Complex-induced proximity effects: the effect of varying directing-group orientation on carbamate-directed lithiation reactions.

A series of selected bicyclic carbamates in which the range of accessible angles and distances between the carbonyl group and the proton removed in an alpha-lithiation reaction are structurally defined have been investigated. Oxazolidinones 7-10 undergo stereoselective lithiation-substitution reactions to provide cis-18-27 and cis-31-35 as the major diastereomers. Two series of competition experiments show that the conformationally restricted carbamates 7, 10, 11, and 15 undergo lithiation via complexes more efficiently than Boc amines 4-6. These results along with semiempirical calculations suggest that a small dihedral angle and a calculated distance of 2.78 A between the carbamate carbonyl oxygen and the proton to be removed are favorable for a carbamate-directed lithiation. A series of tin-lithium exchange experiments on cis- and trans-18 and (S)-39 indicate that the configurational stability of a carbamate-stabilized organolithium species may be enhanced by restrictive geometry.

New strategies in the medical management of asthma.

Asthma, a common chronic inflammatory disease of the airways, may be classified as mild intermittent or mild, moderate, or severe persistent. Patients with persistent asthma require medications that provide long-term control of their disease and medications that provide quick relief of symptoms. Medications for long-term control of asthma include inhaled corticosteroids, cromolyn, nedocromil, leukotriene modifiers and long-acting bronchodilators. Inhaled corticosteroids remain the most effective anti-inflammatory medications in the treatment of asthma. Quick-relief medications include short-acting beta2 agonists, anticholinergics and systemic corticosteroids. The frequent use of quick-relief medications indicates poor asthma control and the need for larger doses of medications that provide long-term control of asthma. New guidelines from the National Asthma Education and Prevention Program Expert Panel II recommend an aggressive "step-care" approach. In this approach, therapy is instituted at a step higher than the patient's current level of asthma severity, with a gradual "step down" in therapy once control is achieved.

Mammographic technologist job satisfaction: what radiologists need to know--results of a large national survey.

PURPOSE: To determine mammographic technologists' overall level of job satisfaction, the variables that correlate with job satisfaction, and whether job satisfaction has changed since 1987. MATERIALS AND METHODS: A 29-item, scannable survey was mailed randomly to 5,000 mammographic technologists. Survey items were related to work setting, job description, rate of pay and other benefits, experience, education, age, and overall job satisfaction. The results were compared with those of a 1987 survey of general radiologic technologists. RESULTS: A total of 1,503 technologists responded to the survey. On a five-point scale, in which 5 represents very satisfied, the mean rating of job satisfaction +/- the standard deviation was 3.4 +/- 0.9; 83.1% of technologists rated overall satisfaction as 3 or higher compared with 86% of general technologists who reported being satisfied with their jobs in 1987. Regression analysis revealed that enjoyment from working with fellow mammographic technologists and enjoyment from working with radiologists (combined adjusted R2, 26.5%) correlated significantly with increased job satisfaction. CONCLUSION: Mammographic technologist job satisfaction is high and similar to that of general radiologic technologists, as reported in 1987. Survey results indicate that the most important variable related to mammographic technologist job satisfaction is the technologist-radiologist relationship; a negative relationship results in lower job satisfaction, which can affect job performance and patient care.

Quality assessment and clinical research: a collaborative approach.

Obtaining physician commitment to and continued involvement in quality assessment activities can be difficult. Some physicians view quality assessment as a bureaucratic morass that fails to improve patient care. However, by combining quality assessment and clinical research, insight into practice patterns can be obtained and physicians might be more likely to express interest in quality assessment issues. We reviewed medical records of patients at our hospital on peritoneal dialysis (PD) to determine the rate of free air found in normal PD patients. This was compared to PD patients with known gastrointestinal perforation; free intra-abdominal air has been described as a sign of gastrointestinal perforation. Documentation of free air and its significance in radiology reports were noted. Fifty-nine of 59 (100%) cases had available radiology reports. Documentation of free air was present in only 5 of 23 (22%) cases, and its significance was noted in the same 5 of 23 (22%). These results were communicated within the hospital, and a subsequent improvement in free-air detection, documentation, and reporting--both oral and written--was noted by the clinical service. The documentation of radiological findings is a frequently used monitor in radiology quality assessment. Our study identified a clinical and documentation problem, quantified the deficiency, and took steps toward improvement while simultaneously performing clinical research. We conclude that quality assessment and clinical research can coexist and serve to improve clinical practice while encouraging physician involvement in quality assessment programs.

