Nonsignificant Research Articles

Influence of ischaemia/reperfusion and LFA-1 inhibition on telomere lengths and CDKI genes in ex vivo haemoperfusion of primate kidneys

Abstract The telomere (T) length, p21(WAF1/CIP1) and p27(kip1) cyclin dependent kinase inhibitor (CDKI) genes are the markers of cell senescence and DNA damage. The aim of the study was to determine the influence of renal ischaemia/reperfusion (I/R) and anti-lymphocyte function-associated antigen-1 (LFA-1) monoclonal antibody (mAb) treatment on the value of the above-mentioned markers. Significantly higher levels of p21 and p27 were expressed by the glomeruli (P = 0.001 and P = 0.0001), tubules (P= 0.0065 and P = 0.0006), and interstitial cells (P = 0.0017 and P = 0.0022, respectively) of the xenoperfused kidneys. The mean T length of non-perfused renal specimens (5.56 ±0.60 kbp) was longer than that of the xenoperfused kidneys (5.46 ±0.36 kbp) [P= non-significant (NS)]. Addition of anti LFA-1 mAb did not significantly influence the gene expression profile in the xenoperfused kidneys. The mean T length was longer in the kidneys with anti-LFA-1 mAb than in those without the medication (5.7±0.11 vs 5.13±0.31 kbp) (P= 0.0661). Kidney I/R is associated with telomere shortening and an over-expression of p21 and p27 CDKIs, which indicates substantial DNA damage and/or accelerated tissue senescence. Although anti-LFA-1 mAb had some protective effect on the telomeres, it did not influence the gene expression profile in this study.

Influence of ischaemia/reperfusion and LFA-1 inhibition on telomere lengths and CDKI genes in ex vivo haemoperfusion of primate kidneys

The telomere (T) length, p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes are the markers of cell senescence and DNA damage. The aim of the study was to determine the influence of renal ischaemia/reperfusion (I/R) and anti-lymphocyte function-associated antigen-1 (LFA-1) monoclonal antibody (mAb) treatment on the value of the above-mentioned markers. Significantly higher levels of p21 and p27 were expressed by the glomeruli (P=0.001 and P=0.0001), tubules (P=0.0065 and P=0.0006), and interstitial cells (P=0.0017 and P=0.0022, respectively) of the xenoperfused kidneys. The mean T length of non-perfused renal specimens (5.56+/-0.60 kbp) was longer than that of the xenoperfused kidneys (5.46+/-0.36 kbp) [P= non-significant (NS)]. Addition of anti-LFA-1 mAb did not significantly influence the gene expression profile in the xenoperfused kidneys. The mean T length was longer in the kidneys with anti-LFA-1 mAb than in those without the medication (5.7+/-0.11 vs 5.13+/-0.31 kbp) (P=0.0661). Kidney I/R is associated with telomere shortening and an over-expression of p21 and p27 CDKIs, which indicates substantial DNA damage and/or accelerated tissue senescence. Although anti-LFA-1 mAb had some protective effect on the telomeres, it did not influence the gene expression profile in this study.

Risk Factors for Bleeding in Patients with Nonvalvular Atrial Fibrillation Who Are Receiving Anticoagulant Therapy with Ximelagatran or Warfarin: Findings from the SPORTIF III and V Trials.

