Grand challenges in biomedical computing.

Advances in computing technology (both algorithms and hardware) over the next several years promise to make increasingly sophisticated computer modeling of biomedical phenomena a routine part of biomedical research. Improvements in both the absolute speed of processors and in their programming and graphics interfaces will allow nonexpert users to bring computing power equivalent to the supercomputers of a few years ago to bear on routine research problems and to display complex data in understandable ways (visualization). Although biomedical applications have traditionally not driven the leading edge of computing and supercomputing, such applications are increasingly being ported to advanced parallel and vector processors. This paper summarizes the current state of biomedical computing, citing examples of the best practice in research today. A number of projects enabled by advanced computing from various subdisciplines are described. Trends in technology for both inexpensive (workstation) and high-end computing (vector supercomputers and parallel processors) are cited; the implications of these for biomedical computing are discussed. "Grand challenges" in biomedical computing, i.e., computational problems of major scientific importance that are beyond our current capabilities but that might be achieved in a 5-year time frame, are outlined.

Spironolactone and estrogen-progestin therapy for hirsutism.

Sixteen women with hirsutism used spironolactone, 100 mg daily without interruption, plus norethindrone (1 mg) and ethinyl estradiol (35 mg) for 21 of each 28 days. Clinical improvement occurred in 11 of the 16 patients and also in an additional patient when the dose of spironolactone was increased to 200 mg daily. Spironolactone 100 mg daily plus norethindrone and ethinyl estradiol resulted in significant reduction in serum total testosterone, serum free testosterone, and percentage of free testosterone. Side effects were infrequent.

High-molecular weight dextran in human infertility surgery.

The use of intraperitoneal 32% high-molecular weight dextran 70 (Hyskon, Pharmacia Inc.) has been reported to reduce the incidence of surgical adhesions in several species. The present study was undertaken to determine the effect of 32% dextran 70 in human females who underwent major abdominal infertility operations. Adhesions were quantitated by means of standardized objective criteria in 44 women in a prospective, randomized, double-blind study, and reevaluated at second-look laparoscopy approximately 6 weeks later. The mean change in the adhesion score for all patients in the 32% dextran 70 group (n = 23) was -2.57 units (i.e., clinically "improved") versus +2.41 units (i.e., clinically "worsened") in the control group (n = 21), p = 0.016. For the subgroup of patients who underwent lysis of adhesions, the 32% dextran 70 group (n = 17) improved significantly, whereas the control group (n = 12) tended not to improve with careful technique alone (-4.2 units versus +0.3 unit, p less than 0.05). These data indicate that 32% dextran 70 not only significantly reduces the formation of adhesions overall in human infertility operations, but also is highly effective in reducing the reformation of adhesions after lysis.

Nocturnal prolactin levels in infertility.

Since serum prolactin rises during sleep in normal women, nocturnal serum prolactin concentrations were determined every 30 minutes in follicular phase and again in luteal phase in 13 regularly menstruating infertile women with daytime normoprolactinemia, 8 of whom had luteal phase defects. When compared with controls, there was an increased serum prolactin elevation in 7 women. Six of the women with nocturnal hyperprolactinemia took bromocriptine for two menstrual cycles. This treatment eliminated the excessive nocturnal prolactin rise but did not result in consistent improvement in endometrial development. Polytomographic findings compatible with a pituitary microadenoma were seen in 5 of 7 women with nocturnal hyperprolactinemia. Random daytime prolactin levels may be normal in infertile women who have nocturnal hyperprolactinemia associated with x-ray evidence of pituitary microadenoma.

Effect of cyproheptadine on chlorpromazine stimulation of prolactin in women.

In five normal women, the expected chlorpromazine-induced rise in serum prolactin was inhibited by pretreatment with a serotonin antagonist, cyproheptadine. This indicated that the serotoninergic system has an excitatory effect on the release of prolactin. When similar studies were done in nine women with hyperprolactinemia and galactorrhea, the administration of chlorpromazine did not consistently produce a rise in serum prolactin, and pretreatment with cyproheptadine did not have a predictable effect. In most cases, this chlorpromazine-induced reduction in the prolactin inhibitory factor could not further increase the secretion of prolactin, so that there was no rise to inhibit.

Identification of differing etiologies of clinically diagnosed premature menopause.

Investigations were performed in eight young women to determine if the findings of secondary amenorrhea and high follicle-stimulating hormone levels were due to primary ovarian follicular atresia or to other causes. Karyotypes were determined from both peripheral leukocytes and ovarian tissue; one woman had XXX/XX/XO mosaicism. Another woman had normal ovarian histology and probably had the "gonadotropin-resistant ovary syndrome." No autoimmune antibodies were detected, but one woman with myasthenia gravis also had ovarian histology that demonstrated primary ova and a developing follicle. Only five of eight women had primary ovarian follicular atresia, and two of the other three women had conditions theoretically compatible with subsequent pregnancy.

Effects of alpha- and beta-adrenergic blocking agents on serum prolactin levels in women with hyperprolactinemia and galactorrhea.

The effects of alpha- and beta-adrenergic blocking agents on the serum prolactin levels of six women with hyperprolactinemia and galactorrhea were investigated. There was no indication that pituitary adenomas were etiologic agents for the hyperprolactinemia. Serum prolactin could be lowered with oral L-dopa. When intravenous phentolamine (an alpha-adrenergic blocking agent) or intravenous propranolol (a beta-adrenergic blocking agent) were administered for 1 hour, there was no significant change in serum prolactin levels.

Contraception with norethindrone 0.35 mg administered continuously.

Microdose norethindrone (0.35 mg taken each day without interruption) was used as an oral contraceptive agent by 168 women for 4,264 months over a five-year span. Seven pregnancies occurred with regular use and two with irregular use, resulting in a drug-effectiveness rate of 1.9 and a use-effectiveness rate of 2.5 per 100 woman-years. Cycle length was variable. During the five years of study there was a tendency toward weight gain, but no definite trend in blood pressure changes was noticed; however, there were no comparable control groups for these latter two observations. Results of metyrapone tests done after 17 to 33 months of treatment were normal.

Serum prolactin levels in galactorrhea.

Some patients with galactorrhea will have normal serum prolactin levels but many will have elevated serum prolactin levels. The galactorrhea may be due to drug ingestion, nipple afferent nerve stimulation, nonneoplastic disease or injury, and intracranial tumors. Serum prolactin levels were measured by radioimmunoassay in 17 women with galactorrhea. Levels 5 and 6 times normal values were found in two women who had proved pituitary adenomas. The latter conditions must be strongly considered and functional tests may help in diagnosis prior to enlargement of a prolactin-secreting tumor to the size where changes in the sella are seen on x-ray or visual field changes occur. If galactorrhea persists when no evidence of tumor can be found, the patient must be periodically re-evaluated, as the tumor may have been too small for detection at the time of the previous examination.