tbuckley/cabot-search huggingface dataset:
RIP1 Kinase Is an Oncogenic Driver in Melanoma
Authors: Xiao Ying Liu, Fritz Lai, Xu Guang Yan, Chen Chen Jiang, Su Tang Guo, Chun Yan Wang, Amanda Croft, Hsin-Yi Tseng, James S. Wilmott, Richard A. Scolyer, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2015)

Abstract Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB–dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB–dependent activation mechanism as a novel approach to treat this disease. Cancer Res; 75(8); 1736–48. ©2015 AACR.
Therapeutic Angiogenesis Inhibits or Rescues Chemotherapy-induced Peripheral Neuropathy: Taxol- and Thalidomide-induced Injury of Vasa Nervorum is Ameliorated by VEGF
Authors: Rudolf Kirchmair, Anne B Tietz, Eleftheria Panagiotou, Dirk H Walter, Marcy Silver, Young-Sup Yoon, Peter Schratzberger, Alberto Weber, Kengo Kusano, David H Weinberg, Allan H Ropper, Jeffrey M Isner, Douglas W Losordo
Journal: Molecular Therapy (2006)

Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder. Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder.
Demand Pacing in Intermittent Heart-Block
Authors: Robert H. Goetz
Journal: JAMA (1968)

In pacing on demand, electric stimulation is coupled to the QRS complex and takes place only if ventricular contraction fails to occur within the preset time interval. Pacing is cancelled if the spontaneous heart rate exceeds the preset pacemaker rate. In demand pacing, the electrode delivering the electric stimulus also monitors the electrocardiogram for purposes of programming the timing device incorporated in the pacemaker. Good endocardial contact of the electrode, therefore, becomes essential to provide an adequate signal for programming of the monitoring and timing circuits. It is recommended that once the electrodes have been placed, an endocardial ECG be obtained. Its signal should at least reach 6 mv, thus providing a 3:1 margin over the threshold of the monitoring system. Twenty-seven patients with the implanted demand pacemaker were successfully treated.
The Teaching of Psychiatry to Medical Students: Past, Present, and Future
Authors: JOHN ROMANO
Journal: American Journal of Psychiatry (1970)

The author, after paying tribute to the late chief of the NIMH training branch, describes past and current psychiatric education. Among the contributions he believes psychiatry has made to medical education are its emphasis on methods of observation and on understanding the personality. However, he believes current psychiatric training has neglected contributions from the biological sciences and fails to completely recognize the importance of the entire life cycle. He also assesses recent changes in medical school curricula.
Perspective From a Quarter Century of Antibiotic Usage
Authors: George Gee Jackson
Journal: JAMA (1974)

We are at a point in the antibiotic era where one can begin to look back on the historical development of chemotherapy. These events have affected our lives in many ways including discovery, investigation, education, regulation, and miraculous cure of disease. It is clear that by our use, overuse, and abuse of chemotherapy in our present practices, we have failed to reach the optimal treatment of infectious diseases and have created some new problems. Our vantage point provides enough experience to have perspective, sufficient new knowledge to make us wiser, and vision to motivate realistic, critical assessment, and find new aspirations and aims.
Special Conference of Local Medical Committees
Authors: L. C. W. Kershaw
Journal: BMJ (1964)

MEDIc~ALJouUNAL 843 tant over the past three-and-a-half years, I have in fact been thinking of some form of tax advisory association, with a view to retaining the services of an accountant, suit- ably experienced in medical tax matters, yet reducing the cost thereof by having a larger number of doctors availing themselves of these services.While discussion continues as to how best we may implement changes in terms and conditions in our future Utopia, there is a great deal that can, and should be, done now.This will be most satisfactorily achieved by skilled guidance.-Iam, etc.,
Interval between insulin injection and eating in relation to blood glucose control in adult diabetics.
Authors: M E Lean, L L Ng, B R Tennison
Journal: BMJ (1985)