Background: Ximelagatran is a novel oral direct thrombin inhibitor that is as effective as warfarin in preventing stroke and other thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). Risk factors for bleeding with warfarin are known, but risk factors for bleeding with ximelagatran have not been described. Unlike warfarin, ximelagatran has a predictable anticoagulant effect, does not require anticoagulation monitoring, has a low potential for interactions with drugs, food, or alcohol, and is not affected by genetic polymorphisms. We undertook an exploratory analysis of a large patient database to identify conventional and novel risk factors for bleeding in ximelagatran-treated patients, in warfarin-treated patients, and in all patients, irrespective of treatment.Methods: We undertook a pooled analysis of the SPORTIF III and V trials trials, which included 7329 patients with nonvalvular AF who received oral ximelagatran, 36 mg twice daily, or warfarin, administered to achieve a target international normalized ratio of 2.0–3.0. Patients had nonvalvular AF and 1 or more risk factors for stroke: hypertension; age ≥75 years; previous stroke, transient ischemic attack (TIA) or systemic embolism; left ventricular dysfunction; age ≥65 years and coronary artery disease; or age ≥65 years and diabetes mellitus. Major exclusion criteria were: mitral stenosis; previous heart valve surgery; transient AF; increased risk for bleeding. Multivariate logistic regression analysis was used to identify independent risk factors for major bleeding. The hazard ratio (HR) for major bleeding, and corresponding 95% confidence interval (CI), was calculated for each variable in the regression model.Results: The Table presents risk factors in which there was a significant or a non-significant (NS) association with major bleeding in ximelagatran-treated or warfarin-treated patients, and in the combined patient population.Risk factorXimelagatran-treated patients, HR (95% CI)Warfarin-treated patients, HR (95% CI)Combined patient population, HR (95% CI)Aspirin use1.65 (1.07, 2.55)2.40 (1.69, 3.42)1.96 (1.49, 2.58)Increasing age1.03 (1.01, 1.05)1.06 (1.03, 1.08)1.04 (1.03, 1.06)Prior liver diseaseNS4.96 (1.57, 15.62)NSPrior stroke or TIA1.78 (1.16, 2.73)NSNSDiabetes mellitus1.80 (1.18, 2.75)NS1.39 (1.05, 1.86)Asian raceNSNS1.99 (1.16, 3.42)Statin use0.62 (0.39, 0.97)0.61 (0.42, 0.88)0.62 (0.39, 0.97)Conclusions: Overall, the bleeding risk was lower with ximelagatran compared with warfarin. Aspirin use and increasing age were associated with an increased risk of bleeding in both ximelagatran- and warfarin-treated patients. Statin use was associated with a decreased risk for bleeding in both groups.

Effect of Caffeine‐Containing versus Decaffeinated Coffee on Serum Clozapine Concentrations in Hospitalised Patients

Clozapine and caffeine are metabolised mainly by the cytochrome P4501A2 (CYP1A2) enzyme. Studies suggest that caffeine in coffee inhibits clozapine metabolism and increases serum clozapine concentrations. Our objective was to study whether coffee in the amounts usually consumed has an effect on steady-state serum clozapine concentrations. A randomised placebo-controlled cross-over design with two phases was used. Twelve hospitalised clozapine-using patients volunteered in the study where, after one-week run-in period, either caffeine-containing or decaffeinated instant coffee was available ad libitum for seven days. Serum concentrations of clozapine, N-desmethylclozapine, clozapine-N-oxide, caffeine, paraxanthine and C-reactive protein were measured after run-in period and on days 4 and 8 of the following study phases. Two patients were excluded from the statistical analysis because of non-compliance based on serum caffeine and paraxanthine determinations. In six fully compliant patients caffeine-containing coffee increased the mean serum trough concentration of clozapine by 26% (non-significant (NS), 95% CI -3% to +54%, P=0.07), N-desmethylclozapine by 6% (95% CI 1% to 12%, P=0.03), and clozapine-N-oxide by 7% (NS, 95% CI -6% to +20%, P=0.22). The ratio of N-desmethylclozapine/clozapine decreased by 13% (NS, 95% CI -1% to +27%, P=0.06) and that of clozapine-N-oxide/clozapine by 7% (NS, 95% CI -5% to +17%, P=0.19). In the analysis of combined data (including day 4 data of the four patients compliant up to that point) serum trough concentration of clozapine was 20% (95% CI 3% to 37% to P=0.03) higher, and that of N-desmethylclozapine 7% (95% CI 2% to 13%, P=0.02) higher during the caffeine phase than during the decaffeinated phase. We conclude that the effect of instant coffee drinking on serum clozapine concentrations is of minor clinical relevance in most of the patients, but some individuals may be more sensitive to this interaction due e.g. to genetic factors. The increase in serum clozapine concentration was most likely due to the inhibition of the CYP1A2 enzyme by caffeine.

