Ciliary membrane alterations occurring in experimental Mycoplasma pneumoniae infection.

Experimental infection of hamster ciliated tracheal epithelium in organ culture with virulent Mycoplasma pneumoniae resulted in the deterioration o ciliary necklaces and an altered distribution of membrane-associated particles on the shafts of the affected cilia. To our knowledge that is the first report of an altered disposition of ciliary membrane-associated particles in response to a specific infectious agent.

Physicochemical basis for dilated intercellular spaces in non-erosive acid-damaged rabbit esophageal epithelium.

Dilated intercellular spaces (DIS) within esophageal epithelium (EE) is a histopathologic feature of non-erosive reflux disease and early lesion in acid-damaged rabbit EE associated with increased paracellular permeability. Its cause remains unknown, but the lesion's morphology suggests a significant fluid shift into the intercellular spaces (ICS). Since water follows osmotic forces and consequently ion movements, we explored the role of active (ion) transport and ion gradients in its pathogenesis. This was done by quantifying the effect of inhibited active transport and altered ion gradients on electrical resistance (R(T)) and ICS diameter in acid-exposed Ussing-chambered rabbit EE. Compared with normal Ringer, pH 7.5, 30 minutes of luminal HCl (100 mmol/L), pH 1.1, increased permeability (R(T): +5 +/- 4% vs-52 +/- 4%) and ICS diameter (0.25 +/- 0.01 microm vs 0.42 +/- 0.02 microm), but had no effect on cell morphology or diameter. Ouabain pretreatment significantly reduced active transport but had no effect on the acid-induced changes. However, negating the chloride gradient created by luminal HCl either by adding choline chloride, 100 mmol/L, serosally or by replacing luminal HCl, pH 1.1, with luminal H(2)SO(4), pH 1.1, prevented the development of DIS while maintaining the increase in permeability. DIS was also prevented in the presence of a 100 mmol/L (choline) chloride gradient by luminal exposure at neutral pH. DIS in HCl-damaged EE is caused by an H(+)-induced increase in epithelial permeability; this enables Cl(-) to diffuse along its gradient into the ICS, creating an osmotic force for water movement into and (hydrostatic) dilation of the ICS.

Selenium deficiency alters epithelial cell morphology and responses to influenza.

It is unknown whether nutritional deficiencies affect the morphology and function of structural cells, such as epithelial cells, and modify the susceptibility to viral infections. We developed an in vitro system of differentiated human bronchial epithelial cells (BEC) grown either under selenium-adequate (Se+) or selenium-deficient (Se-) conditions, to determine whether selenium deficiency impairs host defense responses at the level of the epithelium. Se- BECs had normal SOD activity, but decreased activity of the selenium-dependent enzyme GPX1. Interestingly, catalase activity was also decreased in Se- BECs. Both Se- and Se+ BECs differentiated into a mucociliary epithelium; however, Se- BEC demonstrated increased mucus production and increased Muc5AC mRNA levels. This effect was also seen in Se+ BEC treated with 3-aminotriazole, an inhibitor of catalase activity, suggesting an association between catalase activity and mucus production. Both Se- and Se+ were infected with influenza A/Bangkok/1/79 and examined 24 h postinfection. Influenza-induced IL-6 production was greater while influenza-induced IP-10 production was lower in Se- BECs. In addition, influenza-induced apoptosis was greater in Se- BEC as compared to the Se+ BECs. These data demonstrate that selenium deficiency has a significant impact on the morphology and influenza-induced host defense responses in human airway epithelial cells.

Risk of acute first myocardial infarction and use of nicotine patches in a general population.

