Nighttime administration of high-dose, sustained-release melatonin does not decrease nocturnal blood pressure in African-American patients: Results from a preliminary randomized, crossover trial.

OBJECTIVES: This preliminary study tested whether a high-dose, sustained-release form of melatonin reduced 24-hour blood pressure in African-Americans. DESIGN: Randomized, placebo-controlled, crossover pilot study of 40 self-defined African-American patients with essential hypertension. SETTINGS/LOCATION: Urban, academic medical center and associated outpatient clinics. INTERVENTIONS: Patients ingested either melatonin (high dose [24 mg], sustained-release formulation] or placebo in randomized order over a 4-week period. OUTCOME MEASURES: Mean nighttime and daytime systolic and diastolic blood pressures, as measured with 24-hour ambulatory blood pressure monitors. The primary outcome was mean nighttime systolic blood pressure. RESULTS: There were no statistically differences between melatonin and placebo conditions in mean nighttime or daytime systolic or diastolic blood pressures. CONCLUSIONS: In contrast with studies in other populations, this preliminary study showed that nighttime dosing of continuous-release melatonin had no significant effect on nocturnal blood pressure in African Americans with essential hypertension when compared to placebo.

Factors associated with stereopsis and a good visual acuity outcome among children in the Infant Aphakia Treatment Study.

PurposeTo identify factors associated with stereopsis in children with good visual acuity after unilateral congenital cataract surgery in the Infant Aphakia Treatment Study.Patients and methodsInfants with a unilateral congenital cataract (n=114) were randomized to IOL implantation or contact lens correction after cataract surgery. At age 4.5 years, a masked examiner assessed HOTV acuity and stereopsis. Adherence to patching was assessed using 48-h recall telephone interviews and 7-day diaries throughout the first 5 years of life. Ocular motility was evaluated at age 5 years. Baseline, postoperative, and adherence findings were compared between patients with 20/40 or better acuity in their treated eyes with or without stereopsis.ResultsThirty (27%) of 112 patients who were evaluated at age 4.5 years had 20/40 or better acuity in their treated eye. Stereopsis was present on one or more tests in 15 of these 30 (50%) children. Baseline characteristics and postoperative findings did not differ between patients with or without stereopsis. Children with stereopsis were more likely to be orthotropic at distance (P=0.003) and were patched for fewer hours per day throughout the first 5 years of life and the difference increased over time (P<0.001). On average children with stereopsis were patched for 3.4 h/day during the first year of life and patching steadily decreased to 1.8 h/day by age 4 years.ConclusionAmong children with good vision following unilateral congenital cataract surgery, orthophoria and fewer hours of patching, particularly during years 2, 3, and 4, are associated with some evidence of stereopsis.

Gene amplification as a prognostic factor in primary brain tumors.

The most reliable prognostic factors for patients with primary malignant brain tumors remain histology, age, and functional status. Management of these individuals might be improved by quantifying pertinent molecular markers. We have measured the gene dosage of the epidermal growth factor receptor (EGFR), mouse double minute 2 (MDM2), and cyclin-dependent kinase 4 (CDK4) genes in a series of brain tumor specimens and correlated their amplification status with standard prognostic factors and survival. Individual tumor DNA was successively hybridized with probes for EGFR, MDM2, and CDK4. The signal was quantified by densitometry, and amplification was defined as gene signal > or = 2 times normal. Survival, age, Karnofsky performance status, and histology were correlated with gene amplification. Nineteen astrocytomas, 20 anaplastic astrocytomas, and 70 glioblastomas had complete data available. Median survival with and without any form of gene amplification was 70.7 and 88.6 weeks, respectively (P = 0.0369). For the EGFR gene alone, those with and without amplification had a median survival of 58.9 and 88.6 weeks, respectively (P = 0.0104). By Cox analysis, only tumor histology (P = 0.04) and Karnofsky performance status (P = 0.0157) were significant independent predictors of survival. Gene amplification by itself was not predictive of survival, even for glioblastomas (P = 0.8249). The lack of correlation between gene amplification and survival for patients with primary malignant brain tumors may be because EGFR, MDM2, and CDK4 are only portions of larger signaling systems. Therefore, the lack of a direct correlation between a single gene and outcome is not entirely unexpected.

Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a well-established cause of gastrointestinal disease. There appears to be an association with peptic ulcer disease complications, specifically ulcer-related bleeding. Studies addressing this relationship have primarily evaluated prescription use of these agents. There has been little study of over-the-counter NSAID use in patients with either ulcer or nonulcer-related upper gastrointestinal hemorrhage. METHODS: Consecutive patients with upper gastrointestinal hemorrhage evaluated by a gastroenterology consultative service at a large inner-city hospital from August 1, 1990 to July 31, 1992 were identified. The use of any prescription or over-the-counter NSAID during the week before admission was prospectively assessed. Computerized pharmacy records were available for confirmation of prescription drug use. RESULTS: During the 2-year period of study, 421 patients were evaluated for upper gastrointestinal hemorrhage. The mean age of the patients was 50 years and the majority were male and black. The most common cause of bleeding was peptic ulcer disease, identified in over 50% of patients. Use of an over-the-counter aspirin or nonaspirin NSAID was reported in 145 patients (35%) and 36 patients (9%), respectively, during the week before admission. Prescription use of a nonaspirin NSAID or aspirin was reported in 56 patients (14%) and 27 patients (6%), respectively. The overall prevalence of NSAID use during the week before admission was 56% (95% confidence interval, 51.2% to 60.8%). The use of any NSAID was significantly associated with gastric compared with duodenal ulcer hemorrhage, and ulcer-related bleeding compared with variceal hemorrhage. CONCLUSIONS: Over-the-counter NSAID use is frequent in our patient population and exceeds prescription use. Although ulcer-related bleeding was significantly associated with use of these drugs, NSAIDs were commonly used in patients with nonulcer-related upper gastrointestinal hemorrhage as well. Over-the-counter NSAID use may represent a more important cause of peptic ulcer disease and ulcer-related hemorrhage than previously appreciated.

Time course of regression of left ventricular hypertrophy in treated hypertensive patients.

In a prospective study, 32 hypertensive patients with echocardiographic evidence of left ventricular hypertrophy were treated with methyldopa, hydrochlorothiazide, or methyldopa and hydrochlorothiazide combined. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months thereafter; in 27 patients these studies were also obtained after 12 and 18 months. Left ventricular end-diastolic posterior wall thickness decreased in seven patients whose blood pressure was controlled with methyldopa alone (p less than 0.01) and in 17 patients whose blood pressure was controlled with methyldopa and hydrochlorothiazide combined (p less than 0.01); in both groups, the reduction in left ventricular posterior wall thickness at end-diastole was apparent one month after blood pressure control was established (p less than 0.05). In contrast, no significant reduction in left ventricular posterior wall thickness at end-diastole was observed in eight patients who had equivalent control of blood pressure with hydrochlorothiazide alone (p = 0.34). During the 18-month follow-up period, ventricular septal thickness at end-diastole decreased in the group treated with methyldopa and hydrochlorothiazide combined (p = 0.03); whereas, ventricular septal thickness at end-diastole appeared to increase in the group treated with hydrochlorothiazide alone (p less than 0.01). These results suggest that evidence of regression of left ventricular hypertrophy may be detected as early as one month after blood pressure is controlled with methyldopa or methyldopa and hydrochlorothiazide combined; whereas, long-term control of hypertension with hydrochlorothiazide alone was not associated with evidence of regression of left ventricular hypertrophy. Although the patient number are small, these data suggest that there are differences in the long-term effects of diuretics and sympatholytic drugs on left ventricular anatomy, which may, in part, relate to divergent effects on the sympathetic nervous system.

Quality-of-life changes and psychiatric and neurocognitive outcome after heart and liver transplantation.

A prospective study compared psychiatric, neurocognitive, and quality-of-life changes of heart and liver transplant patients. The 51 heart and 61 liver transplant candidates and recipients completed the Beck depression inventory (BDI), state-trait anxiety inventory (STAI), sickness impact profile (SIP), mini-mental state (MMS), California verbal learning test (CVLT), Wisconsin card sorting test (WCST), trailmaking test (TMT), and the impact message inventory (IMI). Data were gathered before transplant and at 3-month intervals for up to 1 year after transplant. Psychometric tests scores were correlated with electroencephalograms for the liver patients. Both groups showed significant improvements after transplant in neurocognitive functioning, depressive symptoms, and quality of life.