Pre- and Postoperative Aminoacidemia in Breast Cancer: A Study vs. Matched Healthy Subjects

Various alterations of aminoacidemia have been described during breast cancer. The aim of this study was first to establish the specific modifications of plasma-free amino acid concentrations by a comparative study of 19 patients with mammary tumors and 18 healthy volunteers, and, second, to determine the evolution of aminoacidemia after surgical tumor removal. Aminoacidemia was determined the day before (D0), and then five days, one month (M1), and six months after surgical removal of the tumor, and a single determination was performed in control subjects. Plasma levels (µmol/L) of serine and glutamate were higher in cancer-bearing women at D0 (respectively, 124 ± 3 and 68 ± 7) than in healthy volunteers (respectively, 110 ± 6 and 48 ± 5). Surgical tumor removal induced a normalization of aminoacidemia (in µmol/L at D5: serine: 114 ± 4; at M1: glutamate: 55 ± 6 Non Significant (NS) from values of healthy subjects). Among the various patterns reported for breast cancer, we confirm one of those described by Cascino in 1995, and we show that these levels revert to normal after tumor surgical removal.

HLA‐DRB1* alleles and temporomandibular joint erosion in patients with various rheumatic diseases

Objective: To investigate the association between HLA antigens and temporomandibular joint (TMJ) erosion, salivary composition, and focal sialadenitis in patients with rheumatic diseases.Methods: Eighty‐four patients, 24 with rheumatoid arthritis (RA), 19 with mixed connective tissue disease (MCTD), 19 with ankylosing spondylitis (AS), and 22 with spondyloarthropathy (SPA) were studied. Each patient underwent clinical examination of the masticatory system, unstimulated and stimulated saliva collection, and minor salivary gland biopsy. Radiographs (OPTG) of the TMJ were obtained, and HLA allele (A, B, C and DRB1*) analysis was performed. Erosion in OPTG was scored from 0 (no erosion) to 4 (condyles totally eroded). In the analysis, scores 0–2 were grouped as normal or mild changes, and scores 3–4 as distinct erosions. One hundred healthy blood donors served as controls for HLA typing.Results: Distinct erosion of the TMJ in OPTG was observed in 22 (27%) patients. It affected four (17%) of the 24 patients with RA, three (17%) of the 18 with MCTD, seven (37%) of the 19 patients with AS and eight (38%) of the 21 with SPA non‐significant (NS). The mean erosion scores were 1.7 for RA, 1.3 for MCTD, 2.5 for SPA, and 1.6 for AS patients [probability (p)=0.04]. The frequency of HLA‐B27 antigen was higher in the AS and SPA patients, and that of HLA‐DRB1*04 allele higher in RA patients than in control subjects. In the whole patient population, HLA‐DRB1*01 allele was significantly associated with erosions 16/36 (44%) versus 6/46 (13%) (p=0.0014). In the SPA group, patients with HLA‐DRB1*01 allele had a significantly higher occurrence of distinct erosions than patients without this allele [8/10 (80%) versus 0/11 (0%) (p=0.0002)], whereas DRB1*06 was protective [0/8 (0%) versus 8/13 (62%) (p=0.018)]. HLA‐DRB1*04 was associated with increased salivary IgG in the RA patients.Conclusion: HLA antigens are significantly associated with the development of destructive lesions in the TMJ, as well as composition of saliva in patients with various rheumatic diseases.

Outcome of Gram-Positive and Gram-Negative Peritonitis in Patients on Continuous Ambulatory Peritoneal Dialysis: A Single-Center Experience

The spectrum of bacterial peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) in India may be different from that seen in developed countries because of differences in culture and in social, environmental, financial, and educational status. We analyzed our data regarding the incidence and outcome of monomicrobial peritonitis in our CAPD patients. We reviewed the records of 225 patients on CAPD to retrieve data concerning demographics, peritonitis rate, organism isolated, and outcome. Polymicrobial and fungal peritonitis were excluded from the outcome analysis because of their different outcomes. We identified 168 episodes of peritonitis (range: 1 - 6 episodes per patient). Of the 168 episodes, 106 (63.1%) episodes were culture-positive. Total duration of CAPD was 264.16 patient-years. The overall peritonitis rate was 0.63 episodes per patient-CAPD year. The rates of gram-negative, gram-positive, polymicrobial, and fungal peritonitis were 0.17, 0.11, 0.04, 0.09 episodes per patient-year, respectively. Among the 75 episodes of monomicrobial peritonitis, gram-negative episodes [n = 45 (60%)] were significantly more frequent than gram-positive episodes [n = 30 (40%), p = 0.03]. Escherichia coli was the most commonly seen organism. Organisms of fecal origin (40/75) were significantly more frequent than those of skin origin (21/75, p = 0.0016). Catheter loss (17/45 vs 5/20, p = 0.04), hospitalization (31/45 vs 13/30, p = 0.03), death [9/45 vs 3/30, p = nonsignificant (NS)], switch to hemodialysis (8.9% vs 3.3%, p = NS), and reimplantation of the catheter (6.6% vs 3.3%, p = NS) were all more frequent in gram-negative episodes than in gram-positive episodes. Gram-negative peritonitis is more frequent than gram-positive peritonitis in our CAPD population in India and is associated with worse outcome.

Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients: 10-year results of a prospective randomised phase III study comparing carboplatin–cisplatin with cyclophosphamide–cisplatin

This prospective multicentre phase III trial was conducted to assess whether increased platinum dose intensity (DI) by combining carboplatin with cisplatin has an impact on overall survival (OS) and progression-free interval (PFI) compared with the standard combination of cyclophosphamide and cisplatin in patients with epithelial ovarian cancer. A total of 253 patients with epithelial ovarian cancer of stages International Federation of Gynecology and Obstetrics (FIGO) IC–IV were randomised to receive either cyclophosphamide (600 mg/m2, intravenously (i.v.), day 1) and cisplatin (100 mg/m2, i.v., day 2) (n=125) as the standard regimen or carboplatin (300 mg/m2, i.v., day 1) and cisplatin (100 mg/m2, i.v., day 2) (n=128), every 28 days for six courses. The median follow-up was 6.0 years. 124 patients randomised to the platinum dose-intensified arm and 123 patients randomised to the standard arm met all of the eligibility criteria. Patient characteristics were well balanced between the two treatment groups. All eligible patients randomised were included in the analysis of OS and PFI. The median OS of the standard and platinum dose-intensified arms were 41.2 (95% Confidence Interval (CI): 29.2–50.7) and 43.0 months (95% CI: 34.3–63.2), respectively (P=Non-significant (N.S.). The median PFI in the standard arm was 29.7 (95% CI: 17.4–41.7) versus 23.1 months (95% CI: 17.8–35.4) in the platinum dose-intensified arm, respectively (P=N.S.). Toxicity, comprising leucopenia, granulocytopenia, thrombocytopenia, anaemia, emesis and nausea, was statistically significantly higher in the platinum dose-intensified arm than in the standard arm. Unexpectedly, no statistically significant differences were found between the 2 arms’ overall neuro- and ototoxicity. When converting carboplatin-platinum into cisplatin-platinum on the basis of an equivalence ratio of 4:1, patients in the platinum dose-intensified arm received a total platinum dose 1.58 times the platinum dose of the standard arm. With 35.0 mg/m2/week being administered, the total platinum DI of the dose-intensified arm was statistically significantly (P<0.0001) higher than that of the standard regimen (with 22.0 mg/m2 being administered). Calculating the average administered relative dose intensities of the regimens yielded almost identical results with 0.56 and 0.58 for the standard and experimental arms, respectively. Thus, by conventional means, a 1.6-fold increase in the platinum DI could be reached by combining carboplatin and cisplatin without unacceptable morbidity. Nevertheless, this did not translate into any therapeutic benefit for the patient, even in the optimally debulked group of patients for whom dose-intensification would have been expected to be of benefit.

Detection of the human papillomavirus and analysis of the TP53 polymorphism of exon 4 at codon 72 in penile squamous cell carcinomas

Human papillomaviruses (HPV) are thought to be involved in penile squamous cell carcinomas (SCC). A common polymorphism at codon 72 of exon 4 encoding either arginine (Arg) or proline (Pro) has been shown to affect HPV-mediated degradation of p53 in vitro, and may represent a risk factor for HPV-induced carcinogenesis. The presence of HPV DNA as well as the TP53 polymorphism at codon 72 of exon 4 were investigated in a series of 45 penile SCC. HPV detection and typing were carried out by polymerase chain reaction (PCR) with generic primers (MY09-MY11 and FAP59-FAP64), and type-specific DNA probes. TP53 polymorphism was further investigated using Denaturing Gradient Gel Electrophoresis (DGGE). HPV DNA was detected in 67% of penile SCC and 32% of benign lesions (BL) (P<0.05). Among the TP53 amplified samples, the rate of Arg homozygosity in penile SCC was 61% compared with 68% in BL (non-significant (NS)). Our results demonstrate a strong association between penile SCC and the presence of HPV DNA. The TP53 Arg/Arg genotype does not appear to represent a risk factor for the development of genital SCC in men, and no correlation was found between the TP53 polymorphism at codon 72 and the presence of HPV DNA.

Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis.

Although chronic hyperinsulinemia has been shown to induce insulin resistance, the basic cellular mechanisms responsible for this phenomenon are unknown. The present study was performed 1) to determine the time-related effect of physiological hyperinsulinemia on glycogen synthase (GS) activity, hexokinase II (HKII) activity and mRNA content, and GLUT-4 protein in muscle from healthy subjects, and 2) to relate hyperinsulinemia-induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty healthy subjects had a 240-min euglycemic insulin clamp study with muscle biopsies and then received a low-dose insulin infusion for 24 (n = 6) or 72 h (n = 14) (plasma insulin concentration = 121 +/- 9 or 143 +/- 25 pmol/l, respectively). During the baseline insulin clamp, GS fractional velocity (0.075 +/- 0.008 to 0.229 +/- 0.02, P < 0.01), HKII mRNA content (0.179 +/- 0.034 to 0.354 +/- 0.087, P < 0.05), and HKII activity (2.41 +/- 0.63 to 3.35 +/- 0.54 pmol x min(-1) x ng(-1), P < 0.05), as well as whole body glucose disposal and nonoxidative glucose disposal, increased. During the insulin clamp performed after 24 and 72 h of sustained physiological hyperinsulinemia, the ability of insulin to increase muscle GS fractional velocity, total body glucose disposal, and nonoxidative glucose disposal was impaired (all P < 0.01), whereas the effect of insulin on muscle HKII mRNA, HKII activity, GLUT-4 protein content, and whole body rates of glucose oxidation and glycolysis remained unchanged. Muscle glycogen concentration did not change [116 +/- 28 vs. 126 +/- 29 micromol/kg muscle, P = nonsignificant (NS)] and was not correlated with the change in nonoxidative glucose disposal (r = 0.074, P = NS). In summary, modest chronic hyperinsulinemia may contribute directly (independent of change in muscle glycogen concentration) to the development of insulin resistance by its impact on the GS pathway.

Serum lipid levels in an Iranian population of children and adolescents: Tehran lipid and glucose study.

Data from 3148 participants aged 3-19 years (1447 males and 1701 females) in the cross-sectional phase of Tehran lipid and glucose study (February 1999-May 2000) were used to determine serum lipid levels [total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)] after 12-14 hours overnight fast. The values were analyzed by sex and age. Mean serum TC concentration was 170 mg/dl. TC was significantly greater in females than males (173 vs. 167 mg/dl, p < 0.05). The 90th and 95th percentiles for serum TC were 211 and 227 mg/dl, respectively. There was a significant decrease in mean TC in males during puberty. Thirty-one percent of population had TC values between 170 and 199 mg/dl and 16% had values of 200 mg/dl or greater. The mean TGs values were 103 for males and 108 mg/dl for females [non-significant (NS)]. The prevalence of high-risk values of TGs increased with age in males, reaching a peak at 17-19 years. The mean HDL-C level was 45 mg/dl. Mean HDL-C was highest at 7-10 years of age and decreased thereafter. The mean LDL-C was 102 in males and 107 mg/dl in females (NS). Twenty-two percent had LDL-C values between 110 and 129 mg/dl and 17% had values 130 mg/dl or greater. The results showed higher levels of TC, LDL-C and TGs and lower HDL-C in Tehranian children and adolescents than other studies. To design comprehensive public health programs to reduce serum lipid levels among Iranian children and adolescents, underlying factors for the high prevalence of dyslipoproteinemia should be sought.