OBJECTIVES: To determine if nicotine patches, both as prescribed and used over-the-counter, increase the risk of first myocardial infarction (MI). BACKGROUND: Although nicotine patches improve smoking cessation rates, case reports have raised the hypothesis that they may increase the risk of MI. METHODS: A population-based case-control study among 68 hospitals in an eight-county region surrounding Philadelphia was performed to determine if nicotine patches increase the risk of first MI. Cases were smokers (current or within the prior year) admitted to all hospitals in the region with a first MI. Controls were smokers (current or within the prior year) without prior MI selected from the same region using random-digit dialing. Data were collected by telephone interviews and chart reviews. The study had 80% power to detect an odds ratio (OR) of 2.5. RESULTS: A total of 653 cases and 2,990 controls were interviewed. There was no association between nicotine patches and MI (OR 0.46; 95% CI: 0.09, 1.47), and the confidence interval (CI) excluded an effect from nicotine patches equal to that from cigarette smoking itself (OR < 2.5). Among those who abstained from smoking, the OR for use of nicotine patches was 0.25 (95% CI: 0.01, 1.67); among those who smoked concomitantly, the OR for patch use was 0.83 (95% CI: 0.09, 3.81). Adjustment for confounding did not alter the study's findings (OR adjusted for confounders that could mask a harmful effect of patches: 0.70; 95% CI: 0.20, 2.46). CONCLUSIONS: Nicotine patches, as used in actual practice, do not appear to be associated with an increased risk of MI.

Safety of nonsteroidal anti-inflammatory drugs with respect to acute liver disease.

OBJECTIVE: To examine the magnitude of the risk of acute hepatitis associated with the use of nonsteroidal antiinflammatory drugs. METHODS: We calculated the annual incidence rate of hepatitis resulting in hospitalization and then performed a case-control study using 1980 to 1987 Medicaid billing data from Michigan and Florida. The 107 cases included patients with symptomatic acute hepatitis without an identifiable cause of liver disease. Four controls per case were randomly selected and were matched for age, sex, and state. Antecedent drug exposure was assessed 30 days prior to the onset of the disease in the cases and during the same period in the controls. RESULTS: The annual incidence rate (95% confidence interval) of acute idiopathic symptomatic hepatitis resulting in hospitalization was 2.2 (2.0 to 2.4) per 100,000 persons per year. Nine cases (8.4%) and 26 controls (6.1%) were exposed to nonsteroidal anti-inflammatory drugs, yielding an odds ratio of 1.4 (0.6 to 3.1). After adjustment for potential confounding variables, the odds ratio was 1.2 (0.5 to 2.8). CONCLUSIONS: Acute symptomatic idiopathic liver disease severe enough to result in hospitalization is uncommon, and no association was evident between nonsteroidal anti-inflammatory drugs and acute hepatitis. This study was large enough to exclude a relative risk of 2.8. These data suggest that acute symptomatic liver disease from nonsteroidal anti-inflammatory drugs is not a frequent clinical problem.

Nonsteroidal anti-inflammatory drugs and neutropenia.

BACKGROUND: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and neutropenia is based primarily on case reports only. METHODS: A population-based, case-control study was performed with Medicaid claims data from six states. Cases were defined as patients hospitalized with neutropenia. Four controls per case were randomly chosen, matched for age, sex, state, and year. The frequency of exposure to NSAIDs in the 30 days before hospital admission in the cases was compared with the frequency in the identical period in the controls. The diagnosis of neutropenia was validated by review of medical records. RESULTS: The crude odds ratio for NSAIDs as a class was 3.3 (90% confidence interval, 1.6 to 6.6). The multivariate adjusted odds ratio was 4.2 (90% confidence interval, 2.0 to 8.7). No single class of NSAID, nor any individual NSAID, was associated with a unique risk, although the data on individual NSAIDs were sparse. Even excluding phenylbutazone and indomethacin, an increased risk was observed (3.5 [1.6 to 7.6]). CONCLUSIONS: Neutropenia is associated with the use of NSAIDs. However, given the low incidence of this disease, the additional number of cases of neutropenia caused by the use of NSAIDs is small. These data do not support the existence of a risk restricted to selected NSAIDs only.

Descriptive epidemiology of agranulocytosis.

