Diagnostic accuracy of CT angiography and CT perfusion for cerebral vasospasm: a meta-analysis.

BACKGROUND AND PURPOSE: In recent years, the role of CTA and CTP for vasospasm diagnosis in the setting of ASAH has been the subject of many research studies. The purpose of this study was to perform a meta-analysis of the diagnostic performance of CTA and CTP for vasospasm in patients with ASAH by using DSA as the criterion standard. MATERIALS AND METHODS: The search strategy for research studies was based on the Cochrane Handbook for Systematic Reviews, including literature data bases (PubMed, Embase, Cochrane Database of Systematic Reviews, and the Web of Science) and reference lists of manuscripts published from January 1996 to February 2009. The inclusion criteria were the following: 1) published manuscripts, 2) original research studies with prospective or retrospective data, 3) patients with ASAH, 4) CTA or CTP as the index test, and 5) DSA as the reference standard. Three reviewers independently assessed the quality of these research studies by using the QUADAS tool. Pooled estimates of sensitivity, specificity, LR+, LR-, DOR, and the SROC curve were determined. RESULTS: CTA and CTP searches yielded 505 and 214 manuscripts, respectively. Ten research studies met inclusion criteria for each CTA and CTP search. Six CTA and 3 CTP studies had sufficient data for statistical analysis. CTA pooled estimates had 79.6% sensitivity (95%CI, 74.9%-83.8%), 93.1%specificity (95%CI, 91.7%-94.3%), 18.1 LR+ (95%CI, 7.3-45.0), and 0.2 LR- (95%CI, 0.1-0.4); and CTP pooled estimates had 74.1% sensitivity (95%CI, 58.7%- 86.2%), 93.0% specificity (95% CI, 79.6%-98.7%), 9.3 LR+ (95%CI, 3.4-25.9), and 0.2 LR- (95%CI, 0.04-1.2). Overall DORs were 124.5 (95%CI, 28.4-546.4) for CTA and 43.0 (95%CI, 6.5-287.1) for CTP. Area under the SROC curve was 98 ± 2.0%for CTA and 97 ± 3.0% for CTP. CONCLUSIONS: The high diagnostic accuracy determined for both CTA and CTP in this meta-analysis suggests that they are potentially valuable techniques for vasospasm diagnosis in ASAH. Awareness of these results may impact patient care by providing supportive evidence for more effective use of CTA and CTP imaging in ASAH.

Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue repository of the Surveillance, Epidemiology, and End Results (SEER) program.

BACKGROUND: In 2001, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program established Residual Tissue Repositories (RTR) in the Hawaii, Iowa, and Los Angeles Tumor Registries to collect discarded tissue blocks from pathologic laboratories within their catchment areas. To validate the utility of the RTR for supplementing SEER's central database, we assessed human epidermal growth factor receptor-2 (HER2) and estrogen receptor expression (ER) in a demonstration project. MATERIALS: Using a prepared set of tissue microarrays (TMAs) residing in the Hawaii Tumor Registry (HTR), we performed standard immunohistochemistry. Breast cancers in the TMA were diagnosed in 1995, followed through 2006, and linked to SEER's main database. RESULTS: The TMA included 354 cases, representing 51% of 687 breast cancers in the HTR (1995). The HTR and TMA cases were similar with respect to patient demographics and tumor characteristics. Seventy-six percent (76%, 268 of 354) of TMA cases were HER2+ and/or ER+, i.e., 28 HER2+ER-, 12 HER2+ER+, and 228 HER2-ER+. There were 67 HER2-ER- cases and 19 were unclassified. Age distributions at diagnosis were bimodal with dominant early-onset modes for HER2+ER- tumors and dominant late-onset modes for HER2-ER+ breast cancers. Epidemiologic patterns for concordant HER2+ER+ (double-positive) and HER2-ER- (double-negative) were intermediate to discordant HER2+ER- and HER2-ER+. CONCLUSION: Results showed contrasting incidence patterns for HER2+ (HER2+ER-) and ER+ (HER2-ER+) breast cancers, diagnosed in 1995. Though sample sizes were small, this demonstration project validates the potential utility of the RTR for supplementing the SEER program.

Alcohol and prostate cancer in the NHANES I epidemiologic follow-up study. First National Health and Nutrition Examination Survey of the United States.

