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Biomedical subjects

M Kaufman

Publications and source records attributed to M Kaufman.

At least 145 records · Page 8Linked to original sources
PubMed1985

Reduced affinity of the androgen receptor for 5 alpha-dihydrotestosterone but not methyltrienolone in a form of partial androgen resistance. Studies on cultured genital skin fibroblasts.

We have studied a child with posterior labial fusion, clitoral phallus, female urethra, and a short, blind vagina born to a mother with decreased axillary and pubic hair. Her karyotype is 46,XY. At 2 yr of age, the child's basal level of plasma testosterone was less than 0.35 nM and after human chorionic gonadotropin stimulation, it rose to 2.6. Testis and epididymis histology were normal. Her cultured genital (labial) skin fibroblasts have normal testosterone 5 alpha-reductase activity, and metabolize 5 alpha-dihydrotestosterone (DHT) normally, but they do not augment (up-regulate) their basal androgen-receptor binding activity during prolonged incubation with DHT. With DHT, the androgen receptor in her genital skin fibroblasts has a normal binding capacity (maximum binding capacity = 25 fmol/mg protein), but an increased rate constant of dissociation (k = 11.6 X 10(-3) min-1; normal, 6 +/- 1.2 (+/- SD)), and a decreased apparent equilibrium binding affinity (Kd = 0.6 nM; normal, 0.22 +/- 0.09) that is evident in the results of 2-h assays but not of those lasting 0.5 h. With the synthetic androgen, methyltrienolone, all three binding properties of the receptor are normal, and her receptor activity up-regulates normally. We interpret these results to mean that the subject has a ligand-selective defect in the time-dependent transformation of initial, low-affinity androgen-receptor complexes to serial states of higher affinity, presumably as the result of a structural mutation at the X-linked locus that encodes the androgen receptor protein.

Cells, Cultured↗
PubMed1985

Financing nutrition services in a competitive market.

Budget deficits and inflationary medical care costs threaten nutrition services, which until recently have been funded largely by federal, state, and local revenues. Nutritionists and dietitians responding to demands in the marketplace should develop innovative programs and pursue new sources for financing through the private sector, third-party payers, business/industry health promotion, and consumer fees for their services, as well as targeted federal, state, and locally funded food assistance, nutrition education, and health care programs. Trail-blazing dietitians are successfully offering their services in health maintenance organizations (HMOs), hospital or industry fitness programs, private practice, voluntary health agencies, and official agency programs. With the new federalism, nutritionists must articulate their role in comprehensive health care and market their services at the state and local levels in addition to the federal level. Nutrition services are defined to include assessment, planning, counseling, education, and referral to supportive agencies. Data management, managerial, and marketing skills must be developed for dietitians to compete effectively. Basic educational preparation and continuing education for practicing professionals must develop these competencies.

Costs and Cost Analysis↗
PubMed1985

Repair of recurrent inguinal hernia with Marlex mesh.

Fifty-seven patients with large recurrent inguinal hernia had undergone repair using Marlex mesh. Fifty-six patients had excellent results, one patient suffered a recurrence. There were two wound infections and no deaths. Polypropylene is an excellent prosthetic material for replacement of attenuated or destroyed posterior wall of the inguinal canal. It is biologically inert and resistant to infection.

Adult↗
PubMed1985

[Acute intestinal occlusion caused by phytobezoar in Israel. Role of oranges and persimmons].

Forty-one patients were operated upon for acute intestinal obstruction secondary to the presence of phytobezoars, 34 of these patients (83%) having a history of previous gastric surgery for ulcer. The etiologic factor in 44% of cases was oranges and in 56% persimmons (Kakis). Treatment was by enterotomy in 27 patients (65,85%) and by "milking" in 14 (34,15%). Postoperative mortality was 2,44% (1 case). Recurrence was noted in three cases (7,3%) including one with an ileocutaneous fistula, treatment being by enterotomy in 2 cases and "milking" in the third patient. First intention intestinal resection was never required. Five patients required several admissions for subacute obstruction treated conservatively. These findings suggest that gastric surgery predisposes to intestinal obstruction by phytobezoar. Careful exploration of the digestive tube and particularly the stomach should avoid postoperative relapse, while prevention depends on a dietary regimen avoiding excessive intake of foods rich in cellulose, particularly oranges and persimmon fruit.

