Early metabolic improvement following bariatric surgery in morbidly obese adolescents.

Bariatric surgery results in durable weight loss and improved comorbidities. The objectives of this study were to examine the efficacy of gastric bypass in reducing comorbid burden and improving metabolic status among morbidly obese adolescents. The medical records of 15 gastric bypass patients were retrospectively reviewed. Changes in metabolic markers were determined at baseline, 1 and 2 years post-operatively. Comparative analysis demonstrated significant improvement in weight, BMI, insulin, HbA1C, C-peptide, %B, %S, IR, cholesterol, percentile cholesterol, TG, percentile TG, HDL, percentile HDL, LDL, percentile LDL, and VLDL. Results support bariatric surgery as a treatment for morbidly obese adolescents with comorbidities.

The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury. Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A non-neointimal pattern of remodeling after mild monocrotaline-induced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-beta gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.

Pathogenetic mechanisms of impaired glucose tolerance and type II diabetes in African-Americans. The significance of insulin secretion, insulin sensitivity, and glucose effectiveness.

OBJECTIVE: To examine the significance of alterations in insulin sensitivity index (S(t)), glucose effectiveness (Sg), and beta-cell function in the pathogenesis of type II diabetes in African-Americans with varying degrees of glucose intolerance. RESEARCH DESIGN AND METHODS: A total of 154 African-Americans residing in Franklin County, Ohio, were studied. There were 101 subjects with normal glucose tolerance (NGT), 36 with impaired glucose tolerance (IGT), and 17 with type II diabetes. An oral glucose tolerance test (OGTT) was performed on each subject. S(t) and Sg were measured by insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: The mean fasting and postprandial serum glucose levels were significantly greater in the diabetic groups when compared with the IGT and NGT groups. In contrast, while fasting serum insulin and C-peptide levels tended to be greater in the type II diabetic and IGT groups, the postprandial responses were blunted at 30 min in the IGT and type II diabetic groups when compared with the NGT group. The mean acute first-phase insulin release after intravenous glucose was blunted also in the IGT and type II diabetic groups when compared with the NGT group. The S(t) was significantly lower in the IGT (1.51 +/- 0.19) and type II diabetic (0.61 +/- 0.15) groups when compared with the NGT group (2.94 +/- 0.20 x 10(-4).min-1.microU-1.ml-1). The Sg was not significantly different in the NGT (2.90 +/- 0.20), IGT (2.47 +/- 0.19), and the type II diabetic (2.35 +/- 0.15 x 10(-2)/min) groups. The glucose effectiveness at theoretical zero insulin concentration (GEZI) followed similar patterns as the Sg. Furthermore, the basal insulin effect (BIE) was significantly lower in the IGT and type II diabetic groups compared with the NGT group. In addition, the glucose decay constant (Kg) was significantly lower (P < 0.001) in the IGT (1.21 +/- 0.13) and the type II diabetic (1.07 +/- 0.12) groups when compared with the NGT group (2.03 +/- 0.10% per minute). CONCLUSIONS: Our present study demonstrates that African-American patients with IGT and mild type II diabetes have significant reduction in beta-cell function, insulin sensitivity, and BEI but have normal and intact Sg and GEZI when compared with NGT subjects. We conclude the following: 1) a reduction in Sg does not appear to play a significant role in the pathogenetic mechanism of IGT and type II diabetes in African-American patients, and 2) the intact Sg in the IGT and type II diabetic groups could serve as a compensatory mechanism for hyperglycemia in African-Americans.

History of gestational diabetes leads to distinct metabolic alterations in nondiabetic African-American women with a parental history of type 2 diabetes.

