tbuckley/cabot-search huggingface dataset:
Response to Comment on: Smiechowski et al. The Use of Metformin and the Incidence of Lung Cancer in Patients With Type 2 Diabetes. Diabetes Care 2013;36:124–129
Authors: Samy Suissa, Laurent Azoulay
Journal: Diabetes Care (2013)

We thank Lai et al. (1) for the attention given to our article on the effect of metformin on lung cancer incidence (2). We take this opportunity to address an important methodological concern with many of the observational studies published on this topic to date, namely time-related bias.

The authors’ own study used the Taiwanese National Health Insurance databases to identify a cohort of 19,624 patients treated with antidiabetic drugs (3). It found that the use of metformin was associated with a significant 45% (hazard ratio 0.55; 95% CI 0.37–0.82) reduction in the incidence of lung cancer …
Decreased exhaled nitric oxide in subjects with HIV infection
Authors: M. O. Loveless, C. R. Phillips, G. D. Giraud, W. E. Holden
Journal: Thorax (1997)

Nitric oxide (NO) may be an important component of the host defence against infections. Endogenously produced NO is present in exhaled air and may be representative of respiratory tract production of NO. Since subjects infected with HIV are prone to develop respiratory infections, it was postulated that exhaled NO might be reduced in such individuals.The exhaled concentration of NO (nl/l) and minute ventilation (l/min) were measured and exhaled NO release (nl/min/m2) calculated in 36 subjects infected with HIV (20 non-smokers, 16 smokers) and 31 non-smoking subjects with no active medical conditions.Exhaled NO from HIV positive individuals was less than from control subjects of similar age, height, and weight. Cigarette smoking did not account for the decreased exhaled NO in HIV positive individuals as both smoking and non-smoking HIV positive subjects had decreased exhaled NO compared with control subjects.Exhaled NO is decreased in subjects infected with the HIV. Since NO functions in host defence against bacterial, viral, and fungal infections, reduced exhaled NO may indicate a mechanism of impaired host defence in HIV infection.
Surgical treatment of hydatid cysts of the lung: report on 1055 patients.
Authors: R Dogan, M Yuksel, G Cetin, K Suzer, M Alp, S Kaya, M Unlu, B Moldibi
Journal: Thorax (1989)

Of 1055 patients treated surgically for pulmonary hydatid disease, most (950) had isolated lung cysts, the other 105 having both liver and lung cysts. The chest radiograph was most valuable in diagnosis; the Casoni and Weinberg tests and blood eosinophil counts were found to be diagnostically unreliable. One thousand and seventy seven primary operations were performed. Cystotomy and capitonnage were carried out in 906 patients, 40 of whom also had decortication of the pleura. Other procedures included cystotomy with wedge resection of locally damaged lung (29 patients) and cyst removal with capitonnage by Ugon9s method (33) or the Perez-Fontana procedure (8) and with costal resection for osteomyelitis in two cases. More radical surgery was carried out in 99 patients for longstanding infection or severe lung destruction. Postoperative complications occurred in 37 patients (3.5%) and the 30 day mortality rate was 1.7%. It is concluded that a lung conserving surgical operation is the treatment of choice for most patients with pulmonary hydatid disease. In patients with coexisting liver cysts the thoracic transpleural approach allowed the lung and liver cysts to be removed at the same session.
Antitumor effects of specific telomerase inhibitor GRN163 in human glioblastoma xenografts
Authors: Tomoko Ozawa, Sergei M. Gryaznov, Lily J. Hu, Krisztina Pongracz, Raquel A. Santos, Andrew W. Bollen, Kathleen R. Lamborn, Dennis F. Deen
Journal: Neuro-Oncology (2004)

Telomerase is a ribonucleoprotein complex that elongates telomeric DNA and appears to play an important role in cellular immortalization of cancers. Because telomerase is expressed in the vast majority of malignant gliomas but not in normal brain tissues, it is a logical target for gliomaspecific therapy. The telomerase inhibitor GRN163, a 13-mer oligonucleotide N3'-->P5' thio-phosphoramidate (Geron Corporation, Menlo Park, Calif.), is complementary to the template region of the human telomerase RNA subunit hTR. When athymic mice bearing U-251 MG human brain tumor xenografts in their flanks were treated intratumorally with GRN163, a significant growth delay in tumor size was observed (P < 0.01 in all groups) as compared to the tumor size in mice receiving a mismatched oligonucleotide or the carrier alone. We also investigated biodistribution of the drug in vivo in an intracerebral rat brain-tumor model. Fluorescein-labeled GRN163 was loaded into an osmotic minipump and infused directly into U-251 MG brain tumors over 7 days. Examination of the brains revealed that GRN163 was present in tumor cells at all time points studied. When GRN163 was infused into intracerebral U-251 MG tumors shortly after their implantation, it prevented their establishment and growth. Lastly, when rats with larger intracerebral tumors were treated with the inhibitor, GRN163 increased animal survival times. Our results demonstrate that the antitelomerase agent GRN163 inhibits growth of glioblastoma in vivo, exhibits favorable intracerebral tumor uptake properties, and prevents the growth of intracerebral tumors. These findings support further development of this compound as a potential anticancer agent.
Elevated Endothelial Microparticles Following Consecutive Meals Are Associated With Vascular Endothelial Dysfunction in Type 2 Diabetes
Authors: Maarten E. Tushuizen, Rienk Nieuwland, Cees Rustemeijer, Bert E. Hensgens, Augueste Sturk, Robert J. Heine, Michaela Diamant
Journal: Diabetes Care (2007)

