tbuckley/cabot-search huggingface dataset:
Immunomodulation of Autoimmune and Inflammatory Diseases with Intravenous Immune Globulin
Authors: Michel D. Kazatchkine, Srini V. Kaveri
Journal: New England Journal of Medicine (2001)

Intravenous immune globulin has been used in the treatment of primary and secondary antibody deficiencies for more than 25 years. It is a safe preparation with no long-term side effects. Intravenous immune globulin was first demonstrated to be effective in an autoimmune disorder — idiopathic thrombocytopenic purpura — two decades ago. Since then, it has been established to be efficacious in the treatment of the Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, corticosteroid-resistant dermatomyositis, and Kawasaki's syndrome and in the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants. Benefits have been reported in many other autoimmune . . .
Huntington’s case raises questions about passing gene test results to relatives
Authors: Clare Dyer
Journal: BMJ (2017)

Doctors could come under a new duty of care to the families of patients with hereditary illnesses, after the Court of Appeal ruled that a test case should be heard by the High Court in London.

Three appeal court judges unanimously overturned a 2015 decision by a High Court judge to throw out a claim against three NHS trusts by the daughter of a man with Huntington’s disease.1 The unnamed woman’s father was convicted of manslaughter in 2007 after shooting her mother dead. He was sentenced to a hospital order and detained at Springfield University Hospital, run by South West London and St George’s Mental Health NHS Trust.

Doctors there began to suspect that he had Huntington’s disease and referred him to St George’s Hospital, part of St …
Abstract 095: Uncoupling The Mitochondria Facilitates Alternans Formation In The Isolated Rabbit Heart
Authors: Elena Tolkacheva, Jillian Wothe, Iryna Talkachova, Rebecca Smith, Ramjay Visweswaran
Journal: Circulation Research (2013)

Alternans of action potential duration (APD) and intracellular calcium ([Ca 2+ ] i ) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled. This uncoupling may play an important role in alternans formation in the heart. The aim of our study was to investigate the role of mitochondrial depolarization on the formation of APD and [Ca 2+ ] i alternans in the isolated rabbit heart. We performed dual voltage and [Ca 2+ ] i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia (n=6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n=6). We investigated the formation of alternans of APD, [Ca 2+ ] i amplitude (CaA), and [Ca 2+ ] i duration (CaD) in the heart, under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD (192 ± 18 ms vs 136 ± 6 ms, p&lt;0.05), CaD (182 ± 20 ms vs 133 ± 6 ms, p&lt;0.05), and CaA (152 ± 5 ms vs 141 ± 3 ms, p&lt;0.05) alternans, and an increase of intraventricular APD (0.44 ± 0.02 vs 0.2 ± 0.05, p&lt;0.05) but not CaD (0.20 ± 0.03 vs 0.16 ± 0.03, p=N/S) heterogeneity, when compared to control. On the other hand, FCCP does not affect the conduction velocity in the heart (0.95 ± 0.06 m/s vs 1.05 ± 0.11 m/s, p=N/S). Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca 2+ ] i transients, whereas ischemia induces a significantly larger reduction of APD compared to FCCP treatment. Our results demonstrate that uncoupling of mitochondria leads to earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca 2+ ] i alternans in the heart, which in turn creates a substrate conducive to formation of ventricular arrhythmias.
Psoriasis shows no association with filaggrin-null alleles
Authors: M H Allen, Y Zhao, A Terron-Kwiatkowski, H Liao, S P Lee, P R Hull, L M Campbell, Richard Trembath, Francesca Capon, G O'Regan, C E M Griffiths, D Burden, R McManus, R Hughes, B Kirby, O FitzGerald, D Kane, A D Irvine, C N A Palmer, Jonathan Barker, W H I McLean
Journal: British Journal of Dermatology (2007)
Compliance in guideline-based management of febrile neutropenia.
Authors: Michael J Hoffman, Sarah Yentz, Charlotta Weaver, Kevin O'Leary, Suchi Gandhi, Jeremy Katzen, Sarah Sutton
Journal: Journal of Clinical Oncology (2015)

