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In a previous analysis of HIV-1-specific CTLs in lymphoid organs from HIV-seropositive patients, we reported high frequencies of in vivo differentiated CTLs directed against two immunodominant regions in the central and in the C-terminal part of the HIV-1 Nef protein. The present study analyzes the epitopes recognized by CTLs in the carboxyl terminus of Nef (amino acids 182-205). In addition to several epitopes that are recognized in association with different HLA molecules (A1, A2, A25(10), B35, B52), we defined an optimal nonapeptide (190-198). This nonapeptide was recognized by CTLs down to nanomolar concentrations in the context of at least two HLA molecules, HLA-B52 and HLA-A2, including three HLA-A2 subtypes: HLA-A2.1, -A2.2, and -A2.4. We also determined the relative frequencies of effector CTLs directed against peptide 190-198 to be as high as 10(-4), as opposed to lower frequencies ranging between 5 x 10(-5) and 5 x 10(-6) observed for the other peptides recognized in the same region, thus confirming the optimal presentation of this nonapeptide in vivo. Molecular modeling of the interactions between HLA-A2.1 and Nef peptide 190-198 suggests the formation of a stable complex and allowed us to study sequence motifs that are important for the binding of the HIV-1 peptide in the pockets of the HLA-A2.1 molecule.
OBJECTIVE: to evaluate the effectiveness of dietary counseling focusing on fat reduction (20 g/day) compared to calorie reduction (1000 to 1200 kcal/day) in promoting long-term weight loss in moderately obese women. DESIGN: One hundred and twenty-two women were randomized to one of the two treatment groups and received intensive dietary counseling in groups of 20 over a period of 18 months. RESULTS: Among 74 women completing the study, weight losses at 6 months averaged 10.2 lb (n = 39) in the fat counseling group and 8.1 lb (n = 35) in the calorie counseling group. Average weight returned to baseline levels in both groups over the succeeding 12 months despite continued intervention. CONCLUSION: Although these data provide little support for the immediate clinical utility of low-fat dietary counseling in obesity treatment, the observation that women in the low-fat group were more compliant with treatment directions, rated the diet as being more palatable, and experienced greater reduction in binge eating scores suggests that this approach warrants further study. In addition, time dependent covariance analysis showed that change in fat intake predicted weight change better than change in total energy intake, thus reinforcing the idea that dietary fat may be an important factor in the etiology and treatment of obesity.
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1. Lohmann Brown pullets, in one trial, and Hyline Brown pullets in another, were reared from day 2 on short daylengths, and from week 8 in trial 1 (week 16 in trial 2) on food restriction. These restrictions were lifted at various times during the rearing period as a means of determining the relative importance of the day length and food restriction stimuli on the attainment of sexual maturity and subsequent laying performance. 2. A total of 2304 pullets were used in each trial. The birds were reared in light proof rooms, and subjected to 8L:16D until they were moved to a laying facility where a light stimulus of 16L:8D was applied. In trial 1 the six ages at which light stimulation was applied were 115, 122, 129, 136, 143 and 171 d. Within each light treatment, food restriction of pullets, which consisted of feeding 72 g of food/bird d, was lifted at six different ages, namely, 115, 129, 143, 157, 171 and 185 d. In trial 2 both the light stimulation and the lifting of food restriction occured at 111, 125, 139, 153, 167 and 181 d of age, producing 6x6=36 treatments in both trials. 3. The first trial was terminated when the pullets were 28 weeks old, soon after all the birds had commenced laying, because of an outbreak of Egg Drop Syndrome. However, because age at maturity was the variable of major interest, data from this experiment could be used in the analysis. The second trial ended when the birds reached 40 weeks of age. Variables measured were age at maturity, food intake and body weight gain subsequent to the lifting of restrictions and, in the second experiment, rate of lay, peak rate of lay and egg weight at various ages. 4. The mean age at sexual maturity was influenced by the date of release from light restriction (P<0.001) and from food restriction (P<0.001) in both trials. In addition, the interaction between the age at release from light and from food restriction was significant. Regression equations were produced for each trial to describe the relationships between the age at sexual maturity and the age at release from light restriction and food restriction. 5. There was an effect of both light restriction (P<0.001) and of food restriction (P<0.001) on the increase in food intake (g/bird d) in the week following release from food restriction in both experiments. These effects were not independent: the effect of the interaction of light and food restriction on this increase in food intake was also highly significant. The longer the birds were subjected to light restriction, the less dramatic the increase in food intake when food restriction was lifted. The more sustained the period of food restriction, the higher the increase in food intake in the week following release from the restriction. 6. Mean egg weight was 4 g heavier at 22 weeks of age in birds released from food restriction at 16 and 18 weeks, than from those released at 24 and 26 weeks of age. However, by 30 weeks of age, birds restricted for longer produced heavier eggs than their earlier-maturing counterparts. This effect continued to the end of the trial at 40 weeks of age, at which time there was a 2.3 g difference in egg weight between these treatments. 7. Both light and food restriction have an effect on the age of maturity in laying hens. The length of time between the release from light or from food restriction to the onset of laying depended on the age of the pullets when the release occurred. Egg weight at a given age was significantly affected by the age at release from food restriction, but not from light restriction.
