tbuckley/cabot-search huggingface dataset:
Resistance to Recombinant Interferon Alfa-2a in Hairy-Cell Leukemia Associated with Neutralizing Anti-Interferon Antibodies
Authors: Ronald G. Steis, John W. Smith, Walter J. Urba, Jeffrey W. Clark, Loretta M. Itri, Lydia M. Evans, Carolyn Schoenberger, Dan L. Longo
Journal: New England Journal of Medicine (1988)

To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a. (N Engl J Med 1988; 318: 1409–13.)
Compartment-Specific Roles of ATP-Binding Cassette Transporters Define Differential Topotecan Distribution in Brain Parenchyma and Cerebrospinal Fluid
Authors: Jun Shen, Angel M. Carcaboso, K. Elaine Hubbard, Michael Tagen, Henry G. Wynn, John C. Panetta, Christopher M. Waters, Mohamed A. Elmeliegy, Clinton F. Stewart
Journal: Cancer Research (2009)

Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean +/- SD ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 3.07 +/- 0.09, 2.57 +/- 0.17, 1.63 +/- 0.12, and 0.86 +/- 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 0.36 +/- 0.06, 0.42 +/- 0.06, and 0.88 +/- 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b(-/-) mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 +/- 0.09 in wild-type mice and increased to 1.13 +/- 0.13 in Mdr1a/b(-/-)Bcrp1(-/-) mice, whereas the ECF-to-plasma ratio increased to 0.74 +/- 0.14 in wild-type and 1.07 +/- 0.03 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice of 5.69 +/- 0.83, 3.85 +/- 0.64, 3.61 +/- 0.46, and 0.78 +/- 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors.
The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells
Authors: Vincent Sauzeau, María A. Sevilla, María J. Montero, Xosé R. Bustelo
Journal: Journal of Clinical Investigation (2009)

The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide–triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.
Number of dengue cases in Delhi is highest for five years
Authors: Sanjeet Bagcchi
Journal: BMJ (2015)

Public health experts in India are urging the government to do more to control dengue fever in Delhi, as the number of cases reported so far this year has reached the highest number for five years. 

As at 25 July 40 cases of dengue had been reported in Delhi, more than double the 16 cases in the same period last year. In July alone, 20 cases were reported in Delhi, five in children. However, so far this year no deaths have been reported from the disease. Last year 995 …
Inherited Genetic Markers and Cancer Outcomes: Personalized Medicine in the Postgenome Era
Authors: Timothy R. Rebbeck
Journal: Journal of Clinical Oncology (2006)

The report of Tsuchiya et al represents an area of research that has the potential to impact personalized genomic medicine; this area is the use of inherited genetic markers to predict clinical outcomes, including prognosis and recurrence, in cancer patients. Tsuchiya et al report that longer repeat polymorphisms in the IGF1 and/or CYP19 genes are significantly associated with poorer prostate cancer–specific survival among men with metastatic prostate cancer. This research complements other reports that inherited genetic markers predict prostate cancer outcomes, including associations with CYP3A4, SRD5A2, the androgen receptor gene (AR), and the vitamin D receptor gene (VDR). Numerous reports have also been made that relate inherited genetic markers and prognosis or recurrence with tumors at other sites. Prediction of clinical outcome by inherited genetic markers is likely to reflect the natural history of disease progression and, therefore, may involve genes and biochemical pathways that act along the continuum from disease causation, recurrence, and mortality (Fig 1). Indeed, IGF1, CYP19, CYP3A4, SRD5A2, AR, and VDR have all been implicated in prostate cancer etiology and outcomes. Inherited genetic markers may also provide predictive or prognostic information in addition to somatic tumor markers or inherited genetic markers of treatment response and toxicity (eg, pharmacogenetic markers; Fig 1). Despite reports associating inherited genetic markers with clinical outcomes, the existing literature is probably insufficient to warrant clinical translation of these markers at this time. What evidence must be gathered before inherited genetic markers could be applied in a clinical setting? Establishing a causal relationship between risk factor and outcome is a minimal requirement, and a variety of criteria for establishing causal inferences has been proposed. As outlined in the following sections, additional factors must be considered before an inherited genetic marker can be applied to predict cancer prognosis, recurrence, or other clinical outcomes.
Impact of Psychiatric Conditions on Health-Related Quality of Life in Persons With HIV Infection
Authors: Cathy D. Sherbourne, Ron D. Hays, John Fleishman, Benedetto Vitiello, Kathryn M. Magruder, Eric G. Bing, Daniel F. McCaffrey, Audrey Audrey Burnam, Douglas L. Longshore, Ferd Eggan, Samuel A. Bozzette, Martin F. Shapiro
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Little is known about the impact of comorbid psychiatric symptoms in persons with HIV. This study estimates the burden on health-related quality of life associated with comorbid psychiatric conditions in a nationally representative sample of persons with HIV. METHOD: The authors conducted a multistage sampling of urban and rural areas to produce a national probability sample of persons with HIV receiving medical care in the contiguous United States (N=2,864). Subjects were screened for psychiatric conditions with the short form of the Composite International Diagnostic Interview. Heavy drinking was assessed on the basis of quantity and frequency of drinking. Health-related quality of life was rated with a 28-item instrument adapted from similar measures used in the Medical Outcomes Study. RESULTS: HIV subjects with a probable mood disorder diagnosis had significantly lower scores on health-related quality of life measures than did those without such symptoms. Diminished health-related quality of life was not associated with heavy drinking, and in drug users it was accounted for by presence of a comorbid mood disorder. CONCLUSIONS: Optimization of health-related quality of life is particularly important now that HIV is a chronic disease with the prospect of long-term survival. Comorbid psychiatric conditions may serve as markers for impaired functioning and well-being in persons with HIV. Inclusion of sufficient numbers of appropriately trained mental health professionals to identify and treat such conditions may reduce unnecessary utilization of other health services and improve health-related quality of life in persons with HIV infection.
Long-term Sequelae of Acute Venous Thrombosis
Authors: Donald E. Strandness
Journal: JAMA (1983)

