tbuckley/cabot-search huggingface dataset:
Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the<i>ZNF804A</i>Pathway
Authors: Kristin K. Nicodemus, April Hargreaves, Derek Morris, Richard Anney, Michael Gill, Aiden Corvin, Gary Donohoe
Journal: JAMA Psychiatry (2014)

IMPORTANCEWe investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses.Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained.OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score.DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway.Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions.The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURESParticipants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTSHigher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01to .03).Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R 2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11and .001,respectively) but did not explain additional variation in control participants.CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases.Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.
Uptake and Economic Impact of First-Cycle Colony-Stimulating Factor Use During Adjuvant Treatment of Breast Cancer
Authors: Dawn L. Hershman, Elizabeth T. Wilde, Jason D. Wright, Donna L. Buono, Kevin Kalinsky, Jennifer L. Malin, Alfred I. Neugut
Journal: Journal of Clinical Oncology (2012)

In 2002, pegfilgrastim was approved by the US Food and Drug Administration and the benefits of dose-dense breast cancer chemotherapy, especially for hormone receptor (HR) -negative tumors, were reported. We examined first-cycle colony-stimulating factor use (FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy.We identified patients in Surveillance, Epidemiology, and End Results-Medicare greater than 65 years old with stages I to III breast cancer who had greater than one chemotherapy claim within 6 months of diagnosis(1998 to 2005) and classified patients with an average cycle length less than 21 days as having received dose-dense chemotherapy. The associations of patient, tumor, and physician-related factors with the receipt of any colony-stimulating factor (CSF) and FC-CSF use were analyzed by using generalized estimating equations. CSF costs were estimated for patients who were undergoing dose-dense chemotherapy.Among the 10,773 patients identified, 5,266 patients (48.9%) had a CSF claim. CSF use was stable between 1998 and 2002 and increased from 36.8% to 73.7% between 2002 and 2005, FC-CSF use increased from 13.2% to 67.9%, and pegfilgrastim use increased from 4.1% to 83.6%. In a multivariable analysis, CSF use was associated with age and chemotherapy type and negatively associated with black/Hispanic race, rural residence, and shorter chemotherapy duration. FC-CSF use was associated with high socioeconomic status but not with age or race/ethnicity. The US annual CSF expenditure for women with HR-positive tumors treated with dose-dense chemotherapy is estimated to be $38.8 million.A rapid increase in FC-CSF use occurred over a short period of time, which was likely a result of the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. Because of the increasing evidence that elderly HR-positive patients do not benefit from dose-dense chemotherapy, limiting pegfilgrastim use would combat the increasing costs of cancer care.
Myoglobinuria and Sea-snake-bite Poisoning
Authors: H. A. Reid
Journal: BMJ (1961)