OBJECTIVE: Gestational diabetes mellitus (GDM) and positive parental history of type 2 diabetes are predictors of the future development of type 2 diabetes in several populations. However, the relative importance of parental history of diabetes and/or history of GDM as risk factors for the pathogenesis of diabetes in African-Americans remains unknown. Thus, the objectives of the present study were 1) to characterize the glucose homeostatic regulations and 2) to examine the contribution of parental history of type 2 diabetes to the potential metabolic alterations found in nondiabetic African-American women with a history of GDM (HGDM). RESEARCH DESIGN AND METHODS: We evaluated beta-cell secretion, insulin sensitivity (SI), and glucose-dependent glucose disposal (SG) in 15 glucose-tolerant African-American women with a parental history of type 2 diabetes and prior GDM (HGDM) and 35 women with a parental history of type 2 diabetes but without prior GDM (NHGDM). Fifteen healthy nonobese nondiabetic subjects without a family history of diabetes served as control subjects. Body composition was determined by bioelectrical impedance analyzer, and body fat distribution pattern was determined by waist-to-hip ratio (WHR). Insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test was performed in each subject. SI and SG were determined by the minimal model method. RESULTS: The mean age, BMI, percent body fat content, and lean body mass were not different between the subgroups of relatives with and without a history of GDM, but were greater than those of the healthy control subjects. Mean fasting and postchallenge serum glucose levels were slightly but significantly greater in the HGDM versus NHGDM subjects and the healthy control subjects. However, the 2-h glucose levels were greater in the relatives with and without GDM when compared with the healthy control subjects. In contrast, mean postprandial serum insulin responses were significantly lower between t = 30 and 120 min in the HGDM versus NHGDM groups and the healthy control subjects. The mean serum insulin levels were not different in the NHGDM subjects and healthy control subjects. During the FSIGT test, acute first-phase insulin release (t = 0-5 min) was significantly lower in the HGDM versus NHGDM groups and healthy control subjects. Mean SI was significantly (P < 0.05) lower in the HGDM versus NHGDM subjects and healthy control subjects (1.87 +/- 0.47 vs. 2.87 +/- 0.35 and 3.09 +/- 0.27 x 10(-4).min-1.[microU/ml]-1, respectively). SG was significantly lower in HGDM than NHGDM subjects and healthy control subjects (2.11 +/- 0.15 vs. 3.25 +/- 0.50 and 2.77 +/- 0.22 x 10(-2).min-1, respectively). Mean glucose effectiveness at zero insulin concentrations (GEZI) was significantly lower in the HGDM subjects when compared with the NHGDM and healthy control subjects. CONCLUSIONS: The present study demonstrates that in African-American women with a parental history of type 2 diabetes and GDM, defects in early-phase beta-cell secretion, as well as a decreased SI, SG, and GEZI, persist when compared with those without GDM. We suggest that African-American women with a positive history of GDM have additional genetic defects that perhaps differ from that conferred by a parental history of diabetes alone. Alternatively, the metabolic and hormonal milieu during GDM may be associated with permanent alterations in beta-cell function, SI, and glucose effectiveness in African-American women. These defects could play a significant role in the development of GDM, and perhaps in the subsequent development of type 2 diabetes, in African-American women.

The impact of socioeconomic status on cardiovascular risk factors in African-Americans at high risk for type II diabetes. Implications for syndrome X.

OBJECTIVE: The rate of type II diabetes in African-Americans is reaching epidemic proportions. African-Americans with type II diabetes suffer from more cardiovascular diseases (CVDs) associated with diabetes than the general population. Lower socioeconomic status (SES) and family history are often cited as contributory factors to the premature development of diabetes and CVDs in the general population. However, we are not aware of any study that has examined the relationships between SES and CVD risk factors (i.e., syndrome X) in a genetically enriched African-American population at high risk for type II diabetes. RESEARCH DESIGN AND METHODS: We studied 200 healthy first-degree relatives of African-American patients with type II diabetes (age 25-65 years, mean 42.5 +/- 8.4 years; 42 men, 158 women). Standard oral glucose tolerance test, metabolic, and anthropometric parameters, as well as questionnaires on SES, demographic characteristics, and physical activity, were obtained for each subject. SES was divided into quartiles based on annual income. To assess the impact of insulin on CVD risk, we examined clinical characteristics and metabolic parameters according to quartiles of fasting insulin concentrations. RESULTS: Clinical characteristics, including mean age, BMI, waist-to-hip ratio (WHR), percentage body fat and lean body mass, and blood pressure were not statistically different among SES quartiles. There were no significant differences in any of the metabolic, blood pressure, lipid and lipoprotein, or anthropometric parameters among SES quartiles. When examined by insulin quartile, BMI, WHR, and body fat content tended to be greatest in the fourth quartile. Similarly, fasting and postprandial serum C-peptide and glucose levels were significantly higher in the fourth quartile. We observed greater levels of very low density lipoprotein (VLDL) cholesterol and triglycerides and lower levels of HDL cholesterol in the fourth compared with the first through third insulin quartiles. Serum cholesterol and LDL cholesterol were not associated with increasing insulin concentration assessed by quartiles. We found similar systolic and diastolic blood pressure, irrespective of insulin quartiles. We found relationships between fasting insulin and systolic blood pressure (r = 0.181, P < 0.05) and triglycerides (r = 0.247, P < 0.01), VLDL cholesterol (r = 0.237, P < 0.01), WHR (r = 0.268, P < 0.005), BMI (r = 0.308, P < 0.001), and percentage of body fat (r = 0.237, P < 0.01). CONCLUSIONS: The present study demonstrates no SES/income effect on CVD risk factors or syndrome X in African-Americans at high risk for type II diabetes. Clustering of several components of syndrome X was seen in individuals in the highest quartiles compared with the lowest quartiles of insulin in our high-risk African-American population. We conclude that the well-established conventional risk factors for CVD in genetically enriched African-Americans are found only in individuals with the highest insulin levels, independent of SES.

