tbuckley/cabot-search huggingface dataset:
High-risk surgery: the courage to fail
Authors: John R Pepper, Aman S Coonar
Journal: Journal of the Royal Society of Medicine (2015)

Not so long ago, cardiothoracic surgeons were often called to see patients late in the natural history of their disease and asked to consider higher-risk operations. Most surgeons of an earlier era, when routine cases often carried a greater than 5% mortality, were willing to do this. The growth of intense institutional and public scrutiny of 30-day mortality has brought this era to an end. This is despite cardiac and thoracic surgery becoming much safer due to many factors. Diagnosis is now more accurate; anaesthesia and perioperative care have improved greatly. Techniques of anastomosis in the commonest operation, coronary artery bypass, have hardly changed in the last 30 years but other components such as myocardial protection and intraoperative imaging with echocardiography have improved markedly. In thoracic surgery, intensive preoperative optimisation of borderline patients, accelerated recovery pathways, standardisation and minimally invasive techniques are improving outcomes. In a setting of spotlight, sensationalism and social media some surgeons are less willing to take on higher-risk patients. The modern era of transparency, team-working and increasing involvement of well-informed patients are bringing about a major change of attitude and approach. The traditional model of individual mastery gained by many years of individual honing of surgical techniques together with sometime ‘assumed authority’ and autonomy has given way to a new style which encompasses integrity, compassion, altruism, continuous improvement, team-working and partnership with the patient. Of course, there is overlap between these two styles of professionalism but there has been a significant change in emphasis. Simultaneously, the environment has moved towards one of zero tolerance of poorer outcomes even when not due to mistakes. We have moved from paternalism to partnership. In the words of a former head of the General Medical Council (GMC), Sir Donald Irvine, ‘there has been a growth of awareness that medicine cannot be practised solely on the doctor’s ground’. Patients want to hear clear ‘jargon-free’ language, to be heard and to be central.
Immunoregulatory properties of pulmonary surfactant: effect of lung lining fluid on proliferation of human blood lymphocytes.
Authors: M L Wilsher, D A Hughes, P L Haslam
Journal: Thorax (1988)

Human pulmonary surfactant has not been shown to have immunoregulatory properties. A study was designed to examine the effect of whole surfactant (lyophilised bronchoalveolar lavage fluid) and purified surfactant lipids obtained from normal lungs of three species (man, pig, rabbit) on the lymphoproliferative responses of human peripheral blood lymphocytes to mitogens and alloantigens. Whole surfactant and purified surfactant lipids suppressed the proliferative response to phytohaemagglutinin in a dose dependent manner. The purified lipid fraction appeared to cause more suppression than whole surfactant in all the species. There was significant suppression of the proliferative response to B cell mitogens, T cell mitogens (pokeweed mitogen and phytohaemagglutinin), and alloantigens as tested by allogeneic mixed lymphocyte cultures. These results suggest an immunoregulatory role for pulmonary surfactant, most likely due to the lipid fraction.
Acid stimulated alkaline secretion in the rabbit duodenum is passive and correlates with mucosal damage.
Authors: P Vattay, W Feil, S Klimesch, E Wenzl, M Starlinger, R Schiessel
Journal: Gut (1988)

