Qualitative and quantitative performance of ¹8F-FDG-PET/MRI versus ¹8F-FDG-PET/CT in patients with head and neck cancer.

BACKGROUND AND PURPOSE: MR imaging and PET/CT are integrated in the work-up of head and neck cancer patients. The hybrid imaging technology (18)F-FDG-PET/MR imaging combining morphological and functional information might be attractive in this patient population. The aim of the study was to compare whole-body (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT in patients with head and neck cancer, both qualitatively in terms of lymph node and distant metastases detection and quantitatively in terms of standardized uptake values measured in (18)F-FDG-avid lesions. MATERIALS AND METHODS: Fourteen patients with head and neck cancer underwent both whole-body PET/CT and PET/MR imaging after a single injection of (18)F-FDG. Two groups of readers counted the number of lesions on PET/CT and PET/MR imaging scans. A consensus reading was performed in those cases in which the groups disagreed. Quantitative standardized uptake value measurements were performed by placing spheric ROIs over the lesions in 3 different planes. Weighted and unweighted κ statistics, correlation analysis, and the Wilcoxon signed rank test were used for statistical analysis. RESULTS: κ statistics for the number of head and neck lesion lesions counted (pooled across regions) revealed interreader agreement between groups 1 and 2 of 0.47 and 0.56, respectively. Intrareader agreement was 0.67 and 0.63. The consensus reading provided an intrareader agreement of 0.63. For the presence or absence of metastasis, interreader agreement was 0.85 and 0.70. The consensus reading provided an intrareader agreement of 0.72. The correlations between the maximum standardized uptake value in (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT for primary tumors and lymph node and metastatic lesions were very high (Spearman r = 1.00, 0.93, and 0.92, respectively). CONCLUSIONS: In patients with head and neck cancer, (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT provide comparable results in the detection of lymph node and distant metastases. Standardized uptake values derived from (18)F-FDG-PET/MR imaging can be used reliably in this patient population.

Murine models of chronic Pseudomonas aeruginosa lung infection.

The animal model of chronic bronchopulmonary infection using agarose beads laden with Pseudomonas aeruginosa is frequently utilized in cystic fibrosis research, though it is challenging to perform it in mice. This paper reports the most successful methods for the creation of this model. Transtracheal insertion of a 22 G 1" over-the-needle intravenous catheter to preferentially inoculate the right mainstem bronchus using tribromoethanol anaesthesia administered i.p. was better for a successful surgical outcome compared, respectively, to the use of a 27 G (1/2)" needle, bilateral inoculation or an anaesthetic cocktail of xylazine, acepromazine and ketamine administered i.p. Bilateral infection was associated with higher mortality, greater weight loss and higher levels of bronchoalveolar cytokine concentration, compared to mice infected primarily in the right lung. Mucoid clinical strain PA M57-15 was preferred since mucoid clinical strain PA 2192 led to comparatively more severe lesions and higher mortality. Using the same operator for a given task reduced the variability inherent in this model, illustrated using outcome measures such as gross lung pathology. The response of mice inoculated with P. aeruginosa-laden agarose beads was characterized by bronchopulmonary inflammation, high production of cytokines, and significant weight loss; whereas the response to infection with free-living bacteria was characterized by pneumonia, lower production of cytokines and weight loss. The use of free P. aeruginosa pre-mixed with sterile agarose beads may be considered as an alternative to the use of P. aeruginosa-laden agarose beads, since the histopathological features were similar, though further characterization is needed to evaluate its utility as an adequate model of cystic fibrosis.

Reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function: the prospective P(2)C(2) HIV study.