Precedents for meaningful recovery during treatment in a medical intensive care unit. Outcome in patients with hematologic malignancy.

The medical records of 77 patients with hematologic malignancy who were admitted to a medical intensive care unit over a 21-month period were reviewed. The overall hospital mortality rate was 80 percent. Sixteen patients (21 percent) were discharged from the intensive care unit but eventually died in the hospital. The cause of death was the result of a new problem in only three of these 16 patients. Hypotension (shock) and acute respiratory failure were the reasons prompting admission to the intensive care unit in 75 percent, but death in the intensive care unit was almost always the result of intractable hypotension rather than refractory hypoxemia. Only four of 52 patients who required mechanical ventilation left the hospital. In all four, the duration of ventilatory support was less than five days and the cause of respiratory failure was noninfectious in nature. Factors such as congestive heart failure, leukopenia, and abnormalities in mental status modified the hospital course, but did not alter outcome once prolonged mechanical ventilation became necessary. The data suggest that once acute respiratory failure develops in patients with lymphoma or leukemia, presumably as a result of infection, and mechanical ventilation for more than a relatively brief period is required, the prognosis is uniformly grim. Decisions to limit aggressive therapies is subsets of intensive care patients such as these should be aided by data that show a lack of precedent for meaningful recovery.

Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit.

One hundred seventy-four patients (179 admissions) were prospectively evaluated for the subsequent occurrence of upper gastrointestinal ("stress") bleeding after admission to a medical/respiratory intensive care unit. Evidence for either overt or occult gastrointestinal bleeding developed in 25 (14 percent). The group of bleeders had a higher mortality (64 percent versus 9 percent), duration of intensive care unit stay (median 14.2 versus 4.2 days), number of patients requiring mechanical ventilatory support (84 percent versus 26 percent), and duration of such support for those who required it (median 9.5 versus 4.2 days) than the group who did not bleed. In three patients, death was related to bleeding. Upon patients' admission to the intensive care unit, diagnoses of an acute respiratory illness (but not specifically chronic obstructive pulmonary disease), a malignancy, or sepsis were more common among those who subsequently bled. Of factors tested, a coagulopathy and the need for mechanical ventilation were most strongly associated with the risk of bleeding. Other factors did not add to the risk once these two were taken into account. Among patients receiving mechanical ventilation, the risk of overt bleeding was particularly low for those who required such support for less than five days (only 3 percent). It is concluded that (1) significant upper gastrointestinal bleeding occurring after medical intensive care unit admission is an uncommon event, and (2) prolonged mechanical ventilation and/or the presence of a coagulopathy are the most potent risk factors. Medical patients with either of the latter conditions are most likely to benefit from prophylaxis regimens against "stress"-induced upper gastrointestinal bleeding.

The effects of regional pulmonary blood flow on protein flux measurements with PET.

