tbuckley/cabot-search huggingface dataset:
Bacterial Load Predicts Healing Rate in Neuropathic Diabetic Foot Ulcers
Authors: Ling Xu, Susan V. McLennan, Lisa Lo, Anas Natfaji, Thyra Bolton, Yu Liu, Stephen M. Twigg, Dennis K. Yue
Journal: Diabetes Care (2007)

Despite improved treatment, a significant number of diabetic foot ulcers do not heal and eventually lead to amputation (1–5). The important local factors determining the healing rate of ulcers are pressure at the site of the ulcer, adequacy of blood supply, and infection. It is generally accepted that for optimal healing, infection needs to be treated. However, the definition of infection is arbitrary, and, in many borderline cases, clinicians will be uncertain whether antibiotic therapy is indicated. Edmonds et al. (6) showed, in a study of clinically uninfected diabetic foot ulcers, that, even in the absence of overt infection, antibiotic therapy reduced hospitalization and amputation. Conceptually, a high bacterial load by itself can retard ulcer healing by causing a wound environment not conducive to healing. Important factors that may play a role in this regard include secretion of metalloproteinases and their tissue inhibitors from the bacteria, compounds that can cause local tissue destruction (7). Little is known, however, about the effect of bacterial load on the healing rate of neuropathic diabetic foot ulcers. In this study, instead of arbitrarily deciding clinically whether infection was present, a quantitative microbiological method was used to examine the relationship between bacterial load in the wounds of diabetic neuropathic ulcers and the subsequent ulcer healing rate.

Wound fluid was obtained from 32 patients (22 male and 10 female) with neuropathic ulcers at the plantar surface of the foot. Patients were referred to the High Risk Diabetic Foot Clinic at the Diabetes Centre of Royal Prince Alfred Hospital in Sydney, Australia. The mean ± SD age of the cohort was 60.0 ± 9.0 years with a diabetes duration of 14.6 ± 10.1 years and an A1C of 7.9 ± 1.4% (normal  50 V and ankle brachial …
Silica Crystals and Aluminum Salts Regulate the Production of Prostaglandin in Macrophages via NALP3 Inflammasome-Independent Mechanisms
Authors: Etsushi Kuroda, Ken J. Ishii, Satoshi Uematsu, Keiichi Ohata, Cevayir Coban, Shizuo Akira, Kosuke Aritake, Yoshihiro Urade, Yasuo Morimoto
Journal: Immunity (2011)
A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
Authors: Mariana Malvicini, Miguel Rizzo, Laura Alaniz, Federico Piñero, Mariana García, Catalina Atorrasagasti, Jorge B. Aquino, Viviana Rozados, O. Graciela Scharovsky, Pablo Matar, Guillermo Mazzolini
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results: The combined therapy induced a complete tumor regression in &amp;gt;50% of mice in a synergistic fashion, and it significantly prolonged their survival. This strategy was superior to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+ regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-γ-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10 levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide with AdIL-12 allows the generation of good antitumoral responses, thus avoiding undesired side effects of both agents. Conclusions: Our data strongly support the use of a combination of cyclophosphamide and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma. (Clin Cancer Res 2009;15(23):7256–65)
Advance Care Planning for Fatal Chronic Illness: Avoiding Commonplace Errors and Unwarranted Suffering
Authors: Joanne Lynn, Nathan E. Goldstein
Journal: Annals of Internal Medicine (2003)

Patients with eventually fatal illnesses often receive routine treatments in response to health problems rather than treatments arising from planning that incorporates the patient's situation and preferences. This paper considers the case of an elderly man with advanced lung disease who had mechanical ventilation and aggressive intensive care, in part because his nursing home clinicians did not complete an advance care plan and his do-not-resuscitate order did not accompany him to the hospital. The errors that led to his hospitalization and his unwanted treatment there demonstrate how the ordinary lack of advance care planning is deleterious for patients who are nearing the end of life. We discuss serious, recurring, and generally unnoticed errors in planning for care near the end of life and possible steps toward improvement. Repairing these shortcomings will require quality improvement and system redesign efforts, methods familiar from patient safety initiatives. Reliable improvement will also require making it unacceptable for clinicians to fail to plan ahead for care during fatal chronic illness.
Auricular chondritis in rats. An experimental model of relapsing polychondritis induced with type II collagen.
Authors: M A Cremer, J A Pitcock, J M Stuart, A H Kang, A S Townes
Journal: The Journal of Experimental Medicine (1981)