Exercise testing and training in physically disabled men with clinical evidence of coronary artery disease.

A prospective, randomized, controlled clinical trial in patients with coronary artery disease (CAD) and a concurrent physical disability evaluated the effects of a home exercise training program on cardiovascular function and blood lipids. Eighty-eight men between the ages of 42 and 72 years (mean 62) with documented CAD and a physical disability with functional use of > or = 2 extremities including 1 arm were randomized to either a 6-month home exercise training program using wheelchair ergometry or to a control group that received usual and customary care. Both groups received dietary instructions and were requested to follow a fat-controlled diet. Exercise test variables with echocardiography and blood lipids were measured at baseline and at 6 months. The home exercise training group significantly improved both peak exercise left ventricular ejection fraction (p = 0.007) and fractional shortening (p = 0.01) between baseline to 6 months, whereas the control group showed no significant changes. Exercise training effects of decreased resting heart rate (p = 0.03) and decreased peak rate pressure product (p = 0.03) were also found in the treatment group. No exercise-related cardiac complications occurred. Both groups significantly (p < or = 0.01) increased high-density lipoprotein cholesterol levels. These results indicate that physically disabled men with CAD can safely participate in a home exercise training program which may result in intrinsic cardiac benefits. The metabolic cost of activities of daily living imposed on this disabled population may also have a positive effect on high-density lipoprotein cholesterol levels.

Elevated concentrations of dopamine sulfate in plasma of cocaine abusers.

This study investigated the effect of cocaine abuse on peripheral catecholamines. Specifically, we measured the concentration of free dopamine, dopamine sulfate, free norepinephrine, norepinephrine sulfate, free epinephrine and epinephrine sulfate in plasma samples obtained from the blood of a group of patients with cocaine addiction (N = 15). The concentrations of free and sulfoconjugated catecholamines in plasma were measured by a radioenzymatic technique. The results of this study revealed significant (P < 0.0001) elevation in plasma dopamine sulfate (8926 +/- 1204 pg/mL) of cocaine addicts upon admission to an in-patient treatment facility when compared with the level of this dopamine metabolite in plasma of control subjects (2356 +/- 121 pg/mL). Furthermore, there was a significant (P < 0.0001) relationship between elevation in plasma dopamine sulfate levels and severity of cocaine use among these patients, and in the majority of cases the plasma levels of dopamine sulfate declined appreciably in time with abstinence from cocaine. In contrast, no appreciable difference was observed in the concentrations of either free or sulfate-conjugated norepinephrine and epinephrine in plasma of cocaine addicts as compared with controls. Differences in plasma dopamine sulfate among these patients versus controls may be interpreted as a reflection of activation of extracellular dopamine metabolism associated with chronic cocaine exposure in humans.

Analysis of cyclin dependent kinase inhibitors in malignant astrocytomas.

The cyclin-dependent kinase inhibitors p16, p21, and p27 in human brain, and brain tumors were examined to explore clinicopathologic correlations. Western analysis and immunohistochemistry was performed and correlated retrospectively with the patients clinical characteristics. A trend was found between increased progression-free survival and p27 expression. There was no correlation between p27 expression and age or gender. The expression of p27 in malignant gliomas may have prognostic value. In addition, an investigation of the therapeutic benefit of overexpression of this cyclin-dependent kinase inhibitor is warranted given reports of diminished malignant potential of tumors expressing p27.

A multi-center analysis of the use of enalapril and lisinopril in elderly hypertensive patients.

OBJECTIVE: To evaluate the clinical use and adverse effects of enalapril and lisinopril in elderly hypertensive subjects. DESIGN: A multi-center, retrospective, drug use evaluation survey. SETTING: Ambulatory care clinics at 14 VA and 14 academic medical centers. PATIENTS: 422 elderly (> 60 years of age) patients with hypertension and no clinical evidence of congestive heart failure. INTERVENTION: At least 3 consecutive months of anti-hypertensive therapy with either enalapril or lisinopril. MEASUREMENTS: Blood pressure, serum creatinine, serum potassium, concomitant disease states, concurrent medications, and documentation of any adverse event that might be related to ACE inhibitor therapy. RESULTS: There were no significant differences in systolic and diastolic blood pressures, serum creatinine, or serum potassium between enalapril- and lisinopril-treated patients at baseline and after 3 months of therapy. Both treatments resulted in a significant reduction in diastolic blood pressure. There was no significant difference in the incidence of adverse effects between the two treatments. Significantly more patients were dosed on a twice daily regimen of enalapril than lisinopril. CONCLUSION: The data from this retrospective study confirm the safe and effective use of enalapril and lisinopril, two long-acting ACE inhibitors, in elderly hypertensive patients.