Studies were conducted to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as under protocols employing dietary restriction. Specific experiments were designed to evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemical-induced chronic toxicity and carcinogenicity and to evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Two chemicals, butyl benzyl phthalate and t-butylhydroquinone, were administered in feed; one chemical, salicylazosulfapyridine, was administered in corn oil by gavage; and one chemical, scopolamine hydrobromide trihydrate, was administered in distilled water by gavage. In each of four protocols, the effects of the chemical were assessed by a comparison between a group exposed to a single dose concentration of the study chemical and a nonexposed control group. F344/N rats and B6C3F1 mice were fed NIH-07 diet either ad libitum or in amounts that restricted mean body weights according to the following design requirements. For the core bioassay, groups of 50 to 60 ad libitum-fed animals were allotted to a control group and three dosed groups for approximately 104 weeks or up to 128 weeks (t-butylhydroquinone study). The comparison between the control group and the group receiving the highest dose was used to represent the outcome of the bioassay under ad libitum feeding protocols. In a second comparison, outcomes from the group receiving the highest dose were compared with a weight-matched group of 50 to 60 untreated controls; the weight-matched controls received feed in amounts restricted so that the mean body weight matched the mean body weight of the dosed group. Two additional groups of 48 to 60 animals (one control and one dosed group) were offered feed in amounts that limited the mean body weight of the control group to approximately 85% that of the controls fed ad libitum under the first protocol. Animals assigned to this dietary restriction paradigm were evaluated after 104 weeks or 130 weeks (t-butylhydroquinone). A fourth protocol was em- loyed to evaluate whether an additional period of exposure (up to 1 year) would influence the neoplasm profile of animals fed a restricted diet. Two groups of approximately 50 animals (one control and one dosed group) in the butyl benzyl phthalate, salicylazosulfapyridine, and scopolamine hydrobromide trihydrate studies received restricted diets, as under the third protocol, for 3 years or until survival in either group was reduced to 20%. Butyl benzyl phthalate caused an increased incidence of pancreatic acinar cell neoplasms in ad libitum-fed male rats relative to ad libitum-fed and weight-m atched controls. This change did not occur in rats in the restricted feed protocol after 2 years; however, acinar cell adenomas were observed in three exposed, feed-restricted males at 30 months. Feed restriction is known to influence the incidence of pancreatic acinar cell neoplasms and may have prevented the full expression of this chemical-induced effect. Butyl benzyl phthalate also caused an increased incidence of urinary bladder neoplasms in female rats in the 32-month restricted feed protocol. The incidences of urinary bladder neoplasms were not significantly increased in female rats in any of the 2-year protocols, suggesting that the length of study, and not body weight, was the primary factor in the detection of this carcinogenic response. Salicylazosulfapyridine caused an increased incidence of urinary bladder papillomas in male rats fed ad libitum relative to ad libitum-fed and weight- matched controls. This increase was associated with an increased incidence of urinary bladder calculi; the incidences of urinary bladder concretions, dilatation, and hyperplasia were also increased in dosed males. The incidences of urinary bladder papillomas and calculi were not increased in male rats receiving salicylazosulfapyridine that were fed restricted diets. In male mice, salicylazosulfapyridine caused an increased incidence of liver neoplasms relative tsms relative to the ad libitum-fed and weight-matched controls. This increase did not occur in the restricted feed protocols. Liver neoplasms in mice are greatly influenced by body weight, and the marked mean body weight reduction observed in dosed male mice in the restricted feed protocols may have overridden the carcinogenic response. Neither t-butylhydroquinone nor scopolamine hydro bromide trihydrate caused increased neoplasm incidences under any of the experimental protocols. Results consistently show that feed restriction caused decreased incidences of neoplasms and nonneoplastic lesions at a variety of