Changes in telomere length 3-5 years after gastric bypass surgery.

Increased inflammation and oxidative stress associated with obesity can accelerate aging. Telomere length (TL) has the capacity to serve as an aging indicator at the cellular level. Obesity has a known association with shorter TL. This study evaluated TL of immune cells in a population of obese individuals who underwent gastric bypass surgery. Pre- and post-operative DNA samples were available for 50 subjects who had gastric bypass surgery. DNA was analyzed via quantitative polymerase chain reaction to determine TL. Changes in TL were evaluated by comparing TL at baseline to TL at 3-5 years post gastric bypass surgery. Sixty percent of the individuals in the study observed an increase in TL. Significant lengthening was observed for those with the shortest baseline TL (P=0.0011), but not for those with intermediate baseline TL (P=0.411) or longest baseline TL (P=0.207). Change in TL was negatively correlated with age and triglycerides but not correlated with weight loss induced by bariatric surgery. This study confirms that TL lengthening is observed post bariatric surgery and is the first to detect TL lengthening 3-5 years after surgery.

Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity.

OBJECTIVE: The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals. DESIGN: Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism. SUBJECTS AND METHODS: Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR. RESULTS: The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable. CONCLUSIONS: These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated.

Improving detection and treatment of osteoporosis: redesigning care using the electronic medical record and shared medical appointments.

UNLABELLED: To determine whether a process redesign could improve detection and treatment of osteoporosis, at-risk women over the age of 65 were identified using an electronic medical record and proactively contacted by letter and phone call. This resulted in a significant increase in testing for osteoporosis by DXA scan. The high-risk patients were then offered a shared medical appointment, which resulted in improved treatment outcomes compared to usual care. INTRODUCTION: Our objective was to determine if redesigning care through proactive contact with women 65 at-risk of osteoporosis increased BMD testing and to determine if a shared medical appointment (SMA) improved treatment for high-risk women. METHODS: Two primary care sites received the redesign intervention and two other sites served as the usual care controls. At the intervention sites, all women 65 who had not had a DXA scan performed in the prior 2 years were contacted by mail and phone calls. High-risk patients were invited to attend a SMA or follow-up visit with their primary physician. RESULTS: A significantly higher proportion of women at the intervention sites had a DXA (39.6% vs. 13.2%, p < 0.0001). Patients who attended the SMA were more likely to have calcium and vitamin D recommended, a vitamin D level checked, and receive a prescription medicine than those patients who had follow-up with their primary care physician. CONCLUSIONS: The redesigned process was highly effective in improving BMD testing for women 65. The SMA was shown to be a more effective method to make calcium and vitamin D recommendations, to evaluate secondary causes of low bone density, and to prescribe prescription medications, compared to usual care with the PCP.

Feasibility of enhancing well-child visits with family nutrition and physical activity risk assessment on body mass index.

OBJECTIVE: Integration of behavioural risk assessment into well-child visits is recommended by clinical guidelines, but its feasibility and impact is unknown. METHODS: A quasi-experimental study evaluated the feasibility and effectiveness of risk assessment on body mass index (BMI) at 1-year follow-up. Children with assessments (intervention) were compared with those who did not complete assessments (non-respondent) and those who received standard care (non-exposed). RESULTS: Analyses included 10,647 children aged 2-9 years (2,724 intervention, 3,324 non-respondent and 4,599 non-exposed). Forty-five per cent of parents completed the assessments. Intervention and non-respondent groups differed in change in BMI z-score at 1 year by -0.05 (confidence interval [CI]: -0.08, -0.02; P = 0.0013); no difference was observed with non-exposed children. The intervention group had a smaller increase in BMI z-score (0.07 ± 0.63) than non-respondent group (0.13 ± 0.63). For children with normal weight at baseline, intervention versus non-respondent groups differed in BMI z-score change by -0.06 (CI: -0.10, -0.02; P = 0.0025). However, children with overweight at baseline in the intervention versus the non-exposed group differed in BMI z-score change (0.07 [CI: 0.02, 0.14]; P = 0.016). When analysed by age, results were similar for 2- to 5-year-olds, but no differences were found for 6- to 9-year-olds. CONCLUSION: Automating risk assessment in paediatric care is feasible and effective in promoting healthy weight among preschool but not older children.