PURPOSE: We prospectively investigated the association between alcohol consumption and prostate cancer in the Epidemiologic Follow-up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I). METHODS: There were two cohorts: 1) Cohort I, followed from baseline (1971-75) through 1992, included 5766 men ages 25-74 years (median follow-up = 17 years); and 2) Cohort II, followed from the first follow-up round for Cohort I (1982-84) through 1992, included the 3868 men in Cohort I free of prostate cancer in 1982-84 (median follow-up = 9 years). Alcohol consumption was assessed at baseline as usual consumption, and at follow-up as usual consumption and as distant past consumption at the ages of 25, 35, 45, and 55. RESULTS: There were 252 incident cases of prostate cancer. Consistent with most previous studies, we found no significant associations between usual total alcohol consumption and prostate cancer in Cohorts I or II [p = non significant (NS)], except for a significant inverse association at the heaviest level of drinking in Cohort II [relative risk (RR) = 0.23, 95% confidence interval (CI) = 0.06-0.95]. Further study of heavy drinkers in Cohort II revealed significant inverse associations between distant past heavy drinking (defined as > 25 drinks/week) and prostate cancer at age 25 (RR = 0.20, 95% CI = 0.06-0.63), age 35 (RR = 0.30, 95% CI = 0.12-0.77), and age 45 (RR = 0.39, 95% CI = 0.17-0.93), but not at age 55 (RR = 0.43, 95% CI = 0.17-1.10). CONCLUSIONS: These results suggest that it may be important to consider distant past alcohol consumption in etiologic studies of prostate cancer. However, our results were based on small numbers of cases who were heavy drinkers and require replication.

Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3.

BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.

Possible mechanisms mediating an association between physical activity and breast cancer.

The epidemiologic, methodologic, and biologic evidence that physical activity may be related inversely to breast cancer risk was the focus of a recent workshop. This article presents the workshop summary on biologic mechanisms that may mediate this association between physical activity and breast cancer. There is some evidence that physical activity may reduce breast cancer risk, although the exact biologic pathways have not been determined. Among the potential mechanisms discussed at the workshop were reductions in endogenous steroid exposure, alterations in menstrual cycle patterns, delay of age at menarche, increased energy expenditure and reduction in body weight, changes in insulin-like and other growth factors, and enhancement of natural immune mechanisms. Although physical activity may prove to be a modifiable risk factor for breast cancer, further mechanistically oriented research is necessary to both verify whether this is the case and to clarify the details of this association so that public health recommendations can be developed.

Androgen receptor-mediated antagonism of estrogen-dependent low density lipoprotein receptor transcription in cultured hepatocytes.

Postmenopausal women receiving hormone replacement therapy have a lower risk of coronary heart disease than women who do not receive hormone treatment. Multiple mechanisms are likely to underlie estrogen's cardioprotective action, including lowering of plasma low density lipoprotein (LDL) cholesterol. Using an in vitro system exhibiting normal regulation of LDL receptor (LDLR) gene transcription, we show that 17beta-estradiol activates the LDLR promoter in transiently transfected HepG2 cells. LDLR activation by estrogen in HepG2 cells is dependent on the presence of exogenous estrogen receptor, and the estrogen-responsive region of the LDLR promoter colocalizes with the sterol response element previously identified. The estrogen response is concentration dependent, saturable, and sensitive to antagonism by estrogen receptor antagonists. Further, we show that compounds with androgen receptor agonist activity attenuate the estrogen-induced up-regulation of LDLR in our model system. Progestins with androgen receptor agonist activity, such as medroxyprogesterone acetate, also suppress estrogen's effects on LDLR expression through their androgenic properties. Characterization of the interplay between these hormone receptors on the LDLR in vitro system may allow a better understanding of the actions of sex steroids on LDLR gene expression and their roles in cardiovascular disease.

Relation of energy, fat, and fiber intakes to plasma concentrations of estrogens and androgens in premenopausal women.

