tbuckley/cabot-search huggingface dataset:
Organ Preservation Therapy Using Induction Plus Concurrent Chemoradiation for Advanced Resectable Oropharyngeal Carcinoma: A University of Pennsylvania Phase II Trial
Authors: Mitchell Machtay, David I. Rosenthal, Diane Hershock, Heather Jones, Shirnett Williamson, Michael J. Greenberg, Gregory S. Weinstein, Victor M. Aviles, Ara A. Chalian, Randal S. Weber
Journal: Journal of Clinical Oncology (2002)

To determine the efficacy, feasibility, and toxicity of a new regimen for locally advanced oropharyngeal carcinoma.Patients had technically resectable stage III/IV squamous cell carcinoma of the oropharynx, exclusive of T1-2N1. Induction chemotherapy consisted of carboplatin (area under the curve formula equal to 6) and paclitaxel 200 mg/m(2) for two cycles, followed by re-evaluation. Patients with major response continued to definitive radiotherapy (70 Gy over 7 weeks) plus concurrent once-weekly paclitaxel (30 mg/m(2)/wk). Patients with advanced neck disease also underwent post-radiation therapy neck dissection and two more chemotherapy cycles.Fifty-three patients were enrolled. Median follow-up was 31 months (minimum follow-up for survivors was 18 months). The major response rate to induction chemotherapy was 89%; 90% of patients had a complete response after concurrent chemoradiation. Actuarial survival at 3 years was 70%, and 3-year event-free survival was 59%. The 3-year actuarial locoregional control was 82% and the 3-year actuarial rate of distant metastases was 19%. Organ preservation was achieved in 77% of all patients. One patient (2%) died during therapy. Late grade 3 toxicity occurred in 24% of patients, consisting mainly of chronic dysphagia/aspiration and/or radiation soft tissue ulceration. The treatment-related mortality rate was 4% (two patients died from respiratory failure).Response to induction chemotherapy as studied in this trial was not useful as a predictive marker for ultimate outcome or organ conservation. Overall, however, this regimen offers good disease control and survival for patients with locally advanced oropharyngeal carcinoma, comparable with other concurrent chemoradiation programs. Further study of similar protocols is indicated.
Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor
Authors: Bart L. Loeys, Ulrike Schwarze, Tammy Holm, Bert L. Callewaert, George H. Thomas, Hariyadarshi Pannu, Julie F. De Backer, Gretchen L. Oswald, Sofie Symoens, Sylvie Manouvrier, Amy E. Roberts, Francesca Faravelli, M. Alba Greco, Reed E. Pyeritz, Dianna M. Milewicz, Paul J. Coucke, Duke E. Cameron, Alan C. Braverman, Peter H. Byers, Anne M. De Paepe, Harry C. Dietz
Journal: New England Journal of Medicine (2006)

The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome.We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome.Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.
Increased bioavailability and improved efficacy, in severe psoriasis, of a new microemulsion formulation of cyclosporin*
Authors: W.P. GULLIVER, G.F. MURPHY, V.A. HANNAFORD, D.R.N. PRIMMETT
Journal: British Journal of Dermatology (1996)

Cyclosporin, as the microemulsion formulation Neoral, was given to two groups of patients with severe psoriasis (Psoriasis Area and Severity Index: PASI > 12.0). Group A (10 patients) were receiving the traditional formulation of cyclosporin, Sandimmun, at the start of the study, with a partial clinical response, and were switched to Neoral at the same dose (3.3 mg/kg per day). Group B patients, who had previously been treated with Sandimmun but were treatment failures, were given Neoral, 3.5 mg/kg per day. This led to rapid improvement in psoriasis in both groups. In Group A mean PASI fell from 22.3 to 11.6 on Sandimmun, after 82 +/- 30 weeks, and to 4.0 (P < 0.05) after 32 weeks of Neoral. In Group B mean PASI decreased from 20.3 to 3.7 (P < 0.05) at a dose of 3.1 mg/kg per day. Pharmacokinetic data demonstrated significant decrease in tmax from 2.3 to 1.4 hours. After 2 weeks Cmax and the area under the curve (AUC) (0-4 h) were significantly increased by 41% and 61%, respectively. Further pharmacokinetic data at 3 months showed similar results. No significant changes in renal function from pre-treatment status were seen in either group. None of the patients developed hypertension. No serious adverse events were reported. The microemulsion formulation of cyclosporin showed greater efficacy and bioavailability. Improved outcome was seen at doses which were on average 15% lower than with the traditional formulation, leading to a reduction in cost of treatment.
Impaired posthypoxic relaxation in single cardiac myocytes: role of intracellular pH and inorganic phosphate
Authors: A. G Bertoni, S. Adrian, S. Mankad, H. S Silverman
Journal: Cardiovascular Research (1993)