Low luminal acid concentrations stimulate alkaline secretion (AS) by the duodenal mucosa. We investigated acid stimulated alkaline secretion by proximal rabbit duodenal mucosa in an Ussing-chamber under different luminal acid concentrations and its relation to mucosal damage. Luminal alkalinisation and potential difference (PD) were measured and mucosal damage was investigated histologically. Luminal acid caused an increase of alkaline secretion over baseline (0.95 +/- 0.19 mu Eq/cm2/10 min; n = 55): 0.1 mmol: 7%, 1 mmol/l: 17%, 5 mmol/l: 22%, 10 mmol/l: 33%, 20 mmol/l: 34%, 50 mmol: 39%, 100 mmol/l: 27%. At acid concentrations of 10 mmol/l and above the PD fell from 2.0 +/- 1.0 mV to zero. Histology showed [H+]-dependent mucosal damage ranging from villus tip lesions to deep mucosal injury. Stimulation of alkaline secretion was not specific for acid. Ethanol (14%) stimulated alkaline secretion by 26%, and 28% ethanol by 40% over baseline. Ouabain and/or anoxia sensitive (active) alkaline secretion constituted 80% and 100% respectively of basal alkaline secretion. After exposure to various luminal acid concentrations passive diffusion (sensitive only to removal of nutrient HCO3-) was solely responsible for the rise in alkaline secretion. Only after 14% ethanol a small rise in ouabain and/or anoxia sensitive HCO3- transport was observed. Under the conditions of this study stimulation of duodenal alkaline secretion is not specific for luminal acid, but occurs also with luminal ethanol; both agents stimulate alkaline secretion depending on their concentration. In this model passive diffusion of HCO3- associated with increasing mucosal damage is the major component of the rise in alkaline secretion.
Slow Transcranial Magnetic Stimulation, Long-Term Depotentiation, and Brain Hyperexcitability Disorders
Authors: Ralph E. Hoffman, Idil Cavus
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity. METHOD: Studies assessing effects of "slow" rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue. RESULTS: Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects. CONCLUSIONS: Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.
RESPONSE: Re: Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer
Authors: S. Ambs, C. C. Harris
Journal: JNCI Journal of the National Cancer Institute (1999)

Inducible Ca-independent nitric oxide synthase (NOS), also referred to as NOS2, which is expressed in a variety of human cancers (1–4), can generate mutagenic concentrations of nitric oxide (NO) in mice (5). NOS2 is the most active isoform among the three known nitric oxide synthases (6), which also include the neuronal (NOS1) and endothelial (NOS3) isoforms. Only NOS2 is capable of producing sustained NO concentrations in the micromolar range (7). We investigated the hypothesis that NO generated by NOS2 is capable of inducing mutations in the p53 (also known as TP53) gene and contributes to human colon carcinogenesis. We analyzed 118 sporadic colon tumors for NOS2 expression and p53 gene mutations. Colon tumors and surrounding normal tissues were collected from the Cooperative Human Tissue Network and the Department of Pathology, University of Baltimore, with the approval of local boards governing research on human subjects, as described previously (3). The expression of NOS2 was increased in various tumors (Fig. 1, A and B) throughout the right, left, and sigmoid colon. Adenomas showed the highest average NOS2 activity. The NOS2 activity declined with advancing tumor stage and was seen at the lowest level in metastatic tumors (Fig. 1, A). NOS2 activity correlated with NOS2 protein expression. Immunohistochemical analysis localized NOS2 protein mainly in tumor-infiltrating mononuclear cells and less frequently in en-
Monitoring the Rate and Dynamics of Concerted Evolution in the Ribosomal DNA Repeats of Saccharomyces cerevisiae Using Experimental Evolution
Authors: Austen R.D. Ganley, Takehiko Kobayashi
Journal: Molecular Biology and Evolution (2011)

