tbuckley/cabot-search huggingface dataset:
Low-dose Acetazolamide Does Affect Respiratory Muscle Function in Spontaneously Breathing Anesthetized Rabbits
Authors: HEIDRUN F. KIWULL-SCHÖNE, LUC J. TEPPEMA, PETER J. KIWULL
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Patients with chronic obstructive pulmonary diseases (COPD) and/ or central sleep apnea are sometimes treated with the carbonic anhydrase inhibitor acteazolamide to improve blood gas values. Studies have shown that this agent may have a complicated effect on lung ventilation, because carbonic anhydrase has a widespread distribution within the body, particularly in tissues involved in the control of breathing. To investigate whether acetazolamide may have (neuro)muscular effects on respiration, we measured the responses of ventilation, phrenic nerve activity, and transpulmonary pressure to changes in arterial Pco 2 before and after intravenous administration of a low-dose (4.6 ± 0.2 mg · kg− 1, mean ± SEM) of this inhibitor in anesthetized spontaneously breathing rabbits. The agent decreased the mean resting end-tidal Pco 2 by 1 kPa and increased ventilation from 258 ± 15 to 292 ± 14 ml · min− 1 · kg− 1 (p ⩽ 0.05). The ventilatory and tidal volume responses to CO2 were reduced, and the response curves were shifted to lower Pco 2 values. At the level of phrenic activity, however, the response was shifted leftward without altering CO2 sensitivity. With an unchanged lung compliance, the slopes of the relationships between tidal volume and phrenic activity and that between the tidal change in transpulmonary pressure and phrenic amplitude were both reduced by about 40%, indicating an action of acetazolamide on (neuro)muscular level. The results raise the suggestion that treatment of some hypercapnic COPD patients with acetazolamide may have undesired clinical implications, particularly in those with already weakened respiratory muscles.
Risk factors for Helicobacter pylori.
Authors: F C Edwards, N F Coghill
Journal: Gut (1994)

clusions can be drawn from specimens taken from only six patients of whom two had ileostomies.The results show a coefficient of variation of about 50% and the risks of a type 2 statistical error must be very high.In conclusion it is important that Finnie et al suggest an explanation as to why they found such a low protein weight to wet weight ratio.Until they do so it is very difficult to interpret their data.
Combination of Tumor Necrosis Factor-α Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice
Authors: Zamaneh Kassiri, Gavin Y. Oudit, Otto Sanchez, Fayez Dawood, Fazilat F. Mohammed, Robert K. Nuttall, Dylan R. Edwards, Peter P. Liu, Peter H. Backx, Rama Khokha
Journal: Circulation Research (2005)

Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 −/− mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNFα converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-α (TNFα) processing. In addition, TNFα production increased in timp-3 −/− -AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 −/− -AB myocardium. Timp-3 −/− /tnfα −/− mice were generated and subjected to AB for comparative analyses with timp-3 −/− -AB mice. This revealed the critical role of TNFα in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFα, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFα, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 −/− -AB mice. Notably, combining TNFα ablation with MMP inhibition completely rescued heart disease in timp-3 −/− -AB mice. This study provides a basis for anti-TNFα and MMP inhibitor combination therapy in heart disease.
Nonspecific complement activation by streptococcal structures. I. Re-evaluation of HLA cytotoxicity inhibition.
Authors: J W Tauber, J A Falk, R E Falk, J B Zabriskie
Journal: The Journal of Experimental Medicine (1976)

A number of experiments have suggested that there is an antigenic relationship between the HLA complex and streptococcal bacterial structures. Using inhibition of cytotoxicity of HLA antisera as our assay system, it was demonstrated that the inhibitory effect on HLA cytotoxicity by streptococcal antigens is, in reality, due to activation and consumption of components of the alternate complement pathway. In addition, antisera prepared against streptococcal membrane antigens had no cytotoxic effect on a large panel of human lymphocytes, nor did these antisera exhibit immunofluorescent staining of lymphocytes directly. These experiments are compatible with our concept that the HLA complex may have evolved through selective evolutionary pressure as a means of escaping bacterial mimicry.
CD36: promotion from scavenger receptor to mediator of migration?
Authors: C. Erridge
Journal: Cardiovascular Research (2009)

