCEAlthough mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTSClinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURESResults of neurological examinations and radiological evaluations.The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life.Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients.Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G,p.W246G) in both families.Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor.Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCECombined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem.We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent.The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.
Nodular secondary syphilis
Authors: None Papini, None Bettacchi, None Guiducci
Journal: British Journal of Dermatology (1998)

Nodular secondary syphilis in a 23‐year‐old Indian man was characterized by numerous papular, nodular and plaque skin lesions, without involvement of the mucous membranes. The histopathology showed sarcoid‐like granulomata with lymphocytes, histiocytes, eosinophils, plasma cells and multinucleated giant cells. The differential diagnosis included deep mycoses, leprosy, tuberculosis, sarcoidosis and lymphoma. The results of serological tests and the rapid response to penicillin indicated a correct diagnosis.
Mitotically Inactivated Embryonic Stem Cells Can Be Used as an In Vivo Feeder Layer to Nurse Damaged Myocardium after Acute Myocardial Infarction
Authors: Richard K. Burt, You-hong Chen, Larissa Verda, Carolina Lucena, Shankararao Navale, Jesse Johnson, Xiaoqiang Han, Jon Lomasney, Jessa M. Baker, Ka-Leung Ngai, Aya Kino, James Carr, Jan Kajstura, Piero Anversa
Journal: Circulation Research (2012)

Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown.To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences.After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls.As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells
Authors: Nicola J. Curtin, Lan-Zhen Wang, Anthie Yiakouvaki, Suzanne Kyle, Christine A. Arris, Stacie Canan-Koch, Stephen E. Webber, Barbara W. Durkacz, Hilary A. Calvert, Zdenek Hostomsky, David R. Newell
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Mismatch repair (MMR) deficiency confers resistance to temozolomide, a clinically active DNA-methylating agent. The purpose of the current study was to investigate the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells. Experimental Design: The effects of AG14361, in comparison with the methylguanine DNA methyltransferase inhibitor, benzylguanine, on temozolomide-induced growth inhibition were investigated in matched pairs of MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and -deficient (HCT116, CP70, and CP70-ch2) cells. Results: AG14361 enhanced temozolomide activity in all MMR-proficient cells (1.5–3.3-fold) but was more effective in MMR-deficient cells (3.7–5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increased the efficacy of temozolomide in MMR-proficient cells but was ineffective in MMR-deficient cells. The differential effect of AG14361 in MMR-deficient cells was not attributable to differences in PARP-1 activity or differences in its inhibition by AG14361, nor was it attributable to differences in DNA strand breaks induced by temozolomide plus AG14361. MMR-deficient cells are resistant to cisplatin, but AG14361 did not sensitize any cells to cisplatin. PARP-1 inhibitors potentiate topotecan-induced growth inhibition, but AG14361 did not potentiate topotecan in MMR-deficient cells more than in MMR-proficient cells. Conclusions: MMR defects are relatively common in sporadic tumors and cancer syndromes. PARP-1 inhibition represents a novel way of selectively targeting such tumors. The underlying mechanism is probably a shift of the cytotoxic locus of temozolomide to N7-methylguanine and N3-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.
Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?
Authors: Arnaud Millet, Magali Pederzoli-Ribeil, Loïc Guillevin, Véronique Witko-Sarsat, Luc Mouthon
Journal: Annals of the Rheumatic Diseases (2013)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.
Prognostic factors for patellofemoral pain: a multicentre observational analysis
Authors: Natalie J Collins, Sita M A Bierma-Zeinstra, Kay M Crossley, Robbart L van Linschoten, Bill Vicenzino, Marienke van Middelkoop
Journal: British Journal of Sports Medicine (2012)

