tbuckley/cabot-search huggingface dataset:
Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality
Authors: Samy Suissa, Sophie Dell'Aniello, Pierre Ernst
Journal: Thorax (2012)

<h3>Background</h3> The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown. <h3>Methods</h3> The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990–2005, using the healthcare databases from the province of Quebec, Canada. Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified. The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity. <h3>Results</h3> The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively. The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to &lt;4 months from the 9th to the 10th. The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first. Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months. <h3>Conclusions</h3> The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation. Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality.
Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response
Authors: Chanté L. Richardson, Lorrie L. Delehanty, Grant C. Bullock, Claudia M. Rival, Kenneth S. Tung, Donald L. Kimpel, Sara Gardenghi, Stefano Rivella, Adam N. Goldfarb
Journal: Journal of Clinical Investigation (2013)

The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.
Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell–dendritic cell interactions
Authors: Federica Moalli, Jovana Cupovic, Flavian Thelen, Pascal Halbherr, Yoshinori Fukui, Shuh Narumiya, Burkhard Ludewig, Jens V. Stein
Journal: The Journal of Experimental Medicine (2014)

Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell–DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4+ T cells. During inflammation, weak tetramer-binding TP-deficient CD4+ T cells were preferentially expanded compared with TP-proficient CD4+ T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4+ T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4+ T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4+ T cell–DC interactions by TXA2–TP signaling improves the overall quality of adaptive immune responses.
Re: Short-Interval Follow-Up Mammography: Are We Doing the Right Thing?
Authors: S. Yasmeen, P. S. Romano, M. Pettinger, R. T. Chlebowski, J. A. Robbins, D. S. Lane, S. L. Hendrix
Journal: JNCI Journal of the National Cancer Institute (2003)

Kerlikowske et al. concluded that if theprevalence of probably benign lesionsthat are recommended for short-intervalfollow-up is in the range we reported, alarge number of women may be under-going unnecessary surveillance of be-nign lesions. However, the authors alsooffered several potential explanationsfor our results, including improper useof the Breast Imaging Reporting andData System (BI-RADS) category 3(“probably benign findings–short-inter-val follow-up suggested”) assessmentby the participating radiologists and theunavailability of comparison films,which they suggest should limit the im-pact of our findings on clinical practice.Although we did not provide details ofthe associated procedures accompany-ing the recommendations of short-interval follow-up, our findings none-theless reflect a broad spectrum ofcontemporary clinical practice. Themammographic recommendations re-flected the practice of radiologists atmore than 3000 hospitals, clinics, andimaging centers that provided mammog-raphy for the 40 Women’s Health Initia-tive clinical centers. Our results, ratherthan reflecting unique characteristics ofa particular clinical trial, are likely torepresent a snapshot of current clinicaluse of the BI-RADS category 3 assess-ment
Correction of metabolic alkalosis by the kidney after isometric expansion of extracellular fluid
Authors: Jordan J. Cohen
Journal: Journal of Clinical Investigation (1968)

Metabolic alkalosis was induced in dogs by administering ethacrynic acid and sustained by feeding a chloride-deficient diet. At the height of the alkalosis extracellular fluid was expanded "isometrically," i.e., with an infusion that duplicated plasma sodium, chloride, and bicarbonate concentrations. Correction of metabolic alkalosis promptly followed such expansion and was attributed to the selective retention by the kidneys of chloride from the administered solution. Since plasma chloride concentration was not increased as an immediate consequence of the infusion, it is concluded that the change in renal tubular function that led to the selective retention of chloride must have been mediated by factors independent of filtrate chloride concentration.A decrease in circulating mineralocorticoid level, as a consequence of volume expansion, does not seem to account for this change in tubular function since identical studies in dogs receiving excessive amounts of 11-deoxycorticosterone acetate during the day of infusion yielded similar findings. Moreover, no other consequence of volume expansion appears to be sufficient to cause this change in tubular function in the absence of metabolic alkalosis; when the alkalosis was corrected with hydrochloric acid before infusion, isometric expansion of extracellular volume did not induce selective chloride retention. We suggest that isometric expansion during metabolic alkalosis causes a decrease in proximal sodium reabsorption that relinquishes filtrate to a more distal site in the nephron and that this site may retain chloride preferentially when hypochloremia or chloride deficiency is present.
Conversion to Resectability Using Hepatic Artery Infusion Plus Systemic Chemotherapy for the Treatment of Unresectable Liver Metastases From Colorectal Carcinoma
Authors: Nancy E. Kemeny, Fidel D. Huitzil Melendez, Marinela Capanu, Philip B. Paty, Yuman Fong, Lawrence H. Schwartz, William R. Jarnagin, Dina Patel, Michael D'Angelica
Journal: Journal of Clinical Oncology (2009)