Outbred Wistar rats immunized with native type II collagen developed ear lesions resembling those of human relapsing chondritis. As in human disease, these lesions were characterized by intense chondritis, positive immunofluorescence reactions to IgG and C3, and circulating IgG reactive with native type II collagen. Furthermore, electron-dense deposits were seen near the surface of chondrocytes and corresponded with deposits of IgG and C3. These observations suggest a causal relation between humoral immunity to type II collagen and auricular chondritis in the rat and support the hypothesis than human relapsing polychondritis is an autoimmune disease mediated by immunity to type II collagen.
Non-eosinophilic asthma and the innate immune response
Authors: I. D Pavord
Journal: Thorax (2007)

Pathological heterogeneity of asthma

The concept that there may be heterogeneity of the underlying pathology of asthma has a long pedigree: 80 years ago, Rackemann1 suggested that a subgroup of patients with intrinsic asthma had disease driven by bacterial infection of the upper and lower respiratory tract and the authors of an early postmortem study2 were struck by the heterogeneity of lower airway inflammatory response in fatal asthma. However, since then the prevailing view, largely driven by bronchial biopsy studies of limited numbers of patients with relatively mild disease, has been that there are more similarities than differences in the pathology of subtypes of asthma. Thus, asthma is currently viewed as a condition characterised by TH2 cytokine-mediated eosinophilic airway mucosal inflammation.3,4

The development of simple methods to assess airway inflammation non-invasively using induced sputum which are applicable to a wide variety of patients5 has renewed interest in investigation of the pathological heterogeneity of asthma. Using this technique, Turner et al 6 unexpectedly found that just under half of 34 patients studied during a minor asthma exacerbation had no sputum eosinophilia. Fahy et al 7 made a similar observation in patients studied during a more significant exacerbation; many patients had sputum evidence of neutrophilic airway inflammation. Subsequently non-eosinophilic asthma has been shown to be present in 25% of patients presenting to an adult respiratory clinic with symptomatic asthma,8,9 in patients with occupational asthma10 and in up to 50% of patients with asthma treated with high doses of inhaled corticosteroids.11 The concept that non-eosinophilic asthma represents a pathologically distinct form of the disease is supported by work by Wenzel et al 12 showing that a subgroup of patients with …
Effects on patients with asthma of eradicating visible indoor mould: a randomised controlled trial
Authors: M L Burr, I P Matthews, R A Arthur, H L Watson, C J Gregory, F D J Dunstan, S R Palmer
Journal: Thorax (2007)

<b>Background:</b> It is not clear whether associations between respiratory symptoms and indoor mould are causal. A randomised controlled trial was conducted to see whether asthma improves when indoor mould is removed. <b>Methods:</b> Houses of patients with asthma were randomly allocated into two groups. In one group, indoor mould was removed, fungicide was applied and a fan was installed in the loft. In the control group, intervention was delayed for 12 months. Questionnaires were administered and peak expiratory flow rate was measured at baseline, 6 months and 12 months. <b>Results:</b> Eighty-one houses were allocated to the intervention group and 83 to the control group; 95 participants in 68 intervention houses and 87 in 63 control houses supplied follow-up information. Peak expiratory flow rate variability declined in both groups, with no significant differences between them. At 6 months, significantly more of the intervention group showed a net improvement in wheeze affecting activities (difference between groups 25%, 95% CI 3% to 47%; p = 0.028), perceived improvement of breathing (52%, 95% CI 30% to 74%; p&lt;0.0001) and perceived reduction in medication (59%, 95% CI 35% to 81%; p&lt;0.0001). By 12 months the intervention group showed significantly greater reductions than the controls in preventer and reliever use, and more improvement in rhinitis (24%, 95% CI 9% to 39%; p = 0.001) and rhinoconjunctivitis (20%, 95% CI 5% to 36%; p = 0.009). <b>Conclusions:</b> Although there was no objective evidence of benefit, symptoms of asthma and rhinitis improved and medication use declined following removal of indoor mould. It is unlikely that this was entirely a placebo effect.
Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation
Authors: Masatoshi Yamazaki, Sergey Mironov, Clément Taravant, Julien Brec, Luis M. Vaquero, Krishna Bandaru, Uma Mahesh R Avula, Haruo Honjo, Itsuo Kodama, Omer Berenfeld, Jérôme Kalifa
Journal: Cardiovascular Research (2012)

Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12cmH2O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness. We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 ± 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (>3 rotations) were greater in PtAF than normal (lifespan 0.9 ± 0.5 vs. 0.4 ± 0.2 s/(3 s of AF), P< 0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization. The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance.
Efficacy of Insulin Analogs in Achieving the Hemoglobin A1c Target of &amp;lt;7% in Type 2 Diabetes
Authors: Dario Giugliano, Maria Ida Maiorino, Giuseppe Bellastella, Paolo Chiodini, Antonio Ceriello, Katherine Esposito
Journal: Diabetes Care (2011)