Concerted evolution describes the unusual evolutionary pattern exhibited by certain repetitive sequences, whereby all the repeats are maintained in the genome with very similar sequences but differ between related species. The pattern of concerted evolution is thought to result from continual turnover of repeats by recombination, a process known as homogenization. Approaches to studying concerted evolution have largely been observational because of difficulties investigating repeat evolution in an experimental setting with large arrays of identical repeats. Here, we establish an experimental evolution approach to look at the rate and dynamics of concerted evolution in the ribosomal DNA (rDNA) repeats. A small targeted mutation was made in the spacer of a single rDNA unit in Saccharomyces cerevisiae so we could monitor the fate of this unit without the need for a selectable marker. The rate of loss of this single unit was determined, and the frequency of duplication was also estimated. The results show that duplication and deletion events occur at similar rates and are very common: An rDNA unit may be gained or lost as frequently as once every cell division. Investigation of the spatial dynamics of rDNA turnover showed that when the tagged repeat unit was duplicated, the copy predominantly, but not exclusively, ended up near to the tagged repeat. This suggests that variants in the rDNA spread in a semiclustered fashion. Surprisingly, large deletions that remove a significant fraction of total rDNA repeats were frequently found. We propose these large deletions are a driving force of concerted evolution, acting to increase homogenization efficiency over-and-above that afforded by turnover of individual rDNA units. Thus, the results presented here enhance our understanding of concerted evolution by offering insights into both the spatial and temporal dynamics of the homogenization process and suggest an important new aspect in our understanding of concerted evolution.
Chronic Inflammatory Disorders and Risk of Type 2 Diabetes Mellitus, Coronary Heart Disease, and Stroke
Authors: Alex Dregan, Judith Charlton, Phil Chowienczyk, Martin C. Gulliford
Journal: Circulation (2014)

Background— This study sought to evaluate whether risks of diabetes mellitus and cardiovascular disease are elevated across a range of organ-specific and multisystem chronic inflammatory disorders. Methods and Results— A matched cohort study was implemented in the UK Clinical Practice Research Datalink including participants with severe psoriasis (5648), mild psoriasis (85 232), bullous skin diseases (4284), ulcerative colitis (12 203), Crohn’s disease (7628), inflammatory arthritis (27 358), systemic autoimmune disorders (7472), and systemic vasculitis (6283) and in 373 851 matched controls. The main outcome measures were new diagnoses of type 2 diabetes mellitus, stroke, or coronary heart disease. The outcomes were evaluated for each condition in a multiple outcomes model, with adjustment for conventional cardiovascular risk factors. Estimates for different inflammatory conditions were pooled in a random-effects meta-analysis. There were 4695 new diagnoses of type 2 diabetes mellitus, 3266 of coronary heart disease, and 1715 of stroke. The hazard ratio for pooled multiple failure estimate was 1.20 (95% confidence interval [CI], 1.15–1.26). The highest relative hazards were observed in systemic autoimmune disorders (1.32; 95% CI, 1.16–1.50) and systemic vasculitis (1.29; 95% CI, 1.16–1.44). Hazards were increased in organ-specific disorders, including severe psoriasis (1.29; 95% CI, 1.12–1.47) and ulcerative colitis (1.26; 95% CI, 1.14–1.40). Participants in the highest tertile of C-reactive protein had greater risk of multiple outcomes (1.52; 95% CI, 1.37–1.68). Conclusions— The risk of cardiovascular diseases and type 2 diabetes mellitus is increased across a range of organ-specific and multisystem chronic inflammatory disorders with evidence that risk is associated with severity of inflammation. Clinical management of patients with chronic inflammatory disorders should seek to reduce cardiovascular risk.
Microbiota-liver axis in hepatic disease
Authors: Benoit Chassaing, Lucie Etienne-Mesmin, Andrew T. Gewirtz
Journal: Hepatology (2013)

Accumulating evidence indicates that the gut microbiota, long appreciated to be a key determinant of intestinal inflammation, is also playing a key role in chronic inflammatory disease of the liver. Such studies have yielded a general central hypothesis whereby microbiota products activate the innate immune system to drive proinflammatory gene expression, thus promoting chronic inflammatory disease of the liver. This article reviews the background supporting this hypothesis, outlines how it can potentially explain classic and newly emerging epidemiological chronic inflammatory liver disease, and discusses potential therapeutic means to manipulate the microbiota so as to prevent and/or treat liver disease.
Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning".
Authors: R Bolli, J F Triana, M O Jeroudi
Journal: Circulation Research (1990)