Type 2 diabetes is associated with prolonged and exaggerated postprandial hyperglycemia and hypertriglyceridemia, endothelial dysfunction, and cardiovascular disease (CVD) (1–7). Endothelial dysfunction may link postprandial dysmetabolism to CVD (5–7). Since the postprandial state unveils the full scope of metabolic abnormalities in type 2 diabetes, previous studies (1) in fasting subjects may have underestimated the true risk. Currently, endothelial functions can only be estimated from indirect measurements, such as flow-mediated dilation (FMD) (6,8).

Cell-derived microparticles are released by cells in response to stress. Increased numbers of microparticles of various cellular origin circulate in patients at risk of CVD (9,10). Recently, vascular-endothelial cadherin (CD144)-positive microparticles were demonstrated in type 2 diabetic patients with coronary artery disease and patients with end-stage renal disease (11,12). Since vascular-endothelial cadherin is exclusively expressed by endothelial cells, CD144-positive microparticles may be regarded as endothelium-derived microparticles (EMPs), directly reflecting endothelial damage. However, it is unknown whether circulating EMPs are cause or consequence of CVD, and whether their occurrence associates with CVD per se or, rather, with diabetes-related metabolic abnormalities.

We hypothesized that in patients with uncomplicated type 2 diabetes, exposure to three consecutive high-fat mixed meals, given during a 24-h period, will disclose the full scope of their compromised metabolism and subsequent endothelial dysfunction, measured as FMD and circulating EMPs.

After obtaining informed consent, 27 nonsmoking Caucasian male subjects ( n = 15 with uncomplicated type 2 diabetes and n = 12 healthy age-matched volunteers) were studied during a 24-h period. No drug use other than sulfonylureas and/or metformin was allowed. After an overnight fast, subjects received three consecutive, …
Altered Hippocampal-Parahippocampal Function During Stimulus Encoding
Authors: Roberta Rasetti, Venkata S. Mattay, Michael G. White, Fabio Sambataro, Jamie E. Podell, Brad Zoltick, Qiang Chen, Karen F. Berman, Joseph H. Callicott, Daniel R. Weinberger
Journal: JAMA Psychiatry (2014)

Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder.To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia.Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry.All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples.Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score.These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.
Diet and gall stones: effects of refined and unrefined carbohydrate diets on bile cholesterol saturation and bile acid metabolism.
Authors: J R Thornton, P M Emmett, K W Heaton
Journal: Gut (1983)

It has been suggested that consumption of refined carbohydrate foods (notably sugar and white flour) increases bile cholesterol saturation and hence the risk of cholesterol gall stone formation. To test this hypothesis, 13 subjects with probable cholesterol gall stones ate refined and unrefined carbohydrate diets, each for six weeks in random order. On the refined carbohydrate diet, subjects ate more refined sugar (mean = SEM: 106 +/- 7 vs 6 +/- 1 g/day, p less than 0.001), less dietary fibre (13 +/- 1 vs 27 +/- 3 g/day, p less than 0.001), and had a higher energy intake (9.17 +/- 0.66 vs 7.16 +/- 0.64 MJ/day, p less than 0.001). After each diet, the lipid composition of duodenal bile and bile acid kinetics was determined. The cholesterol saturation index of bile was higher on the refined carbohydrate diet in all but one subject, with a mean value of 1.50 +/- 0.10 compared with 1.20 +/- 0.12 on the unrefined diet (p less than 0.005). On the refined carbohydrate diet, bile contained relatively less cholic acid and slightly more deoxycholic acid. There were, however, no significant differences in total or individual bile acid pool sizes. There were also no differences in the rates of primary bile acid synthesis or fractional turnover on the two diets. Consumption of carbohydrate in refined form increases bile cholesterol saturation. The risk of gall stones might be reduced by avoidance of refined carbohydrate foods.
Anti-Erythropoietin Antibody-Mediated Pure Red Cell Aplasia after Treatment with Recombinant Erythropoietin Products
Authors: Denis Cournoyer, Edwin B. Toffelmire, George A. Wells, Dwayne L. Barber, Brendan J. Barrett, Robert Delage, Donna L. Forrest, Raymonde F. Gagnon, Elizabeth A. Harvey, Pierre Laneuville, Bruce J. Patterson, Man-Chiu Poon, Gerald A. Posen, Hans A. Messner
Journal: Journal of the American Society of Nephrology (2004)