ARSENICAL POISONING RAmsnMEDICAL JOUitRNAL the known administration of arsenic (32 gr.-2.079 g.); second, symptoms known to be caused by arsenic were observed before death; and, finally, enough arsenic was found in the liver to account for death.In this connexion it is important to differentiate between examples of arsenical encephalitis following acetarsol administration and acute arsenical poisoning as described here.Although clinically there may be few distinguishing features, post-mortem findings, and in particular toxico- logical analysis, will readily provide the answer.Encephalitis may result from very small amounts of organic arsenical-for example, intravenous arsphen- amine-but acute poisoning must be related to the amount ingested and may have medico-legal significance.Summary and Conclusions A fatal case of acute arsenical poisoning due to acetarsol vaginal pessaries is reported.The treatment of vaginitis due to infection with Trichomonas vaginalis is often satisfactorily and safely carried out with acetarsol (stovarsol or S.V.C.) pessaries.Nevertheless, there is a very small risk of a mild skin reaction, and if treatment is continued the reaction may be severe and generalized.Such reactions may occur in the course of prolonged treatment or they may arise when treatment is recommended after a previous sensitizing dose.Jaundice or haemorrhagic encephalitis may also occur as a sensitivity response to organic arsenicals.There is evidence that arsenic was absorbed from the vagina in the present case, and in theory either acute
DNA Repair Protein Biomarkers Associated with Time to Recurrence in Triple-Negative Breast Cancer
Authors: Brian M. Alexander, Kam Sprott, D. Allan Farrow, XiaoZhe Wang, Alan D. D'Andrea, Stuart J. Schnitt, Laura C. Collins, David T. Weaver, Judy E. Garber
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To evaluate the prognostic utility of immunohistochemical assessment of key proteins in multiple DNA repair pathways in triple-negative breast cancer (TNBC; estrogen receptor negative, progesterone receptor negative, and HER2/neu negative by immunohistochemistry). Experimental Design: Archived clinically annotated tumor specimens from 112 women with TNBC were immunostained with antibodies against DNA repair proteins and scored using digital image analysis. The cohort was divided into training and test sets for development of a multiantibody model. Scores were combined with clinical data to assess association with outcome. Results: Low XPF (P = 0.005), pMK2 (P = 0.01), MLH; P = 0.002), and FANCD2 (P = 0.001) were each associated with shorter time to recurrence (TTR) in univariate analysis. A 4-antibody model could segregate high-risk and low-risk groups on the basis of TTR in both the training (relative risk [RR] = 3.52; P = 9.05E-07) and test (RR 2.67; P = 0.019) cohorts. Conclusions: DNA repair proteins may be useful as prognostic markers in TNBC. Further study in larger, uniformly treated cohorts with additional clinical parameters is warranted. Clin Cancer Res; 16(23); 5796–804. ©2010 AACR.
Intrahepatic markers of hepatitis delta virus infection: A study byin Situ hybridization
Authors: Francesco Negro, Ferruccio Bonino, Adrian Di Bisceglie, Jay H. Hoofnagle, John L. Gerin
Journal: Hepatology (1989)

The intrahepatic distribution of hepatitis delta virus RNA was studied by in situ hybridization in 33 formalin-fixed, paraffin-embedded biopsies from 17 chronic hepatitis B virus carriers superinfected with hepatitis delta virus. The findings were correlated with the expression of the hepatitis delta antigen, the duration of the hepatitis delta virus infection and the eosinophilic degeneration of the hepatocytes. Intranuclear hepatitis delta virus RNA and antigen were found in 28 specimens, whereas the remaining five were negative for both markers. Hepatitis delta virus RNA and antigen were mostly found within the same cell. In 20 specimens, however, a variable number of hepatocytes showed the presence of hepatitis delta virus RNA alone. The percentage of these over the total number of infected cells was higher in the specimens taken within 1 year from the acute delta hepatitis, whereas their absence was invariably associated with a long-established hepatitis delta virus infection. Interestingly, the vast majority of hepatocytes undergoing eosinophilic degeneration, a change significantly associated with hepatitis delta virus infection, did not show the presence of either hepatitis delta virus RNA or the viral antigen, suggesting a lack of association, at the cellular level, between viral replication and cytopathological change. The specificity of the detection of hepatitis delta virus RNA was confirmed by negative findings in nine specimens from seven chronic hepatitis B virus carriers without evidence of past or current hepatitis delta virus infection. The loss in sensitivity due to the formalin fixation was estimated to be 50% of that obtained in frozen biopsies, as determined by counting autoradiographic grains over infected cells. Consistent results were obtained when sections from the same biopsies were hybridized in separate experiments. Detection of hepatitis delta virus RNA by in situ hybridization in formalin-fixed, paraffin-embedded sections is therefore a rapid, specific, sensitive and reproducible assay for monitoring intrahepatic hepatitis delta virus replication and might have diagnostic relevance.
From India to the World — A Better Way to Prevent Cervical Cancer
Authors: Mark Schiffman, Sholom Wacholder
Journal: New England Journal of Medicine (2009)

