The combined effects of dietary fat, protein, and energy intake on azoxymethane-induced intestinal and renal carcinogenesis.

Two 3 x 3 factorial experiments were conducted to examine the effects of dietary protein (8, 16, and 32% of energy from casein) and dietary fat (12, 24, and 48% of energy from corn oil) on the initiation and promotion of azoxymethane-induced carcinogenesis in rats. For the initiation study, 33 weanling male Sprague-Dawley rats were randomized to each of nine diets fed ad libitum. Azoxymethane was administered s.c. between the fourth to sixth weeks of feeding, providing a total dose of 6 mg/100 g body weight. All rats were subsequently fed a common diet containing 16% energy from protein and 24% energy from fat for an additional 30 to 38 weeks. For the promotion study, all rats were fed a common diet containing 16% of energy from protein and 12% of energy from fat until the completion of azoxymethane administration, when 33 rats were randomized to each of nine diets varying in fat and protein content and fed these diets until sacrifice. Low-protein diets during the initiation phase were associated with increased risk of renal adenocarcinomas (P less than 0.001) and mesenchymal (P = 0.005) malignancies. No other statistically significant relationships were found between the levels of dietary fat or protein and the prevalence of malignant lesions of the small intestine, colon, or kidney in either the initiation or promotion study (although polypoid adenocarcinoma of the colon increased suggestively from 13 to 19 to 26% of rats with increasing dietary protein during initiation). Results of a multiple logistic regression analysis, combining both studies, showed that ad libitum energy intake was significantly associated with intestinal carcinogenesis. The odds of finding an intestinal adenocarcinoma increased by 6.2 +/- 2.6% (SE) for each additional kilocalorie of mean daily ad libitum intake (P = 0.014). The quintile of rats which consumed the least averaged 60 kcal/day, while the most voracious quintile averaged 74 kcal/day. This 14 kcal/day difference in mean ad libitum intake corresponded to more than a doubling (146% increase) of the odds of developing an intestinal adenocarcinoma. These studies suggest that ad libitum energy intake is a critical factor modulating experimental colon carcinogenesis.

Infectious disease consultation and microbiologic surveillance for intensive care unit trauma patients: a pilot study.

Infection remains a major cause of posttrauma morbidity. We retrospectively reviewed 2 cohorts of trauma patients admitted to a regional trauma center before and after a policy change integrating prospective microbiologic surveillance and infectious disease (ID) consultation into management of trauma admissions. Primary interests were effects of this policy change on antimicrobial use and diagnostic precision (particularly differentiation of infection from colonization). Associated costs, microflora, survival, and disability were also compared. Patients were stratified for risk of infection. ID consultation was associated with a 49% increased odds that an infection diagnosis was microbiologically based (P=.006) and 57% reduction of antibiotics costs per hospitalized day (P=.0008). Costs of consultation and an 86% increase (P<10(-6)) in total cultures combined to minimally exceed that financial saving. The observed improvements in diagnostic precision and antimicrobial usage, however, suggest consideration of prospective microbiologic surveillance and multidisciplinary physician teams including ID physicians for high-risk trauma patients.

Prevention of postoperative pulmonary complications with CPAP, incentive spirometry, and conservative therapy.

Continuous positive airway pressure (CPAP) administered at intervals with a mask and incentive spirometry (IS) were compared with a regimen of coughing and deep breathing (CDB) to determine which promoted the most rapid recovery of pulmonary function after upper abdominal operations in 65 adults. Postoperatively, FRC of patients in all groups was similar relative to preoperative values. However, mean FRC of patients who received CPAP increased more rapidly than did mean FRC of those receiving CDB when compared to the values obtained following operation (p less than 0.05). Incentive spirometry did not increase FRC to a greater extent than did CDB. Roentgenographic evidence of atelectasis 72 hours postoperatively was observed in 23 percent of CPAP patients (five of 22) and 42 percent and 41 percent of patients who received CDB (eight of 19) and IS (nine of 22). Two patients (3 percent) developed pneumonia. The low incidence of pneumonia regardless of the type of therapy may be attributable to vigorous, vigilant respiratory care in a population at high risk for developing pneumonia. Frequency and supervision of respiratory therapy may be more important than the type of therapy delivered after upper abdominal operations. Mask CPAP offers advantages because it requires no effort from the patient, and therapy is not painful.

Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat.