As the migration of circulating monocytes into the arterial intima and their subsequent differentiation into fat-laden foam cells are critical events in the development of atherosclerosis, the molecular mechanisms underpinning these two events have been the focus of much study in recent years. In particular, since the seminal studies of Goldstein et al. 1 revealed almost 30 years ago that foam cell formation could be triggered by the uptake of oxidized low-density lipoprotein (oxLDL) by macrophage scavenger receptors in vitro , much interest has been focused on the potential of scavenger receptors to modulate atherosclerosis.

To date, the class B scavenger receptor CD36 has received the most attention in this context since early studies identified it as a key mediator of oxLDL uptake in vitro .2 However, the results that have emerged from subsequent studies of CD36 function in vivo are both complex and conflicting.3 Febbraio et al. 4,5 were the first to report the results of breeding mice genetically deficient in both CD36 and apolipoprotein E (ApoE), showing that CD36 deficiency reduced aortic lesion formation by ∼76% and that bone-marrow-specific deletion of CD36 also reduced atherosclerosis in ApoE–/– mice. However, the pro-atherogenic potential of CD36 was soon challenged by Freeman and colleagues,6 who reported that genetic deletion of CD36, or the related scavenger receptor SR-A, had no effect on atherosclerosis in their systems and suggested that insufficient … 

*Corresponding author. Tel: +44 116 256 3048; fax: +44 116 287 5792. E-mail address : ce55{at}le.ac.uk
M24 Mortality prediction by CURB65 in pneumonia with and without complicating COPD: Abstract M24 Table 1.
Authors: T Hartley, J Steer, C Echevarria, GJ Gibson, SC Bourke
Journal: Thorax (2013)

<h3>Introduction</h3> The CURB65 score was developed to predict mortality in community acquired pneumonia (CAP) but is often used in pneumonia complicating acute exacerbations of COPD (pAECOPD). We have previously shown that CURB65 underestimates in-hospital mortality in pAECOPD, particularly in low risk patients (observed mortality 11.2%, CURB65-predicted 1.5%).[1] Of importance, CURB65 was derived in a population with significant exclusions, notably admission from nursing home, and few patients with dementia were included, whereas in our DECAF AECOPD cohort [1] such patients were included. The higher than predicted mortality in pAECOPD may reflect additional risk conferred by co-existent COPD, a less selected population and/or clinical outcomes in participating hospitals. We have therefore investigated whether the mortality of an equivalent population with CAP, but without COPD, is similar to that found previously in pAECOPD. <h3>Methods</h3> Patients admitted with a primary diagnosis of CAP were identified from coding records. Patients with confirmed or suspected COPD were excluded; selection criteria and time frame otherwise matched the DECAF cohort. Demographic, clinical and mortality data were gathered from clinical notes. Categorical variables were compared using Fisher’s exact test. <h3>Results</h3> 115 patients with CAP were included: mean (SD) age 72.1 (16.4) years, 29.6% were admitted from institutional care and 21.7% had dementia. Median (IQR) CURB65 score was 2 (1–3) and in-hospital mortality 16.5%. Compared to the earlier cohort with pAECOPD, mortality in patients with low or intermediate risk CURB65 scores was lower. In the present study, 74% of deaths occurred in patients admitted from institutional care (mortality 35%, non-institutional care 9% p = 0.002) and/or those with dementia (mortality 36%, without dementia 11% p = 0.006). <h3>Conclusions</h3> Compared to the BTS national audit, the proportion of patients with severe pneumonia is higher (49% v 30%) and mortality lower (16.5% v 21.2%). Both dementia and admission from institutional care were associated with high mortality rates. Among patients with low or intermediate risk CURB65 scores the mortality of those with CAP without COPD was lower than we previously found in pAECOPD, confirming that the underestimation of mortality risk by CURB65 in pAECOPD was not attributable to less effective clinical care. <h3>References</h3> Steer. The DECAF score. <i>Thorax</i>, 2012;<b>67</b>:970–6.
The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat
Authors: C M Kozlowski
Journal: Gut (2000)

Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT(3) receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord.To examine the effect of the 5-HT(3) receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord.Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI.CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-effect curves were constructed. Alosetron (1-100 microg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID(50) value of 3.0 microg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 microm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 microg/kg) significantly reduced numbers of Fos-LI neurones to 479.8.The 5-HT(3) receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT(3) receptors are involved in visceral nociceptive transmission, perhaps located on primary afferent or spinal neurones.
Determinants of Increased Primary Health Care Use in Cancer Survivors
Authors: Marianne Heins, Francois Schellevis, Mieke Rijken, Lucas van der Hoek, Joke Korevaar
Journal: Journal of Clinical Oncology (2012)

The number of cancer survivors is increasing, and patients with cancer often experience long-lasting consequences of cancer and its treatment. Because of the variety of health problems and high prevalence of comorbidity, primary care physicians (PCPs) seem obvious candidates to take care of these patients, and insight into primary health care (PHC) use of cancer survivors is needed. We aimed to find determinants for PHC use in cancer survivors.Using data from the Netherlands Information Network of Primary Care, we determined the volume of PHC use in 1,256 adult patients with breast cancer, 503 patients with prostate cancer, and 487 patients with colorectal cancer 2 to 5 years after diagnosis and compared this with age- and sex-matched controls without cancer from the same practice. We also examined whether age, comorbidity, and time since diagnosis were related to PHC use.The mean annual number of primary care contacts was increased compared with control patients by 24% in patients with breast cancer (P<.001) and by 33% in patients with prostate cancer (P<.001). This difference remained constant between 2 and 5 years after diagnosis. In patients with colon cancer, the difference with controls tended to decrease with age (12% per 10 years; P=.005).PHC use is significantly increased 2 to 5 years after diagnosis of cancer, especially in younger patients without a chronic disease. Given the expected increase in cancer survivors, PCPs should prepare themselves for this increasing amount of aftercare. The development of multidisciplinary care standards for cancer survivors could be helpful.
An interim analysis of the phase III riociguat long-term extension study in CTEPH (CHEST-2)
Authors: Gerald Simonneau, Andrea M. D'Armini, Hossein-Ardeschir Ghofrani, Friedrich Grimminger, Marius M. Hoeper, Pavel Jansa, Nick H. Kim, Chen Wang, Martin R. Wilkins, Arno Fritsch, Neil Davie, Gerrit Weimann, Eckhard Mayer
Journal: European Respiratory Journal (2013)

Background 

In the 16-wk CHEST-1 study, riociguat, a novel sGC stimulator, was well tolerated in CTEPH patients (pts) and significantly improved 6-min walking distance (6MWD) and WHO functional class (FC) vs placebo (pbo).

Objectives 

The CHEST-2 open-label extension assessed the long-term safety and efficacy of riociguat.

Methods 

Pts with inoperable CTEPH or persistent/recurrent PH after pulmonary endarterectomy were eligible to enter CHEST-2 after completion of CHEST-1 without ongoing riociguat-related serious AEs. The primary endpoints were safety and tolerability. Secondary endpoints included change in 6MWD and FC.

