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Biomedical subjects

J R Brooks

Publications and source records attributed to J R Brooks.

At least 19 recordsLinked to original sources
PubMed1991

Effect of castration, DES, flutamide, and the 5 alpha-reductase inhibitor, MK-906, on the growth of the Dunning rat prostatic carcinoma, R-3327.

Male rats bearing implants of the Dunning rat prostatic carcinoma, R-3327, were used in a 42-day study to determine the effect of castration or orally administered flutamide (FL), DES (diethylstilbestrol) or the 5 alpha-reductase inhibitor, MK-906, on the growth of this androgen-responsive cancer. The rate of growth and final weights of the tumor and the ventral prostate (VP) were all reduced (P less than 0.05) by castration. Flutamide (25 mg/kg/day) significantly decreased tumor and VP weights in intact rats and castrates given 100 micrograms/day (SC) of testosterone propionate (TP) or dihydrotestosterone propionate (DHTP). It also significantly retarded tumor growth rate in TP- or DHTP-treated castrates and was marginally effective in intact animals. DES (100 micrograms/kg/day) reduced (P less than 0.05) tumor and VP weights of intact rats but did not significantly affect tumor growth rate or weight in castrates given TP or DHTP. These results indicated that the effect of DES on tumor growth is caused by its inhibition of the secretion or release of the gonadotropins necessary for testicular androgen production. MK-906 (25 mg/kg/day) affected neither the gross nor the histomorphology of the tumor in intact rats or castrates given TP or DHTP. Further, it caused no histological changes in the testes of intact rats. It did, however, significantly reduce VP weight in intact animals and TP-treated castrates but not in those given DHTP. This illustrates that the anti-androgenicity of MK-906 stems from its inhibition of DHT formation. The failure of MK-906 to influence tumor growth in the TP-treated castrates strongly suggests that the R-3327 tumor can respond to testosterone directly. If that is true, then its growth is unlikely to be affected by a pure 5 alpha-reductase inhibitor such as MK-906. In ancillary experiments, tumors from MK-906-treated animals were found to have reduced levels of DHT and, when assayed in vitro, to have a reduced capacity to convert [3H]-T to [3H]-DHT.

5-alpha Reductase Inhibitors↗
PubMed1991

Topical anti-androgenicity of a new 4-azasteroid in the hamster.

The topical anti-androgenic activity of L-651,580 (methyl 3-oxo-4-methyl-4-aza-5 alpha-androst-1-ene-17 beta-carboxylate) was established in a series of for experiments using castrated male hamsters. During each 21-day experiment, the animals received a daily subcutaneous injection of 40 micrograms testosterone propionate or 20 micrograms dihydrotestosterone propionate. Test compound in 25 microliters of gel was applied daily to the left flank organ. Compounds assayed included L-651,580, WIN 17,665 (17 alpha-propyltestosterone), and SH-434 (17 beta-hydroxy-1 alpha-methyl-17 alpha-propyl-5 alpha-androstan-3-one). Endpoints were flank organ area, sebaceous gland area, and prostate weight. Very similar results were obtained with L-651,580 and WIN 17,665. Daily doses of 0.25 mg or more of either compound usually produced a significant reduction in the areas of treated flank organs and sebaceous glands underlying treated flank organs. Neither compound caused significant changes in the area of the contralateral flank organs and sebaceous glands, which indicated they possess little or no systemic activity at topically effective treatment levels. In direct comparisons, SH-434 was less anti-androgenic than L-651,580 or WIN 17,665, although in one experiment, 0.5 mg/d of SH-434 significantly reduced the area of treated flank organs and sebaceous glands. Neither WIN 17,665 nor SH-434 caused a change in prostate weight; however, in one of four tests, a significant decrease was induced by the 0.5 mg/d level of L-651,580. The results of these experiments show that the topical anti-androgenicity of L-651,580 compares very favorably with that of WIN 17,665 and SH-434. They also indicate that the topical administration of effective dosage levels of L-651,580 causes few, if any, systemic effects.

Administration, Topical↗
PubMed1989

Total pancreatectomy for ductal cell carcinoma of the pancreas. An update.

Forty-eight patients with ductal cell carcinoma of the pancreas underwent total pancreatectomy. During 1970-1976, there were four deaths (a mortality of 18%). During the last twenty-eight operations (1977-1986), there were no hospital deaths. Seventeen per cent of the patients suffered intraoperative complications involving the mesenteric vessels. Twenty-seven per cent suffered postoperative complications. Twenty-five per cent of the patients left the hospital within 2 weeks, 50% left within 4 weeks, and another 25% remained in the hospital for longer than 4 weeks. Thirty-five per cent of the patients have returned to their preoperative job or similar life activity. Another 35% were able to lead an active life but did not return to regular work, and 30% were to some degree incapacitated by their operative procedure and disease. Twenty-one per cent of the patients lived for 4 years, and 14% survived for 5 years.