We used PET to evaluate whether changes in regional pulmonary blood flow (PBF) or plasma volume (PV) affect calculations of the pulmonary transcapillary escape rate (PTCER) for 68Ga-labeled transferrin. We reduced PBF in five dogs by inflating a right atrial balloon. Regional PBF decreased 25% to 174 +/- 40 ml/min/100 ml lung without a change in PV or PTCER. In eight other dogs, we decreased PBF and PV via controlled arterial hemorrhage. PBF decreased 45% to 110 +/- 33 ml/min/100 ml lung and PV decreased 22% without a change in PTCER. We also used a series of computer simulations to evaluate the effect of even greater reductions in regional PBF on PTCER calculations. These simulations showed, in support of the experimental data, that if PBF was greater than 40 ml/min/100 ml lung, PTCER could be accurately measured. However, below this level, PV was increasingly under-estimated and PTCER overestimated. The results indicate the sensitivity of the PTCER calculation to errors in the PV measurement, especially in regions of markedly reduced regional PBF.

Regional lung water measurements with PET: accuracy, reproducibility, and linearity.

We evaluated the accuracy, reproducibility, and linearity of lung water concentration (LWC) measurements using positron emission tomography (PET) in anesthetized supine dogs. First, we evaluated whether errors in attenuation correction, which might occur during the development of pulmonary edema, significantly affect LWC and pulmonary blood flow (PBF) measurements obtained with PET. In 10 animals, PET scans of LWC and PBF were obtained before and after oleic acid induced lung injury. Changes in LWC and PBF after injury were underestimated by 12%-25% if the postinjury LWC scan was reconstructed using attenuation data obtained prior to injury, before lung density had changed, instead of attenuation data obtained after lung injury. Next, in four other dogs, we did not administer oleic acid, but instead instilled progressive amounts of autologous plasma into the left caudal lobe and obtained LWC measurements after each. Changes in LWC were linearly related to the amount of plasma instilled (r = 0.99). The average coefficient of variation for LWC in the control right lobe was 4 +/- 2% and the average percent change between measurements was 1.5% +/- 5.8%. The correlation of regional LWC determined gravimetrically after the last scan, when corrected for differences in regional lung density, with LWC determined by PET, was excellent (r = 0.92). We conclude that when the correct attenuation scan is used for emission scan reconstruction. PET measurements of LWC are accurate, linear, and reproducible.

Measurement of regional pulmonary blood flow with PET.

UNLABELLED: We have previously reported a method for measuring regional pulmonary blood flow (PBF) in experimental animals using 15O-water and PET. The method requires withdrawing blood from the pulmonary artery during the PET scan, so that the input function can be estimated for the one-compartment model used to analyze the data. The purpose of the present study was to modify and validate this technique for a more general use in humans. METHODS: PBF was measured after injections of 15O-water in 15 normal subjects and in five patients with reduced cardiac output. In ten of the normal subjects, PBF was also measured after the injection of 68Ga-albumin macroaggregates (MAA). In the five other normal subjects and in the cardiomyopathy patients, PBF was measured twice after two separate 15O-water administrations. The input function was estimated from a region of interest (ROI) over the right ventricle (RV), with corrections when necessary, for time delays between RV and lung tissue. RESULTS: The mean value for PBF in the normal subjects was 121 +/- 32 ml/min/100 ml lung, and was 57 +/- 33 ml/min/100 ml lung in the patients with cardiomyopathy. The correlation between PBF measured with 15O-water and PBF measured with 68Ga-MAA was r = 0.96. There was no significant difference in the mean value for PBF or the ventral-dorsal distribution of PBF when sequential measurements were made in the same individual. PBF increased in general in the ventral-dorsal direction in these supine subjects, although PBF was more evenly distributed in the cardiomyopathy patients. CONCLUSION: Measurement of regional PBF with 15O-water and PET appears to be a valid, noninvasive approach for evaluating the pulmonary perfusion pattern of humans.

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin.

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(68Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of [68Ga]citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escape rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.

The evaluation of lung function with PET.