Pneumoperitoneum in peritoneal dialysis patients: significance of diagnosis by CT.

OBJECTIVE: Pneumoperitoneum diagnosed by plain radiography is often a sign of gastrointestinal perforation and is unusual (0.17%) in patients on continuous ambulatory peritoneal dialysis (CAPD). These patients are prone to bacterial peritonitis, which can have overlapping clinical findings with perforated viscus. Because CT is often used to screen symptomatic CAPD patients, the reliability of pneumoperitoneum as a diagnostic sign is examined. MATERIALS AND METHODS: Records of 433 CAPD patients were examined; of these, 56 patients had had CT while on CAPD (rupture, 6; nonrupture, 50). Plain radiography and CT were examined for free air and fluid. Patients were classified according to the amount of free air detected. RESULTS: Patients with ruptured viscus had pneumoperitoneum in 5 of 6 cases by CT and 4 of 6 by plain radiography. Excluding free air, ruptured viscus could only be diagnosed in 1 of the 6 patients by CT. Patients without rupture had pneumoperitoneum in 15 of 50 cases by CT and 2 of 46 by plain radiography. No instance of pneumoperitoneum was discovered on plain radiography and not CT. CONCLUSION: Pneumoperitoneum was found by CT in 30% of nonrupture CAPD patients, therefore, CT appeared to be more sensitive than plain radiography for its detection. The presence, quantity, and distribution of free air are not helpful in separating perforations from nonperforations. The lack of pneumoperitoneum on CT was found to be a useful but not absolute diagnostic sign to exclude gastrointestinal rupture.

Diuretic drug use and the risk for hip fracture.

OBJECTIVE: To test the hypothesis that use of thiazide diuretics prevents hip fracture and to study the risk for hip fracture associated with furosemide use. DESIGN: A case-control study. SETTING: Hospitals owned by a health maintenance organization in Washington. PATIENTS: Elderly patients (n = 462) hospitalized because of a hip fracture between 1977 and 1983 and an equal number of age- and sex-matched population-based control patients. MEASUREMENTS: Use of thiazide diuretics and furosemide was ascertained from medical records and computerized pharmacy records. The relative risk for hip fracture associated with diuretic use was calculated and adjusted for the potentially confounding effects of nursing home residence; previous hospitalizations; a history of stroke, alcoholism, or the organic brain syndrome; body weight; leg paralysis; and use of phenobarbital, corticosteroids, or other diuretics. Current and former users of diuretics were analyzed separately. MAIN RESULTS: The adjusted risk for hip fracture was 1.6 (95% CI, 1.0 to 2.5) for current thiazide users. The adjusted risk for hip fracture for current furosemide use was 3.9 (CI, 1.5 to 10.4). CONCLUSIONS: According to this study, use of thiazide diuretics did not protect against hip fracture and cannot be recommended for fracture prevention. Current furosemide use was also associated with hip fracture.

The importance of signal pattern in the transmission of endocrine information: pituitary gonadotropin responses to continuous and pulsatile gonadotropin-releasing hormone.

