tbuckley/cabot-search huggingface dataset:
Immunological Responses to Exogenous Insulin
Authors: S. Edwin Fineberg, Thomas T. Kawabata, Deborah Finco-Kent, Robert J. Fountaine, Gregory L. Finch, Alan S. Krasner
Journal: Endocrine Reviews (2007)

Regardless of purity and origin, therapeutic insulins continue to be immunogenic in humans. However, severe immunological complications occur rarely, and less severe events affect a small minority of patients. Insulin autoantibodies (IAAs) may be detectable in insulin-naive individuals who have a high likelihood of developing type 1 diabetes or in patients who have had viral disorders, have been treated with various drugs, or have autoimmune disorders or paraneoplastic syndromes. This suggests that under certain circumstances, immune tolerance to insulin can be overcome. Factors that can lead to more or less susceptibility to humoral responses to exogenous insulin include the recipient's immune response genes, age, the presence of sufficient circulating autologous insulin, and the site of insulin delivery. Little proof exists, however, that the development of insulin antibodies (IAs) to exogenous insulin therapy affects integrated glucose control, insulin dose requirements, and incidence of hypoglycemia, or contributes to β-cell failure or to long-term complications of diabetes. Studies in which pregnant women with diabetes were monitored for glycemic control argue against a connection between IAs and fetal risk. Although studies have shown increased levels of immune complexes in patients with diabetic microangiopathic complications, these immune complexes often do not contain insulin or IAs, and insulin administration does not contribute to their formation. The majority of studies have shown no relationship between IAs and diabetic angiopathic complications, including nephropathy, retinopathy, and neuropathy. With the advent of novel insulin formulations and delivery systems, such as insulin pumps and inhaled insulin, examination of these issues is increasingly relevant.
Abstract 3745: The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKcs-mediated DNA damage responses
Authors: Bipasha Mukherjee, Nozomi Tomimatsu, Kaushik Amancherla, Cristel Camacho, Sandeep Burma
Journal: Cancer Research (2012)

Abstract Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy due to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent inhibitor of PI3K/Akt signaling that is currently in phase I/II clinical trials. BEZ235 is reported to specifically inhibit PI3Ks and mTOR with little effect on other kinases. However, we find that BEZ235 also potently inhibits the two major kinases responding to DNA double-strand breaks (DSBs), ATM and DNA-PKcs, both in vitro and in vivo. Consequently, BEZ235 blocks both non-homologous end joining (NHEJ) and homologous recombination (HR) DNA repair pathways, resulting in significant attenuation of DSB repair. Additionally, phosphorylation of ATM targets and implementation of the G2/M cell cycle checkpoint are also attenuated by this drug. The consequence is profound radiosensitization at very low concentrations (100 nM) of BEZ235. This radiosensitizing effect is significantly more potent than that seen with much higher concentrations (10 μm) of inhibitors of DNA-PKcs or ATM that are currently being optimized for clinical testing. Since radiotherapy is the standard of care for GBM, we investigated the potential utility of BEZ235 as a radiosensitizing agent in a panel of GBM lines. We find that BEZ235 treatment confers an extreme degree of radiosensitization and significantly attenuates DSB repair irrespective of Akt activation status in these lines. Finally, we show that BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug in vivo. Our results, showing that BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential clinical utility of BEZ235 as an effective radiosensitizer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3745. doi:1538-7445.AM2012-3745
Defensins and <scp>LL</scp>‐37: a review of function in the gingival epithelium
Authors: Ara Greer, Camille Zenobia, Richard P. Darveau
Journal: Periodontology 2000 (2013)

Abstract Antimicrobial peptides represent an important aspect of the innate defense system that contributes to the control of bacterial colonization and infection. As studies have progressed it has become clear that antimicrobial peptides manifest other functions in addition to their antimicrobial effects. These functions include chemotaxis of numerous types of host cells involved in both the innate and adaptive immune responses. In this review, the antimicrobial activity, the regulation and the contribution to host homeostasis of alpha‐defensins and LL ‐37, as well as of beta‐defensins, are discussed in the context of their specific tissue locations in the junctional epithelium and oral epithelium, respectively.
Ex Vivo Adenoviral Vector Gene Delivery Results in Decreased Vector-associated Inflammation Pre- and Post–lung Transplantation in the Pig
Authors: Jonathan C Yeung, Dirk Wagnetz, Marcelo Cypel, Matthew Rubacha, Terumoto Koike, Yi-Min Chun, Jim Hu, Thomas K Waddell, David M Hwang, Mingyao Liu, Shaf Keshavjee
Journal: Molecular Therapy (2012)