In many ways, the lung is an ideal organ for study with positron emission tomography (PET). First, structure-function relations are homogeneous over larger areas than in other organs (reducing problems associated with otherwise relatively poor spatial resolution and partial-volume averaging). Second, many physiologic and metabolic processes can be studied, including pulmonary blood flow, ventilation, vascular permeability, endothelial receptor and enzyme function, among others. A variety of radiotracers have been used to evaluate pulmonary blood flow with PET, including 68Ga- or 11C-albumin microspheres administered intravenously, H2 15O administered by i.v. infusion, and 13N-N2 administered by inhalation. Pulmonary ventilation has been evaluated with both 13N-N2 and 19Ne gas, also administered by inhalation. In general, the relative advantage of one approach over another depends on site-specific cyclotron capacity and experience, and on the nature and timing of concomitant studies with other positron-emitting radiopharmaceuticals. The various blood flow methods have been used primarily in studies of pulmonary gas exchange, in both experimental animals and in humans. Acute lung injury is usually defined by both an increase in extravascular water (pulmonary edema) and an increase in the permeability of the pulmonary endothelium to protein. Both processes can easily be evaluated with PET. Extravascular water is measured by a combination of scans with i.v. H2 15O and C15O. The latter is administered by inhalation to label the blood pool (to calculate intravascular water concentrations). Pulmonary vascular permeability has been evaluated with dynamic sequential imaging after either 68Ga-transferrin or 11C-methylalbumin infusions. The rate of uptake of either tracer into the pulmonary extravascular space is an index of "leakiness" of the pulmonary endothelium, and is quantified as the pulmonary transcapillary escape rate, or PTCER. PTCER appears to be a highly sensitive index of acute lung injury. Two receptor/ enzyme systems that have been evaluated include the beta-adrenergic receptor system (using 11CGP-12177 as the ligand) and angiotensin converting enzyme (using 18F-fluorocaptopril). In each case, the object is to measure Bmax, or the maximum binding-capacity for the ligand in question. Changes in Bmax can be used to infer changes in protein expression of the receptor or enzyme, or can be used to quantify adequacy of therapy with inhibitor drugs. Given the highly active nature of the pulmonary endothelium, it is likely that many other pulmonary receptor or enzyme systems can be studied in a similar fashion.

Temporary muscle paralysis for accurate measurement of pulmonary artery occlusion pressure.

Succinylcholine, a short-acting neuromuscular blocking agent, was used to accurately measure the pulmonary artery occlusion pressure (PAOP) in eight patients requiring mechanical ventilation for acute respiratory failure, in whom measurement was difficult because of significant respiratory variation in PAOP. The mean decrease in PAOP after paralysis was 9.8 +/- 5.3 mm Hg, with a range of 4 to 20 mm Hg (p less than 0.01). The magnitude of change was closely correlated to the degree of respiratory variation in PAOP observed during spontaneous breathing before paralysis (r = 0.889). Accurate measurement of PAOP affected subsequent management in five of these eight patients. Temporary muscle paralysis with succinylcholine is a useful means of eliminating artifactual elevations in PAOP in patients supported by mechanical ventilation when significant respiratory variation in PAOP is present.

High-frequency jet ventilation during the treatment of acute fulminant pulmonary edema.

High-frequency jet ventilation (HFJV) was used during the treatment of fulminant pulmonary edema in a 45-year-old man so that toxic levels of oxygen could be avoided when conventional methods of ventilation in combination with high levels of PEEP (20 cm H2O) were unsuccessful in raising PaO2. On each of four occasions, HFJV resulted in improved arterial oxygenation when compared with conventional modes.

Fluid balance during pulmonary edema. Is fluid gain a marker or a cause of poor outcome?