Objective: The aim was to examine the effects of alterations in intracellular pH and inorganic phosphate concentration (known to influence myofilament kinetics and to change rapidly during hypoxia) on cell contraction, relaxation, and the Ca2+ transient in normoxic and hypoxic myocytes. Methods: Single adult rat ventricular myocytes were electrically stimulated (0.2 Hz) and cell length (photodiode array), intracellular Ca2+ (indo-1 fluorescence), or intracellular pH (SNARF-1 fluorescence) measured. Hypoxia was induced in a special open chamber in which a laminar layer of argon prevented the back diffusion of atmospheric oxygen. Results: Electrically stimulated contraction was preserved during exposure to hypoxia. At reoxygenation 10 minutes later the time from the stimulus to the peak of contraction (TPK) increased by 30(SEM 9)% and the time from the peak of contraction to 50% recovery of cell length (RT50) increased by 59(13)% relative to prehypoxic values (n = 8). These changes were not accompanied by a change in the kinetics of the Ca2+ transient. pHi fell from a baseline of 7.33(0.04) to 7.25(0.03) during hypoxia and then overshot to 7.44(0.03) at reoxygenation (n = 5). Since an intracellular alkalosis can slow myofilament relaxation, proton extrusion routes were blocked to examine posthypoxic relaxation in the absence of an alkalosis. Despite inhibition of the pHi overshoot, posthypoxic relaxation remained impaired. Intracellular inorganic phosphate levels were manipulated in two protocols (2-deoxyglucose to “trap” phosphate and Tris(hydroxymethyl)-aminomethane to buffer phosphate) and both TPK and RT50 increased in normoxic cells. Having established that these two interventions, which would be expected to decrease intracellular inorganic phosphate, result in a slowing of relaxation, myocytes were first phosphate loaded (exposed to 5.0 mM phosphate) and then made hypoxic and reoxygenated after 10 min to blunt the expected fall in phosphate accompanying reoxygenation. This led to a reduction in the slowing of contraction and relaxation following reoxygenation [TPK increased by 7(5)% and RT50 by 17(9)%, n = 8; p < 0.05 v cells studied in control buffer]. Conclusions: Impaired posthypoxic relaxation is not the result of changes in pHi but is attenuated by phosphate loading of cells and may be due to a rapid decrease in intracellular phosphate accompanying the resynthesis of high energy phosphates at reoxygenation. Cardiovascular Research 1993;27:1983-1990
Abstract 2285: PKC activation sensitizes certain basal breast cancer cell lines to the Smac mimetic LBW242
Authors: Louise Cornmark, Christian Holmgren, Katarzyna Masoumi, Christer Larsson
Journal: Cancer Research (2014)