BACKGROUND: During 1990-1992, 282 Chinese residents of Selangor and the Federal Territory, Malaysia with histologically confirmed nasopharyngeal carcinoma (NPC) were interviewed about occupational history, diet, alcohol consumption, and tobacco use, as were an equal number of Malaysian Chinese population controls, pair-matched to cases by age and sex. METHODS: Exposures to 20 kinds of workplace substances, solar and industrial heat, and cigarette smoke, were analysed by univariate and multivariate methods. RESULTS: Nasopharyngeal carcinoma was associated with occupational exposures to construction, metal and wood dusts; motor fuel and oil; paints and varnishes; certain other chemicals; industrial heat; solar heat from outdoor occupations; certain smokes; cigarette smoking; and childhood exposure to parental smoking. After adjustment for risk from diet and cigarette smoke, only wood dust (OR = 2.36; 95% CI : 1.33- 4.19), and industrial heat (OR = 2.21; 95% CI : 1.12-4.33) remained clearly associated. Wood dust remained statistically significant after further adjustment for social class. No significant crude or adjusted association was found between NPC and formaldehyde (adjusted OR = 0.71; 95% CI : 0.34-1.43). CONCLUSIONS: This study supports previous findings that some occupational inhalants are risk factors for NPC. The statistical effect of wood dust remained substantial after adjustment for diet, cigarette smoke, and social class. Intense industrial heat emerged as a previously unreported risk factor, statistically significant even after adjustment for diet and cigarette smoke. No association was found between NPC and formaldehyde.

Analysis of clinical trials involving non-cavitated caries lesions.

Treatments to halt or reverse the progression of non-cavitated caries lesions are of increasing interest. Diagnostic technologies under development offer potential for the assessment of gradual progression and regression of such lesions. Many therapies directed at correcting demineralization-remineralization imbalance should, in principle, protect enamel similarly across lesion severities from initiation to near cavitation. If this is so, and if acceptable reproducibility and predictive validity can be demonstrated for a diagnostic of acceptable cost, then clinical trials of agents to prevent cavitation can become more efficient by the use of outcome indices that reflect, in addition to cavitation, the expansion and regression of non-cavitated lesions. However, to achieve such a benefit will require data analyses that fully exploit ordinal or continuous-scale outcome measures. We consider comparison of such measures of lesion status between treatment groups, with most attention to ordinal categorical data. Interim data from a clinical trial in Lithuanian children are used for illustration.

Design and analytic concepts for periodontal clinical trials.

Aspects of the design and analysis of periodontal clinical trials are surveyed from a biostatistical perspective. Design issues discussed include protocol preparation, subject selection and its documentation, randomization, problems associated with the sample versus population paradigm in sampling of microbes and gingival fluid constituents, quality control, cross-over and split-mouth versus parallel-arm designs, blinding, and multicenter trials. Analytic discussion deals with the definition and choice of analytic unit, appropriate methods for the analysis of data from multiple sites within the same subject, the nature and application of randomization tests, interim analyses, subgroup analyses, and multiple comparison issues. Examples are provided to illustrate the feasibility of analyzing site-specific data while accounting for intra-subject correlation, which represents the increased similarity of sites chosen from the same mouth as compared to sites from different patients.

Adult root caries survey of two similar communities with contrasting natural water fluoride levels.

For a comparative study of root caries, 502 adult lifelong residents of a naturally fluoridated community (1.6 ppm F) and 465 such residents of a nearby, comparable nonfluoridated community (0.2 ppm F) were examined. Substantially fewer carious lesions were found among adults in the fluoridated community relative to the nonfluoridated community. This was observed in virtually all age- and gender-specific groups. Given a cross-sectional design and considering only exposed root surfaces, root caries was related to age. In addition, the data from this study show that the number of root caries lesions is underestimated but that root caries prevalence is overestimated by the standard Root Caries Index (RCI). A less restrictive form of the RCI may lead to more valid estimation of root caries prevalence.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Considerations in the statistical analysis of clinical trials in periodontitis.

Adult periodontitis has been described as a chronic infectious process exhibiting sporadic, acute exacerbations which cause quantal, localized losses of dental attachment. Many analytic problems of periodontal trials are similar to those of other chronic diseases. However, the episodic, localized, infrequent, and relatively unpredictable behavior of exacerbations, coupled with measurement error difficulties, cause some specific problems. Considerable controversy exists as to the proper selection and treatment of multiple site data from the same patient for group comparisons for epidemiologic or therapeutic evaluative purposes. This paper comments, with varying degrees of emphasis, on several issues pertinent to the analysis of periodontal trials. Considerable attention is given to the ways in which measurement variability may distort analytic results. Statistical treatments of multiple site data for descriptive summaries are distinguished from treatments for formal statistical inference to validate therapeutic effects. Evidence suggesting that sites behave independently is contested. For inferential analyses directed at therapeutic or preventive effects, analytic models based on site independence are deemed unsatisfactory. Methods of summarization that may yield more powerful analyses than all-site mean scores, while retaining appropriate treatment of inter-site associations, are suggested. Brief comments and opinions on an assortment of other issues in clinical trial analysis are preferred.

Logical and analytic issues in dental/oral product comparison research.