The long-term sequelae of acute deep-vein thrombosis were examined prospectively in a series of 61 patients. The location and extent of the involvement were established by either contrast or isotope phlebography. The mean age of the patients was 47 years, with the duration of follow-up averaging 39 months (range, one to 144 months). Pain and/or swelling was noted in 67% of the patients. Pigmentation developed in 15 limbs (23%). Ulceration developed in three patients. The most important factor with regard to prognosis appeared to be the status of the distal deep veins. If these were found to be patent and competent by ultrasonic velocity studies, the long-term outlook was good, both with regard to symptoms and the development of pigmentation. Only 8% of those limbs with normal distal veins were found to have pigmentation during follow-up, as compared with 40% in those with either occlusion or incompetence of the valves.
Irregular Menses, Amenorrhea, and Infertility Following Synthetic Progestational Agents
Authors: M. James Whitelaw
Journal: JAMA (1966)

THE USE OF pure crystalline progesterone which was isolated and prepared for the first time in 1934 was limited mainly in its therapy for the first 13 years to the treatment of habitual and threatened abortion. With the clinical introduction of norethandrolone and norethynodrel in 1956 by Rock'<sup>1,2</sup>and his co-workers as contraceptive agents, as well as steroids to increase fertility, there was a rapid increase in the pharmacological use of these products and related steroidal compounds with progestational activity so that today they are being used in the treatment of several gynecological disorders including amenorrhea, oligomenorrhea, dysfunctional bleeding, dysmenorrhea, infertility, contraception, endometriosis, and others,<sup>3-7</sup>as well as in the diagnosis of pregnancy. It has been claimed that there are few side reactions of a serious nature, except for fetal virilization,<sup>8</sup>persistent edema, and thromboembolic disease.<sup>9</sup>We are presenting these data due to the fact that during
Drugs for the Treatment of Obesity
Authors: Alison Poulton, Ralph Nanan
Journal: JAMA (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
1002 EFFECTS OF METFORMIN AND CARNITINE COMPLEX ON PERIPHERAL BLOOD MITOCHONDRIA COPY NUMBER IN PATIENTS WITH NAFLD
Authors: D.W. Jun, S.S. Jang, W.K. Cho, J.D. Cae, B.K. Son, S.H. Kim, Y.J. Jo, Y.S. Park
Journal: Journal of Hepatology (2009)
PTU-095 Liver Lesions on Ultrasonography: is it Cancer or not?
Authors: B Krishnan, H Alexander, M Abayalingam, A Mitra, V Sehgal, K Besherdas
Journal: Gut (2013)