Abstract There is a need for novel strategies to initiate cancer cell death. One approach is the use of Smac mimetics, such as LBW242, which antagonize inhibitor of apoptosis proteins (IAP)s and facilitates cell death. Recent studies have shown that combinations of Smac mimetics and chemotherapeutic agents increase cancer cell death. Here we show that the protein kinase C (PKC) activator TPA together with LBW242 induce cell death in two basal breast cancer cell lines (MDA-MB-468 and BT549), that are resistant to LBW242 as a single agent. Eleven other LBW242-insensitive cancer cell lines were not influenced by the TPA+LBW242 combination. The TPA+LBW242 effect was suppressed by the PKC inhibitor GF109203X, indicating dependence on PKC enzymatic activity. The PKC effect was mediated via increased synthesis and release of TNFα which can induce death in the presence of LBW242. The cell death, coinciding with caspsae-3 cleavage, was suppressed by caspase inhibition and preceded by the association of RIP1 with Caspase-8, as seen in complex II mediated apoptosis. Our data suggest that in certain basal breast cancer cell lines co-treatment of TPA with LBW242 induces cell death highlighting the potential of using these pathways as molecular targets for basal-like breast cancers. Citation Format: Louise Cornmark, Christian Holmgren, Katarzyna Masoumi, Christer Larsson. PKC activation sensitizes certain basal breast cancer cell lines to the Smac mimetic LBW242. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2285. doi:10.1158/1538-7445.AM2014-2285
Is the incidence of pemphigoid really increasing?
Authors: R. W Groves, B. Bhogal, K. Taghipour, P. Caposciutti, M. Saha
Journal: BMJ (2008)

We found the data reported by Langan et al on the apparent increasing incidence of pemphigoid striking.1

It might reasonably be expected that a fivefold increase in incidence of pemphigoid would be apparent to physicians caring for patients with the disorder. Blistering disorders are perhaps unusual among skin conditions in that they are nearly always reported to dermatologists, and specialised testing is required …
Treatment of Aseptic Wounds without Bandages or Dressings
Authors: J. Mackenzie
Journal: BMJ (1896)

ASEPTIC WVOUNDS.TB [MED BRTISH 267 teresting question whether these bear any, and if so what, relation to the diphtheria bacilli originally present.PERSISTE3NCE OF THE BACILLI IN THE TiiROAT.The I,ooo cases on which our results are based are all pri- mary examinations, but in several further examinations have been made to ascertain whether the diphtheria bacilli had disappeared, and the subjects were free from infection.From such " repeats " it would seem that the bacilli are com- monly to be found in the throat two to three weeks after the attack, but that this period may be greatly exceeded, Thus in one instance the specific organism was found seven weeks, in another nine weeks, and in a third twenty-three weeks after convalescence.In the latter case, the virulence.of the bacilli, as tested by inoculation, was maintained to the last, for a guinea-pig inoculated witll 0.25 c.cm. of a forty-eight hours' broth culture died in thirty-six hours.Another notable case was one in which virulent Klebs-
Determinants of Medical Expenditures in the Last 6 Months of Life
Authors: Amy S. Kelley, Susan L. Ettner, R. Sean Morrison, Qingling Du, Neil S. Wenger, Catherine A. Sarkisian
Journal: Annals of Internal Medicine (2011)

Background: End-of-life medical expenditures exceed costs of care during other years, vary across regions, and are likely to be unsustainable. Identifying determinants of expenditure variation may reveal opportunities for reducing costs. Objective: To identify patient-level determinants of Medicare expenditures at the end of life and to determine the contributions of these factors to expenditure variation while accounting for regional characteristics. It was hypothesized that race or ethnicity, social support, and functional status are independently associated with treatment intensity and controlling for regional characteristics, and that individual characteristics account for a substantial proportion of expenditure variation. Design: Using data from the Health and Retirement Study, Medicare claims, and The Dartmouth Atlas of Health Care, relationships were modeled between expenditures and patient and regional characteristics. Setting: United States, 2000 to 2006. Participants: 2394 Health and Retirement Study decedents aged 65.5 years or older. Measurements: Medicare expenditures in the last 6 months of life were estimated in a series of 2-level multivariable regression models that included patient, regional, and patient and regional characteristics. Results: Decline in function (rate ratio [RR], 1.64 [95% CI, 1.46 to 1.83]); Hispanic ethnicity (RR, 1.50 [CI, 1.22 to 1.85]); black race (RR, 1.43 [CI, 1.25 to 1.64]); and certain chronic diseases, including diabetes (RR, 1.16 [CI, 1.06 to 1.27]), were associated with higher expenditures. Nearby family (RR, 0.90 [CI, 0.82 to 0.98]) and dementia (RR, 0.78 CI, 0.71 to 0.87]) were associated with lower expenditures, and advance care planning had no association. Regional characteristics, including end-of-life practice patterns (RR, 1.09 [CI, 1.06 to 1.14]) and hospital beds per capita (RR, 1.01 [CI, 1.00 to 1.02]), were associated with higher expenditures. Patient characteristics explained 10% of overall variance and retained statistically significant relationships with expenditures after regional characteristics were controlled for. Limitation: The study limitations include the decedent sample, proxy informants, and a large proportion of unexplained variation. Conclusion: Patient characteristics, such as functional decline, race or ethnicity, chronic disease, and nearby family, are important determinants of expenditures at the end of life, independent of regional characteristics. Primary Funding Source: The Brookdale Foundation.
Patients are let down by poor device regulation, warn surgeons
Authors: D. Cohen
Journal: BMJ (2012)