In this issue of the Journal, Sankaranarayanan et al.1 report the results of a randomized clinical trial of screening for cervical cancer involving more than 130,000 women in India. The authors conclusively showed that a single round of screening for human papillomavirus (HPV) dramatically reduced the incidence of advanced cervical cancer and cervical-cancer mortality within 8 years far more than a single conventional cytologic test or visual inspection of the cervix with acetic acid (VIA). The implications of the findings of this trial are immediate and global: international experts in cervical-cancer prevention should now adapt HPV testing for widespread implementation. . . .
Pre-treatment serum vascular endothelial growth factor is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab
Authors: Jianda Yuan, Jun Zhou, Zhiwan Dong, Sapna Tandon, Deborah Kuk, Katherine S Panageas, Philip Wong, Jedd D Wolchok, F Hodi
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Ipilimumab, an antibody that blocks cytotoxic T lymphocyte antigen 4 (CTLA-4), had shown improved overall survival (OS) for patients with metastatic melanoma. However predictive biomarkers for clinical benefit have not been well defined. We aimed to evaluate serum vascular
Serial Change in Echocardiographic Parameters and Cardiac Failure in End-Stage Renal Disease
Authors: ROBERT N. FOLEY, PATRICK S. PARFREY, GLORIA M. KENT, JOHN D. HARNETT, DAVID C. MURRAY, PAUL E. BARRE
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Echocardiographic abnormalities are the rule in patients starting dialysis therapy and are associated with the development of cardiac failure and death. It is unknown, however, whether regression of these abnormalities is associated with an improvement in prognosis. As part of a prospective cohort study with mean follow-up of 41 mo, 227 patients had echocardiography at inception and after 1 yr of dialysis therapy. Improvements in left ventricular (LV) mass index, volume index, and fractional shortening were seen in 48, 48, and 46%, respectively. Ninety patients had developed cardiac failure by 1 yr of dialysis therapy. Twenty-six percent of the remaining 137 patients subsequently developed new-onset cardiac failure. The mean changes in LV mass index were 17 g/m 2 in those who subsequently developed cardiac failure compared with 0 g/m 2 among those who did not ( P = 0.05). The corresponding values were -8 versus 0% for fractional shortening ( P &lt; 0.0001). The associations between serial change in both LV mass index and fractional shortening and subsequent cardiac failure persisted after adjusting for baseline age, diabetes, ischemic heart disease, and the corresponding baseline echocardiographic parameter. Regression of LV abnormalities is associated with an improved cardiac outcome in dialysis patients. Serial echocardiography adds prognostic information to one performed at baseline.
Luminal chloride modulates rat distal tubule bidirectional bicarbonate flux in vivo.
Authors: D Z Levine, D Vandorpe, M Iacovitti
Journal: Journal of Clinical Investigation (1990)

The effects of replacing luminal chloride with gluconate on distal tubule bicarbonate transport were studied in vivo in normally fed rats, overnight-fasted rats, and rats made mildly alkalotic by administration of desoxycorticosterone acetate (DOCA). In paired microperfusions of the same tubule with 0 or 55 mM Cl at 25 nl/min, net secretion of bicarbonate by distal tubules of fed rats was inhibited by chloride replacement. Zero chloride perfusion in DOCA rats also resulted in an inhibition of net bicarbonate secretion at 25 nl/min. In contrast, replacement of 45 mM chloride also perfused at 25 nl/min in fasted rats caused an increase in net bicarbonate reabsorption. To further characterize the effects of changes in luminal chloride, experiments were undertaken in fasted rats with 0, 45, and 100 mM chloride-containing solutions perfused at 8 and 25 nl/min. Perfusion with zero Cl resulted in net bicarbonate reabsorption at 8 nl/min that increased markedly with high flow, whereas bicarbonate reabsorption did not change significantly during perfusion at high flow with a 45-mM Cl perfusate. In marked contrast, perfusion with a 100-mM Cl solution resulted in only minimal bicarbonate reabsorption at 8 nl/min with significant secretion observed at high flow. Thus, chloride-free perfusates inhibit bicarbonate secretion and enhance bicarbonate reabsorption, while high chloride perfusates elicit net bicarbonate secretion in usually reabsorbing distal tubules.
Transcriptomic Evidence That Longevity of Acquired Plastids in the Photosynthetic Slugs Elysia timida and Plakobranchus ocellatus Does Not Entail Lateral Transfer of Algal Nuclear Genes
Authors: H. Wagele, O. Deusch, K. Handeler, R. Martin, V. Schmitt, G. Christa, B. Pinzger, S. B. Gould, T. Dagan, A. Klussmann-Kolb, W. Martin
Journal: Molecular Biology and Evolution (2010)