We tested the hypothesis that pulsatile GnRH stimulation of the pituitary is required for normal gonadotropin secretion in humans. We administered GnRH in pulsatile and continuous regimens in varying order to each of five women with hypothalamic amenorrhea and presumed endogenous GnRH deficiency. Mean serum levels of GnRH were similar during the pulsatile and continuous regimens. All women ovulated during the pulsatile regimen (progesterone, greater than 31.8 nmol/L (10 ng/mL); none ovulated during the continuous regimen. Compared to pretreatment levels, FSH and estradiol, as measured by RIA, and LH, as measured by bioassay, increased significantly during the pulsatile GnRH regimen, but not during the continuous regimen. However, LH and alpha-subunit, as measured by RIA, increased significantly during both continuous and pulsatile GnRH administration. We conclude that a pulsatile pattern of GnRH is essential to normal functioning of the human female reproductive axis. Continuous administration of GnRH, producing mean serum levels of the peptide indistinguishable from those found during pulsatile administration, stimulates some rise in a nonbioactive form of radioimmunoassayable LH-like material and alpha-subunit, but does not stimulate bioactive LH, FSH, estradiol, or progesterone and does not lead to ovulation.

The physiological significance of pulsatile LHRH secretion in man: gonadotrophin responses to physiological doses of pulsatile versus continuous LHRH administration.

This study tested whether pulsatile LHRH stimulation of the pituitary is required for normal gonadotrophin secretion in man. Four men with idiopathic hypogonadotrophic hypogonadism (IHH) and presumed endogenous LHRH deficiency were taken off all hormonal replacement for 5-6 weeks, then 5 micrograms LHRH was administered every 2 h for 1 week in order to prime pituitary gonadotrophin responsiveness. A physiological dose of LHRH (10 micrograms every 2 h) was then administered in both pulsatile and continuous regimens, in varying order, to each man. Pulsatile LHRH was capable of stimulating LH (as measured by bioassay) and FSH secretion, while continuous administration of LHRH was not. Serum LH, measured by RIA and bioassay, and FSH and free alpha-subunit levels, measured by RIA, increased significantly (P less than 0.05) over pretreatment levels during pulsatile LHRH administration. In contrast, bioactive LH and immunoactive FSH did not change significantly compared to pretreatment values during continuous infusion of the same total LHRH dose, although immunoactive LH and free alpha-subunit levels did increase significantly (P less than 0.05). The ratio of LH bioactivity to immunoactivity was significantly lower during the continuous compared to pulsatile LHRH regimen (P less than 0.001). Similar serum LHRH levels were achieved during pulsatile and continuous infusions. Serum testosterone and oestradiol levels did not increase significantly from pretreatment levels during either regimen of LHRH administration. It is concluded that a pulsatile LHRH signal pattern is essential for normal pituitary gonadotrophin secretion in men with IHH. Continuous infusion of a physiological dose of LHRH, which produced serum LHRH levels which were indistinguishable from those found during pulsatile administration, failed to stimulate FSH or bioactive LH secretion.

The luteinizing hormone-releasing hormone pulse generator in men: abnormalities and clinical management.

Most men with hypogonadotropic eunuchoidism have absent luteinizing hormone and presumably absent luteinizing hormone-releasing hormone pulses. Pulsatile luteinizing hormone-releasing hormone therapy is effective in restoring normal gonadotropin secretion and testicular function and inducing fertility in men with hypogonadotropic eunuchoidism. Furthermore, pulsatile (versus continuous) luteinizing hormone-releasing stimulation of the pituitary gland is an absolute requirement for normal gonadotropin secretion. Men with idiopathic oligoazoospermia and selective elevation of follicle-stimulating hormone levels have slow luteinizing hormone and presumably luteinizing hormone-releasing pulse frequency. In these men, pulsatile luteinizing hormone--releasing treatment is effective in decreasing serum follicle-stimulating hormone levels, but it is unclear whether spermatogenesis and fertility are improved.

Hospitalizations because of hypoglycemia in users of animal and human insulins. 2. Experience in the United States.

In a 10-year (1979-1988) follow-up study of young insulin-dependent diabetics carried out at Group Health Cooperative of Puget Sound, the frequency of hospitalization for hypoglycemia remained constant. During the early years only animal insulins were available; during the latter years, human insulins were used in a majority of patients. The adjusted relative risk estimate for hospitalizations for hypoglycemia comparing users of human with users of animal insulins was 0.6 (95% confidence interval 0.2, 2.3). We conclude that the use of human insulins is not associated with an increased risk of hospitalization for hypoglycemia as compared with animal insulins in this population.

