Long-term outcomes in nondiabetic chronic kidney disease.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of strict blood pressure control and dietary protein restriction on the progression of kidney disease. Here, we retrospectively evaluated outcomes of nondiabetic participants with stages 2-4 chronic kidney disease (CKD) from randomized and nonrandomized cohorts of the MDRD Study. Kidney failure and survival status through December of 2000, were obtained from the US Renal Data System and the National Death Index. Event rates were calculated for kidney failure, death, and a composite outcome of death and kidney failure. In the 1666 patients, rates for kidney failure were four times higher than that for death. Kidney failure was a more likely event than death in subgroups based on baseline glomerular filtration rate, proteinuria, kidney disease etiology, gender, and race. It was only among those older than 65 that the rate for death approximated that for kidney failure. In contrast to other populations with CKD, our study of relatively young subjects with nondiabetic disease has found that the majority of the participants advanced to kidney failure with a low competing risk of death. In such patients, the primary emphasis should be on delaying progression of kidney disease.

Intratumoral Bacillus Calmette-Guérin immunotherapy prior to surgery for carcinoma of the lung: results of a prospective randomized trial.

A prospective randomized trial of preoperative intratumoral therapy with Bacillus Calmette-Guérin (BCG) was conducted in non-small cell lung cancer patients. Eighty-eight patients (48 BCG-treated and 40 control subjects) were entered into the study; three control subjects were removed from data analysis because histology revealed pathology other than non-small cell lung cancer. There were no differences between BCG-treated and control patients in sex, age, cigarettes smoked per day, pack-years of cigarette smoking, white blood cell count, or number of peripheral blood lymphocytes. Toxicity of BCG was limited to transient malaise and fever (average peak temperature, 38.7 degrees C). There was no significant difference in outcome (recurrence or survival) between BCG-treated and control groups with Stage I or Stage III tumors; there were too few Stage II tumors for separate statistical analysis. Outcome was not affected within or between the two treatment groups by tuberculin skin test status. Combining both treatment groups, Stage III patients had a worse outcome than did Stage I-II patients, non-squamous cell tumor patients (large cell and adenocarcinoma) had worse outcomes than did squamous cell tumor patients, and men had a worse outcome than women. We conclude that, although preoperative intratumoral BCG therapy is safe, it does not lengthen disease-free interval or prolong survival in patients with non-small cell lung cancer.

Class of cooperative stochastic models: Exact and approximate solutions, simulations, and experiments using ionic self-assembly of nanoparticles.

We present exact and approximate results for a class of cooperative sequential adsorption models using matrix theory, mean-field theory, and computer simulations. We validate our models with two customized experiments using ionically self-assembled nanoparticles on glass slides. We also address the limitations of our models and their range of applicability. The exact results obtained using matrix theory can be applied to a variety of two-state systems with cooperative effects.

Mechanically assisted ventilation in a community hospital. Immediate outcome, hospital charges, and follow-up of patients.

In 100 consecutive patients undergoing mechanically assisted ventilation, we prospectively determined immediate survival, hospitalization charges, and subsequent one-year outcome. Sixty percent of the patients survived the episode of assisted ventilation. This survival decreased to 50% at the time of hospital discharge and to 33% one year after hospitalization. There were no posthospitalization deaths in patients less than age 50 years. In those patients older than 70 years, however, 51% were dead by the time of hospital discharge and 73% died by one year following discharge. Comparison of features that reflect the magnitude of intensive respiratory care, such as hours of ventilation and intensive care unit (ICU) length of stay, disclosed no statistically significant differences between survivors and nonsurvivors at discharge. Hospitalization charges averaged $10,968 per patient. The total charge for respiratory therapy services (including arterial blood gas determinations) averaged $2,200. Respiratory care service charges were only marginally different between survivors and nonsurvivors. By contrast, total charges and total length of stay were greater for the survivors. Resource use in the intensive care setting as reflected by hours of mechanical ventilation and ICU length of stay was similar in both survivors and nonsurvivors, with the larger total cost for survivors relating primarily to care outside the ICU. Also, we confirm that prognosis is excellent in patients less than 50 years of age who survive mechanically assisted ventilation for acute respiratory failure and that extubation in elderly patients is not necessarily indicative of a good prognosis.

Improved assessment of bioactive erythropoietin in human sera using a modified tritiated-thymidine-incorporation assay.