Adult↗
PubMed1989

Enzyme-linked immunosorbent assay and immunoblotting determination of antibody response to major component proteins of soybeans in patients with soy protein intolerance.

To evaluate the role of food-specific antibody response to soy protein and its fractions in patients with soy protein intolerance, allergen-specific IgG and IgE to these proteins were measured by enzyme-linked immunosorbent assays (ELISAS) and immunoblotting. A crude soy extract and the 7S, 11S, and whey fractions were isolated from commercial defatted soy flakes. Of 23 patients who underwent standardized soy challenges, seven were positive. The ELISA results showed no statistically different responses between the challenge-positive and challenge-negative groups in IgG or IgE specific to either the crude soy extract or the 7S, 11S, and whey fractions (p greater than .3 for all variables). In comparing the soy-positive patients, the level of IgE specific for 7S and 11S was significantly different compared with whey; the level of IgE specific for crude soy extract and 7S was significantly different compared with whey. The immunoblots reveal that IgG and IgE are present in varying amounts to multiple fractions of the soy protein. The study does not provide evidence for a pathogenic role of serum food-specific antibodies in soy protein intolerance.

Antibody Formation↗
PubMed1989

Where are we with pancreas transplantation?

The question still remains: What is best for the patient? It appears that whole organ or segmental pancreas transplantation can be carried out, giving anywhere from a 46% to an 84% 1-year pancreas survival rate. At the moment there is no clear-cut evidence that patient survival--at least in the short term--is any better after a combined pancreas-kidney graft than after a kidney graft alone, and there are more complications from the combined procedure. It appears once again that patient survival is a function of control of ketoacidosis and its complications--whether by a pancreas graft or by better insulin delivery. Nevertheless, several things have been learned: (1) Patients who receive a pancreas-kidney graft simultaneously have the best pancreas 1-year survival. (2) A pancreatic graft without a simultaneous kidney graft does poorly. (3) A pancreas graft carried out after a kidney graft will not do as well. (4) A kidney transplanted to a diabetic patient may become nephropathic unless supported by a pancreatic graft. (5) Retinopathy is not improved by pancreatic transplantation. (6) Neuropathy is improved or stabilized by pancreatic transplantation. (7) Nephropathy is improved by pancreatic grafting. (8) There is no clear-cut difference in pancreatic graft survival, whether segmental or whole organ grafts are used. (9) Bladder-drained grafts appear to have slightly better survival at 1 year than enteric-drained or polymer-injected grafts. (10) Human islet cell homotransplantation is not yet an accomplished fact. As Barker has pointed out, the potential benefits of pancreatic grafting are for those who are prone to complications and who do not have irreversible diabetic complications. Predicting those in whom significant complications will develop is not easy, and a large percentage of the grafts done to date have been done for patients with end stage renal disease. It has been suggested that transplants are best used for those with early renal disease and for those with pre-proliferative retinopathy and for those that are metabolically difficult to handle with insulin and for those at high risk for complications with diabetes: namely, those with high levels of inactive renin that are associated with microvascular complications and high levels of insulin-like growth factor. These complications seem to be associated with accelerated progression of retinopathy. Diabetic children whose disease is associated with major neurovascular disease and children with impaired counter regulatory mechanisms may also be candidates for grafting.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus↗
PubMed1988

Allergenicity of major component proteins of soybean determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting in children with atopic dermatitis and positive soy challenges.

Recent studies have implicated soybeans as one of the major food allergens in children. Serum from eight patients with atopic dermatitis and positive double-blind, placebo-controlled food challenges to soy were used to investigate allergen-specific IgE and IgG antibody to soy protein and its fractions. ELISA and immunoblotting techniques were used for this purpose. A crude soy extract, as well as the 7S, 11S, and whey fractions, were isolated and purified for the in vitro studies from commercial defatted soy flakes. ELISA results demonstrated a statistically significant increased IgE and IgG response to the crude soy extract compared to that of normal control subjects. There was also an increase in IgE specific for 7S and IgG specific for 11S in the atopic group. The immunoblots reveal that IgE and IgG are present in varying amounts to multiple fractions of the soy protein. These results indicate that IgE and IgG specific to crude soy are elevated in patients with positive double-blind, placebo-controlled food challenges to soy but that no one fraction is clearly more antigenic.

Adolescent↗
PubMed1988

Surgical therapy for thyroid carcinoma: a review of 1249 solitary thyroid nodules.