Peritoneal Homocysteine Clearance is Inefficient in Peritoneal Dialysis Patients

To investigate the degree and the determinants of peritoneal homocysteine (Hcy) clearance and to compare measured Hcy clearance with the Hcy clearance predicted based on molecular weight (MW). Cross-sectional observational analysis. Tertiary care institutional dialysis center. Sixty-five stable peritoneal dialysis (PD) patients. Fasting blood and 24-hour pooled dialysate effluents were collected for determination of peritoneal clearances of Hcy (CpHcy), urea (CpUr), and creatinine (CpCr). The dialysate-to-plasma creatinine ratio at 4 hours (D/P Cr 4 h) and levels of red cell folate, B12, ferritin, and C-reactive protein (CRP) were measured concurrently. Observed CpHcy was compared with predicted clearance, based on Hcy plasma protein binding and the relative molecular weights of Hcy, urea, and creatinine. Plasma concentrations of Hcy averaged 24.6 +/- 1.1 micromol/L and were elevated above the upper limit of normal in 59 (91%) patients. The mean dialysate concentration of Hcy was 2.9 +/- 0.3 micromol/L, equating to a daily peritoneal elimination of 34.6 +/- 3.6 micromol. Observed CpHcy was closely approximated by predicted CpHcy (8.7 +/- 0.6 L/week/1.73 m2 vs 9.0 +/- 0.3 L/week/1.73 m2 respectively, p = 0.55). Patients maintained on automated PD (n = 5) had a CpHcy similar to that of patients treated with continuous ambulatory peritoneal dialysis (8.9 +/- 1.0 L/week/1.73 m2 vs 8.7 +/- 0.6 L/week/1.73 m2, p = 0.92). The CpHcy was significantly correlated with C-reactive protein (CRP), D/P creatinine, CpUr, CpCr, and peritoneal protein loss, but not with plasma Hcy, albumin, B12, ferritin, age, dialysis duration, peritonitis episodes, or daily dialysate effluent volume. By multivariate analysis, the only variables that remained significant independent predictors of CpHcy were CRP and D/P Cr 4 h. High and high-average transporters had a higher CpHcy than low and low-average transporters (9.7 +/- 0.8 L/week/1.73 m2 vs 7.0 +/- 0.7 L/week/1.73 m2, p < 0.05), despite comparably elevated plasma Hcy concentrations [25.2 +/- 1.5 micromol/L vs 23.4 +/- 1.6 micromol/L, p = nonsignificant (NS)]. Elevated plasma concentrations of Hcy are not efficiently reduced by PD. The relatively low peritoneal clearance of Hcy is largely accounted for by a high degree of plasma protein binding and is significantly influenced by peritoneal membrane permeability.

Immune response to surface protein A of Streptococcus pneumoniae and to high-molecular-weight outer membrane protein A of Moraxella catarrhalis in children with acute otitis media.

The immune response was evaluated in 11 children with Streptococcus pneumoniae and in 9 children with Moraxella catarrhalis otitis media. The age of the children had a range of 4-32 months. The mean IgG, IgM, and IgA antibody responses to surface protein A (PspA) of S. pneumoniae in sera from children at the acute and convalescent stages were 4864 versus 5831 ng/mL, P<.05, 1075 versus 3752 ng/mL, P<.05, and 67 versus 93 ng/mL, nonsignificant (NS), respectively. The mean IgG, IgM, and IgA antibody responses to the high-molecular-weight outer membrane protein (UspA) of M. catarrhalis in sera from children at acute and convalescent stages were 710 versus 935 mg/mL, NS; 1895 versus 2646 ng/mL, NS; and 121 versus 204 ng/mL, P<.05, respectively. These data show that PspA and UspA are immunogenic in children after otitis media.

Effects of smaller tidal volumes during basic life support ventilation in patients with respiratory arrest: good ventilation, less risk?

Objective: When ventilating an unintubated patient in cardiac or respiratory arrest, smaller tidal volumes of 500 ml instead of 800–1200 ml may be beneficial to decrease peak airway pressure, and to minimise stomach inflation. The purpose was to determine the effects of small (∼500 ml) versus large (∼1000 ml) tidal volumes given with paediatric versus adult self-inflatable bags and ∼50% oxygen on respiratory parameters in patients during simulated basic life support ventilation. Methods: While undergoing induction of anaesthesia, patients were randomised to three minutes of ventilation with either an adult ( n=40) or paediatric ( n=40) self-inflatable bag. Results: When compared with an adult self-inflatable bag, the paediatric bag resulted in significantly lower mean (±standard deviation) exhaled tidal volume (365±55 versus 779±122 ml; P<0.0001), peak airway pressure (20±2 versus 25±5 cm H 2O; P<0.0001), but comparable oxygen saturation (97±1% versus 98±1%; NS (nonsignificant)). Stomach inflation occurred in five of 40 patients ventilated with an adult self-inflatable bag, but in no patients who were ventilated with a paediatric self-inflatable bag ( P=0.054). Conclusion: Administering smaller tidal volumes with a paediatric instead of an adult self-inflatable bag in unintubated adult patients with respiratory arrest maintains good oxygenation and carbon dioxide elimination while decreasing peak airway pressure, which makes stomach inflation less likely.