Since 1998, there has been a marked increase in incidence of pure red cell aplasia secondary to development of anti-erythropoietin antibodies (Ab+ PRCA) in patients who have chronic kidney disease (CKD) and receive recombinant erythropoietin. The relationship between incidence of Ab+ PRCA and specific erythropoietin products has not been examined rigorously. Manufacturers provided data regarding exposure to erythropoietin products and incidence of Ab+ PRCA between January 1998 and March 2003 in patients with CKD. Assuming a Poisson distribution, a maximum likelihood estimate for the Poisson rate parameter was calculated for each product. A test for homogeneity of Poisson rates was conducted to compare likelihood estimates between products. Global incidence of Ab+ PRCA was relatively low. Likelihood estimates were not significantly different for Epogen, Procrit, and Aranesp, independent of their formulation or route of administration. Eprex lacking human serum albumin (HSA) and administered subcutaneously was associated with the greatest risk of Ab+ PRCA. HSA-containing Eprex administered subcutaneously was associated with a lower risk than HSA-free Eprex administered subcutaneously, but this risk exceeded that of intravenous Epogen and intravenous HSA-free Eprex. NeoRecormon administered subcutaneously was associated with less risk than subcutaneous HSA-free Eprex but more risk than intravenous Epogen. HSA-free Eprex should not be administered subcutaneously to patients with CKD due to increased risk of Ab+ PRCA. Although the subcutaneous administration of HSA-containing Eprex is riskier than intravenous Epogen and intravenous HSA-free Eprex, and the use of subcutaneous NeoRecormon is riskier than intravenous Epogen, there is currently no evidence that other products are safer.
What makes champions? A review of the relative contribution of genes and training to sporting success
Authors: Ross Tucker, Malcolm Collins
Journal: British Journal of Sports Medicine (2012)

Elite sporting performance results from the combination of innumerable factors, which interact with one another in a poorly understood but complex manner to mould a talented athlete into a champion. Within the field of sports science, elite performance is understood to be the result of both training and genetic factors. However, the extent to which champions are born or made is a question that remains one of considerable interest, since it has implications for talent identification and management, as well as for how sporting federations allocate scarce resources towards the optimisation of high-performance programmes. The present review describes the contributions made by deliberate practice and genetic factors to the attainment of a high level of sporting performance. The authors conclude that although deliberate training and other environmental factors are critical for elite performance, they cannot by themselves produce an elite athlete. Rather, individual performance thresholds are determined by our genetic make-up, and training can be defined as the process by which genetic potential is realised. Although the specific details are currently unknown, the current scientific literature clearly indicates that both nurture and nature are involved in determining elite athletic performance. In conclusion, elite sporting performance is the result of the interaction between genetic and training factors, with the result that both talent identification and management systems to facilitate optimal training are crucial to sporting success.
Administration of insulin-like growth factor-I (IGF-I) peptides for three days stimulates proliferation of the small intestinal epithelium in rats.
Authors: C B Steeb, J F Trahair, L C Read
Journal: Gut (1995)

It has previously been shown that longterm administration of insulin-like growth factor-I (IGF-I) or the analogue Long R3 IGF-I (LR3IGF-I) selectively stimulate growth of the gastrointestinal tract in gut resected, dexamethasone treated, and normal rats. In this study, the short-term effects of IGF-I administration on intestinal proliferation have been investigated. Female rats (110 g, five-six/group) were infused for three days with 2.5 mg/kg/day of either IGF-I or LR3IGF-I and compared with vehicle treated or untreated control rats. LR3IGF-I but not IGF-I increased body weight and wet tissue weight of the small and large intestine (+20%), compared with controls. Tissue weight responses were independent of food intake and were reflected in the histology of the tissue. In LR3IGF-I treated animals, duodenal and ileal crypts length were increased by 13 and 22%, respectively, associated with an increase in crypt cell number. No such histological changes were seen in IGF-I treated rats. Tritiated thymidine labelling indices were significantly increased after administration of either IGF-I or LR3IGF-I (up to 14%) in both the duodenum and ileum. In IGF-I treated rats, increased nuclear labelling was not associated with an increase in the crypt compartment. In contrast, LR3IGF-I induced proportional increments in thymidine labelling and crypt size, suggesting that LR3IGF-I is not only more potent than the native peptide but also induced proliferative events more rapidly. In the colon, the thymidine labelling index was low, however, a non-significant increase in the number of cells labelled with thymidine was seen. These results suggest that within a three day treatment period intestinal mitogenesis is more advanced in animals treated with LR3IGF-I. The differences in proliferative response between the two peptides may be accounted for by variations in pharmacokinetics, clearance rates, and interactions with circulating and tissue specific binding proteins.
ABCG2/BCRP Expression Modulates <scp>d</scp>-Luciferin–Based Bioluminescence Imaging
Authors: Yimao Zhang, Joseph P. Bressler, Jeff Neal, Bachchu Lal, Hyo-Eun C. Bhang, John Laterra, Martin G. Pomper
Journal: Cancer Research (2007)