BACKGROUND: To assess the reliability of pediatric echocardiographic measurements, we compared local measurements with those made at a central facility. METHODS AND RESULTS: The comparison was based on the first echocardiographic recording obtained on 735 children of HIV-infected mothers at 10 clinical sites focusing on measurements of left ventricular (LV) dimension, wall thicknesses, and fractional shortening. The recordings were measured locally and then remeasured at a central facility. The highest agreement expressed as an intraclass correlation coefficient (ICC=0.97) was noted for LV dimension, with much lower agreement for posterior wall thickness (ICC=0.65), fractional shortening (ICC=0.64), and septal wall thickness (ICC=0.50). The mean dimension was 0.03 cm smaller in central measurements (95% prediction interval [PI], -0.32 to 0.25 cm) for which 95% PI reflects the magnitude of differences between local and central measurements. Mean posterior wall thickness was 0.02 cm larger in central measurements (95% PI, -0.18 to 0.22 cm). Mean fractional shortening was 1% smaller in central measurements. However, the 95% PI was -10% to 8%, indicating that a fractional shortening of 32% measured centrally could be anywhere between 22% and 40% when measured locally. Central measurements of mean septal thickness were approximately 0.1 cm thicker than local ones (95% PI, -0.18 to 0.34 cm). Centrally measured wall thickness was more closely related to mortality and possibly was more valid than local measurements. CONCLUSIONS: Although LV dimension was reliably measured, local measurements of LV wall thickness and fractional shortening differed from central measurements.

Respiratory diseases in the first year of life in children born to HIV-1-infected women.

Our objective was to describe the respiratory complications, clinical findings, and chest radiographic changes in the first year of life in infected and uninfected children born to HIV-1-infected women. We prospectively followed a cohort of 600 infants born to HIV-1-infected women from birth to 12 months in a multicenter study. Of these, 93 infants (15.5%) were HIV-1-infected, 463 were uninfected, and 44 were of unknown status prior to death or loss to follow-up. The cumulative incidence ( +/- SE) of an initial pneumonia episode at 12 months was 24.1 +/- 4.7% in HIV-1-infected children compared to 1.4 +/- 0.6% in HIV-1-uninfected children (P < 0.001). The rate of Pneumocystis carinii pneumonia (PCP) was 9.5 per 100 child-years. The HIV-1 RNA load was not higher in the group that developed pneumonia in the first year vs. those who did not. Children who developed lower respiratory tract infections or PCP had increased rates of decline of CD4 cell counts during the first 6 months of life. Lower maternal CD4 cell counts were associated with higher rates of pneumonia, and upper and lower respiratory tract infections. The rates of upper respiratory tract infection and bronchiolitis/reactive airway disease in infected children were not significantly different than in uninfected children. At 12 months, significantly more HIV-1-infected than uninfected children had tachypnea and chest radiographs with nodular and reticular densities. There was no relationship between cytomegalovirus infection in the first year of life and radiographic changes or occurrences of pneumonia. In conclusion, despite a low incidence of PCP, rates of pneumonia remain high in HIV-infected children in the first year of life. The incidence of pneumonia in uninfected infants born to HIV-1-infected mothers is low. Chest X-ray abnormalities and tachypnea suggest that subacute disease is present in infected infants. Further follow-up is warranted to determine its nature.

Analysis of change in the presence of informative censoring: application to a longitudinal clinical trial of progressive renal disease.

The rate of change in a continuous variable, measured serially over time, is often used as an outcome in longitudinal studies or clinical trials. When patients terminate the study before the scheduled end of the study, there is a potential for bias in estimation of rate of change using standard methods which ignore the missing data mechanism. These methods include the use of unweighted generalized estimating equations methods and likelihood-based methods assuming an ignorable missing data mechanism. We present a model for analysis of informatively censored data, based on an extension of the two-stage linear random effects model, where each subject's random intercept and slope are allowed to be associated with an underlying time to event. The joint distribution of the continuous responses and the time-to-event variable are then estimated via maximum likelihood using the EM algorithm, and using the bootstrap to calculate standard errors. We illustrate this methodology and compare it to simpler approaches and usual maximum likelihood using data from a multi-centre study of the effects of diet and blood pressure control on progression of renal disease, the Modification of Diet in Renal Disease (MDRD) Study. Sensitivity analyses and simulations are used to evaluate the performance of this methodology in the context of the MDRD data, under various scenarios where the drop-out mechanism is ignorable as well as non-ignorable.

Thoracoabdominal compression and respiratory system compliance in HIV-infected infants.