To evaluate whether diet may influence the incidence of hormone-dependent cancers through an effect on blood estrogen and androgen concentrations, we analyzed diet-blood hormone relations in a cross-sectional study. Dietary energy, fat, and fiber intakes were estimated from 7-d food records completed by 90 premenopausal women on days 14-20 of their menstrual cycles. Fasting blood specimens were collected on days 5-7, 12-15, and 21-23 of each participant's cycle and pooled to create follicular-, midcycle-, and luteal-phase samples, respectively, for analysis. Energy intake was associated inversely with plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS), averaged across the three menstrual cycle phases, and directly with the probability of a luteal-phase rise in progesterone. For each additional 1 MJ (239 kcal) consumed, androstenedione decreased by 6.0% (95% CI: -8.4%, -3.6%), DHEAS decreased by 5.1% (95% CI: -9.6%, -0.4%), and the probability of a progesterone rise increased by 60% (95% CI: 5%, 145%). After energy intake was adjusted for, the ratio of polyunsaturated to saturated fat (P:S) in the diet was significantly inversely associated with plasma estradiol and estrone during the luteal phase of the menstrual cycle. For each 0.1 increment in the P:S, there was a 7.6% (95% CI: -14.3%, -0.5%) decrease in estradiol and a 6.8% (95% CI: -12.7%, -0.6%) decrease in estrone. Results of this cross-sectional study support a relation between both energy and fat ingestion and plasma sex hormone concentrations in premenopausal women.

Effect of alcohol consumption on plasma carotenoid concentrations in premenopausal women: a controlled dietary study.

This 6-mo controlled dietary study compared the effect of 30 g alcohol/d for three menstrual cycles with three alcohol-free cycles on plasma carotenoid concentrations in 18 nonsmoking, premenopausal women. Participants were randomly allocated within a crossover design to either phase and consumed approximately 6 mg total carotenoids/d under isoenergetic conditions. Blood was drawn during the third menstrual cycle of each alcohol phase. After adjustment for the mean daily specific carotenoid and energy intakes for each alcohol phase, the paired differences in mean plasma alpha- and beta-carotene concentrations were significantly higher by 19% (P = 0.027) and 13% (P = 0.034), respectively, during the alcohol-intake phase of the study. The paired difference in mean plasma lutein/zeaxanthin concentration was significantly lower by 17% (P = 0.031) when the participants consumed alcohol than when they did not. This is the first reported study in women to document the independent effect of alcohol on plasma carotenoid concentrations without the potential interaction of smoking under controlled dietary conditions.

Relationships of age and reproductive characteristics with plasma estrogens and androgens in premenopausal women.

We used data from a cross-sectional study of 107 premenopausal women to evaluate the relation of age, menarcheal age, parity, and age at first live birth with plasma estrogen and androgen levels in premenopausal women. Fasting blood specimens were collected on each of days 5-7, 12-15, and 21-23 of menstrual cycles of the participants and pooled to create follicular, midcycle, and luteal phase samples, respectively, for each woman. Age was associated significantly and positively with plasma estradiol levels during the follicular phase [percentage difference/year = 2.6; 95% confidence interval (CI) = 1.0-4.2] and midcycle (percentage difference/year = 2.7; 95% CI = 0.9-4.7) but not the luteal phase (percentage difference/year = -0.4; 95% CI = -1.9-1.3) of the menstrual cycle. The relation of age to plasma estradiol varied by parity, with significant interactions during midcycle and luteal phase. Among nulliparous women, plasma estradiol levels increased with age midcycle and during the luteal phase, but among parous women estradiol levels decreased with age during these phases of the menstrual cycle. Plasma estrone increased with age in all women during the follicular phase of the menstrual cycle (percentage difference/year = 1.5; 95% CI = 0.2-2.8). During the luteal phase there was a significant interaction with parity; estrone levels in nulliparous women varied only slightly with age, but levels in parous women decreased significantly as age increased. The androgens, androstenedione and dehydroepiandrosterone sulfate decreased, and sex hormone-binding globulin increased as age increased. The results of this cross-sectional study suggest that pregnancy may modify age-related changes in plasma estrogen levels.

Effects of alcohol consumption on lipoproteins of premenopausal women. A controlled diet study.