Treatment of stage D2 prostatic carcinoma with combined gonadal and adrenal suppression in a 60-year-old man.

A 60-year-old man with stage D2 prostatic carcinoma received treatment with a new luteinizing hormone-releasing hormone superagonist. After a seven-month remission; relapse of the disease occurred and an adrenal-suppressing dose of dexamethasone was added. The resulting combined gonadal and adrenal suppression led to another remission that lasted five months. This case supports other observations of the importance of adrenal androgen production in the pathobiology of prostatic carcinoma.

Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man.

To test the hypothesis that the frequency of pulsatile LHRH stimulation can differentially control LH and FSH secretion in man, we administered low doses of LHRH in pulsatile fashion in several different regimens to men with idiopathic hypogonadotropic hypogonadism (IHH) and presumed endogenous LHRH deficiency. In study 1, four men with IHH received a constant amount of LHRH per day in three different frequencies. After an initial 7-day period of LHRH (5.0 micrograms every 2 h), the men received 2.5 micrograms every 1 h and 7.5 micrograms every 3 h, each for 4 days, in varying order. Frequent blood samples were obtained before LHRH administration and at the end of each regimen. Before LHRH administration, mean serum FSH and LH levels were low [28 +/- 3 (+/- SEM) and 6 +/- 2 ng/mL, respectively], and they increased into the normal adult male range during LHRH treatment. As the frequency of LHRH administration decreased from every 1 to 2 to 3 h, serum FSH levels progressively increased from 99 +/- 33 to 133 +/- 34 to 181 +/- 58 ng/mL (P less than 0.05). Serum LH levels (34 +/- 6, 33 +/- 6, and 34 +/- 5 ng/mL) were significantly higher than those before LHRH administration and did not differ significantly among the three regimens. Total serum testosterone (T), estradiol, and free T levels were increased by LHRH, but were not significantly different during the three regions of LHRH administration. In study 2, three men with IHH received the same amount of LHRH per dose, given in two different pulse frequencies; 2.5 micrograms LHRH were administered in frequencies of every 0.5 h and every 1.5 h, each for 4 days, in varying order. During the 0.5 h frequency, the mean serum FSH level was 42 +/- 13 ng/mL, and it rose to 80 +/- 19 ng/mL during the 1.5 h frequency (P less than 0.05). Corresponding mean serum LH levels were 25 +/- 5 and 27 +/- 4 ng/mL. Serum T and estradiol levels were not significantly different during the two LHRH regimens. We conclude that the frequency of LHRH stimulation can differentially control FSH and LH secretion by the human pituitary gland, and the pattern of hormonal stimulation may be a determinant of target organ response.

Increased frequency of pulsatile luteinizing hormone-releasing hormone administration selectively decreases follicle-stimulating hormone levels in men with idiopathic azoospermia.

Men with idiopathic azoo-oligospermia and selective elevations of follicle-stimulating hormone (FSH) levels have evidence for decreased luteinizing hormone-releasing hormone (LH-RH) pulse frequency. We assessed whether increasing the frequency of pulsatile LH-RH stimulation can lower FSH levels in such men. We administered 5.0 microgram of pulsatile LH-RH subcutaneously at intervals of 30, 60, and 120 minutes for 1 week to four men who had azoospermia, elevated FSH levels, and normal LH and testosterone (T) levels. The order of administration was varied among subjects. Frequent blood samples were obtained for 6 hours before LH-RH treatment and during the last 6 hours of each regimen. Before LH-RH treatment, the FSH levels (mean +/- standard error of the mean) were 359 +/- 18 ng/ml (normal range, 30 to 230 ng/ml). During LH-RH treatment, FSH levels progressively declined from 397 +/- 68 ng/ml to 237 +/- 70 ng/ml to 175 +/- 43 ng/ml as the frequency of administration increased from every 120 to 60 to 30 minutes, respectively (P less than 0.05). Unlike the FSH levels, which showed a progressive decline, LH, T, and estradiol levels showed no consistent relationship to LH-RH pulse frequency. We conclude that (1) in men with idiopathic azoospermia and elevated FSH levels, it is possible to decrease FSH levels by increasing the frequency of pulsatile LH-RH stimulation; (2) this decline does not appear to be a result of changes in steroid feedback or pituitary down-regulation; and (3) the frequency of pulsatile LH-RH stimulation can differentially modulate LH and FSH secretion by the pituitary gland.

