tbuckley/cabot-search huggingface dataset:
Morphine, Gabapentin, or Their Combination for Neuropathic Pain
Authors: Ian Gilron, Joan M. Bailey, Dongsheng Tu, Ronald R. Holden, Donald F. Weaver, Robyn L. Houlden
Journal: New England Journal of Medicine (2005)

The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. We compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia.In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine--each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients receiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated doses, mood, and quality of life.Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). The maximal tolerated doses of morphine and gabapentin were lower (P<0.05) with the combination than for each drug as single agent. At the maximal tolerated dose, the gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<0.05) and a higher frequency of dry mouth than morphine alone (P<0.05).Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects.
Nonclassical MHC Class II Molecules
Authors: Christopher Alfonso, Lars Karlsson
Journal: Annual Review of Immunology (2000)

Major histocompatibility complex (MHC) class II molecules are cell surface proteins that present peptides to CD4 + T cells. In addition to these wellcharacterized molecules, two other class II–like proteins are produced from the class II region of the MHC, HLA-DM (DM) and HLA-DO (DO) (called H2-M, or H2-DM and H2-O in the mouse). The function of DM is well established; it promotes peptide loading of class II molecules in the endosomal/lysosomal system by catalyzing the release of CLIP peptides (derived from the class II–associated invariant chain) in exchange for more stably binding peptides. While DM is present in all class II– expressing antigen presenting cells, DO is expressed mainly in B cells. In this cell type the majority of DM molecules are not present as free heterodimers but are instead associated with DO in tight heterotetrameric complexes. The association with DM is essential for the intracellular transport of DO, and the two molecules remain associated in the endosomal system. DO can clearly modify the peptide exchange activity of DM both in vitro and in vivo, but the physiological relevance of this interaction is still only partly understood.
A low-affinity vasopressin V2-receptor gene in a kindred with X-linked nephrogenic diabetes insipidus.
Authors: K Yokoyama, A Yamauchi, M Izumi, T Itoh, A Ando, E Imai, T Kamada, N Ueda
Journal: Journal of the American Society of Nephrology (1996)

In this study, a mutation in vasopressin Type 2 receptor (V2R) in a patient with hereditary nephrogenic diabetes insipidus (NDI) has been identified and characterized. The sequencing of the V2R gene from the patient revealed that there was a missense mutation (TAT to TGT) resulting in the substitution of 205Tyr for Cys in the putative third extracellular domain. The expression analysis in COS cells showed that the binding affinity of the mutant receptor (KD = 19.8 nM) for arginine vasopressin was much lower than that of the wild-type receptor (KD = 1.8 nM) so that intracellular cAMP production stimulated by arginine vasopressin was impaired in cells with the mutant V2R. From these results, it was concluded that the single amino-acid substitution of V2R is responsible for this familial disease.
Cognitive behaviour therapy to prevent complicated grief among relatives and spouses bereaved by suicide: cluster randomised controlled trial
Authors: Marieke de Groot, Jos de Keijser, Jan Neeleman, Ad Kerkhof, Willem Nolen, Huibert Burger
Journal: BMJ (2007)

<b>Objective</b> To examine the effectiveness of a family based grief counselling programme to prevent complicated grief among first degree relatives and spouses of someone who had committed suicide. <b>Design</b> Cluster randomised controlled trial with follow-up at 13 months after the suicide. <b>Setting</b> General practices in the Netherlands. <b>Participants</b> 122 first degree relatives and spouses of 70 people who committed suicide; 39 families (68 participants) were allocated to intervention, 31 families (54 participants) to control. <b>Intervention</b> A family based, cognitive behaviour counselling programme of four sessions with a trained psychiatric nurse counsellor between three to six months after the suicide. Control participants received usual care. <b>Main outcome measures</b> Self report complicated grief. Secondary outcomes were the presence of maladaptive grief reactions, depression, suicidal ideation, and perceptions of being to blame for the suicide. <b>Results</b> The intervention was not associated with a reduction in complicated grief (mean difference −0.61, 95% confidence interval −6.05 to 4.83; P=0.82). Secondary outcomes were not affected either. When adjusted for baseline inequalities, the intervention reduced the risk of perceptions of being to blame (odds ratio 0.18, 0.05 to 0.67; P=0.01) and maladaptive grief reactions (0.39, 0.15 to 1.01; P=0.06). <b>Conclusions</b> A cognitive behaviour grief counselling programme for families bereaved by suicide did not reduce the risk of complicated grief or suicidal ideation or the level of depression. The programme may help to prevent maladaptive grief reactions and perceptions of blame among first degree relatives and spouses. <b>Trial registration</b> Current Controlled Trials ISRCTN66473618.
Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis
Authors: STEPHAN HARBARTH, KATARINA HOLECKOVA, CÉLINE FROIDEVAUX, DIDIER PITTET, BARA RICOU, GEORGES E. GRAU, LASZLO VADAS, JÉRÔME PUGIN
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