STUDY OBJECTIVE: To evaluate the importance of fluid balance and changes in extravascular lung water (EVLW) on survival in the ICU and short-term outcome in patients with pulmonary edema. DESIGN: Retrospective analysis of data (sorting by survival and "treatment received") from a recent randomized controlled trial of fluid restriction in this population. SETTING: Medical ICU of a university-affiliated, tertiary-care medical center. PATIENTS: Eighty-nine patients (from the previously mentioned study) requiring pulmonary artery catheterization with abnormally high EVLW (greater than 7 ml/kg). MEASUREMENTS AND RESULTS: When analyzed by survival, the survivors had no significant fluid gain or change in EVLW but decreased wedge pressure and body weight, compared to nonsurvivors. When analyzed by fluid balance, patients who gained less than 1 L of fluid by 36 hours into the study had a better rate of survival (74 percent) than the rest (50 percent; p less than 0.05). Also, the median duration of days on the ventilator, ICU days, and days of hospitalization was approximately half as long for each variable in the group with less than 1 L of fluid gain. Even accounting for baseline differences in the severity of illness, fluid balance was an independent predictor of survival (p less than 0.05). When analyzed by whether or not EVLW decreased by more than 15 percent between the first and last measurement, only patients with ARDS or sepsis had decreased days on the ventilator and ICU days. CONCLUSIONS: These data support the concept that positive fluid balance per se is at least partially responsible for poor outcome in patients with pulmonary edema and defend the strategy of attempting to achieve a negative fluid balance if tolerated hemodynamically.

Clinical correlation with changing radiographic appearance during partial liquid ventilation.

STUDY OBJECTIVES: To evaluate the chest radiographic filling pattern associated with partial liquid ventilation (PLV) with the perfluorochemical perflubron (LiquiVent; Alliance Pharmaceutical Corp; San Diego CA) as a function of dose and timing. DESIGN: Post hoc review of chest radiographs by three independent observers with correlation to clinical variables. SETTING: Phase II randomized, uncontrolled, prospective, multicenter clinical trial. PATIENTS: Sixteen adult patients with diffuse bilateral infiltrates consistent with acute lung injury and a PaO(2)/fraction of inspired oxygen (FIO(2)) ratio < 300 with positive end-expiratory pressure of 13 cm H(2)O and FIO(2) > or = 0.5. INTERVENTIONS: All patients were treated with either a 10-mL/kg or 20-mL/kg loading dose of perflubron followed by maintenance dosing at 3-h intervals to protocol-determined levels. RESULTS: There was a significant relationship between inhomogeneous radiographic filling during the first 48 h of treatment and the use of the lower loading dose of perflubron. Inhomogeneous radiographic filling (in 5 patients) was associated with a lower high-dose/FIO(2) ratio at 24 h compared with the remaining patients. These differences resolved by 48 h. There were no other statistically significant correlations identified. CONCLUSIONS: The radiographic appearance of PLV with perflubron appears to depend on the dose administered. Lower doses can be associated with both inhomogeneous radiographic filling and a transient deterioration in oxygenation during the first 24 to 48 h of treatment.

Effects of race and ethnicity on insulin sensitivity, blood pressure, and heart rate in three ethnic populations: comparative studies in African-Americans, African immigrants (Ghanaians), and white Americans using ambulatory blood pressure monitoring.

We sought to examine the association of insulin, insulin sensitivity, and blood pressure using ambulatory blood pressure monitor in three ethnically distinct populations. The study population comprised the following. Group 1 (n = 31): African-Americans; Group 2 (n = 27): recent African immigrants; and Group 3 (n = 31): white Americans who were residing in Franklin County, Ohio. Quantitative insulin sensitivity index (Si) was obtained using the minimal model method in both groups of African ancestry and white Americans. The mean insulin sensitivity index (Si) was similar in the African-Americans (3.23 +/- 0.47 x (10)-4 x [min-l x microU/mL (-1)])(-l) and African immigrants (2.53 +/- 0.27). However, these Si values were significantly (P < .01) lower in people of African ancestry than in white Americans (6.56 +/- 1.07). The mean systolic (SBP) and diastolic blood pressure (DBP) and heart rates (HR) during 24-h and daytime periods were not significantly different in the African-Americans and African immigrants. During the night, whereas the mean SBP was not different in the three groups, DBP and HR were significantly (P < .05) higher in both groups of African ancestry than in white Americans. However, we found no significant relationships among serum insulin levels, insulin sensitivity, and ambulatory blood pressure (systolic and diastolic and mean arterial pressure) and heart rates in any of the groups. In summary, our present study demonstrates that people of African ancestry manifest 1) significantly lower insulin sensitivity indices and 2) blunted physiologic reduction in nocturnal DBP and HR when compared to white Americans who reside in the same environment. We speculate that these chronobiological alterations in BP and HR in blacks appear to be genetically determined.