Possible meanings of "superiority" and "equivalence" in comparative dental studies are considered. A proposed refinement of vocabulary is introduced to precisely distinguish between these meanings. Implications for data analysis of different interpretations of "superiority" and "equivalence" are explored, as are implications for study design where design and analytic considerations are inseparable. Conceptual problems of equivalence studies are stressed. Choice of analytic unit(s), scaling of dependent variables, use of surrogate variables, and validity checking are discussed as they pertain to comparative studies. Analytic methods for correlated responses and categorized responses are briefly surveyed, particularly with reference to periodontal research.

On a method for studying family size preferences.

The concept of desired family size is widely accepted, and numerous studies have been undertaken to measure its level in certain population groups. The determination of desired family size has generally followed the direct question procedure through which the respondent states some whole number as representing her family size wishes at some specified period in her life. Limitations of this method have been recognized, and some research has been conducted toward the development of other techniques of measuring desired family size. The purpose of this paper is to discuss a method of estimating desired family size based on the concept of paired comparison, where the response is restricted in order to reduce respondent bias. Emphasis is on estimation of parameters and test statistics appropriate for evaluating the applicability of the underlying model.

Genetic study of infantile spasm with hypsarrhythmia.

Infantile spasms (IS) appear to be a distinct syndrome complicated by heterogeneous etiology. Family data support a multifactorial model involving a polygenic determination of susceptibility to IS but requiring environmental factors such as anoxia, birth trauma, or immunization to precipitate seizures. The empiric recurrence risk among siblings was estimated to be 15 +/- 3 and for all first degree relatives as 7 +/- 5 per 1,000. These risks should be interpreted with caution since possible heterogeneity of IS may result in the occurrence of families in which cases are presumably totally environmental, and other rare families which may be segregating for an autosomal recessive disorder. Careful review of involved medical and family histories and a thorough physical examination should permit discrimination among these possibilities.

The combined effects of dietary protein and fat intake during the promotion phase of 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.

A 3 X 3 factorial experiment was conducted to examine the effects of dietary protein (8, 16 or 32% of energy from casein) and dietary fat (12, 24 or 48% of energy from corn oil) on the promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis in rats. A purified diet with protein and fat supplying 16 and 24% of energy, respectively, was fed to 360 rats. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. Forty rats were then randomly assigned to each of the nine dietary treatments for 28 wk. We observed no effects of protein or interactions between protein and fat on mammary tumorigenesis. At necropsy, rats fed diets containing 12, 24 and 48% of energy from corn oil following DMBA administration showed tumor prevalences of 53, 60 and 70% with 109, 127 and 140 total tumors, respectively. Linear logistic statistical modeling indicated that each doubling of dietary fat concentration multiplied the odds of finding a tumor of any histologic type at necropsy by 1.52. Dietary fat had no significant effects on the prevalence of adenomas or fibroadenomas, whereas those fed corn oil at 12, 24 and 48% of dietary energy showed adenocarcinoma prevalences of 34, 41 and 52% with total adenocarcinoma counts of 66, 75 and 96, respectively. Our results suggest that increasing dietary fat enhanced the promotion of DMBA-induced breast carcinogenesis over a wide range of protein intake.

Secular variation in frequency of premature ventricular contractions in untreated individuals.

Six-hour electrocardiographic monitorings were initially recorded from 40 ambulatory adult subjects (39 male, one female) on successive days. Thirty-eight of the subjects were monitored 6 weeks to 18 months later. Studies of paired time periods, Poisson modeling, and other statistical examinations were performed. Despite an underlying consistency in the data, there was considerable variation in PVC frequency from hour to hour, day to day, and over longer periods of time.

Minor ailments and illness behavior among physicians.

This study examined the illness behavior of a sample (n = 375) of physicians in regard to the treatment of their own minor ailments. The symptoms for each of 13 minor ailments were clearly worded to describe a common ailment which in the normal course of events should disappear if left untreated. For 3 of the ailments, however, there was a high frequency of physician-dependent action; 4 other ailments showed a moderate frequency of physician-dependent action. Assuming that physicians are role models for illness behavior, in the sense that they have the authority to define what illness "is" and that they will then do what they have think "best," this sample of physicians is implicitly demonstrating what lay persons should do. These data suggest that the normative expectation to seek professional assistance (a medical solution) is reinforced by physicians through their own behavior.

Effects of dietary protein, fat and energy intake during an initiation phase study of 7,12-dimethylbenz[a]anthracene-induced breast cancer in rats.