A total of 1249 "cold" solitary thyroid nodules were excised at the Brigham and Women's Hospital from 1948 through 1987. Of these nodules, 241 showed malignant conditions: 123 were papillary, 42 were mixed papillary-follicular, and 43 were pure follicular carcinomas. There were also 23 anaplastic, 8 medullary, and 3 Hürthle cell carcinomas. These patients were followed up from 3 to 31 years, with a mean range of 10 years. Fifty-three patients with well-differentiated tumors underwent total thyroidectomies, and 179 underwent subtotal thyroidectomies (excluding anaplastic, medullary, and Hürthle cell tumors). Regional lymph node involvement was commonly found but appeared not to affect survival; tumor size and local spread and extent of thyroid gland involvement did affect survival. A small percentage of well-differentiated thyroid tumors do, in time, undergo anaplastic change that leads to metastasis and death. There was no 30-day mortality rate. The late mortality rate was 2% for papillary and 14% for follicular carcinomas. Papillary tumors are becoming more common. Older aged patients and male patients appear to carry poorer prognoses for survival. The total thyroidectomy procedure has not improved survival over subtotal thyroidectomy and carries a higher complication rate.

Adenocarcinoma↗
PubMed1986

Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors.

A series of 4-azasteroidal 5 alpha-reductase inhibitors was tested in dogs to determine the effect of chronic (35-44 day) oral administration on prostate size and histology and acute oral administration on prostatic concentrations of testosterone (T) and dihydrotestosterone (DHT). The extent to which the results of the two tests were correlated was also studied in order to see whether the acute test could be used to predict activity in the chronic test. Six delta 1 analogs of the potent 5 alpha-reductase inhibitor, 4-MA (17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one) were uniformly active at low dosage levels (less than or equal to 3 mg/kg) in both types of assay whereas several C1-C2 saturated analogs exhibited little activity in the chronic test. The nature of the side chain and whether there was a methyl or a proton at 4-N did not dramatically influence the activity of delta 1 compounds. There was a broad general agreement between the results of the two kinds of test in that if a compound acutely decreased the prostatic concentration of DHT it was likely to reduce prostate size and alter prostatic histology when given on a chronic basis.

5-alpha Reductase Inhibitors↗
PubMed1986

5 Alpha-reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat.

Inhibition of 5 alpha-reductase and anti-androgenicity were studied in rats treated with various 4-azasteroids. The known inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) served as a reference compound, and analogs of this basic molecule were assayed. Enhancement of enzyme inhibitory potency was usually seen with delta 1 analogs, whereas reduction in activity was noted with substitutuents such as delta 5, a spirotetrahydrofuran ring at C-17 or 4-deaza groups. Many of the 4-azasteroids had a much greater oral anti-androgenic effect against testosterone propionate (TP) than dihydrotestosterone propionate (DHTP). This difference in activity versus the two androgens is believed to reflect the necessity for TP to undergo reduction to DHT before becoming capable of stimulating prostatic growth. Inhibition of 5 alpha-reductase by active compounds prevented the conversion, thereby producing an anti-androgenic effect. In this regard, certain delta 1 analogs of 4-MA, particularly those bearing a 17 beta-(N-tert butylcarbamoyl) group, proved very effective against TP but were relatively inactive versus DHTP.

Androgen Antagonists↗
PubMed1986

Treatment of hirsutism with 5 alpha-reductase inhibitors.

Much os the evidence gathered from studies of 5 alpha-reductase activity levels and androgen metabolism in the skin of hirsute women and the excretion of androgen metabolites by hirsute women indicates that 5 alpha-reduced androgens are probably of primary importance in hirsutism. Unfortunately, until very recently, the lack of a suitable 5 alpha-reductase inhibitor made it very difficult to adequately test the hypothesis that such an inhibitor might be useful in the treatment of hirsutism and certain other androgen-related diseases. No substance was available which had good, unambiguous activity in vivo as a 5 alpha-reductase inhibitor. A number of 4-azasteroids have now been found to possess excellent 5 alpha-reductase inhibitory activity both in vitro and in vivo. Among other properties, several of these compounds show little or no affinity for the androgen receptor of rat prostate cytosol, they attenuate the growth promoting effect of T, but not DHT, on the ventral prostate of castrated male rats, they cause a marked reduction in prostatic DHT concentration in acutely treated rats and dogs and they bring about a significant decline in prostate size in chronically treated rats and dogs. It is expected that, in the near future, one or more of these highly active 5 alpha-reductase inhibitors will be tested in the clinic as a treatment for hirsutism. The results of those studies will be awaited with a great deal of interest since they should considerably advance our understanding of this disease and possibly contribute to its control.

5-alpha Reductase Inhibitors↗
PubMed1986

Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.

A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.

5-alpha Reductase Inhibitors↗
PubMed1985

Surgery for thyroid carcinoma.