Acute Disease↗
PubMed1984

Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone.

We have studied various properties of the binding of 5 alpha-dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17 beta-hydroxy-17 alpha-methylestra-4,9,11-trien-3-one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor-positive, partial androgen insensitivity. The mutant cells form R1881-receptor complexes that dissociate 7 times more rapidly than normal at 30 degrees C, and they do not increase their specific R1881-receptor activity in response to a 72-hr period of incubation with R1881, whereas the cells from normal individuals do so two- to three-fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05-3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen-receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is six-fold greater than that of normal cells (approximately 0.2 nM). Normal GSF have higher, more variable values of Kd (0.3-1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60-min values are intermediate. This explains why we previously reported that the patient's cells had a 30-min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5-8S peak of DHT-receptor complexes. From these data we conclude that normal GSF form initial, low-affinity androgen-receptor complexes that are transformed into one (or more) higher-affinity (? activated) states by a process that depends on time and initial concentration of androgen; the subject's GSF can form low-affinity androgen-receptor complexes but cannot generate the normal high-affinity state of the complexes, and this lack precludes augmentation of their androgen-receptor activity in response to prolonged incubation with either androgen; and failure of molybdate to stabilize the androgen-receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen-receptor proteins than are other qualities described heretofore.

Adolescent↗
PubMed1984

Transurethral polytetrafluoroethylene injection for post-prostatectomy urinary incontinence.

Transurethral polytetrafluoroethylene (Teflon) injections were performed on 69 men with incontinence following prostatectomy. The etiology of incontinence was transurethral resection of the prostate in 27 patients (group 1), open prostatectomy in 15 (group 2) and radical prostatectomy in 27 (group 3). All patients had been incontinent for more than 1 year and had failed to improve with conservative management. Cure or improvement occurred in 85.1 per cent of the patients in group 1, 79.9 per cent in group 2 and 48.1 per cent in group 3. Reasons for failure included severe bladder instability, severe periurethral fibrosis and leakage of paste. Clinically significant particle migration was not observed.

Aged↗
PubMed1984

Partial androgen resistance associated with secondary 5 alpha-reductase deficiency: identification of a novel qualitative androgen receptor defect and clinical implications.

We studied a family in which three brothers were born with ambiguous genitalia and had poor virilization at puberty. One patient (II-5) required less surgery to repair his hypospadias and is lean, muscular, and hairy compared to his brothers (II-1, II-2). Their adult levels of plasma testosterone (T) range from 765-2250 ng/dl. The plasma T to 5 alpha-dihydrotestosterone (DHT) ratios were 29 (n = 5) in patient II-1, 25 (n = 2) in patient II-2, and 14 (n = 2) in patient II-5, compared to 12 +/- 3 (SD) in normal men. The mean urinary etiocholanolone to androsterone ratios were 1.9 (n = 2) in patient II-1, 2.0 in patient II-2, and 1.3 in patient II-5, compared to 0.87 +/- 0.34 in normal men. The mean urinary ratios of 5 beta-tetrahydrocorticosterone to 5 alpha-tetrahydrocorticosterone were 0.98 (n = 2) in patient II-1, 1.25 in patient II-2, and 0.71 in patient II-5, compared to 0.53 +/- 0.22 in normal men. Genital skin fibroblasts (GSF) from patient II-1 had unusually low 5 alpha-reductase (5 alpha-R) activity (0.3 pmol/mg protein X h; n = 6), but those of patient II-5, a normal brother (II-3), and a sister (II-4; with impaired development of sexual hair) had normal values of 6.5 (n = 2), 9 (n = 3), and 9 (n = 2) pmol/mg protein X h, respectively. The maximum specific DHT receptor-binding activity (Bmax) and the rate constant of dissociation (k) of DHT-receptor complexes in the GSF from each of these individuals were normal, but the apparent equilibrium dissociation constants (Kd) for DHT were 1.16 +/- 0.28 (n = 4) in II-1, 0.39 +/- 0.20 (n = 6) in the sister, and it was 0.19 +/- 0.09 (n = 3) in the unaffected brother and 0.22 +/- 0.09 nM (n = 26) in normal men. The Bmax with the synthetic, nonmetabolizable androgen, methyltrienolone (R1881), and the k of R1881-receptor complexes were normal, but the Kd for R1881 in the GSF of II-1 was 1.4 nM (n = 2), compared to 0.16 +/- 0.05 (n = 8) in normal men, and prolonged exposure to R1881 failed to augment (up-regulate) the basal R1881-binding activity in his cells.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor.