Insulin analogs are increasingly used in patients with type 2 diabetes. We compared the effect of basal, biphasic, prandial, and basal-bolus insulin regimens with insulin analogs to reach the hemoglobin A(1c) (HbA(1c)) target of <7% in people with type 2 diabetes.We conducted an electronic search for randomized controlled trials (RCTs) involving insulin analogs. RCTs were included if they lasted at least 12 weeks, reported the proportion of diabetic patients reaching the HbA(1c) target of <7% (primary outcome), and the number of patients in any arm was >30.We found 16 RCTs, with 20 comparisons and 7,759 patients. A greater proportion of patients achieved the HbA(1c) goal of <7% with both biphasic (odds ratio 1.88 [95% CI 1.38-2.55]) and prandial (2.07 [1.16-3.69]) insulin compared with basal insulin; this was associated for biphasic insulin with greater hypoglycemia (event/patient/30 days, mean difference, 0.34 [range 0-0.69]) and weight gain in kg (1.0 kg [0.28-1.73]). Compared with biphasic insulin, the basal-bolus regimen was associated with a greater chance to reach the HbA(1c) goal (odds ratio 1.75 [95% CI 1.11-2.77]), with no greater hypoglycemia or weight gain. The effect of insulin analogs on long-term diabetes complications is still lacking.A greater proportion of type 2 diabetic patients can achieve the HbA(1c) goal <7% with biphasic or prandial insulin compared with basal insulin; in absolute terms, the basal-bolus regimen was best for the attainment of the HbA(1c) goal.
Malignant Transformation of Ovarian Epithelium
Authors: R. C. Bast, I. Jacobs, A. Berchuck
Journal: JNCI Journal of the National Cancer Institute (1992)

Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. In contrast to cervical cancer, where etiologic agents and early neoplastic lesions have been clearly defined, the pathogenesis and natural history of ovarian cancer remain obscure. More than 90% of ovarian cancers in adults are thought to arise from a single layer of epithelial cells that cover the ovarian surface or line inclusion cysts. Following ovulation, the ovarian surface epithelium proliferates to repair the defects produced by rupture of mature follicles. Epidemiologic data suggest that the interruption of ovulation by pregnancy, lactation, or oral contraceptive medications substantially reduces the risk of developing ovarian cancer. Suppression of ovulation may decrease opportunities for tumor progression that are more likely to occur in dividing cells. Conversely, growth of ovarian surface epithelial cells ex vivo, freed from the constraints on proliferation in situ, might lead to malignant transformation. In this issue of the Journal (/), Godwin and colleagues present convincing evidence that repeated passage of rat ovarian surface epithelial cells in culture results in a loss of contact inhibition, as well as in the acquisition of anchorage-ind ependent growth and the ability to form tumors in vivo after injection into athymic mice. Cytogenetic abnormalities have been observed in some cell lines both before and after transformation. Although the correlation between the chromosomal abnormalities described by Godwin et al. and the acquisition of a malignant phenotype is not precise, the potential for this type of analysis is clear. Spontaneous transformation in culture is thought to occur less frequently in cells taken from rats than in those taken from mice (/). Transformation in the absence of apparent carcinogens is not limited, however, to the ovarian epithelium, in that spontaneous transformation has also been observed with repeated passage of rat hepatocytes, fibroblasts, and tracheal epithelial cells (2-4). Whether spontaneous transformation in culture occurs with human ovarian surface epithelial cells remains to be determined. Investigators (5) have defined conditions that facilitate growth of apparently normal human ovarian epithelial cells and that should permit definitive studies with human tissues. Recent reports have begun to compare growth regulation in normal and malignant human ovarian epithelial cells. Preliminary data suggest that a majority of ovarian cancers are derived from single clones of cells. Consistent with studies in other malignancies, multiple genetic changes are likely to be required for malignant transformation of a normal epithelial clone. Different combinations of these changes might produce the same transformed phenotype. Certain changes might be observed more or less frequently in ovarian cancer than in tumors that
Integration of Novel Therapeutics into Combined Modality Therapy of Locally Advanced Non–Small Cell Lung Cancer
Authors: David Gandara, Samir Narayan, Primo N. Lara, Zelanna Goldberg, Angela Davies, Derrick H.M. Lau, Philip Mack, Paul Gumerlock, Srinivasan Vijayakumar
Journal: Clinical Cancer Research (2005)