Endurance exercise training does not alter lipolytic or adipose tissue blood flow sensitivity to epinephrine.

We evaluated the relationship between lipolysis and adipose tissue blood flow (ATBF) in response to epinephrine and the effect of endurance exercise training on these responses. Five healthy untrained men underwent a four-stage incremental epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 microgram. kg fat free mass(-1). min(-1)) plus hormonal clamp before and after 16 wk of cycle ergometry exercise training. Whole body glycerol and free fatty acid (FFA) rates of appearance (R(a)) in plasma were determined by stable isotope methodology, and ATBF was assessed by (133)Xe clearance. After each training session, subjects were fed the approximate number of calories expended during exercise to prevent changes in body weight. Glycerol R(a), FFA R(a), and ATBF increased when plasma epinephrine concentration reached 0.8 nM, but at plasma epinephrine concentrations >1.6 nM ATBF plateaued, whereas lipolysis continued to increase. Exercise training increased peak oxygen uptake by 24 +/- 7% (2.9 +/- 0.2 vs. 3.6 +/- 0.1 l/min; P < 0. 05) but did not alter body weight [70.5 +/- 3.8 vs. 72.0 +/- 3.8 kg; P = nonsignificant (NS)] or percent body fat (18.4 +/- 1.6 vs. 17.8 +/- 1.9%; P = NS). Lipolytic and ATBF responses to epinephrine were also the same before and after training. We conclude that the lipolytic and ATBF responses to epinephrine are coordinated when plasma epinephrine concentration is </=1.6 nM, but that at higher epinephrine concentrations, lipolysis continues to increase while ATBF remains constant. Endurance exercise training does not change lipolytic or ATBF sensitivity to epinephrine infusion in vivo during resting conditions.

Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation.

The in vivo effect of elevated free fatty acids (FFA) on beta-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, approximately 10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity x insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 +/- 1.4 x 10(-3) l2. kg-1. min-2 in control vs. 10.0 +/- 1.9 x 10(-3) l2. kg-1. min-2 with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 +/- 1.2 x 10(-3) l2. kg-1. min-2 in control vs. 6.1 +/- 0.7 x 10(-3) l2. kg-1. min-2 with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this beta-cell compensation.

Alcohol and Prostate Cancer in the NHANES I Epidemiologic Follow-Up Study

PURPOSE: We prospectively investigated the association between alcohol consumption and prostate cancer in the Epidemiologic Followup Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I). METHODS: There were two cohorts: 1) Cohort I, followed from baseline (1971–75) through 1992, included 5766 men ages 25–74 years (median follow-up = 17 years); and 2) Cohort II, followed from the first follow-up round for Cohort I (1982–84) through 1992, included the 3868 men in Cohort I free of prostate cancer in 1982–84 (median follow-up = 9 years). Alcohol consumption was assessed at baseline as usual consumption, and at follow-up as usual consumption and as distant past consumption at the ages of 25, 35, 45, and 55. RESULTS: There were 252 incident cases of prostate cancer. Consistent with most previous studies, we found no significant associations between usual total alcohol consumption and prostate cancer in Cohorts I or II [ p = non significant (NS)], except for a significant inverse association at the heaviest level of drinking in Cohort II [relative risk (RR) = 0.23, 95% confidence interval (CI) = 0.06–0.95]. Further study of heavy drinkers in Cohort II revealed significant inverse associations between distant past heavy drinking (defined as > 25 drinks/week) and prostate cancer at age 25 (RR = 0.20, 95% CI = 0.06–0.63), age 35 (RR = 0.30, 95% CI = 0.12–0.77), and age 45 (RR = 0.39, 95% CI = 0.17–0.93), but not at age 55 (RR = 0.43, 95% CI = 0.17–1.10). CONCLUSIONS: These results suggest that it may be important to consider distant past alcohol consumption in etiologic studies of prostate cancer. However, our results were based on small numbers of cases who were heavy drinkers and require replication.