Acellular normothermic ex vivo lung perfusion (EVLP) is a novel method of donor lung preservation for transplantation. As cellular metabolism is preserved during perfusion, it represents a potential platform for effective gene transduction in donor lungs. We hypothesized that vector-associated inflammation would be reduced during ex vivo delivery due to isolation from the host immune system response. We compared ex vivo with in vivo intratracheal delivery of an E1-, E3-deleted adenoviral vector encoding either green fluorescent protein (GFP) or interleukin-10 (IL-10) to porcine lungs. Twelve hours after delivery, the lung was transplanted and the post-transplant function assessed. We identified significant transgene expression by 12 hours in both in vivo and ex vivo delivered groups. Lung function remained excellent in all ex vivo groups after viral vector delivery; however, as expected, lung function decreased in the in vivo delivered adenovirus vector encoding GFP (AdGFP) group with corresponding increases in IL-1β levels. Transplanted lung function was excellent in the ex vivo transduced lungs and inferior lung function was seen in the in vivo group after transplantation. In summary, ex vivo delivery of adenoviral gene therapy to the donor lung is superior to in vivo delivery in that it leads to less vector-associated inflammation and provides superior post-transplant lung function. Acellular normothermic ex vivo lung perfusion (EVLP) is a novel method of donor lung preservation for transplantation. As cellular metabolism is preserved during perfusion, it represents a potential platform for effective gene transduction in donor lungs. We hypothesized that vector-associated inflammation would be reduced during ex vivo delivery due to isolation from the host immune system response. We compared ex vivo with in vivo intratracheal delivery of an E1-, E3-deleted adenoviral vector encoding either green fluorescent protein (GFP) or interleukin-10 (IL-10) to porcine lungs. Twelve hours after delivery, the lung was transplanted and the post-transplant function assessed. We identified significant transgene expression by 12 hours in both in vivo and ex vivo delivered groups. Lung function remained excellent in all ex vivo groups after viral vector delivery; however, as expected, lung function decreased in the in vivo delivered adenovirus vector encoding GFP (AdGFP) group with corresponding increases in IL-1β levels. Transplanted lung function was excellent in the ex vivo transduced lungs and inferior lung function was seen in the in vivo group after transplantation. In summary, ex vivo delivery of adenoviral gene therapy to the donor lung is superior to in vivo delivery in that it leads to less vector-associated inflammation and provides superior post-transplant lung function.
Percutaneous needle nephrostomy
Authors: C. S. Ogg, H. M. Saxton, J. S. Cameron
Journal: BMJ (1969)

Percutaneous nephrostomy is a simple technique for temporary drainage of an obstructed kidney. Under local anaesthesia a ureteric catheter is passed through a Vim–Silverman needle into the renal pelvis and is connected to a drainage bag. Seven cases (six successful) in which this method was used are described and the indications are discussed. It has been free from complications, is acceptable to patients, and is felt to represent a useful addition to the methods available for the treatment of obstruction of the upper urinary tract.
Nonresponsive Celiac Disease Due to Inhaled Gluten
Authors: Sazzli Shahlan Kasim, Kieran J. Moriarty, Richard Liston
Journal: New England Journal of Medicine (2007)

To the Editor: Celiac disease is a gluten-induced enteropathy, the treatment of which consists of permanently withdrawing dietary gluten. Adherence to diet is crucial for intestinal mucosal recovery, relief of symptoms, and prevention of intestinal T-cell lymphoma.1 The amount of gluten needed to cause mucosal injury varies. Some patients can tolerate up to 5 g of gluten daily; others have intolerance after minimal exposure. Two patients, both living in farming communities, were referred with nonresponsive celiac disease. Characteristics of the patients are shown in Table 1. Despite strict gluten-free diets, their symptoms and histologic changes persisted. Both were feeding cattle in . . .
Compliance with Results Reporting at ClinicalTrials.gov
Authors: Monique L. Anderson, Karen Chiswell, Eric D. Peterson, Asba Tasneem, James Topping, Robert M. Califf
Journal: New England Journal of Medicine (2015)

The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions (highly likely applicable clinical trials, or HLACTs) from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period.From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health (NIH) and 9% of trials that were funded by other government or academic institutions.Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions. (Funded by the Clinical Trials Transformation Initiative and the NIH.).
Serotonin and the control of ventilation in awake rats.
Authors: E B Olson, J A Dempsey, D R McCrimmon
Journal: Journal of Clinical Investigation (1979)