Patients are being “failed” by the poor regulation of hip prostheses and other medical devices, which is potentially allowing dangerous products onto the European market, the Royal College of Surgeons warns today.

In a letter to the Daily Telegraph the college and the British Orthopaedic Association warn that revelations in a joint BMJ and Daily Telegraph investigation about the system are a “stark reminder” of the “urgent need to address the regulatory flaws.”

The investigation today discloses that the regulation of European medical products is also being “sub contracted” to Asian firms.1

One of the firms (ITC), based in Seoul, said that it had a 100% success rate and “there was no case . . . which [is] rejected.”

Executives at the firm, the official Asian representative of a Czech notified body, said that companies should apply for European market access as it was far easier to gain entry than into other countries, such as the United States, South Korea, and Japan.

Asked by undercover journalists why his firm’s services should be used, the company executive rubbed his fingers together and said “money…the profit.”

Another …
Life at the sharp end
Authors: Kinesh Patel
Journal: BMJ (2008)

Just as we’ve got used to excuses about the wrong types of leaves on the line and even the wrong type of snow when we wait for a train, we’ve also now become so accustomed to the wrong type of bureaucracy in the NHS that almost any form of management is resented.

Take venous cannulas, for example—a deeply unglamorous topic, admittedly, and the bane of many junior doctors’ lives. A new batch arrived on our ward a couple of months ago, a special safety model that looked pretty much the same as any other cannula. …
The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation
Authors: S Tavor, M Eisenbach, J Jacob-Hirsch, T Golan, I Petit, K BenZion, S Kay, S Baron, N Amariglio, V Deutsch, E Naparstek, G Rechavi
Journal: Leukemia (2008)
Immunolocalization of P2Y1 and TPα receptors in platelets showed a major pool associated with the membranes of α-granules and the open canalicular system
Authors: Paquita Nurden, Christel Poujol, Joelle Winckler, Robert Combrié, Nathalie Pousseau, Pamela B. Conley, Sylviane Levy-Toledano, Aida Habib, Alan T. Nurden
Journal: Blood (2003)
Clinical Remarks on the Study and Diagnosis of Skin-Diseases
Authors: R. Liveing
Journal: BMJ (1878)