Evaluation of staging lymphadenectomy in prostate cancer.

OBJECTIVES: To prospectively evaluate a clinical algorithm that predicts nodal status in patients with prostate cancer and to assess the impact on the outcome. METHODS: Between September 1988 and December 1994, 192 patients with organ-confined prostate cancer and considered surgical candidates for radical perineal prostatectomy (RPP) were stratified using the algorithm: prostate-specific antigen (PSA) 20 ng/mL or less, Gleason score 7 or lower, and clinical Stage T2a or lower. Patients failing any of these criteria were placed in the high-risk group and underwent a pelvic lymphadenectomy. Patients who satisfied all the criteria were placed in the low-risk group and underwent RPP without evaluation of the pelvic lymph nodes. Another contemporaneous cohort of patients (n = 65) underwent pelvic lymphadenectomy and radical retropubic prostatectomy (RRP) without use of the algorithm and were used as a control group. Patients were monitored for at least 24 months. RESULTS: In the RPP group, 177 patients were considered low risk according to the algorithm and were not offered staging lymphadenectomy before surgery, whereas 15 patients were categorized as high risk for metastasis and underwent staging lymphadenectomy. In the RRP and lymphadenectomy group, 41 patients were considered at low risk and 24 at high risk of disease spread according to the algorithm. In the RPP group, low-risk patients (no lymphadenectomy) had a PSA recurrence rate (27%) similar to that of low-risk patients in the RRP group with negative lymph nodes (29%), P = 0.8. Similarly, high-risk patients with negative lymph nodes in both groups had a similar recurrence rate (53% for RPP and 50% for RRP). Univariate logistic regression analysis showed that PSA was the most significant predictor for disease recurrence (P = 0.0004) followed by preoperative Gleason scores (P = 0.02) and clinical stages (P = 0.03). Multivariate stepwise analysis demonstrated that Gleason score and clinical stage did not add to the prediction of recurrence over PSA alone. CONCLUSIONS: Staging lymphadenectomy can be omitted in low-risk patients without deleterious effects on the outcome as measured by PSA recurrence.

Progesterone receptor immunohistochemical quantitation compared with cytosolic assay: correlation with prognosis in breast cancer.

Quantitation of estrogen and progesterone receptors (PR) represents the standard of care in the treatment of patients with breast cancer. Historically this was performed by cytosolic assay; current methods utilize immunohistochemical staining, which may be quantitated visually or by image cytometry. Formalin-fixed paraffin embedded sections from 95 breast carcinomas were immunostained with an avidin-biotin complex technique. steam antigen retrieval, and a monoclonal PR antibody (1/40 Biogenex). Nuclear immunostain was quantitated visually as the percentage of immunopositive nuclei, scored as 0 to 4. By image cytometry, the percentage of positively staining nuclear area (PPNA) was determined in 15 hpf using the CAS 200 Image Analyzer. Dextran-coated charcoal (DCC) ligand binding assay data were divided into negative (<10 fmol), low positive (10-50), or positive (>50). A statistically significant correlation was found between stage (P = 0.0001), the presence of nodal metastases (P = 0.0001), cytosolic assay (P = 0.036), image cytometry (P = 0.01), and disease-free survival. Only stage (P = 0.0001) and PR quantitation per cytosolic assay (P = 0.0001) correlated with overall survival. The method of choice for the assessment of PR hormone status in breast carcinomas is the DCC ligand binding assay. This method correlates with both survival and disease-free survival. Image cytometric quantitation of PR immunohistochemical staining correlates only with disease-free survival. The commonly used method of visual quantitation of PR immunostaining fails to relate either to survival or disease-free survival.

Hepatocellular carcinoma and markers of apoptosis (bcl-2, bax, bcl-x): prognostic significance.