anatomic sites in control and dosed animals. Furthermore, the sensitivity of the bioassay to detect a carcinogenic response was altered by dietary restriction: two of the four chemicals caused increased incidences of neoplasms at three sites when evaluated under a standard ad libitum feeding protocol for 104 weeks. When control and dosed groups were subjected to dietary restriction, none of these three sites was detected as a target of carcinogenesis after 2 to 3 years. Rather, one different site of carcinogenesis was detected after 32 months. When dosed animals in the ad libitum feeding protocol were compared to weight-matched control groups, three sites were identified as targets of carcinogenesis and corresponded to the three sites discovered under the ad libitum feeding protocol. The magnitude of the response was greater when the weight-matched controls protocol was used. Dietary restriction of dosed and control animals decreased the sensitivity of these carcinogenesis bioassays. Regarding the future use of dietary restriction regimens in long-term studies, only limited conclusions can be drawn because only four chemicals were evaluated and none of these proved to be a strong carcinogen. However, the results of these studies are consistent with previous findings that dietary restriction increases survival rates and decreases the incidences of neoplasms and nonneoplastic lesions at a variety of sites in rats and mice. This association between reduced body weights and decreased neoplasm incidences underlines the necessity that the doses selected for chronic studies not exceed "minimally toxic doses" so that no marked body weight reductions (or increases) will occur in the dosed groups. Such body weight changes complicate the detection of carcinogenic effects. The following tables summarize and compare the findings from ad libitum-fed, weight-matched, and feed-restricted groups for each chemical. Tabular Summary of Dietary Restriction Study of Butyl Benzyl Phthalate is available in web version of this document. TabularSummary of the Dietary Restriction Study of t-Butylhydroquinone is available in web version of this document. TabularSummary of the Dietary Restriction Studies of Salicylazosulfapyridine is available in web version of this document. TabularSummary of the Dietary Restriction Study of Scopolamine Hydrobromide Trihydrate is available in web version of this document.
This study was intended to identify changes caused by short-term reduced feed intake in rats such as may occur with unpalatable feed or other forms of anorexia. For 2 wk, groups of rats (10/sex/group) were fed ad libitum (control group) or given 75% (mildly restricted group), 50% (moderately restricted group), or 25% (severely restricted group) of the amount of feed eaten the day before by controls. The control group and mildly restricted group grew steadily, but the terminal body weights of the mildly restricted group (both males and females) were only about 80% of controls. The moderately restricted group did not grow during the first week but grew slightly during the second week (terminal body weights about 65% of control). The severely restricted group lost weight throughout the study (terminal weight about 40% of control). Restricted groups exhibited hemoconcentration directly related to the degree of feed restriction. White blood cell counts were reduced (principally due to lymphopenia) in severely restricted rats. Platelet counts were decreased in all restricted groups. Total serum protein concentration was reduced (decreased globulins) in all female restricted groups and in the severely restricted males. The severely restricted rats had increased serum bilirubin, electrolyte derangements, and (in females only) decreased cholesterol. Thymus and liver weights (absolute and relative) were decreased in the moderately and severely restricted groups. All the feed-restricted groups had an increased incidence of superficial gastric erosions. The mildly and moderately restricted groups had slightly decreased hematopoietic tissue in sternal bone marrow, while the severely restricted group had bone marrow necrosis, thymic atrophy, and mild testicular degeneration. Findings in the severely restricted group were distinct from those in the other groups on the basis of their severity and were considered adverse. Changes in the mildly and moderately restricted groups were considered adaptive and innocuous since feed restriction of this degree has historically been associated with increased longevity and decreased disease incidence in chronic studies.