In a survey of 225 diabetics treated with insulin 24 (10.6%) claimed never to have received advice concerning the interval between insulin injection and eating. Of the remainder, 67 (33%) admitted disregarding advice and using shorter intervals. There was a significant (p less than 0.01) difference between the reported frequencies of clinical hypoglycaemia in patients using different intervals. The effects on glucose control of intervals between insulin injection and breakfast of zero, 15, 30, and 45 minutes were studied for periods of one week in 11 patients with type I diabetes who were receiving twice daily injections of monocomponent porcine insulins and high fibre, high carbohydrate diets, using standard home blood glucose monitoring techniques to measure blood glucose concentrations each morning. The delay of 45 minutes resulted in the lowest frequency of hypoglycaemia and the most acceptable pattern of glucose concentrations measured one and two hours after breakfast and before lunch. Combining results obtained at these three times, the mean increment in blood glucose concentration was smaller after allowing a delay of 45 minutes than after delays of zero (p less than 0.001), 15 (p less than 0.03), and 30 (NS) minutes. A delay of 30 minutes resulted in smaller mean increments in blood glucose concentration than did delays of zero (p less than 0.001) and 15 (NS) minutes. These results suggest that this aspect of diabetic management may be neglected, with important consequences for blood glucose control. An increase in delay between insulin injection and eating to 45 minutes would be a simple and safe way of improving blood glucose control in at least the 37% of the diabetic population surveyed in this study who currently allow less than 15 minutes.
Studies Probe Restoring Speech in Persons With Chronic Stroke-Related Aphasia
Authors: Anita Slomski
Journal: JAMA (2013)

ing her diet during pregnancy, Boyle said. “We didn’t have the experience of people living to adulthood and having children,” she said. “We need to have follow-up throughout life.” New technologies are also raising new questions. Tandem mass spectrometry makes it possible to test for more disorders, but there is an ongoing debate about whether screening should be offered for rare diseases for which little is known about the impact of early treatment on the course of the disease. Screening for disorders with less clear-cut treatment options may aid research or point to experimental treatments, but it may also expose children to tests or interventions from which they may not benefit. The emergence of less expensive microarray testing is opening the possibility of testing newborns for an even greater range of illnesses or for deleterious genetic mutations. McCabe explained that right now, newborn screening tests focus on identifying disease phenotypes. Shifting toward the use of microarrays would entail a new set of challenges, he cautioned. “It’s something we ought to move toward, but cautiously, because of the ethical, legal, and social implications,” he said.
Phase II Trial of the Pegylated Liposomal Doxorubicin in Previously Treated Metastatic Endometrial Cancer: A Gynecologic Oncology Group Study
Authors: Franco M. Muggia, John A. Blessing, Joel Sorosky, Gary C. Reid
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD. PATIENTS AND METHODS: Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m 2 every 4 weeks; the dosage was modified in accordance with observed toxicity. RESULTS: Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months. CONCLUSION: PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs.
Socioeconomic conditions in childhood and ischaemic heart disease during middle age.
Authors: G A Kaplan, J T Salonen
Journal: BMJ (1990)

<h3>ABSTRACT</h3> <h3>Background:</h3> The Kabeho Mwana project (2006–2011) supported the Rwanda Ministry of Health (MOH) in scaling up integrated community case management (iCCM) of childhood illness in 6 of Rwanda9s 30 districts. The project trained and equipped community health workers (CHWs) according to national guidelines. In project districts, Kabeho Mwana staff also trained CHWs to conduct household-level health promotion and established supervision and reporting mechanisms through CHW peer support groups (PSGs) and quality improvement systems. <h3>Methods:</h3> The 2005 and 2010 Demographic and Health Surveys were re-analyzed to evaluate how project and non-project districts differed in terms of care-seeking for fever, diarrhea, and acute respiratory infection symptoms and related indicators. We developed a logit regression model, controlling for the timing of the first CHW training, with the district included as a fixed categorical effect. We also analyzed qualitative data from the final evaluation to examine factors that may have contributed to improved outcomes. <h3>Results:</h3> While there was notable improvement in care-seeking across all districts, care-seeking from any provider for each of the 3 conditions, and for all 3 combined, increased significantly more in the project districts. CHWs contributed a larger percentage of consultations in project districts (27%) than in non-project districts (12%). Qualitative data suggested that the PSG model was a valuable sub-level of CHW organization associated with improved CHW performance, supervision, and social capital. <h3>Conclusions:</h3> The iCCM model implemented by Kabeho Mwana resulted in greater improvements in care-seeking than those seen in the rest of the country. Intensive monitoring, collaborative supervision, community mobilization, and CHW PSGs contributed to this success. The PSGs were a unique contribution of the project, playing a critical role in improving care-seeking in project districts. Effective implementation of iCCM should therefore include CHW management and social support mechanisms. Finally, re-analysis of national survey data improved evaluation findings by providing impact estimates.
Arthur Lewis Wyman
Authors: C. Madge
Journal: BMJ (2003)