The thoracoabdominal compression technique (TAC) is used to measure expiratory flow in infants. We investigated whether TAC caused a change in total thoracic compliance (Crs), resistance (Rrs), and respiratory system time constant (Trs). We studied 41 infants (mean age, 12.4 mo; SD, 7.5) from five centers studying longitudinal lung and cardiovascular function of infants from HIV-infected mothers. We measured Crs, Rrs, and Trs before and after TAC. Changes in Crs, Rrs, and Trs after TAC were not dependent on the length of time since TAC. Crs and Trs were reduced after TAC, p = 0.013 and p = 0.003, respectively, whereas Rrs did not change. When compared with uninfected infants, HIV-infected infants had a larger post-pre TAC percent decline in Crs (p = 0.003) and a post-pre TAC rise in mean Rrs (p = 0.03). These differences remained significant after adjusting for sex and age. When performing infant pulmonary function testing, TAC itself produces a temporary decrease in Crs and Trs that is more significant in infants at risk for abnormal lung volume or compliance. Therefore, the sequence of performing the infant lung function parameters should be the same each time the testing is repeated with TAC as the last parameter tested at each testing session.

A double-blind pilot study of risperidone in the treatment of conduct disorder.

OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings.

Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV(1) decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV(1) 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV(1) decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV(1) 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments.

The losartan renal protection study--rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan).

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.

Cardiac complications in children with human immunodeficiency virus infection. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group, National Heart, Lung, and Blood Institute.

OBJECTIVE: Although numerous cardiac abnormalities have been reported in HIV-infected children, precise estimates of the incidence of cardiac disease in these children are not well-known. The objective of this report is to describe the 2-year cumulative incidence of cardiac abnormalities in HIV-infected children. DESIGN: Prospective cohort (Group I) and inception cohort (Group II) study design. SETTING: A volunteer sample from 10 university and public hospitals. PARTICIPANTS: Group I consisted of 205 HIV vertically infected children enrolled at a median age of 22 months. This group was comprised of infants and children already known to be HIV-infected at the time of enrollment in the study. Most of the children were African-American or Hispanic and 89% had symptomatic HIV infection at enrollment. The second group included 611 neonates born to HIV-infected mothers, enrolled during fetal life or before 28 days of age (Group II). In contrast to the older Group I children, all the Group II children were enrolled before their HIV status was ascertained. INTERVENTIONS: According to the study protocol, children underwent a series of cardiac evaluations including two-dimensional echocardiogram and Doppler studies of cardiac function every 4 to 6 months. They also had a 12- or 15-lead surface electrocardiogram (ECG), 24-hour ambulatory ECG monitoring, and a chest radiograph every 12 months. OUTCOME MEASURES: Main outcome measures were the cumulative incidence of an initial episode of left ventricular (LV) dysfunction, cardiac enlargement, and congestive heart failure (CHF). Because cardiac abnormalities tended to cluster in the same patients, we also determined the number of children who had cardiac impairment which we defined as having either left ventricular fractional shortening (LV FS) 2) at the time of the first echocardiogram was 8. 3%. The cumulative incidence of LV end-diastolic enlargement was 11. 7% after 2 years. The cumulative incidence of CHF and/or the use of cardiac medications was 10.0% in Group I children. There were 14 prevalent cases of cardiac impairment (LV FS

Unexpected non-HIV causes of death in children born to HIV-infected mothers. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group.