Characterization of alterations in glucose and insulin metabolism in Prader-Willi subjects.

Obesity is a common component of non-insulin-dependent diabetes mellitus (NIDDM) and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi syndrome (PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. It has been assumed that the etiology for this increased rate of NIDDM is related to the morbid obesity and concomitant insulin resistance, but this remains controversial. To shed light on the glucoregulatory mechanisms in PWS, we studied both pediatric and adult PWS patients with normoglycemia. The objectives of our study were (1) to examine glucose, insulin, and C-peptide responses to oral (OGTT) and intravenous (IVGTT) glucose tolerance tests; (2) to characterize acute first- and second-phase insulin secretion during an IVGTT; (3) to assess hepatic insulin extraction (HIE) and insulin clearance (IC) in PWS subjects; and (4) to determine whether beta-cell function in PWS is age-dependent. These results in PWS were compared with values obtained in age-, sex-, and body mass index (BMI)-matched non-PWS obese controls. Three groups were studied. Group I consisted of nine PWS subjects under the age of 13 years and 22 age-, sex-, weight-, and puberty stage-matched obese subjects who underwent OGTT. Group II consisted of 14 adult PWS subjects and 10 age-, weight-, and BMI-matched obese adults who underwent OGTT. Group III consisted of nine adult PWS subjects and eight age-, sex-, and weight-matched obese adults who underwent frequently sampled IVGTT (FSIVGTT). During the OGTT in the pediatric group, fasting (86 +/- 3 v 89 +/- 2 mg/dL), peak (144 +/- 11 v 147 +/- 4 mg/dL), and total area under the curve (AUC) (6,984 +/- 1,320 v 6,963 +/- 615 mg/dL x min) glucose levels were not significantly different in PWS versus obese children, respectively. In contrast, fasting (20 +/- 6 v 37 +/- 4 microU/mL), peak (114 +/- 24 v 214 +/- 23 microU [correction of mU]/mL), and total AUC (12,673 +/- 2,176 v 26,734 +/- 2,608 microU/mL microU/mL min) insulin levels were significantly lower in pediatric PWS. During the OGTT in the adult groups, neither fasting insulin (16.7 +/- 2.8 v 13.5 +/- 2.5 microU/mL) nor total AUC for insulin (10,664 +/- 1,955 v 11,623 +/- 1,584 microU/mL x min) were significantly different in adult PWS and obese groups. During the IVGTT in adults, both first-phase (138 +/- 42 v 454 +/- 102 microU/mL x min) and second-phase (295 +/- 66 v 1,015 +/- 231 microU/mL x min) insulin release were significantly reduced in PWS subjects despite similar glucose levels. Similarly, first-phase (8.6 +/- 2.3 v 21 +/- 4.6 ng/dL x min) and second-phase (47 +/- 4.6 v 75 +/- 14 ng/dL x min) C-peptide responses were also significantly reduced in PWS subjects. In contrast, mean HIE and IC was 33% higher in PWS subjects versus obese controls (15.4 +/- 1.5 v 10.3 +/- 1.6). Similarly, poststimulation HIE and IC was significantly greater (5.2 +/- 0.8 v 2.4 +/- 0.4) in the PWS group compared with the obese group (P < .01). In summary, this study demonstrates that nondiabetic PWS subjects manifest (1) a reduced beta-cell response to glucose stimulation, (2) a significantly increased HIE compared with obese controls, and (3) a dissociation of obesity and insulin resistance, in contrast to normal obese subjects. We conclude that glucoregulatory mechanisms are different in obese PWS versus non-PWS subjects.

Race and ethnicity determine serum insulin and C-peptide concentrations and hepatic insulin extraction and insulin clearance: comparative studies of three populations of West African ancestry and white Americans.