The reproducibility and utility of an in vitro bioassay for erythropoietin were evaluated, and modifications, including the use of frozen target cells, were made. The assay, based on 3H-thymidine incorporation into phenylhydrazine-treated mouse spleen cells, showed a dose-response curve from 0.2 to 20 mU of sheep plasma or human urinary erythropoietin, with a 50-100-fold increase in 3H-thymidine incorporation. The dose-response curve, using purified, recombinant erythropoietin was identical to that from material obtained from other sources. The use of frozen cells simplified the methodology, reduced the time for assay preparation, and lowered costs. The freezing process resulted in 15% attrition of the cells, but after one year of storage, this level was not increased nor was the response to erythropoietin diminished. The nonspecificity of the assay was reduced by supplementing the cells with critical nutrients, depleting fetal bovine serum of endogenous erythropoietin, and reducing solute variability by ultrafiltration and reconstitution of samples with culture medium. Heat inactivation diminished inhibitors in sera samples, but affinity chromatography using wheat-germ lectin-Sepharose was most effective for extracting erythropoietin and reducing nonspecific effects. The assay is sensitive, can be used to measure multiple samples rapidly, and should prove useful for complementing immunoassay techniques.

Neurologic complications of endocarditis: a 12-year experience.

We reviewed the neurologic complications in 113 patients with native and 62 patients with prosthetic valve endocarditis. Neurologic complications occurred with the same frequency (35.3% vs 38.7%) and distribution among the two groups. Death occurred in 20.6% of patients with neurologic complications and in 13.6% of patients without neurologic complications (p = 0.23). Staphylococcus aureus endocarditis correlated statistically with the development of neurologic complications (p less than 0.01) and death (p less than 0.01). Among 50 patients discharged from the hospital after receiving only medical treatment for native valve endocarditis, and followed for a mean period of 48 months, there was one patient with mitral valve prolapse and stroke. We conclude that (1) neurologic complications occur with the same frequency in native and prosthetic valve endocarditis, (2) S aureus endocarditis increases the risk of neurologic complications and death, (3) mortality is not significantly increased in patients with neurologic complications, and (4) an episode of treated native valve endocarditis does not increase the natural history of stroke in valvular disease.

Transcranial Doppler assessment of cerebral perfusion reserve in patients with carotid occlusive disease and no evidence of cerebral infarction.

Using transcranial Doppler ultrasound (TCD), we measured bilateral middle cerebral artery mean blood flow velocities (MCAVs) before and 10 minutes after intravenous infusion of 1 gram of acetazolamide in 20 patients without cerebral infarction. Seven patients had normal carotid arteries (group 1), seven had unilateral internal carotid artery (ICA) stenosis > or = 75% (group 2), and six had unilateral ICA occlusion (group 3). Before acetazolamide infusion, side-to-side differences in MCAV were 0.06 cm/sec in group 1 (p = 0.98), 4.3 cm/sec in group 2 (p = 0.36), and 15.0 cm/sec in group 3 (p = 0.02). Bilateral MCAV increased in all three groups after acetazolamide infusion, and the side-to-side differences in MCAV were 3.2 cm/sec in group 1 (p = 0.40), 11.4 cm/sec in group 2 (p = 0.04), and 27.6 cm/sec in group 3 (p = 0.03). Patients with carotid stenosis or occlusion and ipsilateral transient ischemic attacks (TIAs) had higher side-to-side differences in MCAV before (p = 0.03) and after (p = 0.01) acetazolamide than did asymptomatic patients with carotid disease. The association of impaired cerebral perfusion reserve and TIAs suggests that the TCD-acetazolamide test may enable identification of a subgroup of patients with carotid occlusive disease who are at higher risk for stroke.

A prospective study of asthma in a rural community.