e17667 Background: Neutropenic Fever (NF) is a prevalent complication of myelosuppressive chemotherapy with significant morbidity, mortality, and cost. Despite clear treatment guidelines by the Infectious Diseases Society of America (IDSA), there is variability in physician compliance. We aimed to gauge IDSA guideline compliance for treatment of NF, drivers of non-compliance, and associated outcomes. Methods: We conducted a retrospective chart review of NF admissions to a large tertiary care hospital in Chicago, IL from 1/1/13 - 6/30/13. We identified 74 adult patients with ANC < 1000 and temperature > 100.4°F within 48 hours of admission to a cancer unit or ICU; 65 were managed for NF and included in analysis. Guideline compliance was based on a six point score: 1) fever; 2) neutropenia; 3) blood cultures before antibiotics; 4) appropriate empiric antibiotics; 5) appropriate antibiotics 48-72 hours; 6) appropriate antibiotics day 4-7. Each parameter scored 1 if compliant, with a total of 6 if fully compliant, 4-5 partially compliant, and 0-3 non-compliant. Results: See Table. Drivers of non-compliance: Empiric vancomycin was used in 53.8% of cases, with no indication in 40%. Overall, 27.7%, 21.5%, and 26.2% of patients received improper antibiotics at admission, 48-72 hours, and day 4-7 respectively. Vancomycin use without indication was a common driver of this and was the reason for improper antibiotics in 77.8%, 57.1%, and 35.3% of cases at these time points respectively. At day 4-7 there was no indication for antibiotics at all in 41.2% of patients who received improper antibiotics. Altogether, patients received 126 doses of vancomycin with no indication (mean 5.5 per patient). Conclusions: Despite IDSA’s NF guidelines, compliance is poor and appears to be mainly driven by vancomycin overuse. In light of the relatively high rate of adverse drug reactions, new Clostridium difficile, and new VRE, further intervention is needed to improve compliance with established NF guidelines. Compliance 41.5% Fully Compliant (6) 40.0% Partially Compliant (4-5) 18.5% Non-compliant (0-3) Outcomes 6.2% ICU transfer 4.6% inpatient mortality 4.6% adverse antibiotic reaction 9.2% Clostridium difficile, 90 days 7.7% new VRE, 90 days (60% infection; 40% colonization)
Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability
Authors: Jianying Huang, Carlos G. Vanoye, Alison Cutts, Y. Paul Goldberg, Sulayman D. Dib-Hajj, Charles J. Cohen, Stephen G. Waxman, Alfred L. George
Journal: Journal of Clinical Investigation (2017)

Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.
Persistent Gaps in Use of Advance Directives Among Nursing Home Residents Receiving Maintenance Dialysis
Authors: Manjula Kurella Tamura, Sai Liu, Maria E. Montez-Rath, Ann M. O’Hare, Yoshio N. Hall, Karl A. Lorenz
Journal: JAMA Internal Medicine (2017)

This data analysis seeks to determine whether changes in the use of advance directives between 2000 and 2010 are related to changing patterns of end-of-life care among nursing home residents receiving dialysis.
Biological significance of serum VEGF measurement in renal cell carcinoma
Authors: J. Patard, N. Rioux-Leclercq, K. Bensalah, P. Fergelot
Journal: Journal of Clinical Oncology (2006)

4596 Background: VEGF plays an important role in Renal Cell Carcinoma (RCC) tumor angiogenesis and is a relevant molecular target. Our objective was to correlate serum VEGF measurement to clinical, biological and pathological variables in renal tumors. Methods: 206 patients who were operated for a renal tumor at our institution were prospectively assessed for serum VEGF measurement (enzyme-linked immunosorbent assay, R&amp;D systems). Informed consent was obtained in all cases. Symptoms at presentation, pre-operative biology (haemoglobin, WBC count, platelet count, serum creatinin, calcemia, CRP, ASAT, ALAT, gamma-glutamyltransferase (γGT), Alkaline Phosphatases), TNM stage, Fuhrman grade and final pathology (benign vs malignant histology, histologic subtype) were systematically recorded. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: There were 128 males (62.1%) and 78 females (37.9%). 185 tumors were malignant at histology (89.8%) including 155 tumors with clear cell histology (83.8%). Median serum VEGF level was 361 ng/ml (41–3090). Mean serum VEGF was not significantly different between benign and malignant tumors as well as between clear cell and non clear cell carcinomas (p: 0.4 and 0.8 respectively). Serum VEGF was strongly associated with symptoms, T Stage (p: 0.0001), N Stage (p: 0.004), Fuhrman grade (p: 0.007) and tumor necrosis (p: 0.004) but not with M Stage (p: 0.3). Serum VEGF was also found to be strongly associated with: haemoglobin, CRP, platelet count (p: 0.0001) and Alkaline phosphatases (p: 0.001). A weaker association was found between serum VEGF and γGT, ASAT (p: 0.05) or ALAT (p: 0.09). Finally serum VEGF was associated with cancer specific survival (p: 0.01). Conclusion: Serum VEGF is strongly associated with most usual clinical, biological and pathological prognostic parameters in RCC. Serum VEGF measurement should be further evaluated for prognostic purpose as well as for treatment monitoring. No significant financial relationships to disclose.
Frequency and epitope specificity of anti–factor VIII C1 domain antibodies in acquired and congenital hemophilia A
Authors: Joerg Kahle, Aleksander Orlowski, Diana Stichel, John F. Healey, Ernest T. Parker, Marc Jacquemin, Manuela Krause, Andreas Tiede, Dirk Schwabe, Pete Lollar, Christoph Königs
Journal: Blood (2017)
2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery
Authors: L. David Hillis, Peter K. Smith, Jeffrey L. Anderson, John A. Bittl, Charles R. Bridges, John G. Byrne, Joaquin E. Cigarroa, Verdi J. DiSesa, Loren F. Hiratzka, Adolph M. Hutter, Michael E. Jessen, Ellen C. Keeley, Stephen J. Lahey, Richard A. Lange, Martin J. London, Michael J. Mack, Manesh R. Patel, John D. Puskas, Joseph F. Sabik, Ola Selnes, David M. Shahian, Jeffrey C. Trost, Michael D. Winniford
Journal: Journal of the American College of Cardiology (2011)
Antitumor activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations miR-34a oncogenicity in β-catenin-mutated liver cancer
Authors: Angélique Gougelet, Chiara Sartor, Laura Bachelot, Cécile Godard, Carmen Marchiol, Gilles Renault, Frédéric Tores, Patrick Nitschke, Catherine Cavard, Benoit Terris, Christine Perret, Sabine Colnot
Journal: Gut (2016)