To assess the diagnostic value of procalcitonin (PCT), interleukin (IL)-6, IL-8, and standard measurements in identifying critically ill patients with sepsis, we performed prospective measurements in 78 consecutive patients admitted with acute systemic inflammatory response syndrome (SIRS) and suspected infection. We estimated the relevance of the different parameters by using multivariable regression modeling, likelihood-ratio tests, and area under the receiver operating characteristic curves (AUC). The final diagnosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and septic shock in 25. PCT yielded the highest discriminative value, with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75; CI, 0.63 to 0.87), and IL-8 (0.71; CI, 0.59 to 0.83; p < 0.001). At a cutoff of 1.1 ng / ml, PCT yielded a sensitivity of 97% and a specificity of 78% to differentiate patients with SIRS from those with sepsis-related conditions. Median PCT concentrations on admission (ng / ml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 (0.4 to 6.7) for sepsis; 6.2 (2.2 to 85) for severe sepsis; and 21.3 (1.2 to 654) for septic shock (p < 0.001). The addition of PCT to a model based solely on standard indicators improved the predictive power of detecting sepsis (likelihood ratio test; p = 0.001) and increased the AUC value for the routine value-based model from 0.77 (CI, 0.64 to 0.89) to 0.94 (CI, 0.89 to 0.99; p = 0.002). In contrast, no additive effect was seen for IL-6 (p = 0.56) or IL-8 (p = 0.14). Elevated PCT concentrations appear to be a promising indicator of sepsis in newly admitted, critically ill patients capable of complementing clinical signs and routine laboratory parameters suggestive of severe infection.Keywords: Critical care; biological markers, blood; calcitonin, blood; protein precursors, blood; interleukin-6, blood; interleukin-8, blood; sepsis, blood, diagnosis; sepsis syndrome, blood, diagnosis
Effects of peroxisome proliferator-activated receptor-β activation in endothelin-dependent hypertension
Authors: María José Zarzuelo, Manuel Gómez-Guzmán, Rosario Jiménez, Ana María Quintela, Miguel Romero, Manuel Sánchez, Antonio Zarzuelo, Juan Tamargo, Francisco Pérez-Vizcaíno, Juan Duarte
Journal: Cardiovascular Research (2013)

We analysed the chronic effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt. Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg−1 day−1), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg−1 day−1), DOCA-GSK0660 (1 mg kg−1 day−1), and DOCA-GSK0660-GW0742. Rats receiving DOCA-vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2α excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47phox, p22phox, NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg−1 day−1, attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-β antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects. Vascular protective effects of GW0742 operate via PPAR-β by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-β-independent mechanisms to decrease blood pressure.
Estimation of the familial relative risk of cancer by site from a French population based family study on colorectal cancer (CCREF study)
Authors: N Andrieu
Journal: Gut (2004)