Former consultant physician Charing Cross Hospital (b 1913; q University College Hospital, London, 1935; MD, FRCP), died from heart failure on 18 January 2003.

Arthur's first job was in general practice in south London. He became increasingly interested in hospital medicine and went to Sheffield and then to London's Mile End Hospital. War service interrupted his professional life and he served in Algeria, Egypt, and the allied invasion of Sicily and Italy. He was twice mentioned in dispatches and achieved the rank of lieutenant colonel. From 1950 to 1973 he was medical superintendent at Fulham Hospital. His special interest was diabetes. During retirement he devoted more time to medical history. He leaves a wife, Renate, and two children.
Progress in global access to medicines threatened by funding shortfalls, warns charity
Authors: P. Moszynski
Journal: BMJ (2011)

The past year has seen important advances and serious setbacks in achieving better access to medicines for people in developing countries, according to a report by Medecins Sans Frontieres detailing events that had an impact on people’s ability to access needed drugs, diagnostics and vaccines.

Tido von Schoen-Angerer, director of the charity’s Access Campaign, told the BMJ that “the recent financial crisis has made traditional donor countries much more inward looking,” although the “actual amounts required to make a difference in global health” were dwarfed by the sums used to rescue the banks and struggling Eurozone economies.

He warned that without “renewed prioritisation …
Canadian doctors join campaign against unnecessary tests and treatments
Authors: B. Kermode-Scott
Journal: BMJ (2013)

The Canadian Medical Association joined a growing global initiative within the medical community when it announced that it was creating a working group to identify medical tests, interventions, and procedures “for which benefits have generally not been shown to exceed the risks.”

The decision to set up the group was made during the association’s General Council meeting, held in Calgary, Alberta between 18 and 21August. 

Louis Hugo Francescutti, the association’s incoming president, said, “If we’re going to try and improve the efficiency and reduce errors in our healthcare system, then what we should be doing is only things that we know will …
Skeletal muscle fat oxidation: timing and flexibility are everything
Authors: D. E. Kelley
Journal: Journal of Clinical Investigation (2005)

In order to examine the factors governing the timing and flexibility of skeletal muscle switching between fat and carbohydrate oxidation, Ukropcova et al. studied the effect of glucose and fatty acid availability on the preference for fat oxidation in myocytes cultured from human male quadriceps muscle taken from subjects with varied BMI, fat mass, and insulin sensitivity. The authors found that in vivo insulin sensitivity was related to a higher in vitro capacity for fat oxidation. These findings support the concept that the capacity of skeletal muscle to oxidize fat under appropriate physiological conditions is related to leanness, aerobic fitness, and insulin sensitivity.
Vaccination Against Leprosy
Authors: Robert G. Cochrane
Journal: JAMA (1966)

<h3>To the Editor:—</h3> While lepromatous leprosy was prevalent at the time of Hansen (<b>197</b>:580, 1966), there was an appreciable number of cases of what was then called anaesthetic leprosy, and therefore, it is difficult to evaluate just what the individual terms at the time of Hansen really signified. When one used the term "tuberculoid" in the Latin-American concept, it covers a very broad spectral band from what I would call the tuberculoid to what Ridley and Jopling would call "BT" or borderline-tuberculoid, which I call dimorphous tuberculoid. Most workers unfamiliar with African or Indian leprosy use the term tuberculoid in a very loose manner. If a careful assessment of the case is made, being particular about one's definition, one generally will find that the true tuberculoid is mostly seen in the darker races, and the intermediate dimorphous or borderline lesions in the lighter races. To H. W. Wade and
Hepatitis C virus reinfection in allografts after orthotopic liver transplantation
Authors: Volker König, Jürgen Bauditz, Hartmut Lobeck, Rainer Lüsebrink, Peter Neuhaus, Gerhard Blumhardt, Wolf Otto Bechstein, Ruth Neuhaus, Rudolf Steffen, Uwe Hopf
Journal: Hepatology (1992)

