tbuckley/cabot-search huggingface dataset:
P123 Impulse oscillometry (IOS) indices in severe asthma and healthy controls after deep breath manoeuvres and bronchodilator administration
Authors: I. Umar, D. Desai, S. Corkill, M. Shelley, A. Singapuri, C. Brightling, S. Siddiqui
Journal: Thorax (2010)

<h3>Introduction</h3> Impulse oscillometry is a non-invasive method used to measure airway impedance. There is increasing interest in utilising frequency dependence of airway resistance/reactance to study small airways disease in asthma. We examined frequency dependant behaviour in severe asthma and the response to deep inspiration and bronchodilators. <h3>Methods</h3> 27 healthy controls (C) (Mean (sem) age; 48.4 (2.2), Sex M:F; 9:18, post-bronchodilator FEV<sub>1</sub>% predicted; 108.2 (2.8)%) and 66 GINA stage 4–5 severe asthmatics (A) (Mean (Sem) age; 54.1 (1.4), Sex M:F; 31:35, post-bronchodilator FEV1% predicted; 81.02(2.7)%), were recruited from Glenfield Hospital, UK. Impulse oscillometry (IOS) was performed at 5–35 Hz, with impulses triggered every 0.2 s for 150 s, at (1) baseline (base) (2) immediately after five deep breaths (TLC-RV) (pdb) (3) 15 min after 400 mcg inhaled salbutamol (pbd). Markers of total (R5) and large airway (R20) resistance, and frequency dependant behaviour of resistance (R5-R20) and reactance area (AX) were evaluated.Triplicate measurements of 150 s were performed in 18 randomly selected asthmatics from our cohort to assess repeatability. <h3>Results</h3> Impedence measurements were highly repeatable (an intra-class correlation of 0.9) in the triplicate series. We observed asignificant increase in frequency dependence of both resistance (R5-R20) and reactance (AX) after deep inspiration in asthma, but not in healthy controls, which was reversed by the use of a bronchodilator (Abstract P123 Figures 1A–D). In addition R20 increased in both severe asthma and healthy controls after deep inspiration. <h3>Conclusions</h3> Deep inspiration significantly increased frequency dependence of resistance and reactance in severe asthma suggesting that the small airways may be related to the aberrant deep inspiratory response in severe asthma.
Novel cation-selective mechanosensitive ion channel in the atrial cell membrane.
Authors: D Kim
Journal: Circulation Research (1993)

Stretch of atrial muscle causes the release of atrial natriuretic peptide, but no stretch-sensitive membrane sensors have been clearly identified so far. The existence of an ion channel that could mediate stretch-induced Ca2+ influx and subsequent release of the peptide was examined in rat atrial cells. In this report, the discovery of a novel atrial ion channel whose opening probability is extremely sensitive to either positive or negative pressure (half-maximal activation pressure, approximately 1.5 mm Hg) is described. Activation of the current by pressure applied to the pipette was observed both at the whole-cell and single-channel levels. The channel was permeable to cations including Ca2+. The channels were clustered with six to nine channels in each cluster, and several channels tended to open simultaneously in response to a graded increase in pressure for the inwardly passing current. Hypotonic swelling also activated these channels. These results show that mechanosensitive nonselective cation channels exist in atrial cells and suggest that they could be involved in beat-to-beat regulation of the atrial contraction as well as the stretch-induced expression of proto-oncogenes and secretion of atrial natriuretic peptide via increased Ca2+ entry.
Noninvasive Theranostic Imaging of HSV1-sr39TK-NTR/GCV-CB1954 Dual-Prodrug Therapy in Metastatic Lung Lesions of MDA-MB-231 Triple Negative Breast Cancer in Mice
Authors: Thillai V. Sekar, Kira Foygel, Ohad Ilovich, Ramasamy Paulmurugan
Journal: Theranostics (2014)