A substantial portion of American women consume alcohol, but controlled studies of alcohol-induced changes in lipoproteins of women are rare. In this study, the effects of alcohol consumption (equivalent to two drinks per day) on the lipoprotein profiles of 34 premenopausal women were measured while controlling subjects' diet and various other potentially confounding variables including phase of the menstrual cycle. Alcohol and no-alcohol treatments were administered in a crossover design, and blood samples were obtained during the early follicular phase of the third month of treatment. With alcohol, HDL cholesterol levels increased 10%, LDL levels decreased 8%, and levels of lipoprotein(a) were unchanged. The increase in HDL cholesterol was due to an increase in both HDL2 and HDL3, and the overall size of HDL particles was increased. HDL particles containing apolipoprotein (apo) A-I and apoA-II as well as those containing apoA-I but no apoA-II were elevated in response to alcohol. Although these observations are limited to a single phase of the menstrual cycle, the alcohol-induced changes in lipoproteins are consistent with changes that are thought to confer protection against coronary heart disease.

The relation of body size to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States).

We analyzed data from a cross-sectional study of 107 premenopausal women to evaluate the relations of height, weight, and body mass index (BMI) with plasma hormone levels. Participants were 20- to 40-year old women residing in Maryland (United States), whose reported menstrual cycle lengths were not more than 35 days and whose measured weights for height were 85 to 130 percent of 'desirable' based on 1983 Metropolitan Life Insurance tables. Fasting blood specimens were collected on each of days 5-7, 12-15, and 21-23 of every participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Adjusted for age, taller women had significantly higher follicular-phase plasma-estradiol levels (percent difference/cm = 1.5, 95 percent confidence interval [CI] = 0.3-2.7, and heavier women had significantly lower plasma sex-hormone binding globulin (SHBG) levels averaged across the menstrual cycle phases (percent difference/kg = -1.2; CI = -1.9-(-0.6). Body weight within the range studied, however, was not related significantly to the concentration of SHBG-bound estradiol during any phase of the menstrual cycle. The results of this cross-sectional study suggest a possible mechanism by which height may influence breast cancer risk.

Relationship between dietary intake and plasma concentrations of carotenoids in premenopausal women: application of the USDA-NCI carotenoid food-composition database.

The diet-plasma relationships for carotenoids were examined in a group of 98 nonsmoking premenopausal women who participated in the cross-sectional phase of the National Cancer Institute (NCI)-US Department of Agriculture (USDA) diet study on alcohol-hormone metabolism, 1988-90. With use of the newly developed USDA-NCI carotenoid food-composition database, the mean daily intakes of carotenoids were significantly higher when estimated from the food-frequency questionnaire (FFQ) than from the 7-d diet records. Lycopene (mean = 0.58 mmol/L), lutein plus zeaxanthin (mean = 0.46 mmol/L), and beta-carotene (mean = 0.34 mmol/L) were the major plasma carotenoids. After adjustment for body mass index, energy and alcohol intakes, and total plasma cholesterol concentration, the following significant correlation (P < 0.05) were observed between the diet record and the FFQ-estimated carotenoid intakes and their respective plasma concentrations: alpha-carotene (r = 0.58 vs 0.49), beta-carotene (r = 0.51 vs 0.49), beta-cryptoxanthin (r = 0.49 vs 0.36), lutein plus zeaxanthin (r = 0.31 vs 0.37), lycopene (r = 0.50 vs 0.26), and total carotenoids (r = 0.57 vs 0.49). These data indicate that plasma carotenoid concentrations are reflective of dietary intake, but the magnitude of the correlation varies depending on the specific carotenoid and on the dietary assessment tool.

Acute phase vascular endothelial injury: a comparison of temporary arterial occlusion using an endovascular occlusive balloon catheter versus a temporary aneurysm clip in a pig model.

We compared the degree of acute endothelial injury after temporary vessel occlusion using two different occlusion modalities--external clipping and endovascular balloon occlusion. The common carotid and subclavian arteries in eight weanling pigs were temporarily occluded with either a 5 Fr occlusion balloon catheter or a temporary microvascular clip for 0 (control), 5, 10, and 30 minutes. Two animals (eight vessels; four clip and four balloon occluded) were used at each time interval. Segments of each experimental vessel were harvested and analyzed by scanning electron microscopy. Each vessel specimen was graded on the following scale: Grade 1 showed no evidence of injury; Grade 2 showed minimal evidence of endothelial cell injury; Grade 3 showed moderate evidence of endothelial cell injury; Grade 4 showed marked evidence of endothelial cell injury; Grade 5 showed severe endothelial and subendothelial injury. Control vessels showed no evidence of injury. Grade 2 injuries were seen in both clip- and balloon-occluded vessels at 5 minutes. At 10 minutes, focal Grade 2 and 3 injuries were appreciated in the clip group, with diffuse Grade 2 and 3 injuries in the balloon group. After the 30-minute occlusion, the balloon group showed Grade 2, 3, and 4 injuries, whereas the clip group showed entirely Grade 2 injuries. The degree of injury with either occlusion modality was equivalent and worsened with time. However, clip-occluded vessels displayed injury that was confined to an area closely adjacent to the clip site, whereas balloon-occluded vessels demonstrated a more widespread injury centered around the balloon site.