Total IgE and Specific IgG Levels to β-Lactoglobulin and Ovalbumin and Allergy Outcome in Small for Gestational Age Infants: A Pilot Study

Total IgE and specific IgG levels to β-lactoglobulin and ovalbumin and allergy development were investigated in 22 small for gestational age (SGA) infants monitored for 12 months. A high incidence of allergy was observed at 12 months corrected age relative to published reports on appropriate for gestational age infants. This was particularly noticeable in infants from a nonatopic background, where 56% (5/9) were allergic, as well as in infants with a family history of atopy, where 85% (11/13) were diagnosed as allergic at 12 months corrected age. There was a nonsignificant (NS) trend for total serum IgE levels to increase with age in infants from both atopic and nonatopic backgrounds. Levels of β-lactoglobulin IgG peaked at 4 months corrected age in both groups and had decreased by 12 months corrected age, reflecting the induction of tolerance (median and range, 4 months corrected age vs. 12 months corrected age; atopic: 904 (8-3437) μg/ml vs. 449 (53-3200) μg/ml, p < 0.02; nonatopic: 836 (39-1473) μg/ml ...

Physical activity, skeletal muscle beta-adrenoceptor changes and oxidative metabolism in experimental chronic heart failure.

In chronic heart failure (CHF), changes in sympathetic nervous activity and skeletal muscle metabolism contribute to a limitation in the capacity for exercise. The aim of this study was to investigate the potential relationships between physical deconditioning, skeletal muscle beta-adrenoceptor (beta-AR) characteristics and muscle metabolic changes in rats with coronary ligation-induced experimental CHF. Muscle beta-AR and norepinephrine levels were assessed in rats with CHF that had been treated with propranolol at 28 mg/kg/day and compared with rats with CHF that had not been treated and those that had undergone sham operations. The soleus muscle was investigated because of its predominantly oxidative fibre-type composition. Measurements of spontaneous locomotion activity were carried out using telemetry. After 85 days, muscle energetic phosphate levels were assessed using 31P-magnetic resonance spectroscopy. The phosphocreatine resynthesis rate was decreased in the untreated CHF rats (15 +/- 3 vs 33 +/- 5 mmol L-1 min-1 in the sham-operated rats, p < 0.05), but this had been partially reversed in the rats given propranolol (22 +/- 3 mmol L-1 min-1, non-significant (NS) when compared with the sham-operated rats). Spontaneous activity did not differ among the three groups of animals. Soleus beta-adrenoceptor density was decreased in rats with CHF (8.8 +/- 3.0 fM/mg of protein vs 22.0 +/- 7.0 fM/mg of protein in the sham-operated rats, p < 0.05) and normalized in the propranolol-treated rats (31.9 +/- 7.0 fM/mg of protein, NS vs the sham-operated rats; p < 0.05 vs the untreated rats with CHF). Unchanged spontaneous activity in the rats with CHF suggests that physical deconditioning could not account for the muscle metabolic changes. Changes in skeletal muscle energy metabolism were accompanied by changes in beta-AR density, occurring in typically oxidative beta-AR-rich muscles, reversible after beta-blocker therapy and therefore suggestive of beta-AR downregulation.

Antibodies to pancreatic islet cell antigens in diabetes seen in Southern India with particular reference to fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a type of diabetes secondary to tropical chronic non-alcoholic pancreatitis. Little is known about the aetiopathogenesis of FCPD. We studied glutamic acid decarboxylase antibodies (GAD-Ab) and islet cell antibodies (ICA) in patients with FCPD and compared the results with Type 1 (insulin dependent) diabetes mellitus, Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic subjects in Southern India. The prevalence of GAD-Ab was 7.0% (95% Confidence Interval (CI) 1.9-17.2) in FCPD, 47.5% (CI 31.4-64.0) in Type 1 (p < 0.001 compared to FCPD), 5.6% (CI 1.5-13.9) in Type 2 (non-significant (NS) compared to FCPD) and 0% in controls. The prevalence of ICA was 6.3% (CI 1.2-17.4) in FCPD, 53.8% (CI 37.1-70.0) in Type 1 (p < 0.001 compared to FCPD), 9.9% (CI 4.0-19.4) in Type 2 (NS compared to FCPD) and 4.7% (CI 0.4-16.1) in controls. The data suggest that in FCPD, the frequency of auto-antibodies is low and its aetiology is probably not linked to autoimmunity in the majority of the patients.