Metastatic breast cancer is an obdurate cancer type that is not amenable to chemotherapy regimens currently used in clinic.There is a desperate need for alternative therapies to treat this resistant cancer type.Gene-Directed Enzyme Prodrug Therapy (GDEPT) is a superior gene therapy method when compared to chemotherapy and radiotherapy procedures, proven to be effective against many types of cancer in pre-clinical evaluations and clinical trials.Gene therapy that utilizes a single enzyme/prodrug combination targeting a single cellular mechanism needs significant overexpression of delivered therapeutic gene in order to achieve therapy response.Hence, to overcome this obstacle we recently developed a dual therapeutic reporter gene fusion that uses two different prodrugs, targeting two distinct cellular mechanisms in order to achieve effective therapy with a limited expression of delivered transgenes.In addition, imaging therapeutic reporter genes offers additional information that indirectly correlates gene delivery, expression, and functional effectiveness as a theranostic approach.In the present study, we evaluate the therapeutic potential of HSV1-sr39TK-NTR fusion dual suicide gene therapy system that we recently developed, in MDA-MB-231 triple negative breast cancer lung-metastatic lesions in a mouse model.We compared the therapeutic potential of HSV1-sr39TK-NTR fusion with respective dual prodrugs GCV-CB1954 with HSV1-sr39TK/GCV and NTR/CB1954 single enzyme prodrug system in this highly resistant metastatic lesion of the lungs.In vitro optimization of dose and duration of exposure to GCV and CB1954 was performed in MDA-MB-231 cells.Drug combinations of 1 μg/ml GCV and 10 μM CB1954 for 3 days was found to be optimal regimen for induction of significant cell death, as assessed by FACS analysis.In vivo therapeutic evaluation in animal models showed a complete ablation of lung metastatic nodules of MDA-MB-231 triple negative breast cancer cells following two consecutive doses of a combination of GCV (40 mg/kg) and CB1954 (40 mg/kg) administered at 5 day intervals.In contrast, the respective treatment condition in animals expressing HSV1-sr39TK or NTR separately, showed minimal or no effect on tumor reduction as measured by bioluminescence (tumor mass) and [ 18 F]-FHBG microPET (TK expression) imaging.These highlight the strong therapeutic effect of the dual fusion prodrug therapy and its use in theranostic imaging of tumor monitoring in living animals by multimodality molecular imaging.
Analysis of the IgVH somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course
Authors: Patricia Algara, Marisol S. Mateo, Margarita Sanchez-Beato, Manuela Mollejo, Immaculada C. Navas, Lourdes Romero, Francesc Solé, Marta Salido, Lourdes Florensa, Pedro Martı́nez, Elias Campo, Miguel A. Piris
Journal: Blood (2002)
Catecholamine regulation of human erythrocyte membrane protein kinase.
Authors: T Tsukamoto, M Sonenberg
Journal: Journal of Clinical Investigation (1979)

The effect of catecholamines on membrane-associated protein kinase in the mature human erythrocyte was investigated. Protein kinase activity was assayed after isolation of membranes from intact erythrocytes incubated with and without catecholamines. Activation of the enzyme is expressed as the ratio of the extent of phosphorylation of exogenous protein substrate in the absence to that in the presence of 2.5 microM cyclic AMP (cAMP). The potent beta-adrenergic agonist, (-)isoproterenol (2 microM), (-)epinephrine (10 microM) and (-)norepinephrine (10 microM) stimulated the cAMP-dependent protein kinase in membranes, 38 +/- 7%, 31 +/- 6%, and 30 +/- 6%, respectively. Maximal stimulation of membrane protein kinase by 10 microM (-)epinephrine was obtained approximately equal to 30 min after initiation of the incubation of erythrocytes with the hormone. The concentrations of (-)catecholamines that gave half-maximal stimulation of the membrane protein kinase were 0.17 microM for isoproterenol, 0.35 microM for epinephrine, and 0.63 microM for norepinephrine. The membrane protein kinase response to beta-adrenergic agonists was found to be stereospecific. The stimulation of membrane protein kinase by 10 microM (-)epinephrine was inhibited by the beta-adrenergic antagonist, (-)propranolol with EC50 = 0.60 microM, and the inhibition of agonist stimulation of the cAMP-dependent protein kinase by propranolol was stereospecific. These studies suggest that a functional beta-adrenergic receptor exists in the mature human erythrocyte.
Early Detection and Rapid Isolation of Leukemia-Reactive Donor T Cells for Adoptive Transfer Using the IFN-γ Secretion Assay
Authors: Inge Jedema, Pauline Meij, Esther Steeneveld, Mels Hoogendoorn, Bart A. Nijmeijer, Marian van de Meent, Simone A.P. van Luxemburg-Heijs, Roel Willemze, J.H. Frederik Falkenburg
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The poor immunogenicity of most leukemias and the lack of specificity of the donor T cells limit the in vivo effectiveness of conventional donor lymphocyte infusions in many patients suffering from persistent or recurrent leukemia after allogeneic stem cell transplantation. These limitations may be overcome by the adoptive transfer of in vitro generated leukemia-reactive T cells. Although the potential clinical efficacy of this approach has been shown previously, lack of reproducibility of the procedure and the inability to show persistence and survival of the transferred T cells hampered further clinical application. The purpose of this study was to develop a new, broadly applicable strategy for the efficient generation and isolation of leukemia-reactive T cells with a better probability to survive and expand in vivo. Experimental Design: Myeloid and B-cell leukemias were modified into professional immunogenic antigen-presenting cells, and used to stimulate HLA-matched donor T cells. After two stimulations, responding donor T cells were isolated based on their secretion of IFN-γ and tested for their capacity to recognize and kill the primary leukemia. Results: Using one universal stimulation and isolation protocol for various forms of leukemia, T-cell populations containing high frequencies of leukemia-reactive T cells could reproducibly be generated and early isolated under mild stimulatory conditions. Isolated T cells still had high proliferative potential and their reactivity seemed to be restricted to cells of the patient's hematopoiesis. Conclusion: We here show a new robust procedure for the generation and isolation of leukemia-reactive T cells for adoptive transfer.
Intentionally harmful violations and patient safety: The example of Harold Shipman
Authors: Richard Baker, Brian Hurwitz
Journal: Journal of the Royal Society of Medicine (2009)