Results 

Of 233 pts entering CHEST-2, 194 were eligible for this interim analysis (cut-off May 2012; median treatment duration ∼1 y). Riociguat was well tolerated during CHEST-2; 1% of pts withdrew due to AEs. CHEST-1 baseline (BL) 6MWD was 351 m in riociguat pts and 365 m in pbo pts, increasing by 51 m and 4 m, respectively at the end of CHEST-1. After 12 wks of CHEST-2, 6MWD increased by 63 m in former riociguat pts and 35 m in former pbo pts, vs CHEST-1 BL. After 1 y (overall cohort; n=93), change in 6MWD was 48 m. The number of pts with FC I/II/III/IV at CHEST-1 BL was 2/44/80/3 in the riociguat arm and 0/20/42/2 in the pbo arm. At the end of CHEST-1, FC was improved/stable/worsened in 35/61/4% of riociguat pts and 14/83/3% of pbo pts vs CHEST-1 BL. After 12 wks of CHEST-2, FC was improved/stable/worsened in 41/56/3% of former riociguat pts and 38/58/5% of former pbo pts, vs CHEST-1 BL. Preliminary data suggest improvement in FC for up to 1 y.

Conclusions 

Riociguat has a good long-term safety profile and is the first therapy to show sustained benefits in 6MWD and FC in CTEPH pts.
Impact of a Natural Disaster on Diabetes
Authors: Vivian A. Fonseca, Hayden Smith, Nitesh Kuhadiya, Sharice M. Leger, C. Lillian Yau, Kristi Reynolds, Lizheng Shi, Roberta H. McDuffie, Tina Thethi, Jennifer John-Kalarickal
Journal: Diabetes Care (2009)

OBJECTIVE To examine the impact of Hurricane Katrina on the health of individuals with diabetes. RESEARCH DESIGN AND METHODS This was an observational study in 1,795 adults with an A1C measurement 6 months before and 6−16 months after Hurricane Katrina in three health care systems: private (Tulane University Hospital and Clinic [TUHC]), state (Medical Center of Louisiana at New Orleans [MCLNO]), and Veterans Affairs (VA). Glycemic control (A1C), blood pressure, and lipids before the hurricane were compared with the patients' first measurement thereafter. The CORE Diabetes Model was used to project life expectancy and health economic impact. RESULTS Mean predisaster A1C levels differed between MCLNO and VA patients (mean 7.7 vs. 7.3%, P &amp;lt; 0.001) and increased significantly among MCLNO patients to 8.3% (P &amp;lt; 0.001) but not among VA and TUHC patients. Mean systolic blood pressure increased in all three systems (130–137.6 mmHg for TUHC and 130.7–143.7 for VA, P &amp;lt; 0.001; 132–136 for MCLNO, P = 0.008). Mean LDL cholesterol increased in the VA (97.1–104.3 mg/dl) and TUHC patients (103.4–115.5; P &amp;lt; 0.001). Hurricane Katrina increased modeled direct, indirect, and total health care costs and also reduced life expectancy as well as quality-adjusted life expectancy, with the economic impact being quite substantial because of the large population size affected. We estimate a lifetime cost of USD $504 million for the adult population affected, with the largest economic impact seen among MCLNO patients. CONCLUSIONS A major disaster had a significant effect on diabetes management and exacerbated existing disparities. These effects may have a lasting impact on both health and economic implications.
Activation of FOXO3a Is Sufficient to Reverse Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor Chemoresistance in Human Cancer
Authors: Jer-Yen Yang, Chun-Ju Chang, Weiya Xia, Yan Wang, Kwok-Kin Wong, Jeffrey A. Engelman, Yi Du, Michael Andreeff, Gabriel N. Hortobagyi, Mien-Chie Hung
Journal: Cancer Research (2010)

Drug resistance is a central challenge of cancer therapy that ultimately leads to treatment failure. In this study, we characterized a mechanism of drug resistance that arises to AZD6244, an established mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor currently being evaluated in cancer clinical trials. AZD6244 enhanced the expression of transcription factor FOXO3a, which suppressed cancer cell proliferation. In AZD6244-resistant cancer cells, we observed the impaired nuclear localization of FOXO3a, reduced FOXO3a-mediated transcriptional activity, and decreased the expression of FOXO3a target gene Bim after cell treatment with AZD6244. Resistant cells could be sensitized by phosphoinositide 3-kinase (PI3K)/AKT inhibitors, which are known to enhance FOXO3a nuclear translocation. Our findings define FOXO3a as candidate marker to predict the clinical efficacy of AZD6244. Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors.
Pulmonary reimplantation response in single-lung transplantation
Authors: C Sleiman, H Mal, M Fournier, JP Duchatelle, P Icard, O Groussard, G Jebrak, JL Mollo, O Raffy, C Roue, al. et
Journal: European Respiratory Journal (1995)