BACKGROUND: To determine the incidence of agranulocytosis, a descriptive epidemiologic study was performed. METHODS: With the use of computerized Medicaid billing data from 1980 through 1985 from Minnesota, Michigan, and Florida, the ratio of persons hospitalized with a discharge diagnosis of neutropenia to persons with any claim for medical service was first used as an estimate of the incidence rate of the condition. Patients with cancer and patients receiving cytotoxic and immunosuppressive drugs were excluded. The information provided by a review of medical records for a subset of neutropenia cases was used to determine the proportion with neutropenia after excluding cases with recurrent or chronic neutropenia, and to determine the proportion with agranulocytosis. RESULTS: The incidence rates (95% confidence intervals) of agranulocytosis, excluding recurrent or chronic disease, were 2.3 (1.4 to 3.7), 7.7 (6.6 to 8.9), and 15.4 (11.3 to 20.4) per million per year in each state, respectively. The overall incidence was 7.2 (6.3 to 8.1) per million per year. CONCLUSIONS: Agranulocytosis is an extremely uncommon condition. The excess risk of agranulocytosis due to any drug other than cytotoxic drugs must, therefore, be very low.

The association of nonsteroidal anti-inflammatory drugs with upper gastrointestinal tract bleeding.

To evaluate the risk of developing upper gastrointestinal (UGI) bleeding from nonsteroidal anti-inflammatory drugs (NSAIDs), a retrospective (historical) cohort study was performed, using a computerized data base including 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. Comparing 47,136 exposed patients to 44,634 unexposed patients, the unadjusted relative risk for developing UGI bleeding 30 days after exposure to a NSAID was 1.5 (95% confidence interval 1.2 to 2.0). Univariate analyses demonstrated associations between UGI bleeding and age, sex, state, alcohol-related diagnoses, preexisting abdominal conditions, and use of anticoagulants. This association between NSAIDs and UGI bleeding was unchanged after adjusting for these potential confounding variables using logistic regression. A linear dose-response relationship and a quadratic duration-response relationship were demonstrated. Non-steroidal anti-inflammatory drugs are associated with UGI bleeding, although the magnitude of the increased risk is reassuringly small.

Gastrointestinal tract bleeding associated with naproxen sodium vs ibuprofen.

BACKGROUND: The risk of gastrointestinal tract bleeding requiring hospitalization associated with naproxen sodium was compared with that with ibuprofen, using a prescription database to approximate over-the-counter dosing. OBJECTIVE: To evaluate the safety of naproxen sodium. METHODS: A claims database containing Ohio Medicaid data from January 1986 through February 1993 and Michigan Medicaid data from April 1983 through July 1993 was used to compare 101,318 patients dispensed naproxen sodium with 277,601 patients dispensed ibuprofen. Using a case-cohort design, all 59 patients from the full cohort who had been hospitalized with upper gastrointestinal tract bleeding (UGIB) that developed within 14 days after the first prescription for the study drugs were compared with a subcohort made up of a 10% random sample of subjects selected from the combined drug cohorts. RESULTS: The incidence of UGIB occurring within 14 days after the first prescription in the naproxen sodium cohort was 26 (0.026%) of 101,318 (95% confidence interval [CI], 0.017%-0.038%), compared with 33 (0.012%) of 277,601 patients (95% CI, 0.008%-0.017%) in the ibuprofen cohort. Overall, the use of naproxen sodium vs ibuprofen was associated with an adjusted relative risk of 2.0 (95% CI, 1.1-3.8). Among people with multiple prescriptions, the crude relative risk for those receiving therapy in a dose typical of over-the-counter use was 4.1 (95% CI, 1.2-13.8). CONCLUSIONS: The overall incidence of UGIB is low with both drugs. There is little additional absolute risk posed by the use of low-dose naproxen sodium, compared with low-dose ibuprofen, despite an increased relative risk. However, given the widespread use of these drugs, a substantial number of additional cases of UGIB could result from use of naproxen sodium. This increased risk should be considered, especially for patients whose baseline risk of UGIB is elevated.

Upper gastrointestinal tract bleeding from oral potassium chloride. Comparative risk from microencapsulated vs wax-matrix formulations.