Harold Shipman was an English doctor who killed approximately 15 patients while working as a junior hospital doctor in the 1970s, and another 235 or so when working subsequently as a general practitioner.1 Is it possible to learn general lessons to improve patient safety from such extraordinary events? In this paper we argue that it is not possible fully to understand how Shipman came to be such a successful and prolific serial killer, nor to learn how the safety of healthcare systems can be improved, unless his diabolical activities are studied using approaches developed to investigate patient safety.

The World Health Organization (WHO) defines a patient safety occurrence as ‘an event which resulted in, or could have resulted in, unintended harm to a patient by an act of commission or omission, not due to the underlying medical condition of the patient’.2 Whatever the complexity of his actual motives3 when Shipman administered massive doses of diamorphine he clearly intended harm. But on the WHO's definition Shipman's practice falls outside questions about patient safety. We argue on the contrary that Shipman's case precisely requires to be understood within a patient safety framework (in addition to relevant legal and criminal frameworks).
Advance Care Planning: Ensuring That the Patient's Voice Is Heard
Authors: Jamie H. Von Roenn
Journal: Journal of Clinical Oncology (2013)

Death and dying remain forbidden topics. The threat of death panels that was raised by the 2010 draft regulation supporting Medicare coverage for discussions of advance care planning fueled the fear engendered by these topics and by discussions of preferences for end-of-life care. The 1990 Federal Patient Self-Determination act, which was enacted to address patients’ right to stipulate care preferences at the end of life, was intended to provide patients with the opportunity to communicate their wishes before facing a lifethreatening event and to educate the public about advance directives. 1 Although the law requires health care institutions to document whether or not a patient has executed advance directives, it does not require an evaluation of the patient’s or family’s understanding of advance directives, nor does it require education about them. Current practices have circumvented the spirit of the law. At some institutions, the requirements of the law are satisfied with a box on an admission/ registration form asking the patient if he/she has advance directives, without ensuring that a discussion has taken place. In others, the electronic medical record requires the admitting physician to enter a code status as a component of the admitting orders, leading to a 100% documentation rate. In at least one institution, the admitting physician can circumvent the need for discussion by selecting the most commonly used designation, “Full Code— discussion with patient/ surrogate not appropriate or possible at this time.” 2 More than half a million Americans died as a result of cancer in 2011, and most of them had inadequate documentation of their preferences for end-of-life care, specifically with regard to resuscitation. The majority of the discussions that elicit preferences for resuscitation occur in the hospital without time for thoughtful discourse. One large cancer hospital reported that 86% of patients who died in the hospital had a documented do-not-resuscitate (DNR) order. 3 This is an encouraging statistic until one recognizes that the median time between signing the order and death was 0 days. Because the patients were close to death, about a third of the DNR orders were signed by surrogates. Again, there was no time for considered discussion with the patient and family. A recent study noted that oncologists discussed end-of-life issues with only about a quarter of patients with non–small-cell lung cancer, and more than half of these discussions took place in the inpatient setting, a mean of 33 days before death. 4 Less than 15% of ambulatory patients with advanced cancer have documented ad
Two cases of Mycobacterium avium septic arthritis
Authors: M J Bridges
Journal: Annals of the Rheumatic Diseases (2002)