Objective: Hepatocellular carcinoma (HCC) is the most prevalent primary tumor of the liver. About a third of these tumors presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. Design: We used a mouse model, in which β-catenin signaling was overactivated exclusively in the liver, by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumors with properties similar to human HCC. Results: We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signaling in mouse tumors and in HCC patients. An inhibitor of miR-34a (LNA-34a) exerted anti-proliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumor suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumors displaying β-catenin activation together with an activation of caspases 2 and 3. Conclusion: This work demonstrates the key oncogenic role of miR-34a in liver tumors with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumor suppressor HNF-4α, which targets cyclin D1, and the induction of a pro-apoptotic program.
Risk score model for the development of hepatocellular carcinoma in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B
Authors: Won Sohn, Ju-Yeon Cho, Ji Hoon Kim, Jung Il Lee, Hyung Joon Kim, Min-Ah Woo, Sin-Ho Jung, Yong-Han Paik
Journal: Clinical and Molecular Hepatology (2017)

This study aimed to develop and validate a risk prediction model for the development of hepatocellular carcinoma (HCC) in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B (CHB).We investigated 2,061 Korean treatment-naïve patients with CHB treated with entecavir as an initial therapy. A risk score model for HCC development was developed based on multivariable Cox regression model in a single center (n=990) and was validated using the time-dependent area under the receiver operating characteristic curve (AUROC) in three other centers (n=1,071). The difference of HCC development among risk groups (low, intermediate, and high) categorized by risk score was also investigated.The cumulative incidence rates of HCC at 5 years were 11.2% and 8.9% in the testing and validation cohorts, respectively. HCC-Risk Estimating Score in CHB patients Under Entecavir (HCC-RESCUE) is formulated as (age+15×gender [female=0 / male=1]+23×cirrhosis [absence=0 / presence=1]). The AUROCs at 1 year, 3 years, and 5 years were 0.82, 0.81, and 0.81, respectively, in the validation cohort. A significant difference of HCC development in each risk group was determined by the 5-year HCC risk score in the validation cohort (low risk group, 2.1%; intermediate risk group, 9.3%; high risk group, 41.2%, p<0.001).The study presents a new risk score model with a good ability to predict HCC development and determine high risk patients for HCC development consisting of readily available clinical factors in treatment-naïve CHB patients receiving entecavir.
The Outcome of Congenital Cytomegalovirus Infection in Relation to Maternal Antibody Status
Authors: Karen B. Fowler, Sergio Stagno, Robert F. Pass, William J. Britt, Thomas J. Boll, Charles A. Alford
Journal: New England Journal of Medicine (1992)

Intrauterine transmission of cytomegalovirus (CMV) can occur whether a mother has prior immunity or acquires CMV for the first time during pregnancy. The degree of protection afforded an infected infant by the presence of antibody in the mother before conception is uncertain.
Lessons to Be Learned From 22q11.2 Syndromes
Authors: Simon Vann Jones
Journal: JAMA Psychiatry (2017)