A retrospective cohort study was performed to assess the relative risk of upper gastrointestinal (UGI) tract bleeding from two formulations of potassium chloride. Relevant information was obtained from 1980 through 1984 Medicaid billing data from the states of Michigan, Minnesota, Florida, and Ohio. After patients with a history of UGI tract bleeding prior to their first prescription for either of the two potassium chloride preparations under study were excluded, data were analyzed for 28,790 patients (143,512 patient-months) dispensed a microencapsulated formulation exclusively and 76,118 patients (560,341 patient-months) dispensed a wax-matrix formulation exclusively. The risk of UGI tract bleeding within 30 days after each prescription for the drug of interest was examined. After sampling from the undiseased study subjects and adjusting for multiple potential confounding variables using logistic regression, an odds ratio (95% confidence interval) of 0.67 (0.52 to 0.85) was observed.

The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.

To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.

Lack of hepatotoxic effects of parenteral ketorolac in the hospital setting.

BACKGROUND: No large controlled studies to date have examined the hepatic safety of parenteral ketorolac, which is used to treat acutely ill hospitalized patients who may be at greatest risk of liver injury. OBJECTIVE: To measure the association between the use of parenteral ketorolac and subsequent liver injury. METHODS: A nonexperimental cohort study conducted in 35 hospitals in the greater Philadelphia, Pa, region examined 10,272 courses of parenteral ketorolac (the exposed group) and 10,247 courses of parenteral opioid (the comparison group). Liver injury was defined by a modified international consensus definition that relied exclusively on liver function tests. Proportional hazards regression was used to calculate the rate ratio and 95% confidence interval for the association between ketorolac exposure and the occurrence of liver injury, controlling for potentially confounding factors, and to explore the possible effects of duration and dose. RESULTS: The incidence of liver injury was 1.0% in the ketorolac group and 1.2% in the opioid group, yielding an unadjusted rate ratio of 0.77 (95% confidence interval, 0.59 1.01). Simultaneously adjusting for multiple potentially confounding factors did not change this result. There was no evidence for a duration-response relationship (P = .96) or a dose-response relationship (P = .23). We were unable to identify any subgroups that were susceptible to possible hepatotoxic effects of parenteral ketorolac. CONCLUSIONS: This study failed to find evidence of a hepatotoxic effect of parenteral ketorolac use in the hospital setting and provides strong evidence against the existence of a clinically meaningful association between exposure to parenteral ketorolac in the hospital setting and liver injury.

The effect of gastric bypass surgery on hypertension in morbidly obese patients.

BACKGROUND: Hypertension is the most common medical disorder associated with obesity. The relationship between dietary weight loss and the reduction of blood pressure is well established. However, the effect of gastric bypass surgery on blood pressure has not been well studied. METHODS: We evaluated the relationship between weight loss and blood pressure in patients with diastolic hypertension who had gastric bypass surgery for morbid obesity. Patients were defined as hypertensive if taking antihypertensive medication or if both the preoperative office and mean hospital diastolic blood pressures were greater than 90 mmHg. Two of the authors (J.L.C., M.E.R.), blinded to all postoperative weights, classified the follow-up hypertensive status into one of four categories: resolved, improved, no change, or worse. The relationship between postoperative changes in blood pressure status and mean weight loss, percent excess weight loss, and body mass index were examined using a one-way analysis of variance. The relationship between postoperative weight loss and blood pressure was assessed in the baseline normotensive population using linear regression analysis. RESULTS: There were 45 patients with diastolic hypertension; 91% were taking an antihypertensive medication. The mean follow-up was 39 months. The mean preoperative weight was 137 kg and the mean weight loss at 1, 12, and 24 months following surgery was 13, 21, and 45 kg, respectively. Twelve months after surgery, hypertension had resolved in 22 patients (54%) and had improved in six patients (15%). These findings persisted through 48 months postoperatively. There was a significant relationship between the percentage of excess weight lost and improvement of hypertension at the 6-month and 12-month follow-up visits. There was also a significant relationship between the body mass index and improvement of hypertension at the 1-month, 12-month, 24-month, and 48-month follow-up visits. In the baseline normotensive patients there was not a significant relationship between our weight loss measures and changes in blood pressure. CONCLUSIONS: We conclude that postoperative weight loss in patients undergoing gastric bypass surgery was associated with resolution or improvement of diastolic hypertension in approximately 70% of cases. Resolution or improvement of hypertension occurred more often in patients with a lower postoperative body mass index.