Patients with tumors expressing promoters of apoptosis (bax) versus inhibitors of apoptosis (bcl-2, bcl-x) may have increased survival. The purpose of this study was to determine the frequency of expression of apoptotic markers in hepatocellular carcinoma (HCC) and their relationship with prognosis. Seventy HCC were immunostained for bcl-2, bax, and bcl-x. Staining intensity in tumor cells was graded 0 to 3+. Follow-up data were available for mean survival (57 cases) and death rates (58 cases). These values and clinical parameters were related to prognosis. Staining frequency for bcl-2, bax, and bcl-x was 20%, 66%, and 60%, respectively. Immunostaining intensity of bax correlated with overall survival and death rates: of 57 patients, the 37% with 0 to 1+ intensity had a median survival of 6.6 months, the 63% with 2 to 3+ intensity had a median survival of 31.9 months (P = 0.05); 86% of 19 patients with 0 to 1+ intensity died, and 50% of 36 patients with 2 to 3+ intensity died (P < 0.05). Intensity of bcl-x staining tended to correlate with survival: of the 57 patients with 0 to 1+, 42% had a median survival of 32.7 months compared with 5.8 months in the 58% with 2 to 3+ intensity (P = 0.06). By multivariate analysis, this relationship held for bax (P = 0.011) and bcl-x (P = 0.048). There was no correlation between bcl-2 expression, stage, or gender and prognosis. Patients with bax-expressing HCC experience improved survival compared with those with no or low bax expression, in uni- and multivariate models. Patients with no or low bcl-x tended toward improved survival compared with patients with more bcl-x in their HCC. bcl-2 expression did not correlate with prognosis.

Analysis of residents' performances on the In-Training Examination of the American Board of Anesthesiology-American Society of Anesthesiologists.

An analysis of the results of the In-Training Examination of the American Board of Anesthesiology-American Society of Anesthesiologists has been developed using a new question-categorization method and a new form of calculation, the resident index score. Resident index scores permit comparison of the performance of any program's residents with the performance of all U.S. residents who took the examination. This study analyzed examination results from eight residency programs for a five-year period, 1983-1987. Statistically significant differences in the residents' performances were found both within and among the residency programs during this time. Areas of educational strength and weakness were identified by levels of training for each program. The analyses of the individual programs' results were provided to the respective program directors on a confidential basis, and have been used to change curriculum content, modify lectures for residents, and provide structured review for residents. Similar analyses can be provided as a service to other residency program directors.

Resting metabolic rate: measurement reliability.

Resting metabolic rate (RMR) usually is measured by indirect calorimetry for a brief interval, and the results are then extrapolated to 24-hr resting energy production. The aim of the current study was to examine the validity of this approach by measuring the within- and between-day variability in RMR. The RMR was measured hourly in 14 healthy adults from 8:00 am to 4:00 pm after an overnight fast on two separate days. The results indicated that, during day 1, RMR remained unchanged from early morning to late afternoon, and there was no significant difference between RMR measurements 1 through 8. Based upon analysis of variance and intraclass correlation coefficients, the averages of the first and the last three RMR measurements were found to be unreliable. RMR reliability was improved by averaging all measurements taken during the day, and maximum reliability was obtained by averaging the middle three RMR measurements. A similar pattern of results was observed during day 2, although the overall trend was for the reliability of RMR measurements to improve relative to day 1. The average RMRs on days 1 and 2 were not significantly different. These results indicate that the current practice of establishing a patient's RMR based upon a single measurement potentially can lead to large errors in determining energy needs. Measurement reliability can be improved by serially measuring RMR, eliminating the initial measurement, and averaging the remaining two to three values.

Experimental peri-implantitis in consecutively placed, loaded root-form and plate-form implants in adult Macaca mulatta monkeys.

This study is part of an on-going project describing the character of round- and plate-form implants placed in a primate model. In this paper 20 loaded plate-form and 23 root-form implants were connected to prostheses and experimental peri-implantitis was induced by ceasing scaling procedures and placing braided silk ligature around the implants. Twenty-four prostheses utilizing natural teeth were studied for comparison. Clinical measurements were carried out monthly for 6 months and radiographic measurements at 3 and 6 months post-ligature placement and cessation of scaling. Both root-form implants and plate-form implants showed a significant loss of crestal bone height at 3 and 6 months after ligature placement (P < .001 after 6 months). The difference in bone loss between plate- and root-form implants, however, was not significant.