The cases of thyroid carcinoma treated at this hospital during the period 1948 to 1981 were reviewed retrospectively. Nine hundred eighty-six patients with thyroid nodules were operated on. One hundred fifty-two were thyroid carcinoma (59 papillary, 36 mixed papillary-follicular, 30 follicular, 20 anaplastic, 5 medullary, and 2 Hurthle cell tumors). There was a 92% follow-up for a mean of 10 years. In the last decade, patients presented at a younger age, the female predominance was diminished, and 15% had had previous neck irradiation. Surgery consisted of total (27) or subtotal thyroidectomy (89), lobectomy or nodulectomy (24), and biopsy (12). Total thyroidectomy had an incidence of postoperative complications that was 20 times higher than that with partial thyroidectomy (P less than 0.001). Disease-related death, recurrence, and survivor status were discussed. There was no significant difference between total versus subtotal thyroidectomy. This study reaffirms the usefulness of subtotal resection and the avoidance of morbidity of more radical total thyroidectomy surgery.

Adenocarcinoma↗
PubMed1985

Surgical management of gastric adenocarcinoma.

This paper has analyzed the results of surgical management of 196 patients with gastric carcinoma treated from 1958 through 1982 at the Brigham and Women's Hospital in Boston and compares the experience during this time period with that of the previous 45 years. Surgical technique, operative mortality and complications, and 5 year survival were recorded. The resectability rate of the tumor in patients explored was 78.1 percent, and the 5 year survival rate for all 153 gastrectomies was 24.9 percent (36.2 percent for curative gastrectomy and 8.6 percent for palliative gastrectomy). Chronologic comparison over the years showed a decrease in the incidence of cancer of the stomach over the past 65 years, a steady increase in the 5 year absolute survival of patients with gastric carcinoma, and a significant decrease in the operative mortality and an increase in the 5 year survival after subtotal gastrectomy.

Adenocarcinoma↗
PubMed1979

Lethal pancreatitis: a diagnostic dilemma.

Clinical and pathological information from forty patients who died with pathologically severe acute pancreatitis was correlated. Patients were classified into four etiologic groups: those with biliary pancreatitis (11 patients), alcoholic pancreatitis (13 patients), idiopathic pancreatitis (10 patients), and renal failure (6 patients). Antemortem diagnosis was made in only 57 per cent of the patients studied. The diagnosis was determined before death in 91 per cent of the biliary patients but in none of the renal patients. Thirty-seven patients died from their first clinical attack of pancreatitis. Operation in patients with biliary pancreatitis failed when biliary decompression was not provided. Peripancreatic sepsis was a frequent lethal mechanism in patients with biliary pancreatitis, but renal and respiratory failure were more common in patients with alcoholic pancreatitis.

Acute Disease↗
PubMed1979

Histopathology in the evaluation of total pancreatectomy for ductal carcinoma.

Whipple resections for pancreatic head carcinoma are often inadequate because tumor is left behind in the body and tail. Thirty-six patients have undergone total pancreatectomy for various conditions, of which 25 have undergone total pancreatectomy, for ductal carcinoma. Thirty-seven per cent of these 25 patients have shown histologic evidence that a Whipple resection would not have adequately removed tumor-bearing pancreatic tissue. Three patients had carcinoma spreading up and along the common bile duct from a primary ductal carcinoma in the head of the pancreas. Four patients had tumor infiltrating in continuity into the pancreatic body and tail at a distance from the palpable tumore in the head well to the left of a Whipple transection site. Five patients had widespread multifocal autonomous tumor involving other areas in the gland but with tumor palpable only in the head of the pancreas. Three patients (12%) died postoperatively. The two year survival rate is 32%, and the five year survival, 19%. Histological factors affecting the survival prognosis include 1) positive nodes, 2) tumor extension up the common duct, and 3) intrapancreatic extension and multicentricity of tumor mandating total pancreatectomy for hope of cure in at least 38% of cases.

Humans↗
PubMed1979

Operative approach to pancreatic carcinoma.

It is apparent that we are dealing with a very lethal disease. It is also apparent that this disease is increasing in frequency. In terms of treatment, it is clear that the survival figures between carcinoma of the pancreas and carcinoma of the common duct, papilla of Vater, or duodenum present great differences. The pancreatic tumors do very poorly by comparison. A comparison of the survival figures following a Whipple resection and following a bypass procedure reveal similar results, except when dealing with a very small pancreatic head lesion or when dealing with a malignancy of the papilla of Vater, lower end of common duct, or duodenum. The latter tumor types do better with a Whipple resection than a bypass. A comparison between total pancreatectomy and a Whipple resection for ductal carcinoma of the pancreatic head reveals better results in terms of length of survival following total pancreatectomy as long as one considers only Stage I or Stage II disease and excludes Stage III disease. A Whipple procedure is advocated for carcinoma of the papilla of Vater, common duct, or duodenum, because survival figures are quite good and many patients escape the need for insulin and pancreatic extract replacement. It is too early to evaluate the survival figures that follow regional pancreatectomy.

Ampulla of Vater↗