Changes in symptoms and pulmonary function among asthmatic subjects in the general population remain poorly characterized. We studied 1,303 white residents aged seven years and older in Lebanon, Conn, a rural community largely unaffected by air pollution or major occupational exposures. These residents were examined in 1972 and again in 1978. There were 73 asthmatic subjects seen in 1972 who were followed. In addition, we identified 278 persons in 1972 who complained of wheezing who were also seen in 1978. Of the original asthmatic subjects, 50 (68 percent) were in remission; and from the original nonasthmatic population, 19 (1.4 percent) new asthmatic subjects were identified. Similarly, the condition of 215 (77 percent) of those who initially complained of wheeze had improved, whereas 56 (4.6 percent) of those initially studied either developed new wheeze or saw their wheezing worsen. When the groups of persons complaining of wheeze and the asthmatic subjects were analyzed for the presence of chronic bronchitis, we found a significant correlation between wheeze and chronic bronchitis in individuals aged 18 years and older (p less than 0.001) for both men and women, and a significant correlation (p less than 0.001) between asthma and chronic bronchitis in women aged 18 years and older. Loss of pulmonary function over time measured in terms of the forced expiratory volume in one second and the forced expiratory flow at 50 percent of total lung capacity was consistently greater for asthmatic adults than for nonasthmatic adults. Furthermore, when individuals were studied by the severity and duration of their asthmatic symptoms, a trend of worse pulmonary function was seen in those individuals with chronic asthma. We conclude that remission rates among asthmatic subjects and persons with wheeze are high in individuals aged seven years and older, that chronic bronchitis is frequently associated with wheezing and a history of asthma in adults, and that significant abnormalities in pulmonary function as well as accelerated loss of pulmonary function are associated with asthma.

The shape of the maximum expiratory flow volume curve.

Differences in the shape of the maximum expiratory flow volume (MEFV) curve have been associated with pathologic states and physiologic differences between normal individuals. We describe variations in a new parameter, angle beta, which characterizes the general configuration of the MEFV curve among healthy subjects and subjects with disease in 5,140 white individuals. Women had consistently larger beta angles than men. There was a progressive decline in beta with advancing age. Cigarette smokers had lower beta angles than did lifetime never-smokers. Subjects with abnormal lung function patterns had lower beta angles than individuals with a normal pattern. Finally, individuals with asthma, chronic bronchitis, dyspnea and wheezing had significantly lower beta angles than healthy individuals. Further clinical and epidemiologic studies are needed to evaluate this measurement's possible value in pulmonary function evaluation.

Airway reactivity and cotton bract-induced bronchial obstruction.

Most seemingly healthy persons challenged with an aerosol of cotton bract extract develop some degree of bronchospasm. The role of nonspecific reactivity of the airways in this reaction to cotton bract extract is undefined. We examined the relationship between airway responses to cotton bract extract and to methacholine, as well as between airway responses to cotton bract extract and to a bronchodilator. Twenty-two healthy subjects were screened for sensitivity to inhaled cotton bract extract. Pulmonary function was measured using partial expiratory flow-volume curves on which flow at 60 percent of the control vital capacity below total lung capacity was measured (MEF40%[P]) following ten minutes of inhalation of cotton bract extract. In the group screened, 12 were found to be responders to the extract, with drops in MEF40%(P) of 20 percent or more, and ten were found to be nonresponders. On separate days, we measured the responses of our subjects' airways to inhaled metaproterenol and methacholine. The mean threshold dose for methacholine in the responding group was 26.8 mg/ml, as compared to 55.6 mg/ml for the nonresponders (t = 2.52; p less than 0.05). Furthermore, the mean percent increase in MEF40%(P) following inhalation of metaproterenol was 41 percent in responders and 24 percent in nonresponders (t = 2.19; p less than 0.05). We conclude that some responders to cotton bract extract exhibit greater reactivity of the airways than nonresponders.

Smoking and cotton dust effects in cotton textile workers.

Cotton textile workers have an increased prevalence of both obstructive and restrictive lung function patterns compared with control subjects. Similar abnormal patterns may occur with respiratory diseases of other etiologies, notably those associated with cigarette smoking. The shape of the maximum expiratory flow volume (MEFV) curve has been used to characterize patterns of lung function abnormality. To better evaluate the respiratory effects of cotton dust exposure and to contrast them with those of cigarette smoking, we defined a new functional parameter (angle beta) related to the shape of the MEFV curve. We compared 477 cotton textile workers, both current smokers and never smokers, 45 years and older, with 932 similarly aged control subjects from three communities. Smokers, regardless of their occupational exposure or sex, have smaller beta values than nonsmokers. Cotton textile workers, despite a greater prevalence of abnormal lung function, have beta values that do not differ from those of persons without occupational exposure to cotton dust. We suggest that morphologic patterns of flow volume curves reflect separate effects of cotton dust exposure and smoking and may be related to different sites of airway injury.