Elevated blood pressure in primary care varies in relation to circadian and seasonal changes.

Blood pressure (BP) is known to vary by time of day and day of year. Studies differ substantially on the magnitude of the effect and there is doubt whether variation is clinically meaningful. We used more than 2 million BP measurements obtained between 1996 and 2004 from Geisinger Clinic primary care patients. General estimating equations were used to determine the effect of time of day and month of year on the probability of identifying BP values above four diagnostic cutoff points (SBP > or =120 mm Hg, SBP > or =140 mm Hg, DBP > or =80 mm Hg, DBP > or =90 mm Hg). Time of day and month of year were significantly associated with the odds of measuring elevated BP, regardless of definition. The odds ratio (OR) for SBP > or =120 mm Hg in the evening (1900 hours) versus midday (1200 hours) was 1.32 (P < 0.001). The OR for SBP > or =120 mm Hg in winter to summer months was 1.24 (P < 0.001). Similar results were found for each age/gender group. These data indicate that in clinical practice, measurement of an elevated BP may vary by 40% depending on the time of day and month of year. The magnitude of the variability in BP measurement attributable to the combined effect of these temporal factors is clinically significant. Anticipation of changes in BP attributable to temporal factors may improve accuracy of diagnosis and precision of therapy.

Electronically captured, patient-reported physical function: an important vital sign in obesity medicine.

OBJECTIVES: Impaired physical function (i.e., inability to walk 200 feet, climb a flight of stairs or perform activities of daily living) predicts poor clinical outcomes and adversely impacts medical and surgical weight management. However, routine assessment physical function is seldom performed clinically. The PROMIS Physical Function Short Form 20a (SF-20a) is a validated questionnaire for assessing patient reported physical function, which includes published T-score percentiles adjusted for gender, age and education. However, the effect that increasing levels of obesity has on these percentiles is unclear. We hypothesized that physical function would decline with increasing level of obesity independent of gender, age, education and comorbidity. MATERIALS AND METHODS: This study included 1,627 consecutive weight management patients [(mean ± SEM), 44.7 ± 0.3 years and 45.1 ± 0.2 kg/m2] that completed the PROMIS SF-20a during their initial consultation. We evaluated the association between obesity level and PROMIS T-score percentiles using multiple linear regression adjusting for gender, age, education and Charlson Comorbidity Index (CCI). RESULTS: Multiple linear regression T-score percentiles were lower in obesity class 2 (-12.4%tile, p < 0.0001), class 3 (-17.0%tile, p < 0.0001) and super obesity (-25.1%tile, p < 0.0001) compared to class 1 obesity. CONCLUSION: In patients referred for weight management, patient reported physical function was progressively lower in a dose-dependent fashion with increasing levels of obesity, independent of gender, age, education and CCI.

Purification of granulocyte neutral protease from human blood and rheumatoid synovial fluid.

The neutral protease activity of human synovial fluid cells, like that of peripheral blood leucocytes, is located in a granule fraction. It can be solubilised by various agents but only 1 M neutral salts do so without inactivation. Salt-solubilised neutral protease has been purified (300 X) from synovial fluid cells; like preparations obtained in the same way (600 X purified) from peripheral blood leucocytes, it has a broad pH profile of activity (pH 7--10.5) and in this, as well as in substrate specificity and sensitivity to activators and inhibitors, it behaves as a serine-histidine type protease similar to elastase (EC 3.4.21.11). The product showed two major components on polyacrylamide gel electrophoresis. Collagenase or chymotrypsin-like activity were not detected.

Kinetic studies of latent microsomal UDP-glucuronyltransferases. Kinetics of glucuronidation in intact and perturbant-treated membranes.