Objectives Describe proportions of individuals with patellofemoral pain (PFP) with an unfavourable recovery over 12 months; identify clinical predictors of poor recovery at 3 and 12 months; and determine baseline values of predictors that identify those with poor 12-month prognosis. Methods An observational analysis utilised data from 310 individuals with PFP enrolled in two randomised clinical trials. Thirteen baseline variables (participant, PFP, study characteristics) were investigated for their prognostic ability. Pain, function and global recovery were measured at 3 and 12 months. Multivariate backward stepwise regression analyses (treatment-adjusted, p&lt;0.10) were performed for each follow-up measure. Receiver operator characteristic curves identified cut-points associated with unfavourable recovery at 12 months. Results 55% and 40% of participants had an unfavourable recovery at 3 and 12 months, respectively. Longer baseline pain duration was significantly associated with poor 3-month and 12-month recovery on measures of pain severity (β 11.36 to 24.94), Anterior Knee Pain (AKP) Scale (−4.44 to −11.33) and global recovery (OR: 2.32 to 6.11). Greater baseline pain severity and lower AKP Scale score were significantly associated with poor recovery on multiple measures (p&lt;0.05). Baseline duration &gt;2 months and AKP Scale score &lt;70/100 were associated with unfavourable 12-month recovery. Conclusions A substantial number of individuals with PFP have an unfavourable recovery over 12 months, irrespective of intervention. Knee pain duration &gt;2 months is the most consistent prognostic indicator, followed by AKP Scale score &lt;70. Sports medicine practitioners should utilise interventions with known efficacy in reducing PFP, and promote early intervention to maximise prognosis. Trial registration Australian study: Australian Clinical Trials Registry (ACTRN012605000463673), ClinicalTrials.gov ( NCT00118521 ); Dutch study: International Standard Randomised Controlled Trial Number Register ( ISRCTN83938749 )
Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells
Authors: Beatrice E Bachmeier, Cristina M Iancu, Peter H Killian, Emanuel Kronski, Valentina Mirisola, Giovanna Angelini, Marianne Jochum, Andreas G Nerlich, Ulrich Pfeffer
Journal: Molecular Cancer (2009)

Curcumin induces apoptosis in many cancer cells and it reduces xenograft growth and the formation of lung metastases in nude mice. Moreover, the plant derived polyphenol has been reported to be able to overcome drug resistance to classical chemotherapy. These features render the drug a promising candidate for tumor therapy especially for cancers known for their high rates concerning therapy resistance like melanoma. We show here that the melanoma cell line M14 is resistant to Curcumin induced apoptosis, which correlates with the absence of any effect on NFκB signaling. We show that CXCL1 a chemokine that is down regulated in breast cancer cells by Curcumin in an NFκB dependant manner is expressed at variable levels in human melanomas. Yet in M14 cells, CXCL1 expression did not change upon Curcumin treatment. Following the hypothesis that Curcumin is rapidly removed from the resistant cells, we analyzed expression of known multi drug resistance genes and cellular transporters in M14 melanoma cells and in the Curcumin sensitive breast cancer cell line MDA-MB-231. ATP-binding cassette transporter ABCA1, a gene involved in the cellular lipid removal pathway is over-expressed in resistant M14 melanoma as compared to the sensitive MDA-MB-231 breast cancer cells. Gene silencing of ABCA1 by siRNA sensitizes M14 cells to the apoptotic effect of Curcumin most likely as a result of reduced basal levels of active NFκB. Moreover, ABCA1 silencing alone also induces apoptosis and reduces p65 expression. Resistance to Curcumin thus follows classical pathways and ABCA1 expression should be considered as response marker.
Origin of the atrial electrogram recorded from the esophagus.
Authors: E N Prystowsky, E L Pritchett, J J Gallagher
Journal: Circulation (1980)

The purpose of this study was to ascertain the origin of the atrial electrogram recorded on the esophageal lead. The atria and esophagus were mapped during reciprocating tachycardia in 11 patients with the Wolff-Parkinson-White syndrome and one patient with atrioventricular nodal reentry, and during right ventricular pacing in four additional patients. The esophagus was mapped by recording atrial electrograms at 1-cm intervals throughout the esophagus beginning at the most distal area where atrial depolarization was seen. The retrograde atrial activation time recorded on the esophageal lead in its distal position occurred at the same time as atrial septal depolarization in all patients. In 14 of 16 patients, the distal esophageal ventriculoatrial (VA) conduction time was also the shortest esophageal VA conduction time recorded. In two of five patients with left lateral accessory pathways, the shortest esophageal VA conduction time was noted during pullback of the lead from the esophagus instead of at the most distal area. The most likely explanation for this was an unusual anatomic relationship between the esophagus and left atrium in these two patients. We conclude that 1) the most distal esophageal atrial electrogram probably records posterior paraseptal atrial depolarization; 2) it is unusual to record clearly identifiable left atrial activation in the esophagus; and 3) the esophageal lead is not useful in locating left-sided accessory pathways.
PTU-150 Eo: Are We Getting The Message Yet?
Authors: IA Murray
Journal: Gut (2014)