We examined the importance of ethnicity in terms of beta-cell secretion and hepatic insulin extraction (HIE) and insulin clearance (IC) to peripheral insulin levels before and after stimulation in three populations of West African ancestry, namely African-Americans, Ghanaian immigrants, and native Ghanaians living in diverse environments, and white Americans. Following 10 to 12 hours of overnight fasting, each subject ingested a 75-g oral glucose load. Blood samples for determination of serum glucose, insulin, and C-peptide were obtained at baseline and after the oral glucose load at 30-minute intervals for 240 minutes. Basal HIE and IC were calculated as the molar ratios of C-peptide and insulin concentrations at basal steady state, and postprandial values as molar ratios of the incremental integrated C-peptide and insulin areas. Clinical characteristics of the patients were not significantly different among the four groups. During the fasting and postprandial state, serum glucose levels were not significantly different among the four groups. Surprisingly, the mean fasting insulin concentration was significantly greater in native Ghanaians (21.19 +/- 0.93 microU/mL, P < .05) than in African-Americans (11.90 +/- 1.02,microU/ML), Ghanaian immigrants (8.14 +/- 0.96 microU/mL), and white Americans (7.03 +/- 0.78 microU/mL). Following the oral glucose load, the mean serum peak and incremental integrated areas of insulin were significantly (P < .05) greater in native Ghanaians, African-Americans, and Ghanaian immigrants compared with white Americans. In contrast, there were no significant differences in postprandial serum insulin responses among the three groups of West African ancestry, irrespective of country of origin or residence. Despite the higher insulin concentrations in blacks of West African ancestry compared with whites, the corresponding basal and postprandial serum C-peptide levels were not significantly different among the four groups. Mean basal and postprandial HIE and IC were significantly (P < .05 to .01) reduced (25% to 52%) in the three populations of West African ancestry compared with the white Americans, but these values were not significantly different among the West African descendants. When comparing metabolic responses in obese (body mass index [BMI] > 27 kg/m2) and non-obese (BMI < 27 kg/m2) native Ghanaians, we found no significant differences in fasting insulin, C-peptide, and basal HIE or IC. Also, there were no significant relations between fasting and postprandial serum insulin, obesity indices, and HIE and IC in any of the groups. In summary, our study demonstrates that glucose-tolerant native Ghanaians, Ghanaian immigrants, and African-Americans of West African ancestry manifest hyperinsulinemia and a decreased HIE and IC compared with white Americans. We conclude that race and ethnicity may be the major determinants of the mechanism(s) of beta-cell secretion, insulin action, and peripheral insulin levels and HIE or IC in humans. We speculate that the lower HIE and IC in blacks of West African descent appears to be a highly conserved metabolic trait irrespective of the country of residence.

Pulmonary blood flow distribution after lobar oleic acid injury: a PET study.

We evaluated the importance of hypoxic vasoconstriction as a mechanism for pulmonary blood flow reduction during unilobar oleic acid lung injury in dogs. Pulmonary blood flow (PBF) and lung water were measured with positron emission tomography. Data from the injured left (LCL) and right (RCL) caudal lobes were compared in 23 dogs. Six dogs were used to demonstrate that endotoxin (15 micrograms/kg) prevents changes in regional PBF during selective hypoxic ventilation of the LCL. In 17 dogs, oleic acid (OA, 0.015 ml/kg) was injected into the LCL through a balloon-wedged pulmonary arterial catheter. Five dogs received OA only (control group), eight received endotoxin (15 mcg/kg) before OA was administered (endotoxin group), and four were treated with prostaglandin E1 (PGE1) after OA (PGE1 group). The base-line left-to-right PBF ratio (LCL/RCL PBF) was 1.01 +/- 0.11 (SD) for the control group and 1.07 +/- 0.16 for the PGE1 group. One minute after OA, LCL/RCL PBF feel significantly (0.32 +/- 0.15 and 0.32 +/- 0.13 for the control and PGE1 groups, respectively) before any significant increase in lung water was detected. In all 17 dogs that received OA, the LCL/RCL PBF remained severely reduced 60 min after OA compared with base-line values (0.41 +/- 0.15, 0.49 +/- 0.06, and 0.26 +/- 0.13 for the control, PGF1, and endotoxin groups, respectively) despite treatment with endotoxin or PGE1. Lung water measurements obtained 60 min after OA increased significantly (P less than 0.05) in the injured lobe (LCL) but not in the normal lobe (RCL) in all dog groups, whereas PBF to the LCL remained significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)