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Dual photon microscopy based quantitation of fibrosis‐related parameters (q‐FP) to model disease progression in steatohepatitis: Methodological issues
Authors: Saeid Safiri, Erfan Ayubi
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read the valuable article authored by Wang et al. published in Hepatology in 2017, with great interest.1 The aim of their study was to examine hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). In the study, they used dual photon microscopy based quantitation of fibrosis‐related parameters (q‐FPs). In addition, the univariate and multivariate analyses were conducted on 50 patients with NAFLD and the full spectrum of fibrosis (fibrosis stage I [n = 9], stage II [n = 12], stage III [n = 12], stage IV [n = 7], and stage V [n = 10]). The main finding of their study was that both in the univariate (odds ratio [OR] = 7.16; 95% confidence interval [CI], 3.10‐16.53) and multivariate models (OR = 11.98; 95% CI, 1.47‐97.30), strand length was significantly associated with fibrosis stage. It seems that the finding of their study may be problematic and cannot be valid. Generally, it is argued that large effect estimates such as OR with remarkably wide CI should not be regarded as a large effect. It is because of the fact that they may result from sparse data in which the number of events in different combinations of Exposure and Outcome variables is scarce.2 In other words, in multivariate models, when the number of combination increases, data sparsity is aggravated.2 While, as shown, in Wang et al.'s study, the adjusted OR on the association between the strand length and fibrosis stage was inflated. Furthermore, in comparison with the corresponding univariate association, its CI was expanded, which resulted in high sparsity on the multivariate model. Indeed, this phenomenon is expected given that the number of events in different stages of fibrosis in the univariate model is low and would be very low in the multivariate model. Fortunately, there are a number of methods that have been suggested to control sparse data bias. Probably, the method introduced by Greenland et al. is one of the most robust ones that effectively removes or decreases the aforementioned bias. Greenland et al.'s method is known as Penalization via Data Augmentation.2 We aimed to utilize Greenland et al.'s method, to reanalyze the univariate and multivariate association between the strand length and fibrosis stage of Wang et al.'s study. However, the individualized data were required to carry out the whole procedure. Hence, we suggest Wang et al. to use the introduced method to remove sparse data bias and present more valid and precise estimates. Also, there is an important methodological issue in the model building, which should have been regarded by Wang et al. The more detailed information can be found in Supporting File S1.
Subgroup analysis of efficacy and safety analysis of a randomized, double-blinded controlled phase II study of STA-4783 in combination with paclitaxel in patients with metastatic melanoma
Authors: S. O'Day, R. Gonzalez, D. Lawson, R. Weber, L. Hutchins, C. Anderson, M. McLeod, C. Hurwitz, J. Haddad, E. Jacobson
Journal: Journal of Clinical Oncology (2007)

8528 Background: STA-4783 (S), an inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to up-regulation of hsp70 in tumor cell lines. Xenograft models of solid tumors showed synergistic anti-tumor activity in combination with paclitaxel (P). The combination P + S, in phase I and II studies, showed dose-related hsp70 induction (evidence of biological activity) and tolerability. Methods: Eligibility was based on a diagnosis of metastatic cutaneous melanoma, ECOG &lt;=2, and prior treatment with 1 or no chemotherapy regimens. A total of 81 patients (pts) were randomized 2:1 (P 80 mg/m 2 + S 213 mg/m 2 :P 80 mg/m 2 ) 3 weeks out of 4 at 21 US clinical sites. The primary endpoint was progression free survival (PFS); secondary endpoints were response rate (RR), and adverse events (AEs). Results: Based on intent-to-treat analysis, the median PFS was 3.68 months (m) for P + S vs. 1.84 m in the P only arm (p=.035). RR was 15.1% in the P + S arm and 3.6% in the P arm. Subgroup analysis showed chemo- naive pts (n=23) with P + S showed a median PFS of 8.28 m vs. 2.40 in the P arm (n=9). For pts with 1 prior chemotherapy, (n=29), PFS on P + S was 3.12 m vs. 1.77 m on P (n=19). Of 19 pts who crossed over at progression, data are available for 14. PFS ranged from 0.72 to 5.5 m. Three of the 14 evaluable pts treated with P alone had rapid progression (0.95, 1.6, and 1.7 m) then significant inversion of the time to progression with the addition of S to P (2.3, 5.5, and 4.2 m) suggesting study drug effect. Scans were done at identical intervals (8 weeks). The proportion of pts with AEs of grade 3 or higher was 54% (n=52) in the P + S group and 57% in the P group (n=28); pts on P received a median of 2 cycles, while pts in the P + S group received a median of 4. Adverse events leading to discontinuation were low in both groups: 10% for the P + S, and 14% for P. Conclusions: The addition of S to P showed an increase in PFS vs. P alone particularly in chemo-naïve pts. A few pts failing single agent P appeared to benefit from P + S. Despite the additional treatment duration in the P + S group the drugs were well- tolerated, and showed mainly P related adverse events. A phase III study is planned to confirm a role for P + S in metastatic melanoma. [Table: see text]