<h3>Introduction</h3> Eosinophilic oesophagitis (EO) is the underlying diagnosis in at least 10% of those with dysphagia. To make the diagnosis, oesophageal biopsies showing an eosinophil count &gt;15 per hpf are required. It is most frequent in males under aged 50 years. <h3>Methods</h3> All patients having a gastroscopy for dysphagia were identified retrospectively for 6 consecutive years from our endoscopy reporting system. Patient demographics, endoscopic findings and whether biopsies were taken were recorded together with histology results. <h3>Results</h3> 3068 patients had a gastroscopy with an indication of dysphagia (1489 female, age 15–100 years, average 67.7 y). The number of patients varied little between years (486–550 patients/year). Common endoscopic diagnoses were normal (20.4%), benign stricture (12.6%), oesophagitis (18.1%), Barrett’s (4.8%), dysmotility (3.7%) and hiatus hernia (10%). 1620 (52.8%) had oesophageal biopsies. 44 patients (1.5% of all patients) were diagnosed with EO, 32 of who were males. This equates to 2.8% of those who were biopsied and 4.7% of those biopsied without cancer, stricture or Barrett’s. Although only 13.3% of those with dysphagia were aged 50 years or under, they equated to 45.4% of those diagnosed with EO. Of those with EO, 6 had food bolus, 6 “typical” EO changes e.g., feline oesophagus, ridges etc, 4 an irritable oesophagus and 3 Schatzki rings. <h3>Conclusion</h3> EO is a relatively common cause of dysphagia but is almost certainly under-recognised due to lack of oesophageal biopsies at endoscopy. Reliance on endoscopic changes of EO at endoscopy will miss the majority of cases. Although biopsying only those under 50 years would be more cost effective than biopsying all, it would also miss the majority of cases. It may be appropriate for the BSG to use frequency of oesophageal biopsies in dysphagic patients as a quality assurance measure for upper GI endoscopy. <h3>Disclosure of Interest</h3> None Declared.
Population-Based Risk Assessment of APOL1 on Renal Disease
Authors: David J. Friedman, Julia Kozlitina, Giulio Genovese, Prachi Jog, Martin R. Pollak
Journal: Journal of the American Society of Nephrology (2011)

Case-control studies suggest that African Americans with genetic variants in both copies of APOL1 have increased risk for hypertension-attributable ESRD and focal segmental glomerulosclerosis. Here, we tested these risk variants in the Dallas Heart Study to ascertain the prevalence of APOL1-associated renal disease in a large population-based study and to estimate the contribution of APOL1 risk variants to disparities in renal disease. We determined the genotype of 1825 African Americans and 1042 European Americans. Among participants without diabetes, we identified microalbuminuria in 2.3% of European Americans, 6.0% of African Americans with no or one APOL1 risk allele, and 16.5% of African Americans with two risk alleles. In addition, the proportions of participants with estimated GFR < 60 ml/min per 1.73 m2 was 1.5% for nondiabetic European Americans, 1.7% for African Americans with no or one APOL1 risk allele, and 6.7% for African Americans with two risk alleles. The APOL1 genotype did not associate with any differences in rates of CKD for study participants with diabetes. Our data suggest that more than 3 million African Americans likely have the high-risk genotype and are at markedly increased risk for nondiabetic CKD. In contrast, African Americans without the risk genotype and European Americans appear to have similar risk for developing nondiabetic CKD.
Asthma in Inner-City Children at 5–11 Years of Age and Prenatal Exposure to Phthalates: The Columbia Center for Children’s Environmental Health Cohort
Authors: Robin M. Whyatt, Matthew S. Perzanowski, Allan C. Just, Andrew G. Rundle, Kathleen M. Donohue, Antonia M. Calafat, Lori A. Hoepner, Frederica P. Perera, Rachel L. Miller
Journal: Environmental Health Perspectives (2014)