Reperfusion after brief, reversible myocardial ischemia is associated with prolonged depression of contractile function (myocardial "stunning"); however, the effect on coronary vascular function has not been defined. Thus, open-chest dogs (n = 14) underwent a 15-minute left anterior descending coronary artery (LAD) occlusion followed by reflow. Four hours after reperfusion, regional myocardial blood flow (microspheres) was significantly (p less than 0.01) lower and coronary vascular resistance significantly (p less than 0.01) higher in the postischemic as compared with the nonischemic endocardium. Furthermore, during maximal vasodilation elicited by intravenous adenosine (n = 6), myocardial blood flow was lower (p less than 0.05) and coronary vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic myocardium, both in the endocardial and in the epicardial layers. Similarly, during maximal dilation elicited by intravenous papaverine (n = 8), myocardial blood flow was lower (p less than 0.05) and vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic endocardium; a directionally similar trend was observed in the epicardium. Four hours after reperfusion, all indexes of reactive hyperemia after a 40-second coronary occlusion were significantly lower in the LAD than in the control circumflex coronary artery (n = 8). There was no appreciable correlation between systolic wall thickening in the stunned myocardium and 1) the resting myocardial perfusion, 2) the hyperemia attained during adenosine or papaverine, and 3) the hyperemic response to a 40-second coronary occlusion. In control dogs that did not undergo a 15-minute LAD occlusion (n = 15), there were no differences in myocardial blood flow or vascular resistance between the LAD-dependent and the circumflex-dependent bed, either before or during adenosine (n = 7) or papaverine (n = 8). Furthermore, reactive hyperemia after a 40-second occlusion did not differ between the LAD and the circumflex artery (n = 8). In conclusion, a brief (15 minute), reversible ischemic insult causes a prolonged increase in resting vascular resistance and a prolonged impairment in vasodilator responsiveness, both of which persist for at least 4 hours. The severity of these vascular derangements is not related to the severity of contractile depression, suggesting that they may represent a relatively independent phenomenon. It is proposed that, in addition to myocardial "stunning," reversible ischemia also causes a microvascular "stunning."
Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update
Authors: L.M. Fabbri, S.S. Hurd
Journal: European Respiratory Journal (2003)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) programme was initiated in January 1997 to increase awareness of chronic obstructive pulmonary disease (COPD) and to decrease morbidity and mortality from this chronic lung disorder. One strategy to help achieve the objectives of the GOLD programme is to provide healthcare workers, healthcare authorities and the general public with state-of-the-art information about COPD and specific recommendations on the most appropriate management and prevention strategies.

The GOLD Workshop Report, Global Strategy for the Diagnosis, Management and Prevention of COPD 1 was published in April 2001. It was prepared by a panel of experts nominated by the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health and the World Health Organization with the aim of providing the best validated current concepts of COPD pathogenesis and the best available evidence on the most appropriate management and prevention strategies. In an effort to keep the GOLD Workshop Report as up to date as possible, GOLD assembled a Scientific Committee whose aim was to review clinical research that has an impact on COPD management. The initial review included publications that were published in June 2000 (approximately the time of completion of the 2001 report) through to March 2003. The results of the first 2 yrs of activity were posted on the GOLD website (www.goldcopd.com) in July 2003 2. Each year, a new update report will be posted. The GOLD Scientific Committee will also prepare a revision of the entire GOLD Workshop Report approximately every 5 yrs. The process for the first complete revision (to appear in 2006) will be developed in the autumn of 2003.