In an article on Rubens' painting "The Three Graces" Dequeker suggests that hypermobility is a medical explanation of the seeming scoliosis and Trendelenburg sign in the middle figure . 1 But the posture of this middle figure should probably be interpreted as an artistic phenomenon without medical reference.Sculptors in classical Greek and Roman periods often used the contrapposto posture.In this, by putting most weight on one leg, the other leg can be shown in a relaxed and semiflexed position.This undulating between tension and relaxation will animate the figure.A person with normal muscular function and a normal back can perfectly well pose in this way with relaxed hip abductors on the weightbearing side, a descending hip on the opposite side, and a compensating scoliotic posture.This posture is facilitated by support from the arm as in Rubens' painting.If the person tries to take a forward step, relaxation of the muscles of the weightbearing hip can no longer be maintained, and the positive Trendelenburg sign will disappear.In the Renaissance period the use of this contrapposto posture was revived.During his stay in Rome Rubens eagerly studied the then recently excavated Laokoön sculpture with its three distorted figures. 2 He often used such distorted postures in his paintings to give the impression of vigorous muscular characters capable of performing great tasks.The best example is probably "The Debarkation at Marseilles" in the Maria de Medici cycle from 1622 to 1625 for the Luxembourg Palace in Paris. 3 Here, three young women, nereides, with curved muscular backs at the bottom of the picture nearly seem to carry the ship of Maria de Medici.
Possible role of a defect in hepatic bilirubin glucuronidation in the initiation of cholesterol gallstones.
Authors: P Duvaldestin, J L Mahu, J M Metreau, J Arondel, A M Preaux, P Berthelot
Journal: Gut (1980)

Abnormally low activity of hepatic bilirubin UDP-glucuronosyltransferase was found in 25% of 81 unselected patients with gallstones, as compared with only 3% in 35 controls. At the time of cholecystectomy, the stones were taken for analysis in 48 of 81 patients, and a bile sample was obtained in 42 of them. Among the stones, 75% were cholesterol stones, 15% pigment stones, and 10% 9intermediate9 stones. Low hepatic conjugating activity was not preferentially associated with a given type of stone. No relation was found between the enzymic deficiency and the biliary cholesterol saturation index. A high proportion of biliary bilirubin monoglucuronide (over 40%) was found in four of seven patients with low transferase activity, as was earlier demonstrated in patients with overt Gilbert9s syndrome. Raised biliary bilirubin monoglucuronide was also found in three patients, out of 46, who had normal transferase but raised biliary beta-glucuronidase activity. There was no evidence that deficient bilirubin conjugation could be a consequence of gallstones: the activity of another hepatic microsomal enzyme, glucose 6-phosphatase, taken as a reference, was measured in 12 patients and was always normal. Taking into account the very high frequency of a bilirubin centre in the cholesterol stones (87% of the cases in the present series), it is suggested that the increased proportion in poorly soluble biliary bilirubin monoglucuronide, which was associated with defective conjugation, could act as a trigger for gallstone initiation, regardless of the final composition of the stone.
Testimony Psychotherapy in Bosnian Refugees: A Pilot Study
Authors: Stevan M. Weine, Alma Dzubur Kulenovic, Ivan Pavkovic, Robert Gibbons
Journal: American Journal of Psychiatry (1998)