Analysis of consecutively placed loaded root-form and plate-form implants in adult Macaca mulatta monkeys.

The present paper describes 36 consecutively treated non-human primates (Macaca mulatta) as part of a balanced block design study to examine osseointegration in root- and plate-form implants prepared by atraumatic preparation of bone. Clinical measurements around selected teeth and digital radiology were utilized to monitor periodontal disease and bone loss around root- and plate-form implants which were loaded with a fixed prosthesis. Results indicate that once monthly regimen of scaling and root planing can prevent attachment loss in natural teeth, serving as abutments of loaded bridges. Root-form implants exhibited a significant loss of crestal bone height during the first year (P < 0.03) while plate-form implants showed less loss in bone height. There was an increase in bone mass over time for root-form or plate-form implants. Both root-form and plate-form implants provided radiographic evidence of osseointegration in loaded bridges.

The incidence of meconium-stained amniotic fluid from 1980 through 1986, by year and gestational age.

The annual incidence of meconium-stained amniotic fluid was analyzed for changes in a total obstetric sample of 45,115 singleton, vertex, liveborn infants over a 7-year study period. The incidence of meconium-stained amniotic fluid for the total obstetric population was calculated for each year of the study period. The sample was then stratified by estimated gestational age, and the incidence of meconium-stained amniotic fluid was calculated for each gestational age group. The incidence of meconium-stained amniotic fluid increased 40.9% over the study period, from 18.8% in 1980 to 26.5% in 1986 (P less than .001). This increase was found to be in a consistent linear trend (P less than .05). The incidence of meconium-stained amniotic fluid was also found to increase significantly in a linear trend as gestational age of the fetus increased. These findings lend support to both the maturational theory and the stress theory of meconium passage in utero.

Risk factor status and vascular events in patients with symptomatic intracranial stenosis.

BACKGROUND: There are limited data on the relationship between control of vascular risk factors and vascular events in patients with symptomatic intracranial arterial stenosis. METHODS: We utilized the Warfarin Aspirin Symptomatic Intracranial Disease study database to analyze vascular and lifestyle risk factors at baseline and averaged over the course of the trial. Cutoff levels defining good control for each factor were prespecified based on national guidelines. Endpoints evaluated included 1) ischemic stroke, myocardial infarction, or vascular death or 2) ischemic stroke alone. Univariate associations were assessed using the log-rank test and multivariable analysis was done using Cox proportional hazards regression. RESULTS: From baseline until year 2 follow-up, there was not a significant improvement in blood pressure control. During the same period, there were improvements in patients with total cholesterol <200 mg/dL (54.6% to 79.2%, p < 0.001) or low-density lipoprotein <100 mg/dL (28.7% to 55.9%, p < 0.001). Multivariable analysis showed that systolic blood pressure >or=140 mm Hg (HR = 1.79, p = 0.0009, 95% confidence limits 1.27 to 2.52), no alcohol consumption (HR 1.69, 1.21 to 2.39, p = 0.002), and cholesterol >or=200 mg/dL (HR 1.44, 1.004 to 2.07, p = 0.048) were associated with an increased risk of stroke, myocardial infarction, or vascular death. The same risk factors were predictors of ischemic stroke alone in multivariable analysis. CONCLUSIONS: Elevated blood pressure and cholesterol levels in symptomatic patients with intracranial stenosis are associated with an increased risk of stroke and other major vascular events.

Models for the statistical analysis of infectious disease data.

The Longini-Koopman model (1982, Biometrics 38, 115-126) describes the process underlying the transmission of an infectious disease in terms of household and community level transmission probabilities. This model is generalized by allowing for different transmission probabilities that may correspond to various levels of risk factors on both the household and community levels. Two types of models are considered: (i) models for household data, where the numbers of susceptible and infected members in each household are known along with the values of household level risk factors; and (ii) models for individual data, where the infection status and risk factor level are known for each individual in the household. Although the type (i) models can be expressed as special cases of the type (ii) models, they deserve special attention as they can be represented and analyzed as log-linear models. Both types of models can be analyzed using maximum likelihood methods, while the type (i) models, when expressed as log-linear models, can also be analyzed by the weighted least squares method. Data from influenza epidemics in Tecumseh, Michigan and Seattle, Washington are used to illustrate these methods.