In awake, unrestrained, intact rats, reserpine, para-chlorophenylalanine, 6-fluorotryptophan, and para-chloroamphetamine depleted whole brain serotonin and produced a substantial and sustained hyperventilation as evidenced by a 5--9 torr drop in PaCO2. Administration of 5-hydroxytryptophan to rats treated with para-chlorophenylalanine partially alleviated the hyperventilation. No change in ventilation was observed after alpha-methyltyrosine. 5,7-Dihydroxytryptamine produced contradictory results. On the basis of these pharmacological studies, we propose that some serotonin-mediated nerve transmissions might function under physiological conditions to inhibit the central nervous system output which controls normal breathing.
The burnt patient: a general view.
Authors: R Sanders
Journal: BMJ (1974)

Many burns occur in patients in whom awareness or ability to avoid the danger has not yet developed or is impaired for example, children; the aged or infirm; alcoholics; drug addicts; and epileptics or psychotics. Some occur as a result of a domestic, industrial, or other disaster. Most patients with major burns ae tnsported, as emergencies, direody to hos pitals without prior consultation with the patient's general practitioner, who first becomes involved if a burn is minor, or when distressed relatives require help. Expert first aid to burns is therefore often not available. If so, it should comprise the immediate cooling of the bumt area for 10 minutes with ,tepid water. This probably dimin ishes the depth of injury, which is progressive after the burn ing source has been *removed. Cooling relieves pain and swelling so long as continued. Active washing of chemical burns from acid or alkali with wa-ter for the same period, especially if the eyes are affected, is advantageous. Sub sequently wet clothing should be removed and the bum covered with clean, dry linen. Intravenous pethidine, in a dose proportional to body weight, will help to relieve the pain and anxiety of injury and transport to hospital. Accident departments may be expected to deal with all minor superficial burns. These are best treated by removal of all loose epithelium and dressing with silver sulphadiazine applied on dry gauze and changed daily. Electrical conduction burns are always full thickness and should be considered for surgical management. There is a belated and welcome trend in Britain for estab lishing regional centres for itreating major burn injury (rather than major centres for burn injury). A major burn (for ex ample, one affecting over 10% of the body surface) presents a highly complex pathological situation. It is no longer in the patient's interest for such cases to be managed by rule of ithumb (formula) methods applied by medical and nursing staff who meet the problem rarely. They are better referred to regional centres where facilities for medical and nursing intensive care should be available. Since they are regionally situated, such centres are often remote from the referring hospitals. Two factors are essential for such referral. Firstly, accurate information as to the name, age, and race of the patient, to gether with an exact assessment of pre-existing disease and associated injuries. The date, time, nature, and extenit of the burn injury should be noted and given. Secondly, an intra venous infusion should be established which will not give trouble during transport. Analgesics should be given intra
1058-73 Microsimulation to support prosthetic aortic valve selection
Authors: Johanna J.M Takkenberg, John P.A Puvimanasinghe, Marinus J.C Eijkemans, Lex A van Herwerden, Ewout W Steyerberg, J Dik, F Habbema, Ad J.J.C Bogers
Journal: Journal of the American College of Cardiology (2004)
Outlook with conservative treatment of peptic oesophageal stricture.
Authors: A L Ogilvie, R Ferguson, M Atkinson
Journal: Gut (1980)

In order to assess the outlook for patients with peptic oesophageal strictures treated by Eder Puestow dilatation at fibreoptic endoscopy, 50 patients were followed up for periods ranging from nine months to four years. Twenty patients (40%) required only a single dilatation, and the remaining 30 (60%) required multiple dilatations. The frequency of dilatation tended to decrease with time. There was one death attributable to the procedure. Two patients developed an adenocarcinoma at the site of the stricture. We conclude that conservative management of peptic oesophageal stricture combining the use of dilatation at fibreoptic endoscopy with medical measures to control gastro-oesophageal reflux offers a relatively safe means of providing symptomatic relief, maintaining nutrition, and allowing the patient an acceptable quality of life.
Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors
Authors: Tetsuya Hamaguchi, Toshihiko Doi, Takako Eguchi-Nakajima, Ken Kato, Yasuhide Yamada, Yasuhiro Shimada, Nozomu Fuse, Atsushi Ohtsu, Shin-ichi Matsumoto, Masaya Takanashi, Yasuhiro Matsumura
Journal: Clinical Cancer Research (2010)

Abstract Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38–incorporating micellar nanoparticle. Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively. Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058–66. ©2010 AACR.
The in vivo transfer of antigen-induced airway reactions by bronchial lumen cells.
Authors: R Patterson, I M Suszko, K E Harris
Journal: Journal of Clinical Investigation (1978)