BACKGROUND: Restricted activity is a potentially important indicator of health and functional status. Yet, relatively little is known about the incidence, precipitants, or health care utilization associated with restricted activity among older persons. OBJECTIVE: To more accurately estimate the rate of restricted activity among community-living older persons, to identify the health-related and non-health-related problems that lead to restricted activity, and to determine whether restricted activity is associated with increased health care utilization. DESIGN: Prospective cohort study. SETTING: New Haven, Connecticut. PARTICIPANTS: 754 nondisabled members of a large health plan, 70 years of age or older, who were categorized according to their risk for disability (low, intermediate, or high). MEASUREMENTS: Occurrence of restricted activity (defined as having stayed in bed for at least half a day or having cut down on one's usual activities because of an illness, injury, or another problem), problems leading to restricted activity, and health care utilization were ascertained during monthly telephone interviews for up to 2 years. RESULTS: In median follow-up of 15 months, 76.6% of participants reported restricted activity during at least 1 month and 39.3% reported restricted activity during 2 consecutive months. The rates of restricted activity per 100 person-months were 19.0 episodes for all participants and 16.9, 27.3, and 22.7 episodes for participants at low, intermediate, and high risk for disability, respectively. Of the 24 prespecified health-related and non-health-related problems, the rates per 100 person-months of restricted activity ranged from 0.1 episode for "problem with alcohol" to 65.5 episodes for "been fatigued." On average, participants identified 4.5 different problems as a cause for their restricted activity. Health care utilization was substantially greater during months with restricted activity than months without restricted activity. The corresponding rates per 100 person-months were 63.8 and 45.1 for physician office visits, 12.5 and 1.0 for emergency department visits, 14.1 and 0.3 for hospital admissions, and 67.6 and 45.1 for any health care utilization (P < 0.001 for each pairwise comparison). CONCLUSIONS: Restricted activity is common among community-living older persons, regardless of risk for disability, and it is usually attributable to several concurrent health-related problems. Although restricted activity is associated with a substantial increase in health care utilization, older persons with restricted activity often do not seek medical attention.
Physiologic weight restriction is defined as the difference between the genetic and real weight in a normal fetus. The aims of this study were (1) to obtain, in normal pregnancies, reference values of mean weight restriction between 32 and 42 weeks for both male and female fetuses, and (2) to observe how weight restriction may influence intrauterine growth retardation. In the first part of the study, 1004 ultrasonograms of 389 different women were studied and the estimated fetal weights with their regression curves were calculated and drawn for all fetuses by sex. Differences between the 50th percentile of the genetic curves in normal population and the estimated fetal weight values for each of the 1004 examinations were calculated and weight restriction 50th and 90th percentiles were described. In the second part of the study, genetic curves were constructed retrospectively for 20 fetuses with intrauterine weight restriction whose examinations were performed before week 28 and were compared with curves for the normal population. Finally, for the 20 patients with intrauterine weight restriction, differences between genetic and real weight at delivery were plotted and compared with weight restriction 50th and 90th percentiles. Also, fetuses with intrauterine weight restriction were compared according to differing degrees of restriction. Weight restriction began between 31 and 33 weeks of gestation and was earlier and marked in female fetuses. Genetic percentiles were higher in normal fetuses than in fetuses with intrauterine weight restriction. In addition, pregnancies of intrauterine growth restricted fetuses with greater degrees of weight restriction were more abnormal than those of fetuses with a lesser degree of weight restriction. Both facts imply that some of the fetuses included in the classic diagnosis of intrauterine weight restriction may be genetically small fetuses. Concepts of weight restriction and physiologic weight restriction might be applied to discriminate between normal, genetically small fetuses and fetuses affected with intrauterine growth retardation.
Restriction of antibiotic use in 112 hospitals that are primary teaching facilities for medical schools was studied by mail questionnaire to pharmacy directors and infectious disease physicians. Questions involved whether use of certain antipseudomonal penicillins, aminoglycosides, and second- and third-generation cephalosporins was restricted, reasons for restrictions, existence of a formal education program on new antibiotics, whether the physician respondents agreed with the practice of antibiotic restriction, what percent of requests for use of restricted agents was denied, formulary status of the drugs, the procedure for authorizing dispensing of restricted agents, and the percent of drug expenditures represented by restricted agents. Direct control (specialist authorization or restricted indications for use) was used in 62 (57%) of 108 institutions responding. Nonformulary status indirectly controlled use in 35 institutions. No significant differences in the prevalence of restrictions were found for hospital size, ownership, physician's view of the restrictions, or presence of an education program. Most (85%) of the physicians agreed with restriction practices. Cost was the reason given most frequently for restriction of the penicillins and cephalosporins, while aminoglycosides were most frequently restricted because of bacterial resistance. The specialist's oral authorization was the most common method of approval for use of restricted agents. Expenditures for restricted drugs varied widely, suggesting that different levels of control were considered "restriction" by the responding institutions. Control of antibiotic use is common in these teaching hospitals associated with medical schools. No best method for antibiotic restriction was evident.