Abstract Novel therapeutic agents (NTA) directed against a wide array of newly described molecular targets are now entering clinical investigation, many in the treatment of non–small cell lung cancer (NSCLC). The great majority of these clinical trials have been directed toward patients with advanced stage (metastatic) disease. More recently, study of NTAs has turned toward earlier-stage disease. Locally advanced, or stage III, NSCLC represents a large and heterogeneous group of patients and several clinically distinct substages. During the last 15 years, randomized clinical trials have shown improved survival with sequential chemoradiation compared with radiation alone and, more recently, the superiority of concurrent versus sequential chemoradiation. As NTAs have increasingly shown clinical activity against NSCLC, questions of how to incorporate them into clinical trials in stage III disease, whether they should be given together with radiotherapy, substituting for chemotherapy, or whether they should be added to current chemoradiation strategies, all remain as issues. Here, we describe conceptual issues, preclinical rationale, and ongoing or planned clinical trials incorporating NTAs into current treatment paradigms for unresectable stage III NSCLC.
Electrophysiological Consequences of Acute Regional Ischemia/Reperfusion in Neonatal Rat Ventricular Myocyte Monolayers
Authors: Carlos de Diego, Rakesh K. Pai, Fuhua Chen, Lai-Hua Xie, Jan De Leeuw, James N. Weiss, Miguel Valderrábano
Journal: Circulation (2008)

Background— Electrophysiological changes promoting arrhythmias during acute regional ischemia/reperfusion are challenging to study in intact cardiac tissue because of complex 3-dimensional myocardial and vascular geometry. We characterized electrophysiological alterations and arrhythmias during regional ischemia/reperfusion in a simpler 2-dimensional geometry of cultured neonatal rat ventricular myocyte monolayers. Methods and Results— Optical mapping of intracellular Ca (Ca i ) and voltage was performed with the use of Rhod 2-AM and Rh-237, respectively. Regional ischemia was mimicked by covering the central portion of monolayer with a glass coverslip, and reperfusion was mimicked by removing the coverslip. Monolayers were stained with fluorescent antibodies to detect total and dephosphorylated connexin-43 at various time points. During coverslip ischemia, action potential duration shortened, Ca i transient duration was prolonged, and local conduction velocity (CV) slowed progressively, with loss of excitability after 10.6±3.6 minutes. CV slowing was accompanied by connexin-43 dephosphorylation. During ischemia, spontaneous reentry occurred in 5 of 11 monolayers, initiated by extrasystoles arising from the border zone or unidirectional conduction block of paced beats. On reperfusion, excitability recovered within 1.0±0.8 minutes, but CV remained depressed for 9.0±3.0 minutes, promoting reentry in the reperfused zone. As connexin-43 phosphorylation recovered in the reperfused zone, CV normalized, and arrhythmias resolved. Conclusions— Acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers recapitulates electrophysiological alterations and arrhythmias similar to those observed during acute coronary occlusion/reperfusion in intact hearts. During early reperfusion, slow recovery from connexin-43 dephosphorylation leads to persistent CV slowing, creating a highly arrhythmogenic substrate.
Mechanisms of Fast and Slow Axonal Transport
Authors: R B Vallee, G S Bloom
Journal: Annual Review of Neuroscience (1991)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Reversal of Central Anticholinergic Syndrome by Galanthamine
Authors: Anis Baraka
Journal: JAMA (1977)

Ten volunteers were given 2 mg scopolamine intravenously (IV) to produce substantial drowsiness and sleepiness. Galanthamine, 0.5 mg/kg IV, effectively reversed the central anticholinergic syndrome produced by scopolamine. Electroencephalographic monitoring of two subjects matched the observed changes of consciousness: scopolamine replaced the dominant awake alpha rhythm with a disorganized, slow, 4- to 6-Hz activity. Galanthamine promptly returned the EEG pattern to the control, awake state. Galanthamine produces effective, safe, and long-lasting reversal of the central anticholinergic syndrome in man. (<i>JAMA</i>238:2293-2294, 1977)
An unusual cause of death in Wegener's granulomatosis
Authors: E Suresh
Journal: Annals of the Rheumatic Diseases (2006)

Mortality among patients with Wegener’s granulomatosis (WG) is more likely among those with renal disease.1,2 Among the non-renal causes, laryngeal involvement with airway obstruction is a rare but important preventable cause of death.3 Here, we describe a patient with WG and laryngeal involvement, in whom death occurred by inhalation of a nasal crust.

The patient, a 26 year old woman, first presented to us in 1998 with a 3 year history of intermittent stridor associated with hoarseness of voice, intermittent nasal stuffiness, nasal crusting, and recurrent sinusitis. Serum perinuclear antineutrophil cytoplasmic antibody was positive at a titre of 1/80 by indirect immunofluorescence, with myeloperoxidase-ANCA of 28 AU/ml (normal range 0–5) by enzyme linked immunosorbent assay (ELISA), while cytoplasmic ANCA was negative and proteinase 3-ANCA …