<b>Background:</b> Colorectal cancer (CRC) is the second most common cause of death from cancer in France. A family history of CRC increases an individual’s risk of developing CRC. Family history has been suggested to have a greater impact on proximal than distal tumours. <b>Aim:</b> We estimated the familial risk of CRC and other cancers, and examined how risk varies according to localisation of the tumour in the colorectal tract. <b>Subjects:</b> We recorded all cases of CRC diagnosed between 1993 and 1998 in the region served by the Calvados Cancer Registry. A trained interviewer asked all participants about their family history of cancer. <b>Statistical methods:</b> Familial risk was estimated from a cohort analysis of the relatives of the CRC cases. The expected numbers of cancers were calculated from Calvados incidence rates. Familial relative risks were calculated using standardised incidence ratios. <b>Results:</b> Our findings showed that colon cancer had a stronger familial/genetic component (relative risk (RR) 1.47) than rectal cancer (RR 0.98). The familial/genetic component appeared stronger for proximal colon cancer than for distal colon cancer only among women (RR 2.24 <i>v</i> RR 1.45). CRC appeared to be positively associated with leukaemia (RR 1.77), stomach cancer (RR 1.32), and testicular cancer (RR 3.13), and negatively associated with urinary bladder cancer (RR 0.57) within families. The cancer spectrum associated with CRC among younger participants included prostate (RR 1.93), uterus (RR 2.49), and thyroid (RR 3.85) cancers. <b>Conclusion:</b> If our results are confirmed, follow up guidelines for patients with a family history of CRC should depend on the sex and tumour site of affected relatives to avoid needless invasive screening.
The Canadian C-Spine Rule for Radiography in Alert and Stable Trauma Patients
Authors: Ian G. Stiell
Journal: JAMA (2001)

PAtients with blunt trauma and potential cervical spine (C-spine) injury are treated each year in US emergency departments (EDs). 1,2[12][13][14][15][16] Furthermore, there is considerable practice variation among well-trained emergency physicians, with radiography rates ranging as much as 6-fold. 17Cervical spine radiography is an example of a "little ticket" item, a low-cost procedure that significantly adds to health care costs due to its high volumes of use. 18,19
Improved Pancreatic β-Cell Function in Type 2 Diabetic Patients After Lifestyle-Induced Weight Loss Is Related to Glucose-Dependent Insulinotropic Polypeptide
Authors: Thomas P.J. Solomon, Jacob M. Haus, Karen R. Kelly, Michael Rocco, Sangeeta R. Kashyap, John P. Kirwan
Journal: Diabetes Care (2010)

OBJECTIVE Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in β-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis. RESEARCH DESIGN AND METHODS Twenty-nine older, obese (aged 65 ± 1 years; BMI 33.6 ± 1.0 kg/m2) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. β-Cell function (oral glucose–induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined. RESULTS After exercise and diet-induced weight loss (−5.0 ± 0.7 kg), oral glucose–induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P &amp;lt; 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 ± 0.26 vs. 2.04 ± 0.46 arbitrary units; P &amp;lt; 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group. CONCLUSIONS After lifestyle-induced weight loss, improvements in oral glucose–induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated β-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells.
MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis
Authors: Tomohiro Ogawa, Masaru Enomoto, Hideki Fujii, Yumiko Sekiya, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada
Journal: Gut (2012)

<h3>Background</h3> MicroRNAs (miRNAs) are important in hepatic pathophysiology and the development of liver cancer. <h3>Objective</h3> To explore miRNAs that are regulated with the progression of liver fibrosis caused by chronic liver disease. <h3>Design</h3> The regulated miRNAs in human livers infected with hepatitis C virus were identified by microarray analysis. Their expression in human livers with non-alcoholic steatohepatitis, mouse livers from two fibrosis models and cultured stellate cells was validated by real-time RT-PCR. The regulation of miR-222 expression in stellate cells by nuclear factor kappa B (NF-κB) was assayed. Finally, the effects of an miR-222 precursor or inhibitor on the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and the growth of LX-2 cells were determined. <h3>Results</h3> It was found that miR-199a-5p/199a-3p and miR-221/222 were upregulated in the human liver in a fibrosis progression–dependent manner. Among these miRNAs, miR-221/222 were upregulated in LX-2 cells and increased during the course of culture-dependent activation of mouse primary stellate cells, in a manner similar to the expression of α1(I) collagen and α-smooth muscle actin mRNAs. The expression of miR-221/222 increased in mouse models of liver fibrosis. In contrast, an NF-κB inhibitor significantly suppressed the miR-222 induction that was stimulated in culture by transforming growth factor α or tumour necrosis factor α. Although overexpression or downregulation of miR-222 failed to regulate the growth of LX-2 cells, miR-222 bound to the <i>CDKN1B</i> 3′UTR and regulated the expression of the corresponding protein. <h3>Conclusion</h3> miR-221/222 may be new markers for stellate cell activation and liver fibrosis progression.
Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial
Authors: Annie M Young, Lucinda J Billingham, Gulnaz Begum, David J Kerr, Ana I Hughes, Daniel W Rea, Stephen Shepherd, Andrew Stanley, Ann Sweeney, Jonathan Wilde, Keith Wheatley
Journal: The Lancet (2009)
Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis
Authors: Baptiste N. Jaeger, Jean Donadieu, Céline Cognet, Claire Bernat, Diana Ordoñez-Rueda, Vincent Barlogis, Nizar Mahlaoui, Aurore Fenis, Emilie Narni-Mancinelli, Blandine Beaupain, Christine Bellanné-Chantelot, Marc Bajénoff, Bernard Malissen, Marie Malissen, Eric Vivier, Sophie Ugolini
Journal: The Journal of Experimental Medicine (2012)