Sacoglossan sea slugs are unique in the animal kingdom in that they sequester and maintain active plastids that they acquire from the siphonaceous algae upon which they feed, making the animals photosynthetic. Although most sacoglossan species digest their freshly ingested plastids within hours, four species from the family Plakobranchidae retain their stolen plastids (kleptoplasts) in a photosynthetically active state on timescales of weeks to months. The molecular basis of plastid maintenance within the cytosol of digestive gland cells in these photosynthetic metazoans is yet unknown but is widely thought to involve gene transfer from the algal food source to the slugs based upon previous investigations of single genes. Indeed, normal plastid development requires hundreds of nuclear-encoded proteins, with protein turnover in photosystem II in particular known to be rapid under various conditions. Moreover, only algal plastids, not the algal nuclei, are sequestered by the animals during feeding. If algal nuclear genes are transferred to the animal either during feeding or in the germ line, and if they are expressed, then they should be readily detectable with deep-sequencing methods. We have sequenced expressed mRNAs from actively photosynthesizing, starved individuals of two photosynthetic sea slug species, Plakobranchus ocellatus Van Hasselt, 1824 and Elysia timida Risso, 1818. We find that nuclear-encoded, algal-derived genes specific to photosynthetic function are expressed neither in P. ocellatus nor in E. timida. Despite their dramatic plastid longevity, these photosynthetic sacoglossan slugs do not express genes acquired from algal nuclei in order to maintain plastid function.
Familial Aggregation of Psychotic Symptoms in Huntington’s Disease
Authors: Debby Tsuang, Elisabeth W. Almqvist, Hillary Lipe, Franc Strgar, Lilly DiGiacomo, David Hoff, Charisma Eugenio, Michael R. Hayden, Thomas D. Bird
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.
Impaired IL-18 processing protects caspase-1–deficient mice from ischemic acute renal failure
Authors: Vyacheslav Y. Melnikov, Tevfik Ecder, Giamila Fantuzzi, Britta Siegmund, M. Scott Lucia, Charles A. Dinarello, Robert W. Schrier, Charles L. Edelstein
Journal: Journal of Clinical Investigation (2001)

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.
Effects of Breeding Environments on Generation and Activation of Autoreactive B-1 Cells in Anti-red Blood Cell Autoantibody Transgenic Mice
Authors: Masao Murakami, Kazuo Nakajima, Ken-ichi Yamazaki, Takehiko Muraguchi, Tadao Serikawa, Tasuku Honjo
Journal: The Journal of Experimental Medicine (1997)

In anti-red blood cell autoantibody transgenic (autoAb Tg) mice almost all B cells are deleted except for B-1 cells in the peritoneal cavity and the gut. About one-half of the auto Ab Tg mice suffer from autoimmune hemolytic anemia (AIHA) in the conventional condition. Oral administration of lipopolysaccharides activates B-1 cells and induces autoimmune symptoms in the Tg mice, suggesting that the autoimmune disease in anti-RBC autoAb Tg mice is triggered by infections. To examine the association of bacterial infections with the generation of B-1 cells and the occurrence of the autoimmune disease, we analyzed anti-RBC autoAb Tg mice bred in germ-free and specific pathogen-free conditions. In germ-free conditions, few peritoneal B-1 cells were detected, while a significant number of peritoneal B-1 cells existed in specific pathogen-free conditions. In both conditions, no mice suffered from AIHA. However, when these Tg mice were transferred to the conventional condition or injected with lipopolysaccharide, peritoneal B-1 cells expanded and some of these mice suffered from AIHA. These results clearly showed that bacterial infections are responsible for both the expansion of B-1 cells and the onset of the autoimmune disease in these Tg mice.