Background: Studies suggest that phthalate exposures may adversely affect child respiratory health.Objectives: We evaluated associations between asthma diagnosed in children between 5 and 11 years of age and prenatal exposures to butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), and diethyl phthalate (DEP).Methods: Phthalate metabolites were measured in spot urine collected from 300 pregnant inner-city women. Children were examined by an allergist or pulmonologist based on the first parental report of wheeze, other respiratory symptoms, and/or use of asthma rescue/controller medication in the preceding 12 months on repeat follow-up questionnaires. Standardized diagnostic criteria were used to classify these children as either having or not having current asthma at the time of the physician examination. Children without any report of wheeze or the other asthma-like symptoms were classified as nonasthmatics at the time of the last negative questionnaire. Modified Poisson regression analyses were used to estimate relative risks (RR) controlling for specific gravity and potential confounders.Results: Of 300 children, 154 (51%) were examined by a physician because of reports of wheeze, other asthma-like symptoms, and/or medication use; 94 were diagnosed with current asthma and 60 without current asthma. The remaining 146 children were classified as nonasthmatic. Compared with levels in nonasthmatics, prenatal metabolites of BBzP and DnBP were associated with a history of asthma-like symptoms (p &lt; 0.05) and with the diagnosis of current asthma: RR = 1.17 (95% CI: 1.01, 1.35) and RR = 1.25 (95% CI: 1.04, 1.51) per natural log-unit increase, respectively. Risk of current asthma was &gt; 70% higher among children with maternal prenatal BBzP and DnBP metabolite concentrations in the third versus the first tertile.Conclusion: Prenatal exposure to BBzP and DnBP may increase the risk of asthma among inner-city children. However, because this is the first such finding, results require replication.Citation: Whyatt RM, Perzanowski MS, Just AC, Rundle AG, Donohue KM, Calafat AM, Hoepner LA, Perera FP, Miller RL. 2014. Asthma in inner-city children at 5–11 years of age and prenatal exposure to phthalates: the Columbia Center for Children’s Environmental Health Cohort. Environ Health Perspect 122:1141–1146; http://dx.doi.org/10.1289/ehp.1307670
A Homozygous<i>CARD9</i>Mutation in a Family with Susceptibility to Fungal Infections
Authors: Erik-Oliver Glocker, Andre Hennigs, Mohammad Nabavi, Alejandro A. Schäffer, Cristina Woellner, Ulrich Salzer, Dietmar Pfeifer, Hendrik Veelken, Klaus Warnatz, Fariba Tahami, Sarah Jamal, Annabelle Manguiat, Nima Rezaei, Ali Akbar Amirzargar, Alessandro Plebani, Nicole Hannesschläger, Olaf Gross, Jürgen Ruland, Bodo Grimbacher
Journal: New England Journal of Medicine (2009)

Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described.
Cardiovascular therapeutic uses of targeted ultrasound contrast agents
Authors: S. T. Laing, D. D. McPherson
Journal: Cardiovascular Research (2009)

The therapeutic use of ultrasound contrast agents (UCAs) is an emerging methodology with high potential for enhanced directed therapeutic gene, bioactive gas, drug, and stem cell delivery. Ultrasound-targeted microbubble destruction has already demonstrated feasibility for plasmid DNA delivery. Similarly, therapeutic ultrasound for thrombolysis treatment has been taken into the clinical setting, and the addition of UCAs for therapeutic delivery or enhanced effect through cavitation is a natural progression to this investigation. However, as with any new technique, safety needs to be first demonstrated before translation into clinical practice. This review article will focus on the development of UCAs for cardiac and vascular therapeutics as well as the limitations/concerns for the use of therapeutic ultrasound in clinical medicine in order to lay a foundation for investigators planning to enter this exciting field or for those who want to broaden their understanding.
Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment
Authors: H.J. Schmoll, M.S. Aapro, S. Poli-Bigelli, H.-K. Kim, K. Park, K. Jordan, J. von Pawel, H. Giezek, T. Ahmed, C.Y. Chan
Journal: Annals of Oncology (2006)