Evidence for decreased luteinizing hormone-releasing hormone pulse frequency in men with selective elevations of follicle-stimulating hormone.

To examine the hypothesis that the frequency of endogenous pulsatile LHRH stimulation controls the relative secretion of FSH and LH from the pituitary, we studied men with elevated FSH levels and normal LH levels to determine whether they have an altered frequency of pulsatile LHRH secretion compared to normal men. Because peripheral blood measurements of LHRH do not reflect the pulsatile characteristics of hypothalamic LHRH secretion, and it is generally accepted that the pulse frequency of LH secretion is an index of the frequency of endogenous LHRH pulsation, we used LH pulse frequency as the indicator of LHRH pulse frequency. Frequent blood sampling was performed to characterize LH pulse patterns in five men with selective elevations of FSH and seven age-matched normal men. Beginning at 0800-0930 h, blood samples were obtained every 10 min for 24 h through an indwelling iv catheter. Serum LH and FSH levels were measured by RIA in each sample, and the pattern of LH secretion was determined. Testosterone (T), estradiol, sex hormone-binding globulin, and free T were measured in a pooled serum sample from each man. Men with selective elevations of FSH had fewer LH pulses per 24 h (mean +/- SEM, 10.6 +/- 0.5) than the control group (12.9 +/- 0.6; P less than 0.01). There was no statistically significant difference in LH pulse amplitude (23 +/- 4 vs. 17 +/- 3 ng/ml). There were no statistically significant differences in T (4.9 +/- 0.5 vs. 6.1 +/- 0.5 ng/ml), estradiol (23 +/- 7 vs. 31 +/- 5 pg/ml), sex hormone-binding globulin (7.7 +/- 1.4 vs. 7.7 +/- 1.2 ng bound dihydrotestosterone/ml), or free T (0.16 +/- 0.02 vs. 0.23 +/- 0.04 ng/ml) in these men vs. normal subjects. We conclude that 1) compared to normal men, men with selectively elevated FSH levels have decreased LH pulse frequency, which suggests decreased LHRH pulse frequency; and 2) the relative secretion rates of LH and FSH by the pituitary may be regulated by the frequency of pulsatile LHRH secretion from the hypothalamus.

Verapamil and propranolol in essential hypertension.

Twenty-four subjects with mild to moderate essential hypertension completed this 9-wk parallel, randomized, double-blind study of the antihypertensive effects of verapamil (V) (240 to 480 mg%) and propranolol (P) (120 to 360 mg%). V lowered systolic and diastolic blood pressures in all postural positions, with an average reduction of 20/16 mm Hg. With the exception of standing systolic blood pressure, P also lowered systolic and diastolic blood pressures in all postural positions, with an average reduction of 9/11 mm Hg. Differences between V and P were significant only for sitting systolic blood pressure. Heart rate was decreased by P but was not affected by V. The PR interval was prolonged by V. Plasma levels of V and P were directly related to dose. Plasma levels of V were linearly related to those of its major metabolite, norverapamil (r = 0.81). There was no correlation between clinical response and the dose or plasma level of V or P, but all subjects who received 480 mg% V had an average blood pressure reduction of 20/16 mm Hg and plasma levels of the parent drug above 200 ng/ml. V is an effective antihypertensive for mild to moderate essential hypertension. Constipation, pedal edema, and a maculopapular rash were reported as side effects of V.