The epidemiology of the acute flank pain syndrome from suprofen.

Suprofen, a new nonsteroidal anti-inflammatory drug, was marketed in early 1986 as an analgesic agent. Until physicians began reporting an unusual acute flank pain syndrome to the spontaneous reporting system, 700,000 persons used the drug in the United States. Through August 1986, a total of 163 cases of this syndrome were reported. To elucidate the epidemiology of the syndrome, a case-control study was performed, comparing 62 of the case patients who had been reported to the spontaneous reporting system to 185 suprofen-exposed control subjects who did not have the syndrome. Case patients were more likely to be men (odds ratio, 3.8; 95% confidence interval, 1.2-12.1), suffer from hay fever and asthma (odds ratio, 3.4; 95% confidence interval, 1.0-11.9); to participate in regular exercise (odds ratio, 5.9; 95% confidence interval, 1.1-30.7), especially in the use of Nautilus equipment (p = 0.02); and to use alcohol (odds ratio, 4.4; 95% confidence interval, 1.1-17.5). Possible risk factors included young age, concurrent use of other analgesic agents (especially ibuprofen), preexisting renal disease, a history of kidney stones, a history of gout, a recent increase in activity, a recent increase in sun exposure, and residence in the Sunbelt. These were findings that were suggestive but did not reach conventional statistical significance. These findings are consistent with the postulated mechanism for this unusual syndrome: acute diffuse crystallization of uric acid in renal tubules.

No causal relationship between transdermal scopolamine and seizures: methodologic lessons for pharmacoepidemiology.

Because of case reports suggesting that use of transdermal scopolamine might be associated with the subsequent development of seizures, a retrospective cohort study was performed with computerized Medicaid claims data. Patients receiving transdermal scopolamine were compared with patients receiving diphenhydramine, meclizine, prochlorperazine, and promethazine. A four-fold increased risk of seizures after transdermal scopolamine use was observed in the claims data. However, this was not supported by the primary medical records. All patients who had seizures after using transdermal scopolamine either had seizures before receiving the drug as well or did not really suffer from seizures. The original finding appeared to be the result of the use of transdermal scopolamine for "dizziness, rule out seizures"; the ICD-9-CM coding system does not include "rule out" diagnoses. Thus these data do not confirm the existence of an association between seizures and the use of transdermal scopolamine. In addition, this study demonstrates the usefulness of pharmacoepidemiology studies in documenting drug safety and the importance of obtaining primary medical records when performing pharmacoepidemiologic studies with claims data.

The feasibility of studying drug-induced acute hepatitis with use of Medicaid data.

To determine the feasibility of the use of Medicaid data to study drug-induced acute liver disease, we reviewed the medical records of 414 patients receiving Medicaid, age 20 or older, with an ICD-9-CM inpatient billing code consistent with acute hepatitis. Of the patients whose records were reviewed, 15.9% were alcoholics, 31.9% had acute hepatitis A or B, 13.5% were intravenous drug users, 8.2% had acute cholecystitis or choledocholithiasis, and 4.1% had received a blood transfusion within the previous 6 months. No diagnosis of liver disease was found in 10.6% of the patients, and 5.7% had chronic liver disease. Of the 169 patients with idiopathic acute liver disease identified, many had very mild liver disease and were hospitalized for reasons other than liver disease. We conclude that Medicaid billing data has high reliability and validity for the diagnosis of acute liver disease. However, primary medical records are essential for the study of drug-induced hepatitis, to be able to exclude other causes of liver disease, and to obtain information not included in the computer data.