A factorial experiment was conducted to examine the effects of dietary protein (8, 16, 32% of energy from casein) and dietary fat (12, 24, 48% of energy from corn oil) on the initiation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in rats. Forty weanling female Sprague-Dawley rats were assigned to each of nine diets fed ad libitum. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. For an additional 22 wk after carcinogen administration all rats consumed a diet containing 16% of dietary energy from protein and 24% from fat. Dietary fat, protein and ad libitum energy consumption exhibited statistically significant effects on final tumor prevalence, but interactive effects were not found. At necropsy, rats fed corn oil at 12, 24 and 48% of energy prior to DMBA administration showed tumor prevalences of 58, 58 and 85% with 116, 153 and 231 total tumors, respectively. The data indicate a significant nonlinear effect of dietary fat. Corresponding numbers for rats fed casein at 8, 16 and 32% of energy prior to DMBA were prevalences of 79, 65 and 59%, with total tumor counts of 194, 144 and 162. Higher dietary protein during the initiation phase was associated with a significant reduction in tumor prevalence, which was most striking between 8 and 16% of energy from protein. In addition, results of multiple logistic regression showed that tumorigenesis was increased with greater ad libitum energy intake. The odds of a tumor at necropsy were multiplied by 1.19 for each kilocalorie increase in ad libitum energy intake averaged over the post-DMBA phase of the experiment. An additional six weanling rats fed each diet for 4 wk were killed for assay of hepatic carcinogen metabolizing enzymes at the time corresponding to DMBA administration in the initiation experiment. Both protein and fat showed independent effects on the activity of several enzymes. However, enzyme activity did not suggest a unifying mechanism whereby these nutrients influence DMBA-induced mammary carcinogenesis.

Plasma amino acids and excretion of protein end products by mice fed 10 or 40% soybean protein diets with or without dietary 2-acetylaminofluorene or N,N-dinitrosopiperazine.

Studies were conducted with 5- to 8-week-old male and female B6C3F1 mice to determine the influence of two carcinogens, 2-acetylaminofluorene (AAF) and N,N-dinitrosopiperazine (DNP), on plasma amino acid concentrations and on the excretion of lipids and nitrogenous metabolites. The carcinogens, AAF and DNP, were fed at concentrations of 0.25 and 0.05 g/kg of purified diet, respectively. Soybean protein constituted either 10 or 40% of the diet. Nutritional balances were measured over a 7-day period, after 7 days of acclimatization. Females ate less feed, gained less weight during acclimatization and excreted less fecal lipid as a percentage of intake than males. On the average, animals fed 40% protein consumed less total feed than those fed 10% protein. During acclimatization, DNP-fed animals ate and gained significantly less than controls. During week 2 DNP-fed animals gained significantly less than controls, although their feed intake was not significantly different. Fecal lipid excretion as a percentage of intake was significantly lower with carcinogens in the diet. The 40% protein diets increased lipid excretion in total and as a percentage of intake. With the exception of decreasing fecal lipid, AAF caused no consistent changes in feed intake, body weight, nitrogen (N) retention or N excretion. Neither carcinogen significantly influenced total fecal or urinary N, or the relative concentrations of the different forms of urinary N, when expressed as a percentage of N intake. Plasma ammonia rose with AAF feeding and plasma histidine rose with DNP feeding. Plasma concentrations of other amino acids were not changed consistently by either carcinogen. Feeding 40% protein caused a significant rise in plasma branched-chain amino acids, glycine and phenylalanine, and a significant decline in aspartate, threonine, serine, proline, citrulline, lysine and arginine.

The combined effects of dietary protein and fat on 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.

A 3 X 3 factorial experiment was conducted to examine how protein content (8, 16, 32% of kilocalories from casein) and fat content (12, 24, 48% of kilocalories from corn oil) interact to influence 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis in rats. Forty weanling Sprague-Dawley rats were assigned to each of 9 diets fed ad libitum. After 4 weeks each rat received DMBA (20 mg/kg) via gastric intubation. No substantial statistical interactions of protein and fat were observed on tumor incidence. Increasing dietary corn oil increased the percentage of rats with palpable tumors. Rats fed diets containing 12, 24 and 48% of kilocalories from corn oil showed 35, 49 and 70% tumor prevalence at necropsy, and the total number of tumors per fat level was 65, 81 and 182, respectively. Each doubling of dietary fat concentration approximately doubled the odds of a rat developing a tumor. Multiple tumors were more common with the highest corn oil intake. The odds of finding a second tumor in rats with one tumor increased by a factor of 7.5 when fat kilocalories were increased from 24 to 48% compared to a decrease of one-third when fat kilocalories were increased from 12 to 24%. Dietary corn oil significantly increased the prevalence of adenocarcinomas and adenomas but not fibroadenomas. Dietary protein did not significantly affect tumor prevalence. However, tumors palpated in rats fed 16% of kilocalories as protein regressed more frequently than in rats fed low or high protein diets. Multiple logistic-regression results indicate that, in addition to the response to dietary corn oil, tumorigenesis was increased in rats with greater ad libitum food consumption. This conclusion is supported by reanalysis that used direct rate adjustment and average partial association tests.