We have studied a kindred in which two parts of siblings, maternal first cousins, have a form of "minimal" androgen insensitivity that permits morphogenesis of unambiguous male external genitalia, but interferes with normal virilization at puberty. All four had gynecomastia that required reductive surgery. Apart from this common phenotype, they varied considerably in the temporal and regional aspects of their subvirilization and appreciably in their androgenic responsiveness to pharmacological doses of testosterone. The cultured genital skin fibroblasts from one set of siblings have an androgen-receptor activity with the following properties: (1) a normal maximum-binding capacity (Bmax) with 5 alpha-dihydrotestosterone (DHT), or the synthetic androgen, methyltrienolone (MT; R1881) as ligand; (2) a higher than normal apparent equilibrium dissociation constant (Kd) for DHT (0.77 nM) but not for MT; and (3) an elevated dissociation rate (k) of DHT-receptor (0.013 min-1, 37 degrees C), but not MT-receptor, complexes within intact cells. In addition, prolonged incubation with MT, but not DHT, augments the specific androgen-binding activity of the mutant cells as much as that of the controls. Normal cells yield lower values of apparent Kd for DHT (0.1-0.3 nM) after 2- than after 0.5-hr incubation (0.3-1.8 nM), and 1-hr values are intermediate. This occurs despite concurrent catabolic consumption of DHT from the medium and is considered to reflect transformation of initial, low-affinity DHT-receptor complexes to subsequent, higher-affinity states by a process that depends on time and initial ligand concentration. The mutant complexes described here can readily attain the highest state of affinity with MT, but have an impeded, variably expressed ability to do so with DHT. These findings suggest that a structural mutation at the X-linked locus that encodes the androgen-receptor protein is responsible for its androgen-selective dysfunction. Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT, may be therapeutically useful for these subjects.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Regulation of the androgen receptor by androgen in normal and androgen-resistant genital skin fibroblasts.

Normal genital skin fibroblast (GSF) monolayers incubated with serum-free medium containing 3 nM [3H]-5 alpha-dihydrotestosterone (DHT) at 37 degrees C for 20 h have about 35% more specific DHT-binding than replicates incubated in serum-free medium with [3H]-DHT for only 1 h to saturate basal specific androgen-receptor activity. If, after 19 h, spent medium is replaced by fresh medium with 3 nM [3H]-DHT for 1 h, specific DHT binding is 85% more than basal. The acquisition of increased binding is temperature dependent (37 greater than 27 degrees C) and cycloheximide (2 microM) suppressible. The increased binding activity is considered to represent an augmentation of androgen receptor concentration because it has the same equilibrium dissociation constant (KD approximately 0.5 nM), rate constant of dissociation (k-1 approximately 6 x 10(-3) min-1) and ligand specificity as basal androgen-receptor activity, and because basal DHT-binding activity is stable in cells preincubated in androgen-free or serum-free medium alone for up to 72 h before assay. Prolonged incubation with methyltrienolone (R1881), a nonmetabolizable synthetic androgen, causes a greater, more persistent increment of androgen receptor activity than does equimolar DHT. The fibroblasts from two subjects with receptor-positive, partial androgen resistance lose their basal receptor activity during prolonged incubation with DHT, but augment it normally with R1881. This suggests that defective DHT metabolism is somehow involved in the pathogenesis of their androgen resistance.