We studied the characteristics of the pulmonary reimplantation response (PRR) in single-lung transplantation (SLT), and detailed the occurrence, evolution, prognosis and risk factors of this complication. Forty single-lung transplant recipients were studied. Twenty four patients developed hypoxaemia and allograft infiltrates consistent with the PRR. In 40% of the cases hypoxaemia was severe, precluding weaning and requiring prolonged mechanical ventilation with high fractional inspiratory oxygen (FIO2). The mean duration of ventilation was 7 days (range 1-19 days). Clearing of the chest radiographs was progressive, with complete resolution between 6 and 21 days. In all cases, the pulmonary arterial wedge pressure was normal (6 +/- 2 mmHg) suggesting low pressure oedema. Sampling of the pulmonary oedema fluid revealed that the ratio of protein concentration in oedema fluid to that in serum exceeded 0.5. In patients with severe PRR (40% of cases) clinical, radiographic and haemodynamic abnormalities were identical to adult respiratory distress syndrome (ARDS), but the prognosis was more favourable with no death directly related to PRR in our patients. The mean duration of graft ischaemia of the oedematous grafts (241 +/- 103 min) was significantly longer than that of nonoedematous grafts (155 +/- 71 min). These date suggest that prolongation of graft ischaemia increased the incidence of PRR.
Response of Asymptomatic Brain Metastases From Small-Cell Lung Cancer to Systemic First-Line Chemotherapy
Authors: Tatjana Seute, Pieter Leffers, Jan T. Wilmink, Guul P.M. ten Velde, Albert Twijnstra
Journal: Journal of Clinical Oncology (2006)

The purpose of this study was to investigate the radiologic response of asymptomatic brain metastases (BM) from small-cell lung cancer (SCLC) to first-line systemic chemotherapy.From 1990 to 2003, 181 consecutive patients with SCLC were enrolled onto this study. Patients were examined by a neurologist on a regular basis. Magnetic resonance imaging (MRI) of the brain was performed routinely before (at diagnosis of SCLC) and after first-line systemic chemotherapy. Patients were treated with combination chemotherapy consisting of cyclophosphamide, doxorubicin, and etoposide. Clinically manifest BM were treated with whole-brain radiotherapy (WBRT). The response rate (RR) of BM was assessed by changes in the size or the number of enhanced lesions on MRI using standard criteria.Synchronous asymptomatic BM were found in 24 SCLC patients (13%). In six (27%) of the 22 assessable patients, the asymptomatic BM responded to systemic chemotherapy. A systemic response was found in 16 patients (73%). All patients became symptomatic during follow-up. The symptom-free survival did not differ between cranial responders and cranial nonresponders.The RR of asymptomatic BM from SCLC to systemic chemotherapy is 27% and evidently lower than the systemic RR. Future studies should focus on the possible beneficial effect of WBRT for patients with asymptomatic synchronous BM.
Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis
Authors: Weiying Zhou, Miranda Y. Fong, Yongfen Min, George Somlo, Liang Liu, Melanie R. Palomares, Yang Yu, Amy Chow, Sean Timothy Francis O’Connor, Andrew R. Chin, Yun Yen, Yafan Wang, Eric G. Marcusson, Peiguo Chu, Jun Wu, Xiwei Wu, Arthur Xuejun Li, Zhuo Li, Hanlin Gao, Xiubao Ren, Mark P. Boldin, Pengnian Charles Lin, Shizhen Emily Wang
Journal: Cancer Cell (2014)