Rhesus monkeys with airway responses to aerosol challenge with Ascaris antigen constitute a primate model of inhalant asthma. Previous studies have shown that bronchial lavage cells from airway-reactive animals will release histamine or a slow-reactive substance of anaphylaxis after challenge with antigen. Because these bronchial lumen cells are the first cells in contact with inhaled antigen, they may play a role in induction of antigen-induced airway responses. To evaluate this possibility, bronchial lumen lavage cells from animals with airway reactivity were transferred to the bronchial lumens of animals with negative airway responses to antigen challenge. The transfer of the bronchial lumen cells resulted in transient airway reactivity of the recipients to aerosol antigen challenge. It is suggested that the mast cells which constitute a component of the bronchial lumen cells may be the active cell alone, or in combination with other cells, which results in this primate immunoglobulin E-mediated airway response and its transfer to nonreactivie recipients.
Pseudo-von Willebrand's Disease
Authors: Leon W. Hoyer
Journal: New England Journal of Medicine (1982)

It is now recognized that von Willebrand's disease, a disorder characterized by a long bleeding time and reduced factor VIII, is a frequent cause of a mild hemorrhagic diathesis.1 Recent studies of the structure and function of factor VIII have provided some understanding of the abnormal hemostasis in patients with this disease, and it is apparent that several different defects in plasma can cause impaired platelet function.2 In this issue of the Journal, Weiss and his co-workers provide evidence that clinical and laboratory findings associated with von Willebrand's disease can be mimicked by an intrinsic platelet defect.3 They suggest . . .
Oxytocin and neonatal jaundice.
Authors: P Boylan
Journal: BMJ (1976)

results obtained in the treatment of hyper- glycaemic diabetic men by the recommended weight-maintaining American Diabetes Asso- ciation (ADA) diet with an isocaloric high unrefined carbohydrate diet.The ADA diet contained refined starch 23%, sucrose 20%, fat 340/, protein 23%, crude fibre 4-7 g/d.The high unrefined carbohydrate diet con- tained unrefined starch 55%, sucrose 20%, fat 9%, protein 16%, crude fibre 15 g/d.Daily estimations of fasting plasma glucose moni- tored the response and permitted a safe re- duction of insulin or hypoglycaemic agent in many patients.Among 13 hyperglycaemic diabetic patients who ate the high carbo- hydrate diet for two weeks five insulin-treated men, previously receiving for many years from 15 to 25 units a day, had insulin discontinued, and all five sulphonylurea-treated men had this therapy discontinued.Three men, pre- viously receiving a higher dose of insulin from 40 to 55 units a day, remained unaltered in their requirements.Mean fasting serum cholesterol and triglyceride levels both fell significantly.Two patients could not tolerate the high- carbohydrate low-fat diet, but only one patient chose not to continue the diet as an outpatient.The main difficulty in eating this diet is one of unpalatability; fat is very low at 9%, sugar is high at 20%, so is protein at 16%.A more palatable diet would be unrefined starch 5000, fat 20%, sugar 15%,, protein 15%.Refractory patients might benefit by further increases of unrefined starch but decreases of fat and sugar, but such a diet is less palatable.The dietary change may be sudden or gradual.If gradual, then fat and sucrose percentages of the pre- vious diet could be decreased stepwise and the unrefined starch increased to equalise the calories.Careful questioning would reveal whether fat is missed more than sucrose and would constitute a guide to future stepwise reductions.Unrefined high-fibre starchy foods should come from a wide variety of sources and the scanty fat and sucrose diverted to increase their palatability.Wholemeal bread and flour, potatoes, ryemeal crispbread, whole- grain breakfast cereals rather than those enriched with bran, whole maize, brown rice, bananas, beans, and peas offer a wide choice.
ANC promises national health service
Authors: M Curtin
Journal: BMJ (1994)

The Medical Association of South Africa (MASA) is asking to meet the African National Congress (ANC) to discuss the ANC's plans to revolutionise South Africa's health service. The ANC said last month that it would provide a national health service and develop a system of primary health care. Any expansion of private health care would be discouraged.

Presenting the plan, Ms Cheryl Carolus, a member of the ANC's national executive committee, said that the ANC had a five year programme to establish a comprehensive system of primary care available to everyone and financed within current tax levels. Rural areas in particular would be provided with health clinics. Health care would be free for children under 6; pregnant and nursing mothers; and elderly, disabled, …