Cycloheximide↗
PubMed1983

The dissociation of testosterone- and 5 alpha-dihydrotestosterone-receptor complexes formed within cultured human genital skin fibroblasts.

We have studied the rate and character with which testosterone (T) and 5 alpha-dihydrotestosterone (DHT) dissociate from the androgen receptor both within intact cultured genital skin fibroblasts of a subject with 5 alpha-reductase deficiency and after the androgen-receptor complexes have been extracted from the cells. Within the cells, the kinetics of the dissociative process for each hormone was first-order, but T dissociated four times faster than DHT. An Arrhenius plot of the variation of the dissociation rate constants with temperature for T was linear and yielded an activation energy of 28 kcal/mol. This value is identical with the one previously determined for activated DHT-receptor complexes. T-receptor complexes extracted from the cells dissociated with complex kinetics: at 37 degrees C the rate constants of the "fast" and "slow" components were 40 and 14 X 10(-3) min-1, respectively. In contrast, DHT-receptor complexes extracted from the cells dissociated with first-order kinetics and at a rate identical to that observed within cells, except after exposure to pyridoxal 5'-phosphate (5 mM) or concentration by Amicon (B-15) filtration, when their dissociation kinetics became complex. We interpret these data to mean that, within the cells, both T- and DHT-receptor complexes exist predominantly in the activated state whereas, when extracted from the cells, DHT-receptor complexes remain activated, unless perturbed, while T-receptor complexes become unstable spontaneously, probably by reverting to a preactivated state.

Cells, Cultured↗
PubMed1983

Possible implications of the comparative dissociative behavior of testosterone- and 5 alpha-dihydrotestosterone-receptor complexes formed by human skin fibroblasts.

We have studied the dissociative behavior of 5 alpha-dihydrotestosterone (DHT)- or testosterone (T)-receptor complexes extracted from normal and 5 alpha-reductase-deficient human genital skin fibroblasts, respectively. The rate at which each hormone dissociates from the androgen receptor is temperature-dependent (29-40 degrees C), but DHT does so in a first-order (monophasic) manner, while T yields complex (biphasic) dissociation kinetics. Prior exposure to 0.1 M sodium thiocyanate induces DHT-receptor complexes to dissociate with complex kinetics. The temperature dependence of these complex dissociation profiles can be simulated identically by a kinetic model involving three conformational states of the androgen-receptor complex. Neither the rate constants of the rapidly- or slowly-dissociating components of T-receptor dissociation, nor the magnitude of the latter are affected by sodium molybdate (5 mM). Similarly, neither sodium molybdate nor potassium chloride (0.1-0.3 M) alters the complex dissociative behavior of DHT-receptor complexes that is induced by 0.1 M sodium thiocyanate.

Dihydrotestosterone↗
PubMed1983

Regulation of the androgen receptor in human genital skin fibroblasts, with a review of sex steroid receptor regulation by homologous and heterologous steroids.