<h3>Introduction</h3> The ultimate goal of the United Kingdom Cancer plan is to ‘offer patients a maximum one month wait from an urgent referral for suspected cancer to the beginning of treatment’.The North London Cancer Network has devised and implemented a suspected cancer referral form for General Practitioners in London for patients to be seen within two weeks of referral to secondary care. One group referred on the suspected cancer referral form is patients with a liver lesion on ultrasound(USS). However, for a service to be effective it is essential that it is not overloaded with inappropriately referred patients. <h3>Methods</h3> The aim of the study was to assess the appropriateness and findings in patients referred to secondary care with a liver lesion on USS. A retrospective analysis of all patients referred to the gastroenterology clinic with a liver lesion on USS on the suspected cancer referral form during a 12 month period from 1st January 2011 at a District General Hospital in North London(Chasefarm Hospital) was performed. Data was collected using medical records and electronic patient results. <h3>Results</h3> In the study period, a total of 379 patients were referred with suspected upper GI cancer. Of these 39(10.3%) were specifically referred in view of an abnormal liver lesion. The USS findings which prompted a referral was liver metastasis in 10(26%), hypoechoic lesion in 7(18%), liver mass in 6(15%), hemangioma in 4(10%), area of increased echogenicity in 3(8%), isoechoic lesion in 3(8%), cyst in 2(5%) and hyperechoic lesion, echo poor area, echo bright area, calcified foci in 1 patient each(3%). All patients were seen in the clinic within 2 weeks and 29(74%) had a CT and 7(18%) had an MRI scan. After review of images and/or histology in the clinic/multidisciplinary meeting, 10 patients had normal scan, 9 patients had hemangioma, 8 had liver metastasis, 5 had liver cysts, 2 patients did not attend follow up, 1 patient was too frail for further imaging, 1 patient each had hepatoma, adenoma, focal nodular hyperplasia and focal fat sparing. 7/10(70%) patients with suspected metastasis on USS had confirmed metastatic disease on subsequent imaging. The 2 patients with liver cysts on USS had cysts on CT scan. <h3>Conclusion</h3> The majority (77%) of patients with suspected cancer referred to the service did not have cancer. However, 70% of patients with suspected liver metastasis on USS had this confirmed on CT scan. Simple cysts on USS proved to be cysts on CT. We recommend that if initial USS suggests metastases it is likely to be so and would recommend CT staging and tumour markers prior to outpatient review to expedite management. USS is highly sensitive in differentiating a cyst from a solid lesion and patients with cysts on USS can be offered a routine appointment rather than being seen as a potential cancer referral. <h3>Disclosure of Interest</h3> None Declared
Telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in chronic hepatitis C patients
Authors: Stefan Zeuzem
Journal: Journal of Hepatology (2008)

The first potent and specific inhibitor of the NS3/4A serine protease to be tested in a randomized, placebocontrolled pilot study in patients with chronic hepatitis C was ciluprevir (BILN 2061). In previously untreated patients with genotype 1 infection, treatment with ciluprevir for 2 days resulted in HCV RNA reductions of 2–3 log10 copies/mL in most of the patients, thus providing proof-of-concept that HCV NS3/4A protease inhibitors are a therapeutic option for patients with chronic hepatitis C [1]. However, further clinical development of ciluprevir was suspended following reports of cardiotoxicity in animal studies [1]. The NS3/4A protease inhibitors telaprevir and boceprevir have been shown to reduce serumHCVRNA levels when used alone [2,3] and to produce additive reductions in levels when administered with peginterferon (PEGIFN) [3,4]. Telaprevir monotherapy for 2 weeks was associated with a more than 4 log10 median reduction of HCV RNA in patients with chronic hepatitis C genotype 1 infection [2]. When used as monotherapy, current protease inhibitors show a low barrier to genetic resistance, a potential problem for antivirals given the high rate and error-prone nature of HCV replication [5]. The study by Lawitz et al. [6] in the current issue of this Journal assessed the safety and antiviral effects of telaprevir (750 mg q8h) in combination with peginterfer-
'Tin-tack' sign in seborrhoeic dermatitis
Authors: N.C. Cowley, C.M. Lawrence
Journal: British Journal of Dermatology (1991)

Journal Article ‘Tin‐tack’ sign in seborrhoeic dermatitis Get access N.C. Cowley, N.C. Cowley Department of Dermatology, Royal Victoria Infirmary, Newcastle Upon Tyne NF1 4LP, U. K. Search for other works by this author on: Oxford Academic Google Scholar C.M. Lawrence C.M. Lawrence Department of Dermatology, Royal Victoria Infirmary, Newcastle Upon Tyne NF1 4LP, U. K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 124, Issue 4, 1 April 1991, Pages 393–394, https://doi.org/10.1111/j.1365-2133.1991.tb00609.x Published: 01 April 1991
A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study
Authors: R A Furie, G Leon, M Thomas, M A Petri, A D Chu, C Hislop, R S Martin, M A Scheinberg
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To evaluate the efficacy and safety of subcutaneous blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial. <h3>Methods</h3> 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI). <h3>Results</h3> Although SRI-5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of blisibimod (200 mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1–6 at baseline, significant reductions in proteinuria were observed with blisibimod. Significant (p&lt;0.01) changes in anti-double stranded DNA antibodies, complement C3 and C4, and reductions in B cells were observed with blisibimod. No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for blisibimod compared with placebo. <h3>Conclusions</h3> This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of blisibimod effect in Phase 3. <h3>Trial registration number</h3> NCT01162681.
Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice
Authors: Takahiro Kodama, Tetsuo Takehara, Hayato Hikita, Satoshi Shimizu, Minoru Shigekawa, Hinako Tsunematsu, Wei Li, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Tatsuya Kanto, Naoki Hiramatsu, Satoshi Kubota, Masaharu Takigawa, Yoshito Tomimaru, Akira Tomokuni, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Norio Hayashi
Journal: Journal of Clinical Investigation (2011)

The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.