PURPOSE To determine the conversion to resectability in patients with unresectable liver metastases from colorectal cancer treated with hepatic arterial infusion (HAI) plus systemic oxaliplatin and irinotecan (CPT-11). PATIENTS AND METHODS Forty-nine patients with unresectable liver metastases (53% previously treated with chemotherapy) were enrolled onto a phase I protocol with HAI floxuridine and dexamethasone plus systemic chemotherapy with oxaliplatin and irinotecan. Results Ninety-two percent of the 49 patients had complete (8%) or partial (84%) response, and 23 (47%) of the 49 patients were able to undergo resection in a group of patients with extensive disease (73% with > five liver lesions, 98% with bilobar disease, 86% with > or = six segments involved). For chemotherapy-naïve and previously treated patients, the median survival from the start of HAI therapy was 50.8 and 35 months, respectively. The only baseline variable significantly associated with a higher resection rate was female sex. Variables reflecting extensive anatomic disease, such as number of lesions or number of vessels involved, were not significantly associated with the probability of resection. CONCLUSION The combination of regional HAI floxuridine/dexamethasone and systemic oxaliplatin and irinotecan is an effective regimen for the treatment of patients with unresectable liver metastases from colorectal cancer, demonstrating a 47% conversion to resection (57% in chemotherapy-naïve patients). Future randomized trials should compare HAI plus systemic chemotherapy with systemic therapy alone to assess the additional value of HAI therapy in converting patients with hepatic metastases to resectability.
Severe imbalance of cell proliferation and apoptosis in the left colon and in the rectosigmoid tract in subjects with a history of large adenomas
Authors: M Anti
Journal: Gut (2001)

<h3>BACKGROUND</h3> Alterations in epithelial proliferation and apoptosis in colonic mucosa are associated with an increased risk of colon cancer. It is unclear if these alterations represent a generalised "field defect". <h3>AIMS</h3> To analyse segmental patterns of cell proliferation and apoptosis in the colon of subjects with a high and no apparent risk of colon cancer. <h3>METHODS</h3> Pancolonoscopy was performed in 15 patients with resected adenomas (⩾1.5 cm) and in nine subjects without an apparent risk of colorectal cancer. Mucosal biopsies were taken from the right colon, left colon, and sigmoid rectum. Crypt cell proliferation and apoptosis were evaluated, respectively, with bromodeoxyuridine immunohistochemistry and terminal deoxyuridine nucleotidyl nick end labelling of DNA strand breaks. Results are expressed as total labelling index (TLI) and labelling index (LI) for each of the five compartments in which colonic crypts were divided (fourth and fifth compartments were evaluated together) for cell proliferation and as apoptotic index (AI) for apoptosis assessment. <h3>RESULTS</h3> No significant segmental variations in proliferation were found in either group. Compared with controls, adenoma patients had higher TLIs for the right (p&gt;0.05), left (p&lt;0.005), and sigmoid rectum (p&lt;0.05) segments, and higher left colon LIs for crypt compartments (compartment 1, p&lt;0.01; compartment 2, p&lt;0.005; compartment 3, p&lt;0.001; compartments 4–5, p&lt;0.01). Control AIs were similar in all segments but in the adenoma patients left colon and sigmoid rectum AIs were lower than their right colon indexes (p&lt;0.05, p&lt;0.05) and corresponding values for controls (p&lt;0.01, p&lt;0.05). <h3>CONCLUSIONS</h3> The colonic mucosa of patients with past adenomas presents diffuse hyperproliferation and, distally, abnormally distributed proliferating cells and markedly reduced apoptosis. These changes represent a significant risk for malignancies and could account for the high prevalence of left colon tumours.
A model for the differentiation of human natural killer cells. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562.
Authors: J H Phillips, L L Lanier
Journal: The Journal of Experimental Medicine (1985)