Abstract Bioluminescence imaging (BLI) is becoming indispensable to the study of transgene expression during development and, in many in vivo models of disease such as cancer, for high throughput drug screening in vitro. Because reaction of d-luciferin with firefly luciferase (fLuc) produces photons of sufficiently long wavelength to permit imaging in intact animals, use of this substrate and enzyme pair has become the method of choice for performing BLI in vivo. We now show that expression of the ATP-binding cassette (ABC) family transporter ABCG2/BCRP affects BLI signal output from the substrate d-luciferin. In vitro studies show that d-luciferin is a substrate for ABCG2/BCRP but not for the MDR1 P-glycoprotein (ABCB1/Pgp), multidrug resistance protein 1 (MRP1/ABCC1), or multidrug resistance protein 2 (MRP2/ABCC2). d-Luciferin uptake within cells is shown to be modulated by ABC transporter inhibitors, including the potent and selective ABCG2/BCRP inhibitor fumitremorgin C. Images of xenografts engineered to express transgenic ABCG2/BCRP, as well as xenografts derived from the human prostate cancer cell line 22Rv1 that naturally express ABCG2/BCRP, show that ABCG2/BCRP expression and function within regions of interest substantially influence d-luciferin–dependent bioluminescent output in vivo. These findings highlight the need to consider ABCG2/BCRP effects during d-luciferin–based BLI and suggest novel high throughput methods for identifying new ABCG2/BCRP inhibitors. [Cancer Res 2007;67(19):9389–97]
Preoperative Chemoradiotherapy Using Concurrent Capecitabine and Irinotecan in Magnetic Resonance Imaging–Defined Locally Advanced Rectal Cancer: Impact on Long-Term Clinical Outcomes
Authors: Simon Gollins, Arthur Sun Myint, Brian Haylock, Marcus Wise, Mark Saunders, Rekha Neupane, Sharadah Essapen, Les Samuel, Mark Dougal, Arwel Lloyd, Jackie Morris, Clare Topham, Shabbir Susnerwala
Journal: Journal of Clinical Oncology (2011)

Purpose To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)–defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine. Patients and Methods One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (≤ 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m 2 twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m 2 once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection. Results Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (&gt; 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci. Conclusion This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes.
Acid-Base Alterations and Renal Gluconeogenesis: Effect of pH, Bicarbonate Concentration, and PCO2*
Authors: Donald E. Kamm, Robert E. Fuisz, A. David Goodman, George F. Cahill
Journal: Journal of Clinical Investigation (1967)

In previous studies it was found that renal cortical slices from rats with induced metabolic acidosis have an increased capacity to produce glucose, whereas cortical slices from rats with metabolic alkalosis manifest decreased gluconeogenesis. To evaluate the relative influence of extracellular fluid pH, [HCO(3) (-)], and carbon dioxide tension on renal gluconeogenesis, we observed glucose production by cortex from rats with induced respiratory acidosis, and by cortex taken from normal animals and incubated in acid and alkaline media. We found glucose production to be increased in cortex from rats with respiratory acidosis, as is the case in metabolic acidosis. Glucose production by slices from normal rats was increased in media made acidic by reducing [HCO(3) (-)], and decreased in media made alkaline by raising [HCO(3) (-)]. These effects were evident whether the gluconeogenic substrate employed was glutamine, glutamate, alpha-ketoglutarate, or oxalacetate. Glucose production was also increased in media made acidic by raising CO(2) tension and decreased in media made alkaline by reducing CO(2) tension. These data indicate that both in vivo and in vitro, pH, rather than CO(2) tension or [HCO(3) (-)], is the most important acid-base variable affecting renal gluconeogenesis. The findings suggest that a decrease in extracellular fluid pH enhances renal gluconeogenesis through direct stimulation of one of the rate-limiting reactions involved in the conversion of oxalacetate to glucose. We hypothesize that the resultant increase in the rate of removal of glutamate, a precursor of oxalacetate, may constitute an important step in the mechanism by which acidosis increases renal ammonia production.