Natural killer (NK) cells are bone marrow (BM)-derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases.
The Effects of Oral Fructose, Sucrose, and Glucose in Subjects with Reactive Hypoglycemia
Authors: Phyllis A Crapo, John A Scarlett, Orville G Kolterman, Leonard R Sanders, Fred D Hofeldt, Jerrold M Olefsky
Journal: Diabetes Care (1982)

We have evaluated the acute effects of orally administered 100-g loads of fructose, sucrose, or glucose given as drinks and of 100-g loads of fructose and sucrose given in cakes on the postprandial serum glucose, insulin, and cortisol responses in seven subjects with reactive hypoglycemia. We defined reactive hypoglycemia as a serum glucose nadir of 65 mg/dl or less, symptoms compatible with hypoglycemia occurring at or after the serum glucose nadir, a hypoglycemic index of greater than 1.0, and a rise in serum cortisol to greater than 20 μg/dl after the serum glucose nadir. The data demonstrated that (1) pure fructose given as a drink resulted in relatively flat serum glucose and insulin responses and did not cause a hypoglycemic reaction in any of the subjects, compared with the glucose drink, which caused a hypoglycemic reaction in all subjects; (2) ingestion of pure sucrose as a drink elicited significantly flatter serum glucose and insulin responses than did the glucose drink and was associated with some episodes of chemical hypoglycemia and symptoms, but did not result in a hypoglycemic reaction by our definition in any patient; and (3) ingestion of fructose cake led to serum glucose and insulin responses that were lower than those caused by ingestion of sucrose cake, but ingestion of neither fructose nor sucrose cake led to a hypoglycemic reaction by our definition in any patient. In conclusion, the use of fructose as a sweetening agent given either alone, in a drink, or with other nutrients in a cake resulted in markedly flatter serum glucose and insulin responses in subjects with reactive hypoglycemia. Fructose may thus prove useful as a sweetening agent in the dietary treatment of selected patients with reactive hypoglycemia.
Effect of Oxygen on Growth of Cultured Myocardial Cells
Authors: MILTON HOLLENBERG
Journal: Circulation Research (1971)

The present study was designed to explore the effects of environmental oxygen as a possible regulator of cardiac cell division and growth. Trypsindispersed heart cells from the ventricles of chick embryos 8 to 12 days old were grown in culture at 37°C in a nutrient medium (NCI) with 10% fetal calf serum. They were exposed to constant 5% CO 2 gas environments in which the percent of O 2 was varied. Net protein synthesis increased progressively as O 2 was reduced from 80% to 2 to 5%. After the first 24 hours, little further protein synthesis occurred in plates grown in 80% O 2 . The rates of cellular incorporation of 14 C-amino acids and uridine-2- 14 C increased progressively as the fraction of O 2 was reduced. In cells grown at 80% O 2 , incorporation of uridine-2- 14 C into RNA was impaired before that of 14 C-amino acid into protein. After actinomycin-D (5 µg/ml) (which quickly halted uridine incorporation into the rapidly labeled fraction of RNA), the rate of incorporation of 14 C-amino acid into protein declined exponentially. This allowed for calculation of the half-life of messenger RNA (mRNA), which was the same for cells grown at 80% O 2 as for cells grown at 20% O 2 ; increased degradation of mRNA at higher P o 2 is thus ruled out. Decreased O 2 tension results in increased rates of cell division and protein synthesis in vitro. The molecular site of action appears to be at or before RNA readout from DNA.