A subpopulation of low density granular lymphocytes that express the natural killer (NK) cell-associated Leu-11 antigen (IgG Fc receptor) were stimulated directly by coculture with an NK-sensitive tumor cell, K562. T lymphocytes (Leu-11-) responded only weakly when cocultured with K562. The response of Leu-11+ cells apparently did not require exogeneous factors or accessory cells. The K562-activated cells retained expression of Leu-11 antigen, acquired activation antigens, and were highly cytotoxic against NK-sensitive and -insensitive tumor cells. Anti-IL-2 receptor monoclonal antibody minimally inhibited the activation of Leu-11+ cells by K562, but completely inhibited the phytohemagglutinin-induced activation of the Leu-11- cells from the same individual. Leu-11+ cells can be divided into Leu-7-11+ and Leu-7+11+ subpopulations using anti-Leu-7 antibody. These subsets were separated by two-color fluorescence-activated cell sorting and cocultured with K562. Proliferation by Leu-7-11+ cells was significantly greater than by Leu-11+7+ cells. Leu-7+11- granular lymphocytes and T lymphocytes (Leu-7-11-) typically proliferated only weakly when cocultured with K562. A proportion of the Leu-7-11+ cells acquired Leu-7 antigen after stimulation with K562, whereas the phenotype of Leu-7+11+, Leu-7+11-, and Leu-7-11- subsets was unaffected. These results demonstrate a developmental relationship between the Leu-7-11+ and Leu-7+11+ lymphocytes and suggest that Leu-7 antigen may be expressed late in the differentiation pathway of NK cells. The direct activation of highly purified Leu-11+ cells by coculture with K562 provides an in vitro model with which to study the activation and maturation of human NK cells.
Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis
Authors: K.A. Toulis, D.G. Goulis, D. Farmakiotis, N.A. Georgopoulos, I. Katsikis, B.C. Tarlatzis, I. Papadimas, D. Panidis
Journal: Human Reproduction Update (2009)

Conflicting results regarding adiponectin levels in women with polycystic ovary syndrome (PCOS) have been reported. To evaluate adiponectin levels in PCOS, a systematic review of all studies comparing adiponectin levels in women with PCOS with healthy controls and a meta-analysis of those involving women with similar body mass index (BMI) were performed. The influence of possible effect modifiers, such as insulin resistance (IR) and testosterone, was investigated. The influence of obesity was investigated through a 'nested' meta-analysis after within-study BMI stratification and appropriate pooling. Literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL (through June 2008), references from relevant studies and personal contact with the authors. Thirty-one studies, reporting data on 3469 subjects, were reviewed and 16 included in the main meta-analysis. Women with PCOS demonstrated significantly lower adiponectin values [weighted mean difference (95% confidence interval) −1.71 (−2.82 to −0.6), P < 10−4], yet with significant between-study heterogeneity. Lower adiponectin levels are associated with the IR observed in women with PCOS, compared with controls. IR, but not total testosterone, was found significant among biological parameters explored in the meta-regression model. Hypoadiponectinaemia was present in both lean and obese women with PCOS when compared with non-PCOS counterparts. Data on high molecular weight (HMW) adiponectin are limited (three studies). After controlling for BMI-related effects, adiponectin levels seem to be lower in women with PCOS compared with non-PCOS controls. Low levels of adiponectin in PCOS are probably related to IR but not to testosterone. Total adiponectin should not be used as a biomarker of PCOS severity. Further investigation is needed for HMW adiponectin levels in PCOS.
Prophylactic Oophorectomy Reduces Breast Cancer Penetrance During Prospective, Long-Term Follow-Up of <i>BRCA1</i> Mutation Carriers
Authors: Joan L. Kramer, Isela A. Velazquez, Bingshu E. Chen, Philip S. Rosenberg, Jeffery P. Struewing, Mark H. Greene
Journal: Journal of Clinical Oncology (2005)

Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates.Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy.Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers.Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.
Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice
Authors: J. Kishi, Y. Nishioka, T. Kuwahara, S. Kakiuchi, M. Azuma, Y. Aono, H. Makino, K. Kinoshita, M. Kishi, R. Batmunkh, H. Uehara, K. Izumi, S. Sone
Journal: European Respiratory Journal (2011)

Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
Sudden cardiac tamponade after chemotherapy for marrow transplantation in thalassaemia
Authors: E. Angelucci, G. Lucarelli, D. Baronciani, S.M.T. Durazzi, M. Galimberti, C. Giardini, P. Polchi, E. Mariotti, P. Cesaroni, E. Sgarbi, P. Muretto
Journal: The Lancet (1992)
Birth weight, osteoarthritis of the hand, and cardiovascular disease in men
Authors: J Poole
Journal: Annals of the Rheumatic Diseases (2003)

<h3>Background</h3> To date, no study has clinically focused on primary Sjögren’s Syndrome (pSS) patients presenting without or with low level of dryness features. <h3>Objectives</h3> To describe pSS patients presenting no dryness or with low level of dryness and to compare them with pSS patients with dryness features to determine whether a specific clinical presentation can be identified in these patients. <h3>Methods</h3> All patients diagnosed with pSS according to AECG or ACR/EULAR criteria in our tertiary reference center were included. All patients were recruited between 1999 and 2020. Patient were considered without subjective dryness if the VAS for dry eyes or dry mouth was ≤ 30/100 and/or without objective dryness if having both normal Schirmer and salivary flow rate. <h3>Results</h3> Overall, 509 patients were included in the subjective dryness comparison group and 434 in the objective one (Table 1). Compared to patients with subjective dryness (n=456), patients without subjective dryness (n=53) were significantly younger (p=0,0025), were diagnosed earlier (p=0,0056), were more frequently anti-SSA positive (p=0,008), had lower levels of fatigue (p=0,0005). But no difference was observed regarding the level of disease activity or frequency of organ involvement. By contrast, patients reporting subjective dryness had more frequently chronic cough (p=0,022), with no more frequent objective lung involvement. Thus, the higher prevalence of chronic cough might be explained by dryness of the upper airways. The patients without objective dryness (n=108) were also younger (p=0,0026), and had more frequently anti-SSA positive (p=0,0042). They also had a higher disease activity (mean ESSDAI: 3,46 versus 2,96, p=0,056). In this group of patients, the higher frequency of anti-SSA might be explained by the need of other criteria to fulfil diagnostic criteria, in the absence of abnormal Schirmer and salivary flow. Patients with objective dryness had more frequently arthralgia (p=0,04), a higher level of pain VAS (p=0,03) and subjective dryness VAS (p=0,019 for ocular and p=0,01 for oral) than patients without objective dryness. Among the 108 patients with no objective dryness, only 17 had also had no subjective dryness (VAS &lt;30mm). <b>P value corresponds to the comparison of the two strata with Student’s t or Mann Whitney-U test</b> <h3>Conclusion</h3> Among the patients with pSS, those without subjective or objective dryness features had a younger profile, shorter diagnosis delay which may result from a more acute onset, were more frequently anti-SSA positive. Those having no objective dryness also had more systemic disease, arthralgias and pain than patients with dryness features. Subjective dryness was associated with higher level of fatigue. <h3>References</h3> [1]Characters from table content including title and footnotes: <h3>Disclosure of Interests</h3> None declared
Case Number 23: Tuberculous tenosynovitis
Authors: U A Walker
Journal: Annals of the Rheumatic Diseases (2002)

A 58 year old woman presented with a several month history of painful swelling of the second and fifth fingers of her left hand (fig 1). The flexor tendon sheath of the index finger had been excised six months before. Median nerve entrapment led to surgical release of the transverse carpal ligament three months ago. In both instances histopathological examination disclosed necrotising granulomas with Langerhans'cells. The …