Double-reciprocal plots (with UDP-glucuronate as varied substrate) of the rate of glucuronidation of p-nitrophenol by the latent UDP-glucuronyltransferases of intact guinea pig and rat liver microsomal membranes (prepared with 154 mM KCl and 0.25 M sucrose) were continuously curved concave-downwards. Good fits to the kinetic data were obtained by using two different calculation methods which assume that two forms (high K and low K) of the transferase catalyse the reaction simultaneously. No evidence of cooperativity in binding of UDP-glucuronate to the enzyme was found. When latency of the enzymes of these preparations was destroyed by disrupting the membranes with Triton X-100 or lysophosphatidylcholine, double-reciprocal plots were linear. With guinea pig membranes, lysophosphatidylcholine generated an activated single-enzyme form obeying the simple Michaelis-Menten rate law; K for the activated species was close to that (K1) for the native low K form and its value of V was greater than the combined maximum velocities (V1 + V2) of the two forms in intact membranes. With rat membranes, both perturbants produced a single activated form also with V greater than (V1 + V2) and with K2 greater than K greater than K1. These results are discussed and are consistent with the view of transferase latency which envisages that there are two populations (buried and exposed) of enzyme molecules in intact microsomal membranes. The effects of membrane perturbants on the kinetic parameters of the two native transferase forms were assessed by accounting for the possibility that the reactivity of the buried transferase is controlled by the rate of transport of UDP-glucuronate across the membrane matrix. The data are compatible with a model which supposes that UDP-glucuronate gains access to the buried population by a process with the kinetic characteristics of a facilitated transport system.

Incidence of intracranial hemorrhage complicating treatment with glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of major clinical trials.

PURPOSE: The major risk of therapy with platelet glycoprotein IIb/IIIa receptor inhibitors is bleeding. We reviewed trials using these agents to determine if bleeding risks include an increased incidence of intracranial hemorrhage. METHODS: A Medline search identified 14 randomized trials of intravenous platelet glycoprotein IIb/IIIa receptor inhibitors for patients undergoing percutaneous coronary intervention or who had an acute coronary syndrome. We compared the incidence of intracranial hemorrhage among 15,850 patients treated with glycoprotein IIb/IIIa inhibitors with that among 12,039 patients treated with placebo. RESULTS: The incidence of intracranial hemorrhage with heparin plus any IIb/IIIa inhibitor was similar to placebo with heparin (0.12% vs 0.09%, odds ratio = 1.3, 95% confidence interval: 0.6 to 3.1, P = 0.59). The incidence of intracranial hemorrhage with glycoprotein IIb/IIIa drugs alone was similar to that with heparin alone (0.07% vs 0.06%), albeit with a wide confidence interval (odds ratio = 1.2, 95% confidence interval: 0.1 to 16, P = 1.0). CONCLUSIONS: Intravenous glycoprotein IIb/IIIa receptor inhibitors alone or in combination with heparin do not cause a statistically significant excess of intracranial hemorrhage as compared with heparin alone. Because of small numbers, the data do not exclude the possibility of an excess of intracranial hemorrhage in some groups of patients treated with glycoprotein IIb/IIIa receptor inhibitors.

Effect of route of nutrition on recovery of hepatic organic anion clearance after fasting.

BACKGROUND: Previous work documented a 40% depression of hepatic indocyanine green (ICG) clearance (ClICG) in pigs fasted to 20% weight loss, with return to normal within 12 days of food refeeding. ClICG in pigs is insensitive to changes in hepatic blood flow but very sensitive to changes in hepatic function (HF). Serial ClICG determinations were performed to quantify the effect of route of nutrient delivery on recovery of HF. METHODS: Fourteen pigs were fasted to 20% weight loss (12.8 days average) with both gastrostomy and intravenous catheters placed in each animal midway through the fast. ClICG was measured before fast, after fast, and after 12 days refeeding through the enteral or parenteral route at 125 kcal/kg/day with isonitrogenous, isocaloric diets containing 9% fat. Urine and stool were analyzed for total nitrogen. RESULTS: No significant differences appeared between groups in nitrogen output during fasting (4.5 +/- 1.2 gm/kg enteral, 4.6 +/- 1.2 gm/kg parenteral), in nitrogen intake (800 +/- 19 mg/kg/day enteral, 810 +/- 10 mg/kg/day parenteral), or in before or after fast ClICG, but enteral feeding produced more positive nitrogen balance. ClICG improved significantly with enteral but not with parenteral feeding. CONCLUSIONS: Enteral feeding produces faster nitrogen accrual and reverses the depression of major pathways of bilirubin and organic anion excretion associated with malnutrition. Parenteral feeding failed to improve organic anion clearance despite weight gain.

Aerosolized antimicrobial therapy in acutely ill patients.