The process included a PubMed search using search fields established by the GOLD Scientific Committee: 1) COPD OR chronic bronchitis OR emphysema, All Fields, All Adult, 19+ yrs, only items …
A probable double heterozygous type II von Willebrand's disease with increased ristocetin induced platelet aggregation
Authors: Seiji Kinoshita, Keiichiro Yoshioka, Motoko Kasahara, Osamu Takamiya
Journal: American Journal of Hematology (1992)

We have identified a patient with von Willebrand's disease (vWD) resembling type IIB vWD, with increased ristocetin induced platelet aggregation (RIPA), the absence of the large multimers of von Willebrand factor (vWF) in plasma, and the presence of the large multimers in platelets in whom a family study indicated a probable double heterozygous inheritance pattern. The propositus was a 12-year-old boy with frequent epistaxis and bruising. Abnormal hemostatic findings included a prolonged bleeding time (BT), decreased levels of factor VIII coagulant activity (VIIIC), von Willebrand factor antigen (vWF:Ag), ristocetin cofactor (RCof), and an increased RIPA. In the presence of ristocetin, binding of the patient's plasma vWF to normal platelets was increased but binding of normal vWF to his platelets was normal. SDS-agarose gel (1.5%) electrophoresis revealed that plasma vWF lacked the large multimers, and 3.0% gel electrophoresis revealed that the multimers had a 5-band pattern similar to normal. The above findings were consistent with type IIB vWD, but 1-deamino[8-D-arginine]-vasopressin (DDAVP) infusion resulted in a shortened BT and the transient appearance of large multimers without a decrease in the platelet count. Family studies revealed that his mother has mild bleeding symptoms, decreased VIIIC, vWF:Ag, and RCof levels and normal to slightly reduced RIPA with a multimer pattern consistent with type I vWD. In contrast, the father, sister, and paternal grandfather were asymptomatic, with a slightly decreased VIIIC level but a normal BT and vWF:Ag and RCof levels. Their RIPA and vWF binding to normal platelets were increased, but unlike the propositus their plasma contained large multimers. We concluded that the propositus is a type IIB-like variant differing from previously reported IIB variants in two ways: 1) his response to DDAVP and 2) a possible double heterozygous mode of inheritance rather than the usual dominant route.
Oral prednisone for chronic active liver disease: dose responses and bioavailability studies.
Authors: M Uribe, S W Schalm, W H Summerskill, V L Go
Journal: Gut (1978)

Serum concentrations of prednisolone were measured by radioimmunoassay after the administration of prednisone (10, 20, or 30 mg) by mouth to five healthy volunteers, five patients with severe chronic active liver disease (CALD), and five patients with CALD in remission induced by prednisone. Only minor differences were found between the groups and bioavailability was linearly related to the dose of prednisone (r = 0.993). After prednisone (10 mg) was given by mouth and by vein to similar groups of volunteers and 11 additional patients with CALD, bioavailability of oral prednisone approximated 100% of the intravenous dose and no differences were found in the pharmacokinetics of prednisolone. We conclude that prednisone is effectively absorbed and converted to prednisolone in health and CALD and find no pharmacological evidence that either drug would be superior to the other for treating CALD.
Pervasive Antisense Transcription Is Evolutionarily Conserved in Budding Yeast
Authors: A. J. Goodman, E. R. Daugharthy, J. Kim
Journal: Molecular Biology and Evolution (2012)

Antisense transcription, or transcription on the opposite strand of the same genomic locus as another transcript, has been observed in many organisms, including yeast. Several antisense transcripts are known to be conserved across various species of yeast, and a few antisense transcripts are associated with functional regulation of the sense transcript. We detect antisense transcription from approximately 90% of protein-coding genes, and antisense transcription is generally associated with histone modifications indicative of a transcriptionally active state. The pattern of genome-wide antisense transcription in two species of budding yeast, Saccharomyces cerevisiae and S. paradoxus, is widely evolutionarily conserved: Antisense transcripts exhibit conserved expression levels and localization with respect to gene annotations. Regions of genes exhibiting conserved antisense transcription also show less sequence divergence than regions of genes without antisense transcription. These findings provide further support that widespread antisense transcription is functional in yeast, and expand the catalog of putative functional antisense transcripts to include nonpolyadenylated transcripts. Because antisense transcripts are less divergent in sequence than expected, they likely contain sequences important to their function.