Airway reactivity and exercise in healthy subjects.

The interaction of exercise, methacholine challenge, and beta-adrenergic blockade was investigated in eight healthy subjects. We measured the response to increasing doses of aerosolized methacholine, examining maximum expiratory flow rates. These responses were compared with those obtained on separate days when each methacholine challenge followed submaximal exercise or submaximal exercise in the presence of Beta-blockade. The possible independent effect of increased ventilation (20 +/- 6.7 L/min) was also studied during methacholine challenge. Methacholine-induced bronchospasm was not augmented by exercise alone or by exercise in the presence of beta-blockade, nor was this response significantly altered by hyperventilation during methacholine aerosol challenge. These findings suggest that airway hyperreactivity cannot be induced in healthy subjects by levels of exercise that commonly provoke exercise-induced bronchospasm in asthmatic patients.

Tantalum oxide, silica and latex: effects on alveolar macrophage viability and lysozyme release.

Tantalum an experimental bronchographic material, may be retained in the lungs for a prolonged period following bronchography. The alveolar macrophage (AM) is a cell with potential for clearing tantalum particles from the airways. We studied the in vitro effects of tantalum oxide and two other particles, silca and latex, on rabbit AM viability and lysozyme release over 30 hours. Results indicate: 1) tantalum oxide, silica, and latex particles are ingested by rabbit AM in culture; 2) tantalum oxide and silica are both toxic to AM in vitro; and 3) tantalum oxide exerts its toxic effects less rapidly on AM than does silica. On the basis of these in vitro culture results we conclude that tantalum oxide may be toxic to alveolar macrophages in vivo. Delayed lung clearance of tantalum oxide particles may be due in part to their toxic effects on alveolar macrophages.

Early gestational bleeding and pregnancy outcome: a multivariable analysis.

The effect of early vaginal bleeding on pregnancy outcome was assessed for 16 305 singleton stillborn and liveborn deliveries at three obstetric units in Jerusalem, Israel during 1975-1976. A total of 2385 women (14.6%) reported gestational bleeding before the seventh month of pregnancy. Of these, 2166 reported light bleeding (spotting), 191 heavy bleeding, and 28 both light and heavy bleeding. Logistic regression models revealed an unexpected interaction among light bleeding, hormone usage, and pregnancy outcome in that the risks of a low birth weight, pre-term and small-for-dates term delivery were significantly increased only for those women who had light bleeding and who had not used therapeutic hormones. Heavy vaginal bleeding, in contrast, was associated with an excess risk of these perinatal complications regardless of hormone usage. There was also a suggestion that certain subgroups of women with vaginal bleeding might be at an increased risk of delivering an offspring with congenital malformations.

Calcium supplements and colorectal adenomas. Polyp Prevention Study Group.

Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95% CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95% CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95% CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.

Colectomy with ileorectal anastomosis for familial adenomatous polyposis: the risk of rectal cancer.

One hundred thirty-three patients with familial adenomatous polyposis undergoing colectomy and ileorectal anastomosis have been reviewed for the occurrence of cancer in the rectal stump. Ten patients developed rectal cancer (Actuarial survivorship rate of 88% for those patients free of rectal cancer at 20 years). Potential risk factors for the development of rectal cancer, including age at colectomy, previous colon cancer, number of rectal polyps, and length of the rectal stump, were analyzed and no significant differences were found. A policy of total colectomy with ileorectal anastomosis at 12 to 15 cm with conscientious lifelong follow-up thereafter is advocated for persons affected by familial adenomatous polyposis.

ICU admission score for predicting morbidity and mortality risk after coronary artery bypass grafting.

BACKGROUND: This study was performed to develop an intensive care unit (ICU) admission risk score based on preoperative condition and intraoperative events. This score provides a tool with which to judge the effects of ICU quality of care on outcome. METHODS: Data were collected prospectively on 4,918 patients (study group n = 2,793 and a validation data set n = 2,125) undergoing coronary artery bypass grafting alone or combined with a valve or carotid procedure between January 1, 1993, and March 31, 1995. Data were analyzed by univariate and multiple logistic regression with the end points of hospital mortality and serious ICU morbidity (stroke, low cardiac output, myocardial infarction, prolonged ventilation, serious infection, renal failure, or death). RESULTS: Eight risk factors predicted hospital mortality at ICU admission, and these factors and five others predicted morbidity. A clinical score, weighted equally for morbidity and mortality, was developed. All models fit according to the Hosmer-Lemeshow goodness-of-fit test. This score applies equally well to patients undergoing isolated coronary artery bypass grafting. CONCLUSIONS: This model is complementary to our previously reported preoperative model, allowing the process of ICU care to be measured independent of the operative care. Sequential scoring also allows updated prognoses at different points in the continuum of care.