The activity of parafusin is distinct from that of phosphoglucomutase in the unicellular eukaryote Paramecium.

In this paper we identified the presence of a Paramecium phosphoglucomutase enzymatic activity which is clearly distinct from that of parafusin-the exocytosis-related phosphoglycoprotein. Since the recently cloned parafusin showed homology to rabbit muscle phosphoglucomutase, we have designed a specific peptide parafusin antibody-generated to a region not present in any known sequenced phosphoglucomutases-to distinguish parafusin from the Paramecium phosphoglucomutase. Separation of these two proteins was obtained using liquid chromatography, enzymatic activity assay and immunoblotting analysis with the specific parafusin peptide antibody. Parafusin fractions incorporated [B35S]UDP-Glc but not [35S]Glc-1-P whereas Paramecium phosphoglucomutase fractions incorporated [35S]Glc-1-P but not [B35S]UDP-Glc. This indicates that these two proteins are separate entities exhibiting different properties and most likely distinct functions in the cell.

The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States).

We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5-7, 12-15, and 21-23 of each participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.

N-substituted dibenzoxazepines as analgesic PGE2 antagonists.

8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide (1, SC-19220) has been previously reported by us and others to be a PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activities. Analogs of SC-19220, in which the acetyl moiety has been replaced with pyridylpropionyl groups and their homologs, have been synthesized as illustrated by compounds 13 and 29. These and other members of this series have been shown to be efficacious analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure activity relationships within this series.

Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women.

BACKGROUND: Most epidemiologic studies of the relationship between alcohol consumption and breast cancer risk over the past decade have shown that persons who consume a moderate amount of alcohol are at 40%-100% greater risk of breast cancer than those who do not consume alcohol. Dose-response effects have been observed, but no causal relationship has been established. PURPOSE: This study examines the hypothesis that alcohol consumption affects levels of reproductive hormones. METHODS: A controlled-diet study lasting for six consecutive menstrual cycles was conducted. Participants were randomly assigned to two groups, and a crossover design was used. During the last three menstrual cycles, alcohol consumption of the two groups was reversed. Thirty-four premenopausal women, aged 21-40 years, with a history of regular menstrual cycles, consumed 30 g of ethanol (equivalent to approximately two average drinks) per day for three menstrual cycles and no alcohol for the other three. All food and alcohol consumed were provided by the study. Caloric intake was monitored to ensure that each woman would maintain body weight at approximately the baseline level. Hormone assays were performed on pooled plasma or 24-hour urine specimens collected during the follicular (days 5-7), peri-ovulatory (days 12-15), and mid-luteal (days 21-23) phases of the third menstrual cycle for subjects on each diet. RESULTS: Alcohol consumption was associated with statistically significant increases in levels of several hormones. Plasma dehydroepiandrosterone sulfate levels were 7.0% higher in the follicular phase (P = .05). In the peri-ovulatory phase, there were increases of 21.2% (P = .01) in plasma estrone levels, 27.5% (P = .01) in plasma estradiol levels, and 31.9% (P = .009) in urinary estradiol levels. In the luteal phase, urinary estrone levels rose 15.2% (P = .05), estradiol levels increased 21.6% (P = .02), and estriol levels rose 29.1% (P = .03). No changes were found in the percent of bioavailable estradiol, defined by the sum of percent free estradiol and percent albumin-bound estradiol. However, increased total estradiol levels in the peri-ovulatory phase suggest elevated absolute amounts of bioavailable estradiol. CONCLUSION: This study has shown increases in total estrogen levels and amount of bioavailable estrogens in association with alcohol consumption in premenopausal women. IMPLICATION: This possible explanatory mechanism for a positive association between alcohol consumption and breast cancer risk merits further investigation.