OBJECTIVE: To determine the value of transvaginal color Doppler assessment of the uterine arteries at 23 weeks of gestation in predicting the subsequent development of pre-eclampsia and fetal growth restriction. PATIENTS AND METHODS: Women with singleton pregnancies attending for routine ultrasound examination at 23 weeks in any one of seven hospitals underwent Doppler assessment of the uterine arteries. The presence of an early diastolic notch in the waveform was noted, and the mean pulsatility index of the two arteries was calculated. Screening characteristics in the prediction of pre-eclampsia and the delivery of a low birth-weight infant were calculated. RESULTS: Doppler examination of the uterine arteries was attempted in 8335 consecutive singleton pregnancies, satisfactory waveforms were obtained from both vessels in 8202 (98.4%) cases and complete outcome data were available in 7851 (95.7%) of these. The mean gestational age was 23 (range, 22-24) weeks. The mean uterine artery pulsatility index did not change significantly with gestation (r = -0.0078; P = 0.483); the median value was 1.04 and the 95th centile was 1.63. In 9.3% of cases early diastolic notches in the waveform from both uterine arteries were present and in an additional 11.1% of cases there were notches unilaterally. Pre-eclampsia with fetal growth restriction occurred in 42 (0.5%) cases, pre-eclampsia without fetal growth restriction in 71 (0.9%) and fetal growth restriction without pre-eclampsia in 698 (8.9%). The sensitivity of increased pulsatility index above the 95th centile (1.63) for pre-eclampsia with fetal growth restriction was 69%, for pre-eclampsia without fetal growth restriction was 24%, for fetal growth restriction without pre-eclampsia was 13%, for pre-eclampsia irrespective of fetal growth restriction was 41% and for fetal growth restriction irrespective of pre-eclampsia was 16%. The sensitivity of fetal growth restriction defined by the 5th rather than the 10th centile was higher (19% vs. 16%). The sensitivity for both pre-eclampsia and fetal growth restriction was inversely related to the gestational age at delivery; when delivery occurred before 32 weeks, the sensitivity for all cases of pre-eclampsia with fetal growth restriction, pre-eclampsia without fetal growth restriction and fetal growth restriction without pre-eclampsia increased to 93%, 80% and 56%, respectively. The sensitivity of bilateral notches in predicting pre-eclampsia and/or fetal growth restriction was similar to that of increased pulsatility index but the screen-positive rate with notches (9.3%) was much higher than that with increased pulsatility index (5.1%). CONCLUSIONS: A one-stage color Doppler screening program at 23 weeks identifies most women who subsequently develop severe pre-eclampsia and/or fetal growth restriction.
OBJECTIVE: To determine the accuracy with which spirometric measurements of FVC and expiratory flow rates can diagnose the presence of a restrictive impairment. DESIGN: The pulmonary function tests of 1,831 consecutive white adult patients who had undergone both spirometry and lung volume measurements on the same visit over a 2-year period were analyzed. The probability of restrictive pulmonary impairment, defined as a reduced total lung capacity (TLC) below the lower limit of the 95% confidence interval, was determined for each of several categoric classifications of the spirometric data, and additionally for each of several interval levels of the FVC and the FEV1/FVC ratio. SETTING: A large clinical laboratory in a university teaching hospital using quality-assured and standardized spirometry and lung volume measurement techniques according to American Thoracic Society standards. RESULTS: Two hundred twenty-five of 1,831 patients (12.3%) had a restrictive defect. The positive predictive value of spirometry for predicting restriction was relatively low; of 470 patients with a low FVC on spirometry, only 41% had restriction confirmed on lung volume measurements. When the analysis was confined to the 264 patients with a restrictive pattern on spirometry (ie, low FVC and normal or above normal FEV1/FVC ratio), the positive predictive value was 58%. Conversely, spirometry had a very favorable negative predictive value; only 2.4% of patients (32 of 1,361) with a normal vital capacity (VC) on spirometry had a restrictive defect by TLC measurement. The probability of a restrictive defect was directly and linearly related to the degree of reduction of FVC when the FVC was < 80% of predicted (p = 6.002). Combining the FVC and the FEV1/FVC ratio improved the predictive ability of spirometry; for all values of FVC < 80% of the predicted amount, the likelihood of restrictive disease increased as the FEV1/FVC ratio increased. CONCLUSIONS: Spirometry is very useful at excluding a restrictive defect. When the VC is within the normal range, the probability of a restrictive defect is < 3%, and unless restrictive lung disease is suspected a priori, measurement of lung volumes can be avoided. However, spirometry is not able to accurately predict lung restriction; < 60% of patients with a classical spirometric restrictive pattern had pulmonary restriction confirmed on lung volume measurements. For these patients, measurement of the TLC is needed to confirm a true restrictive defect.