INTRODUCTION: A high incidence of sudden, unexplained deaths in infants born to HIV-infected mothers has been noted in several epidemiologic studies. During the course of a prospective study of heart and lung disease in children born to HIV-infected mothers, we noted that of 5 unexpected non-HIV-related deaths, 4 were attributed to traumatic events. METHODS: The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2) study is a multicenter, prospective investigation of the incidence of heart and lung disease in HIV-infected children. A total of 805 children were enrolled and followed for 5 to 7 years with serial immunologic, pulmonary and cardiac function studies. During the study, a multidisciplinary committee was formed to review the cause of death for those patients who died. The committee used results of pulmonary, cardiac, and laboratory tests, hospital summaries, as well as autopsy and coroners' reports. The committee formed a consensus about the underlying and contributing causes of death for each subject using the definitions from the 1989 US Standard Certificate of Death. RESULTS: A total of 121 deaths occurred during the course of the P2C2 study. Of the 121 deaths, 5 were traumatic or sudden and unexpected and judged by the Mortality Review Committee to be unrelated to HIV infection. The median age at the time of death was 1.3 months and ranged from 1.2 to 37.8 months. Two infants died of trauma: a skull fracture and subdural hematoma in 1 infant and multiple skeletal fractures consistent with battered child syndrome in the other infant. The third infant died of accidental suffocation at home at 1.2 months of age. The fourth infant died suddenly and unexpectedly at home at 1.3 months of age. The autopsy showed no sign of HIV or other infection and was consistent with sudden unexpected death or SIDS. One non-HIV-related death occurred when a 38-month-old child died together with the mother in an unwitnessed drowning. The cumulative mortality rate attributable to trauma and sudden death at 4 months of age was 0.95% (95% CI: 0.02-1. 87%) and the infant mortality rate was 9.5/1000 live births. Three children were born prematurely at 30, 33, and 36 weeks' gestational age, respectively, and 3 mothers admitted using recreational drugs before or during pregnancy. DISCUSSION: These traumatic and sudden non-HIV-related deaths accounted for 4.1% (5/121) of the deaths during the entire P2C2 study period and for 20% (4/20) of the deaths in the first year of life. Four deaths were attributable to accidental and nonaccidental trauma rather than to other common causes of infant death. One death was a sudden unexpected death, similar to SIDS, a leading cause of infant death in the United States. The majority of previously reported non-HIV-related deaths in infants born to HIV-infected mothers have been attributed to SIDS or to unexplained sudden death. In contrast with other reports, 4 of the 5 children in our series died of accidental or nonaccidental trauma and only 1 was a sudden unexplained death. It is unlikely that HIV exposure is related directly to the deaths described in this report; however, maternal HIV infection may be a marker for factors that place the child at risk for sudden or traumatic death. SUMMARY: This report suggests that children born to HIV-infected mothers may be at increased risk for traumatic or sudden, unexplained, non-HIV-related death. These children seem to be at risk regardless of their own HIV infection status. Furthermore, 4 of the deaths in our study occurred within the first few months of life, suggesting that this is a period of increased vulnerability. Studies to identify associated risk factors for non-HIV-related deaths are needed to identify these high-risk infants. Children born to HIV-infected mothers may be more vulnerable than was recognized previously and may be in need of increased social services, especially in early infancy.

Left ventricular structure and function in children infected with human immunodeficiency virus: the prospective P2C2 HIV Multicenter Study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group.

BACKGROUND: The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood. METHODS AND RESULTS: A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area-adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up. CONCLUSIONS: Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.

Mitochondrial calcium content in isolated perfused heart: effects of inotropic stimulation.

We tested the hypothesis that in the intact heart, mitochondrial metabolism is activated by mitochondrial Ca2+ uptake during increased work. We measured left ventricular pressure (LVP), pyruvate dehydrogenase (PDH) activity, and mitochondrial and A band elemental content by electron probe microanalysis (EPMA) in Langendorff-perfused hamster hearts under control conditions, after isoproterenol (10(-6) M) stimulation, and after increasing perfusion pressure from 60 to 100 mmHg. Hearts were rapidly frozen, then EPMA was performed on cryosections cut from the surface of the frozen hearts; PDH activity was measured from the same area. Isoproterenol and elevated perfusion pressure increased LVP by 185 +/- 21 and 58 +/- 14%, respectively, versus controls. PDH activity increased from 10.4 +/- 1.5 (mean +/- SE) nmol.min-1. mg protein-1 (controls) to 21.6 +/- 3.5 (isoproterenol) and 18.5 +/- 3.2 nmol.min-1.mg protein-1 (increased perfusion pressure). There was no significant change in mitochondrial Ca1 in response to isoproterenol [1.2 +/- 0.1 (mean +/- SE) mmol/kg dry wt] or increased perfusion pressure (1.1 +/- 0.1) versus controls (1.0 +/- 0.1). These results suggest that, in the intact heart, mechanisms other than mitochondrial Ca2+ uptake may contribute to PDH activation and increased cardiac work.