Thyrotropin-releasing hormone (TRH) in murine motor neuron disease (the wobbler mouse).

Clinical benefits of thyrotropin-releasing hormone (TRH) were tested in wobbler mice, an animal model of motor neuron disease. After the disease was clinically recognized at 3-4 weeks, the animals were divided into two groups, each group consisting of 5 pairs of wobbler mice and normal littermates. TRH (50 mg/kg) and normal saline (NS) were injected intraperitoneally daily, 6 times per week for 9 weeks, in a double-blind study. Weekly assessments consisted of front paw grip strength, push walking, body weight, and semiquantitative grading. At the end of the trial, the brain and spinal cord were sampled to measure TRH and cyclo (His-Pro) concentrations. Progression of motor neuron disease was evident in wobbler mice, regardless of treatment. Descriptive semiquantitative gradings showed the tendency of improvement in TRH-treated wobbler mice. In saline-injected controls, TRH levels in the cervical spinal cord were significantly increased (P less than 0.01) in wobbler mice compared to littermates. However, with TRH treatment, there was no significant difference in TRH and cyclo (His-Pro) levels in any neural tissue between wobbler and controls. The lack of clinical benefits with TRH in wobbler mice may be due to increased TRH levels found in diseased spinal cord in murine motor neuron disease.

The effect of subarachnoid hemorrhage on blood and CSF atrial natriuretic factor.

Atrial natriuretic factor (ANF) is a diuretic natriuretic peptide hormone produced by both the heart and brain which has been postulated to play a role in the hemodynamic and sodium instability that frequently follows subarachnoid hemorrhage (SAH). Levels of ANF were measured in 12 patients with nontraumatic SAH and nine control patients with unruptured cerebral aneurysms. At surgery, the mean plasma ANF level (+/- standard deviation) of the SAH group was significantly higher than that of the control group (158.1 +/- 83.8 vs. 57.8 +/- 45.3 pg/ml, respectively; p = 0.01). There was no significant difference in serum sodium concentration, blood pressure, or central venous pressure between these groups. Nine patients with SAH due to aneurysm rupture had plasma ANF levels similar to those in three patients with SAH due to other causes. Four patients with moderate to severe SAH had significantly higher mean cerebrospinal fluid (CSF) ANF values (17.7 +/- 12.8 pg/ml) than five patients with minimal SAH (0.6 +/- 0.9 pg/ml) or the control group of nine patients (3.7 +/- 1.3 pg/ml) (p less than 0.05). Five patients with moderate to severe SAH had significantly higher plasma ANF values (202.6 +/- 72.2 pg/ml) than five with minimal SAH (86.8 +/- 29.2 pg/ml) or the control group (57.8 +/- 45.3 pg/ml) (p less than 0.05). Plasma ANF values were substantially higher than CSF ANF content in the SAH group (p less than 0.01) and in the control group (p = 0.05). From these data it is concluded that: 1) plasma ANF is elevated significantly after SAH; 2) this rise appears unrelated to the cause of hemorrhage, serum sodium concentration, blood pressure, or central venous pressure, but is related to the extent of the hemorrhage; 3) ANF concentrations in the CSF are significantly lower than in plasma, and are elevated after moderate to severe SAH; and 4) the source of CSF ANF is probably the plasma, and the source of plasma ANF is likely the heart.

A simple, sensitive assay for the spermicide nonoxynol-9 in biological fluids by high-performance liquid chromatography.

A new high-performance liquid chromatographic technique has been developed to quantitate nonoxynol-9 in serum, urine, and vaginal fluid. The method is rapid, involves minimal sample preparation, and can be used to analyze a large number of biological fluid samples. The assay elutes a single nonoxynol-9 peak with no interfering components. This was accomplished using a 10-microns pelicular packed amine column, a normal-phase solvent system, and fluorescence detection. Nonoxynol-9 levels as low as 0.23 micrograms/mL in urine can be detected.