The authors sought to describe the use of the testimony method of psychotherapy in a group of traumatized adult refugees from genocide in Bosnia-Herzegovina.The subjects were 20 Bosnian refugees in Chicago who gave written informed consent to participate in a case series study of testimony psychotherapy. All subjects received testimony psychotherapy, averaging six sessions, approximately 90 minutes, weekly or biweekly. Subjects received standardized instruments for posttraumatic stress disorder (PTSD), depression, traumatic events, global functioning, and prior psychiatric history. The instruments were administered before treatment, at the conclusion of the treatment, and at the 2- and 6-month follow-ups.The posttreatment assessments demonstrated significant decreases in the rate of PTSD diagnosis, PTSD symptom severity, and the severity of reexperiencing, avoidance, and hyperarousal symptom clusters. Depressive symptoms demonstrated a significant decrease, and there was a significant increase in scores on the Global Assessment of Functioning Scale. Two-month and 6-month follow-up assessments demonstrated further significant decreases in all symptoms and an increase in scores on the Global Assessment of Functioning Scale.This pilot study provides preliminary evidence that testimony psychotherapy may lead to improvements in PTSD and depressive symptoms, as well as to improvement of functioning, in survivors of state-sponsored violence.
Neuropsychological function in high-risk breast cancer survivors after stem-cell supported high-dose therapy versus standard-dose chemotherapy: evaluation of long-term treatment effects
Authors: A. Scherwath, A. Mehnert, B. Schleimer, L. Schirmer, F. Fehlauer, R. Kreienberg, B. Metzner, E. Thiel, A.R. Zander, F. Schulz-Kindermann, U. Koch
Journal: Annals of Oncology (2005)
Hypoxic and hypercapnic response in asthmatic subjects with previous respiratory failure.
Authors: A A Hutchison, A Olinsky
Journal: Thorax (1981)

Three children and two young adults with severe asthma who had frequent episodes of respiratory failure were studied. Isocapnic hypoxia and hyperoxic hypercapnia were produced separately using a rebreathing apparatus. Alveolar carbon dioxide tension and oxygen tension were estimated by continuously sampling expired gases. The three young children had a diminished response to hypoxia but a normal response to hypercapnia when compared to control asthmatic children (p less than 0.05) or healthy children (p less than 0.05). The two young adult patients had a normal response to hypoxia but one had a low response to hypercapnia. Studies of parents of these patients suggested that the chance combination of a possibly familial, inappropriate response to hypoxia with severe asthma would lead to a risk of respiratory failure.
Soundings: GUBU: grotesque, unbelievable, bizarre, unprecedented
Authors: Liam Farrell
Journal: BMJ (2004)

“I don't really know what to say, doctor,” the patient said.

I closed my eyes in resignation; could he be any more ambiguous?

One of the skills in general practice is defining the problem. Anything, just anything, can walk though that surgery door. Tragic, comic, or unremittingly trivial—it's our job to reduce it to some form of manageable problem. But in terms of vagueness and sheer unhelpfulness it's hard to beat that opening gambit.

Country practice, though, has its advantages, and I already had an important clue. That same network of family, friends, and neighbours that lends such support in times of crisis has a dark side: in the Valley of the Squinting Windows nothing is missed, and at a recent football match he'd been reported as walking funny.

A few questions further defined the problem. We men are simple creatures; we hate to lose face, and my patient claimed to have haemorrhoids the shape and size of the Mountains of the Moon—not usually the kind of thing one boasts about, even to one's best mates.

A rectal exam was indicated, but as I palpated, I felt a GUBU coming on—a big, big sneeze. What with my hands being both occupied and repulsive, there was no way to hold my nose or grab a hanky. I tried wrinkling my nose, tried supratentorial over-ride (it works for hiccups, as also, curiously, does digital rectal massage); I begged the gods for succour, but the gods are capricious and hate doctors because people trust us.

“Wazoo,” I screamed, catarrh exploding across the room. The elemental force of the blast was stunning, almost like an orgasm but without the emotional commitment, and left me in awe of my body's musculature: such power, such elegance, such coordination. It is the small details I still remember of that climactic moment: the beat of opalescent body fluids on pearly white Irish buttocks that haven't seen much sunshine and have therefore remained commendably youthful and free of wrinkles, the patient's squeal of protest as an already uncomfortable experience became suddenly a disturbing one, the attending nurse's auburn hair wafting in the gale, reminding me of those Woody Allen comedies about autumn in New York.

“I don't really know what to say,” I said.