Fentanyl and sufentanil increase intracranial pressure in head trauma patients.

Although opioids frequently are administered to patients with severe head trauma, the effects of such drugs on intracranial pressure are controversial. Nine patients with severe head trauma were studied for the effects of fentanyl and sufentanil on intracranial pressure (ICP). In all patients, ICP monitoring was instituted before the study. Full neuromuscular blockade was achieved with vecuronium bromide before the administration of either fentanyl (3 micrograms.kg-1) or sufentanil (0.6 microgram.kg-1) as an intravenous bolus over a 1-min period in a masked and random fashion. Patients received the other opioid in the same fashion 24 h later. Arterial blood pressure, heart rate, and ICP were recorded continuously for the 1 h after drug administration. Fentanyl was associated with an average ICP increase of 8 +/- 2 mmHg, and sufentanil with an increase of 6 +/- 1 mmHg. These increases were statistically significant. Both drugs produced clinically mild decreases in mean arterial blood pressure (fentanyl, 11 +/- 6 mmHg; sufentanil, 10 +/- 5 mmHg) that nevertheless were statistically significant. No significant changes in heart rate occurred. These results indicate that modest doses of potent opioids can significantly increase ICP in patients with severe head trauma.

Analogs of the delta opioid receptor selective cyclic peptide [2-D-penicillamine,5-D-penicillamine]-enkephalin: 2',6'-dimethyltyrosine and Gly3-Phe4 amide bond isostere substitutions.

In order to develop systemically-active opioid peptides, the delta-selective, opioid pentapeptide [D-Pen2,D-Pen5]-enkephalin (DPDPE) was modified by esterification and by substitution of 2',6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8- and 800-fold more active than DPDPE in both delta and mu opioid radioligand binding assays, respectively, in rat neural membrane suspensions. Compound 4 was considerably more potent than DPDPE at inhibiting contractions of electrically-stimulated mouse vas deferens in vitro, and this effect was very sensitive to naltrindole, a delta-selective opioid antagonist. These observations can be taken as indication that 4 exerts its effects through delta opioid receptors. This interpretation is supported by the finding that the EC50 value of 4 derived in the smooth muscle assay is very similar to that derived in NG108-15 neuroblastoma cells, a preparation devoid of mu receptors. Unlike DPDPE, 4 exhibited significant, naloxone-sensitive, antinociceptive activity when administered systemically, as measured by inhibition of phenylbenzquinone-induced stretching in mice (ED50 = 2.1 mg/kg). Compound 4 also displayed significant antinociceptive activity following systemic administration as measured by its action in mice to increase latencies for tail withdrawal from radiant heat (ED50 = 50 mg/kg). Compound 4 did not produce morphine-like discriminative stimulus effects in rats trained to discriminate 3.0 mg/kg morphine from vehicle at doses ranging from 30 to 120 mg/kg. This observation can be interpreted as indication that within this dosage range there is an absence of morphine-like subjective effects. Physical dependence, however, could be induced in mice at higher doses of 4 under a progressively-graded, 4-day dose regimen. Congeners of 4 with amide bond surrogates for the Gly-Phe amide bond (oxymethylene, trans-double bond, and bismethylene isosteres) in the cyclic core of DPDPE were prepared in an attempt to increase the antinociceptive activity of 4. While some of the congeners were active in the in vitro assays, they did not display significant antinociceptive activity following systemic administration. The preparation of all the compounds was accomplished by solution-phase methods. The mechanisms which might underlie the biological and systemic activity of 4 are discussed.

Effect of dietary fat on length of the follicular phase of the menstrual cycle in a controlled diet setting.

The length of the follicular phase of the menstrual cycle (defined as the time from the first day of menses until the day of urinary LH peak, inclusive) was examined in 30 healthy, premenopausal women. The women consumed defined, weight maintaining diets, with a ratio of polyunsaturated to saturated fatty acids (P/S ratio) of either 0.3 or 1.0. Both P/S groups consumed a high fat diet (40% energy from fat) for 4 menstrual cycles, followed by 4 menstrual cycles of a low fat diet (20% energy from fat). There was a significant increase (P less than 0.006) in the length of the follicular phase of the menstrual cycle during consumption of the low fat diet. Two thirds of the women showed increases in follicular phase length with an average increase of 1.9 days.