Recent data are sparking renewed interest in therapy with aerosolized antimicrobials in critically ill patients as well as other populations such as those with neutropenia, human immunodeficiency virus infection, and cystic fibrosis. Pneumonia is a common complication in these patients and is associated with substantial morbidity and increased mortality. Clinical trials evaluated aerosolized antimicrobials for the prevention and treatment of pneumonia in hospitalized patients. In addition, factors that affect the pulmonary deposition of aerosolized drugs in mechanically ventilated patients were identified.

Intermittent and continuous ceftazidime infusion for critically ill trauma patients.

BACKGROUND: The adequacy of intermittent and continuous infusion ceftazidime for the treatment of nosocomial pneumonia in critically ill trauma patients was assessed by analyzing ceftazidime pharmacokinetics in relation to the minimum inhibitory concentration (MIC) and treatment outcome. METHODS: Serial blood samples were obtained during ceftazidime therapy in 31 trauma patients. Ceftazidime pharmacokinetics were compared with that of previously studied healthy volunteers. Ceftazidime pharmacokinetics were analyzed according to the time above the MIC and treatment outcome. RESULTS: Critically ill trauma patients had a significantly increased volume of distribution and clearance (0.32 +/- 0.14 L/kg and 2.35 +/- 0.89 mL. min(-1). kg(-1), respectively) compared with healthy volunteers (0.21 +/- 0.03 and 1.58 +/- 0.23 mL. min(-1). kg(-1)). The time above the MIC was >/=92% of the dosing interval for all patients and treatment outcomes were similar between the two treatment groups. CONCLUSIONS: Ceftazidime pharmacokinetics are significantly altered in critically ill trauma patients. Both intermittent and continuous ceftazidime regimens were equally effective for the treatment of nosocomial pneumonia caused by less virulent bacteria.

Use of limited color-flow duplex for a carotid screening project.

BACKGROUND: Although the efficacy of carotid endarterectomy for asymptomatic carotid stenosis has been established, no cost-effective approach for identification of these patients has yet been devised. The purpose of this study was to develop a limited carotid duplex screening examination to be utilized for the detection of asymptomatic carotid stenoses. METHODS: Carotid screening examinations employed rapid identification of the carotid bifurcation using color-flow duplex imaging and an immediate Doppler-derived velocity of the segment of the internal carotid artery with the most turbulent flow. Complete examinations were then finished using well-established protocols in our accredited vascular laboratory. A total of 512 patients were referred for complete studies based upon standard indications. Criteria for at least a 50% internal carotid artery stenosis on the complete examination was defined as a peak systolic velocity (PSV) of at least 125 cm/sec. Receiver operator characteristic (ROC) curves were then constructed to identify the optimal screening velocity criteria as compared with the final results on the complete examination. RESULTS: Five screening examinations were technically limited yielding a total of 507 patients with 1,014 carotid arteries available for analysis. Comparison of screening examinations versus complete examinations for a PSV of 125 cm/sec yielded sensitivity 86%, specificity 98%, positive predictive value (PPV) 95%, and a negative predictive value (NPV) 93%. ROC analysis identified a "cut point" of 115 cm/sec on the screening examinations to achieve sensitivity 91%, specificity 95%, PPV 89%, and NPV 96%. Time to perform screening examinations averaged 3.2 minutes per patient. Three patients had common carotid lesions not identified on the limited internal carotid screening examinations. CONCLUSIONS: Screening carotid examinations are a rapid, reliable, and relatively inexpensive method for detection of patients with asymptomatic internal carotid artery stenosis. Limited screening examinations should be developed in each vascular laboratory and utilized in high-risk patients.

Bioavailability of dyphylline and dyphylline-guaifenesin tablets in humans.

A six-way-crossover bioavailability study was conducted with twelve healthy male volunteers to evaluate the relative bioavailability of three tablet formulations containing dyphylline and three tablet formulations containing dyphylline-guaifenesin. Each subject was administered two tablets of each product with greater than or equal to 3 d separating each dose. Blood samples were obtained just prior to each dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0 h following each dose. An HPLC method was used to assay dyphylline in the serum. The mean tmax ranged from 0.6 to 1.0 h for the six products. The mean values for Cmax differed by 29%, and the AUC values differed by less than 8%. It was noted that the dyphylline-guaifenesin products exhibited a lower bioavailability than the products which only contained dyphylline. It was concluded that the three combination products were bioequivalent, as were the three dyphylline products.