Is cimetidine associated with neutropenia?

BACKGROUND: Cimetidine is perceived as sufficiently safe that it is being considered for over-the-counter use. However, because of residual concerns about cimetidine-induced neutropenia, a study was conducted to evaluate this association. METHODS: A population-based, case-control study was undertaken using a large database with Medicaid data from six states. Cases were defined as patients hospitalized with a discharge diagnosis of neutropenia. Medical records were sought to validate the diagnoses of neutropenia and to characterize the severity of disease. Four controls were randomly selected for each case, matched for age, sex, state, and year of diagnosis. The frequency of exposures to cimetidine in the 30 days prior to hospital admission in the cases was compared to that in the identical time periods in the controls. RESULTS: When investigators simultaneously controlled for multiple, potentially confounding variables by using conditional logistic regression, the odds ratio associated with the use of cimetidine was 1.2 (P = 0.33), with a one-sided upper 95% confidence limit of 2.6 for all patients over 20 years of age, and 0.6 (P = 0.30) with a one-sided upper 95% confidence limit of 3.1 for validated cases over 12 years of age. Neither a dose-response relationship was evident (P = 0.899 and P = 0.716, respectively, when excluding the nonusers, or P = 0.245 and P = 0.215, respectively, when including the nonusers). From these data, one can exclude the occurrence of hospitalization with neutropenia or agranulocytosis due to cimetidine occurring more often than once in every 116,000 patients and once in every 573,000 patients receiving a 6-week course of the drug, respectively. CONCLUSION: If there is an association between cimetidine and neutropenia, it appears to be very small.

The low risk of upper gastrointestinal bleeding in patients dispensed corticosteroids.

PURPOSE: To determine the incidence of upper gastrointestinal bleeding in patients treated with corticosteroids. PATIENTS AND METHODS: The incidence of upper gastrointestinal tract bleeding was assessed in a cohort of 19,880 patients from the Michigan Medicaid billing database with dermatitis and/or asthma treated with corticosteroids during 1980 to 1984. The frequency of upper gastrointestinal bleeding was assessed within 60 days after each corticosteroid prescription. RESULTS: The incidence of upper gastrointestinal bleeding in patients without a past history of upper gastrointestinal bleeding who were exposed to corticosteroids was only 2.8 cases per 10,000 person-months. The rate of upper gastrointestinal bleeding was notably higher in patients receiving anticoagulants and those with a prior history of upper gastrointestinal bleeding (23.0 and 15.9 cases per 10,000 person-months, respectively). CONCLUSION: Because the incidence of upper gastrointestinal bleeding in ambulatory patients treated with corticosteroids is so low, prophylactic therapy should be restricted to high-risk patients, if it is to be used at all.

Physician demographics and the risk of medical malpractice.

PURPOSE: This study was undertaken to clarify which, if any, physician demographic characteristics are associated with an increased rate of medical malpractice claims. METHODS: We analyzed the malpractice experience of 9,250 physicians insured for at least 2 years from 1977 to 1987 in the state of New Jersey. After adjusting for years at risk, physician claims per year was categorized into low, medium, and high. RESULTS: Male physicians were three times as likely to be in the high-claims group as female physicians, even after adjusting for other demographic variables (relative risk, 3.1; 99% confidence interval, 2.2 to 4.4). Specialty was strongly associated with claims rate, with neurosurgery, orthopedics, and obstetrics/gynecology having 7 to 12 times the number of claims per year as psychiatry, the specialty with the fewest claims. The rate of claims varied with age (p < 0.001) and peaked at approximately age 40. No association was evident between claims rate and a physician's site of training or type of degree. CONCLUSION: Male physicians are three times as likely to be in a high-claims category as female physicians. We suspect that the most likely explanation for this finding is that women interact more effectively with patients. Understanding the reasons for the variation in claim rates between physicians may lead to the development of methods to reduce the overall rate of malpractice claims.