Quality control of spirometry testing in the registry for patients with severe alpha1-antitrypsin deficiency. alpha1-Antitrypsin Deficiency Registry Study Group.

As part of the multicenter National Heart, Lung, and Blood Institute registry of patients with severe deficiency of alpha1-antitrypsin with 1,129 enrollees, this report describes measures undertaken to achieve high-quality FEV1 measurements, the rates of satisfying reproducibility and acceptability criteria, and clinical features of participants unable to achieve reproducible FEV1 values at baseline. Spirograms were performed both before and after an inhaled bronchodilator in enrollees followed up at 37 participating clinical centers. Using a reproducibility criterion of < 100 mL or 5% (whichever greater), high reproducibility rates for FEV1 measurements at baseline were observed for both prebronchodilator (95.0% of 1,090 sessions) and postbronchodilator measurements (95.7% of 1,077 sessions). Using the more recently published reproducibility criterion of < or = 200 mL, reproducibility rates were even higher. Eighty-four percent of clinical centers submitted FEV1 values that satisfied reproducibility criteria for at least 90% of spirograms. Also, the mean coefficient of variation for prebronchodilator FEV1 values measured over serial visits separated by up to 9 months was 5.6% for participants with baseline FEV1 55 to 90% predicted. This degree of reproducibility is similar to that observed in the Lung Health Study. Rates of satisfying acceptability criteria for prebronchodilator spirograms were lower, almost universally (98% of tests) due to failure to achieve end-of-test criteria (which usually required 15 s of expiration in this population with mean FEV1 = 42.6+/-29.6% [SD] predicted). Multivariate logistic regression models show that clinical correlates of failure to achieve reproducible prebronchodilator FEV1 efforts include symptoms of chronic wheeze, chronic cough, and chronic phlegm, and the degree of airflow obstruction. We conclude that highly reproducible FEV1 measurements are achievable in a population with severe airflow obstruction despite the additional challenges posed by testing in multiple centers on a variety of spirometers. Furthermore, the difficulty of satisfying end-of-test criteria in a large cohort with severe airflow obstruction did not preclude achieving high rates of reproducibility for FEV1 measurements. Finally, our study confirms prior observations that failure to achieve reproducible efforts is associated with the presence of pulmonary symptoms and the degree of airflow obstruction. Thus, excluding patients with nonreproducible FEV1 efforts from epidemiologic studies would bias results by including only healthier participants.

Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group.

OBJECTIVE: alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder characterized by a high risk for the development of emphysema at an early age. In 1988, the National Heart, Lung and Blood Institute, National Institutes of Health, initiated a registry of individuals with alpha 1-AT deficiency to help define the natural history and clinical course of this disorder. This article describes demographic and clinical characteristics of subjects enrolled in the Registry at baseline. DESIGN: Prospective longitudinal natural history study. SETTING: Thirty-seven clinical centers in the United States (36 centers) and Canada (one center). PATIENTS: There were 1,129 subjects 18 years of age or older with severe deficiency of alpha 1-AT, defined as having serum alpha 1-AT levels < or = 11 mumol/L confirmed by a Central Phenotyping Laboratory, or a ZZ or ZNull genotype identified by genomic DNA analysis. RESULTS: Most enrollees were symptomatic white subjects in their fourth to sixth decade, with a ZZ phenotype, a history of having smoked cigarettes, and pulmonary function tests demonstrating a pattern consistent with emphysema. Interestingly, only a small percentage were current smokers on enrollment, suggesting that this population is amenable to smoking cessation. A subgroup of individuals in the Registry with relatively normal lung function were younger, more likely to have never smoked and more likely to have come to medical attention owing to a family history of alpha 1-AT deficiency rather than symptomatic involvement. CONCLUSIONS: These results emphasize the need for increased awareness and early detection of alpha 1-AT deficiency. In this endeavor, dissemination of the information contained in the Registry to health-care professionals and the general population, along with initiation of appropriate preventative measures before significant lung damage has occurred, could have considerable benefits for individuals with this condition.

Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.

This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.

The hemodynamic responses to an intravenous test dose in vascular surgical patients.