Impact of correlated factors on bone density in individuals with a family history of osteoporosis.

Previous studies have suggested that 14-47% of the variation in bone mineral density (BMD) can be predicted using clinical risk factors. The aim of our study was to determine, for the first time, the importance of these factors in individuals with evidence of a genetic predisposition to the disease. The subjects studied were 147 female and 86 male Caucasians, all with a family history of osteoporosis. Linear regression was used to determine whether age, height, weight, and years of reduced estrogen exposure were significant predictors of BMD. Males and females were examined separately, and BMD was measured at the hip and spine. The results show that these risk factors, known to be at work in the general population, are equally important in those with a family history of osteoporosis. It is clear, therefore, that they must be taken into account, and corrected for in genetic studies of the disease.

A brief mental fatigue questionnaire.

A brief mental fatigue questionnaire was administered to normal subjects and muscle-diseased, Chronic Fatigue Syndrome (CFS), recovered CFS and depressed patients. The questionnaire was found to have excellent internal consistency and discriminated effectively between CFS and depressed patients on the one hand and recovered CFS, normal and muscle-diseased patients on the other. However, the scale failed to discriminate between CFS and depressed subjects, who were found to experience qualitatively and quantitatively similar mental fatigue symptoms.

A prospective study comparing i.m. ketorolac with i.m. meperidine in the treatment of acute biliary colic.

Ketorolac is a nonsteroidal anti-inflammatory medication that is used widely for pain management. Its effects are mediated through the inhibition of prostaglandins, which makes it uniquely different from opioids in relieving pain. We conducted a randomized, prospective, double blind study of patients presenting to our Emergency Department (ED) with a diagnosis of acute biliary colic. Study patients were randomized into one of two treatment groups, meperidine 1.5 mg/kg with a maximum dose of 100 mg or ketorolac 60 mg given intramuscularly (i.m.). The patients rated their pain before and 30 min after medication on a scale of 1 to 10 using a Visual Analog Pain Scale. Overall pain relief was compared between the two groups using a two-sample t test. Thirty patients were enrolled in the study, 16 in the ketorolac group and 14 in the meperidine group. Patients ranged in age from 18 to 71 years and 6 (20%) were male. The average pain score at time 0 was 7.6 for the ketorolac group and 7.3 for the meperidine group. Pain relief at time 30 min was 3.8 in the ketorolac group and 3.9 in the meperidine group, which was not statistically different. The mean global pain score and need for an emergency cholecystectomy were similar in the two groups. Rescue medication for additional analgesia at 30 min was needed in 4 patients in the meperidine group and in 2 patients in the ketorolac group (28.6% versus 12.5%, respectively; NS). In this study of patients with acute biliary colic there was no significant difference in the pain relief achieved by using either ketorolac or meperidine.

Improving emulsification efficacy of lecithin by formulation design. I: Effect of adding a secondary surfactant.

The objective of this study was to seek improvement in the emulsification efficacy of lecithin by formulation design. A Base Emulsion was developed containing lecithin as the primary emulsifier. The lecithin concentration and method of preparation of the Base Emulsion were optimized to obtain minimum particle size and creaming of the emulsion. Selected hydrophilic and hydrophobic synthetic surfactants were evaluated as secondary emulsifiers for their ability to reduce particle size of the Base Emulsion. The selection of type and concentration of the secondary emulsifier was done by application of the HLB method. The hydrophilic emulsifiers selected were Tween 80, Tween 20, Pluronic F68, and Pluronic F127. The hydrophobic surfactants studied included Span 20, Span 80, Pluronic P103, and Pluronic P123. The median droplet size of the Base Emulsion was 2.7 microns. Addition of the hydrophilic emulsifiers caused an increase in particle size and substantial creaming of the emulsions. Addition of three of four hydrophobic surfactants resulted in particle size reduction, but the emulsions showed substantial creaming. Span 20 was found to be the most effective secondary emulsifier. The median particle size of the emulsion was 1.7 microns. These results suggest that supplementing the hydrophilic attributes of lecithin with an appropriate type and amount of hydrophobic surfactant improves the emulsion properties by applying principles of formulation design.