ABSTRACT From September 1988 to May 1991, 160 orthotopic liver transplantations were performed in our hospital. Twenty–four patients had end–stage cirrhosis caused by chronic non–A, non–B hepatitis. Antibodies against hepatitis C virus were documented before and after orthotopic liver transplantation in 13 patients. Studies using the polymerase chain reaction demonstrated hepatitis C virus RNA in the serum and liver tissue of 17 patients (10 of whom tested positive for hepatitis C virus antibodies) before orthotopic liver transplantation. Tissue samples taken from liver grafts during the operation were hepatitis C virus RNA negative in every case. Ten of these 17 patients had positive hepatitis C virus RNA findings in serum and liver biopsy specimens within the first month after surgery. One patient died of Mucor sepsis 2 mo after orthotopic liver transplantation. Another patient died of multiorgan failure 3 mo after a retransplantation. Two patients underwent retransplantation for graft rejection at 2 and 3 mo, respectively. One year after orthotopic liver transplantation, hepatitis C virus RNA was demonstrated in allograft biopsy specimens in 13 of 15 patients. Two patients remained hepatitis C virus RNA negative in repeated biopsies up to 12 mo. Mild portal and lobular hepatitis developed within 6 months of orthotopic liver transplantation in four patients and within 1 yr in five additional patients. The data suggest that persistent hepatitis C virus reinfects the allograft in most cases, but the risk of acute organ damage caused by hepatitis C virus reinfection is low. (Hepatology 1992;16:1137-1143.)
Serum Markers of Collagen Type I Metabolism in Spontaneously Hypertensive Rats
Authors: Javier Díez, Angel Panizo, María J. Gil, Ignacio Monreal, Marta Hernández, Javier Pardo Mindán
Journal: Circulation (1996)

The assay of serum peptides of extracellular collagen synthesis and degradation could provide an indirect estimate of the rate of fibrillar turnover. This study was designed to investigate whether serum peptides of collagen type I synthesis and degradation are altered in spontaneously hypertensive rats (SHR) with left ventricular hypertrophy and whether these serum collagen-derived peptides are related to myocardial fibrosis.We measured serum levels of carboxyterminal propeptide of procollagen type I (PIP) as a marker of collagen I synthesis and serum levels of the pyridinoline crosslinked telopeptide domain of collagen type I (CITP) as a marker of fibrillar collagen I degradation in ten 36-week-old normotensive Wistar-Kyoto (WKY) rats, ten 36-week-old SHR, and ten 16-week-old SHR treated with the angiotensin-converting enzyme inhibitor quinapril (10 mg /kg body wt per day, orally) for 20 weeks. PIP and CITP were determined by specific radioimmunoassays. Histomorphometric and immunohistochemical studies of the left ventricle were performed in all rats. In untreated SHR compared with WKY rats, we found a more extensive interstitial and perivascular fibrosis, an increased (P<.01) collagen volume fraction, a more marked deposition of collagen type I, an increased (P<.01) serum concentration of PIP, and a similar serum concentration of CITP. In quinapril-treated SHR compared with untreated SHR, we found an absence of left ventricular hypertrophy, a marked decrease of fibrosis, a lower (P<.01) collagen volume fraction, a diminished deposition of collagen type I, a decreased (P<.01) concentration of PIP, and a similar concentration of CITP. A direct correlation was found between the collagen volume fraction and serum PIP (r=.753, P<.05) in untreated SHR.These results suggest that tissue metabolism of collagen type I is abnormal in SHR and can be normalized by treatment with quinapril. On the basis of our findings, we propose that serum PIP may be a marker of collagen type I-dependent myocardial fibrosis in rats with genetic hypertension.