The study was designed to investigate the hemodynamic responses to intravenous (IV) injections of various epidural test doses in vascular surgical patients to determine whether previously established criteria in healthier populations were valid in this inherently sicker population. A double-blind, prospective randomized study was performed on 50 patients, not receiving beta-adrenergic antagonists, presenting for vascular surgery and requiring an arterial line. Patients were randomly assigned to receive a 3-mL injection of one of five solutions, either saline (Group 1), lidocaine 45 mg (Group 2), lidocaine 45 mg and epinephrine 5 micrograms (Group 3), lidocaine 45 mg and epinephrine 10 micrograms (Group 4), or lidocaine 45 mg and epinephrine 15 micrograms (Group 5). After injection, a blinded observer recorded arterial blood pressure and heart rate (HR) every 15 s for 3 min. The changes in HR, systolic (SBP), mean (MBP), and diastolic (DBP) blood pressure as well as time to maximum change were analyzed both within and between groups. Only Group 5 had significant within-group changes for all hemodynamic variables measured. Only in the comparison between Groups 1 and 5 and between Groups 2 and 5 were there significant changes in both HR and SBP. The mean increase in HR and SBP within Group 5 was 17.0 +/- 5.9 bpm and 31.0 +/- 10.5 mm Hg, respectively. No differences were found between groups for time to maximum change for HR and SBP which for Group 5 were 64.5 +/- 37.4 s and 90.0 +/- 56.7 s, respectively. To achieve 100% sensitivity and specificity for HR increase, the criterion established was > or = 9 bpm.(ABSTRACT TRUNCATED AT 250 WORDS)

Evolutionary conservation of both the hydrophilic and hydrophobic nature of transmembrane residues.

An algorithm (HRG), developed to allow the pairwise comparisons of the aligned residues of several members of large gene families of polytopic integral membrane proteins is described. Using hydrophobicity scales, application of this algorithm allows the number and size of the membrane-spanning domains of bacteriorhodopsin, a polytopic protein whose structure has been partially determined, to be predicted with a high degree of accuracy (sensitivity 94%, specificity 82% for predicting the membrane embedded or extramembranous location of residues). As opposed to previously reported structure-prediction algorithms, delineation of putative transmembrane segments from connecting loops is also more clearly evident with the application of the HRG algorithm, even with proteins from widely divergent species. This indicates strong evolutionary pressure for the conservation of both the hydrophobic and hydrophilic character of residues in membrane-embedded regions of polytopic proteins, such as those of the G-protein-coupled receptor superfamily. These and other structural and functional implications evident from the application of the HRG algorithm are considered.

Measurement of subcellular Ca2+ redistribution in cardiac muscle in situ: time resolved rapid freezing and electron probe microanalysis.

To directly assess the physiological roles of sarcoplasmic reticulum (SR) and mitochondria (MT), we have utilized energy dispersive electron probe microanalysis (EPMA) on ultrathin freeze-dried cryosections from isolated papillary muscles, rapidly frozen at precise time points of the contractile cycle. Using this approach, we can detect redistribution of subcellular Ca2+ during the cardiac contractile cycle. Changes in Ca2+ of less than 1.0 mmol/kg dry wt can be detected. By determining the variability of the Ca2+ measurements in preliminary experiments, we have also demonstrated that it is possible to optimize experimental design, i.e., to predict the number of animals per treatment group and the number of X-ray spectra per animal that are required in order to detect a specified Ca2+ difference. Quantitative EPMA of rapidly frozen contracting papillary muscle has also allowed us to correlate the Ca2+ content of SR and MT with the contractile state of the muscle. Our results show a decrease of 40% in the amount of Ca2+ stored in the junctional SR during a cardiac muscle twitch, thus providing direct evidence for a role of the SR as a primary site of Ca2+ release. In addition, we have demonstrated dissociation between MT Ca2+ uptake and activation of regulatory enzymes, such as pyruvate dehydrogenase, indicating that MT Ca2+ uptake is not required for activation of MT metabolism.

Glomerular filtration rate measurements in clinical trials. Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group.

To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GRF was measured as the renal clearance of [125I]iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation [CV]) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (> 90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (< 13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (interest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median interest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice.(ABSTRACT TRUNCATED AT 400 WORDS)