IN the foll; wing remarks on the best method of observing diseases of the skin, I would point out, in the first place, that the diagnosis of a disease, to be of any practical value, includes much more than assigning to it a name: it involves a correct estimate both of its nature and of its affinities.The great majority of skin-affections are forms of inflamma- tion, and as such are very much alike as regards details, though they may differ altogether in other important respects.Thus, in almost all inflam- mations of the skin we may chance to find red patches, papules, vesi- cles, blebs, pustules, scales, or crusts; and, therefore, the first point of importance is the recognition of the fact that these varying phenomena of cutaneous inflammation are simply brought about by the anatomical structure of the skin, and are, therefore, of uncertain value in deter- mining the nature of the inflammation.The extent and degree of the inflammation, the tissue involved, the grouping of the eruption, and the part affected, may all be of more importance than the minute characters of the elementary changes.Bat, although I wish at the out- set to guard against an overestimate of the diagnostic value of minute characteristics, I nevertheless attach considerable importance to them, especially in certain cases, as I shall hereafter explain."For the recognition of a disease of the skin", says Hebra, "no other assistance is required than a knowledge of the objective symp- toms, which are visible on the surface of the body in each particular case.We do not attach any value whatever either to the history or to the subjective phenomena in investigating a cutaneous affection, for we ought to be guided in this matter only by those symptoms which are appreciable by the sight, the touch, or sometimes by the smell.These afford certain and infallible grounds for the establishment of a diagnosis, for they have their origin in the malady itself.They are, so to speak, the alphabet of which the letters are traced on the skin; and our task is but that of deciphering the writing."This statement of Hebra, that we do not attach any value whatever either to the history or to the subjective phenomena in investigating a cutaneous affection, must be received with reservation.It is, how- ever, valuable, inasmuch as it tends to impress strongly and, as it were, to exaggerate the leading feature in our means of diagnosis.On
Experts consider whether replacing intravenous devices every three days is clinically indicated
Authors: M. Pownall
Journal: BMJ (2010)

US experts in infection control are reviewing advice issued in 2002 that intravenous devices should be replaced every 72 to 96 hours as a matter of routine.

Updated guidance from the Centers for Disease Control infection control advisory group (HICPAC) is expected to be published this winter. A draft says that peripheral intravenous devices should be replaced “no more frequently than every 72-96 hours” but that evidence for leaving catheters in place unless clinically indicated was an “unresolved issue.”

The 2002 guidelines are based on findings from early small studies that suggested routine replacement might limit complications such as phlebitis. But the proposed change comes as evidence mounts that replacing intravenous devices every three days is not clinically indicated. A Cochrane review published earlier …
Electrophysiologic and behavioral effects of perinatal and acute exposure of rats to lead and polychlorinated biphenyls.
Authors: David O Carpenter, Rifat J Hussain, David F Berger, John P Lombardo, Hye-Youn Park
Journal: Environmental Health Perspectives (2002)

Lead and polychlorinated biphenyls (PCBs) both cause a reduction of intelligence quotient and behavioral abnormalities in exposed children that have features in common with attention deficit hyperactivity disorder. We have used rats as a model to study the effects of both perinatal and acute exposure to lead or PCBs in an effort to compare and understand the mechanisms of these nervous system decrements. Long-term potentiation (LTP) is an electrophysiologic measurement that correlates well with cognitive ability. We have determined the effects of chronic perinatal exposure to lead or PCB 153 as well as acute application of these substances to isolated brain slices, with recordings in two areas of the hippocampus, CA1 and CA3. Both substances, whether chronically or acutely applied, significantly reduced LTP in CA1 in animals at age 30 and 60 days. In CA3, they reduced LTP in 30-day animals but potentiated it in 60-day animals. Although neither lead nor PCB 153 alters baseline synaptic transmission at low stimulus strengths, at higher levels they induce changes in the same direction as those of LTP. These results show surprisingly similar actions of these quite different chemicals, and the similarity of effects on chronic and acute application indicates that effects are both pharmacologic and developmental. Behavioral studies of rats exposed to PCBs from contaminated fish show hyperactivity, impulsiveness, and increased frustration relative to unexposed controls. These results demonstrate that lead and PCBs have similar effects on synaptic plasticity and behavior and suggest that the compounds may act through a common mechanism.
Glucosamine synthetase activity of the colonic mucosa in membranous colitis.
Authors: M J Goodman, P W Kent, S C Truelove
Journal: Gut (1977)

Glucosamine synthetase, the first enzyme in glycoprotein synthesis, has been measured in serial rectal biopsies in four patients with membranous colitis. In two of the patients the levels of the enzyme were very high initially and in the other two patients the enzyme levels rose to a peak above the normal range after a delay of up to 10 days. These high levels may be related to the mucus hypersecretion which is a feature of membranous colitis but it seems more likely that they represent the healing of the mucosa.