When normal human genital skin fibroblasts are cultured for 3 days with 2-3 nM methyltrienolone (R1881, a synthetic nonmetabolizable androgen), they augment their specific androgen-receptor activity (two- to four-fold) with a time pattern that is always most rapid in the first 24 h, usually peaks by 48 h, and often declines, sometimes substantially, in the third 24-h interval. The time pattern is highly reproducible within experiments on confluent monolayers and is not influenced by the presence or absence of 10% fetal calf serum in the medium, the temperature (37 vs. 40 degrees C) at which the incubation is conducted, or the basal activity (up to 40 fmol/mg protein) that is saturated by incubation for 30-45 min at 37 degrees C. It does appear to be influenced by an unusually rapid increase in the first 24 h and by nonconfluent density of the monolayers, but these factors do not explain the considerable interexperimental variation, within and among cell lines, under nominally identical conditions. The time pattern is interpreted to represent an initial phase of "up-regulation" that is followed by one of compensatory adjustment, despite a constant level of unmetabolized ligand. A review of sex steroid receptor regulation by homologous and heterologous sex steroids reveals numerous examples of apparently homologous regulatory behavior.

Animals↗
PubMed1983

Individualized diets for diabetic patients.

A flexible system for diet education and meal planning for diabetic patients is presented. Although this program may be accomplished by interested, knowledgeable physicians, it is best done by a diet counselor (registered dietitian or nurse educator). Nevertheless, physicians should be intimately involved by discussing the patient's progress with the diet counselor and by providing reinforcement of the efforts of the counselor.

Adult↗
PubMed1983

Diagnosis of breast lesions by fine needle aspiration biopsy.

The authors performed 480 fine needle aspiration biopsies (FNAB) of breast masses for cytologic diagnosis in 464 patients. Parallel surgical biopsy with histologic examination was carried out in 163 patients; the results were identical in 161. Two hundred eight of 297 benign lesions and 83 of 96 malignant tumors were diagnosed positively by FNAB. In 87 instances FNAB was not diagnostic but excluded malignancy, while in 87 others, the cytologic specimen was inadequate for diagnosis. There was one false-positive and one false-negative result. There were virtually no complications. FNAB of breast masses is a simple and reliable method, easy to carry out in ambulatory patients.

Adolescent↗
PubMed1982

Defective activation of androgen-receptor complexes: a marker of androgen insensitivity.

Partially-purified 5 alpha-dihydrotestosterone-receptor (DHT-R) complexes, extracted from normal genital skin fibrolasts (GSF) previously labelled with [3H]DHT, dissociate with monophasic kinetics and dissociation rate constants (k-2) of 10, 6, 3 and 2 x 10(-3) min-1 at 40, 37, 32 and 29 degrees C, respectively. An Arrhenius plot yields an activation energy of 28 kcal/mole. We studied 2 subjects who have constitutional androgen insensitivity (AI) despite a normal level of specific DHT-R activity in their GSF. Subject 1 has complete AI and unambiguous female external genitalia; subject 2 has partial AI and had ambiguous external genitalia at birth. In contrast to normal, the DHT-R complexes extracted from the GSF of these 2 subjects dissociate with biphasic kinetics. At 37 degrees C the k-1 of their early ('fast') component is 21 +/- 0.4(+/-SEM) x 10(-3) min-1(n = 7), while that of their late ('slow') component (k-2) is 7.8 +/- 0.3 x 10(-3) min-1 (n = 7). The latter value is very similar to the single k-2 (6.1 +/- 0.1 x 10(-3) min-1, n = 9) of the DHT-R complexes extracted from normal fibroblasts. When dissociation of DHT-R complexes is studied with intact fibroblasts, monophasic kinetics are observed for both the normal and mutant subjects. A k-1 of 18 x 10(-3) min-1 was previously observed for both mutant subjects at 37 degrees C (normal: K-2, 5.9 +/- 0.3 x 10(-3) min-1, n = 15). At 40 degrees C subject 1 has a rate constant of 25 while that of subject 2 is 50 x 10(-3) min-1(normal: 10 x 10(-3) min-1). An Arrhenius plot of the results from subject 1 yields an activation energy of 18 kcal/mole. The 2 sets of data suggest that inability of DHT-R complexes to transform from a rapidly dissociating to a slowly-dissociating form within intact target cells is a marker of genetic mutations that alter the androgen receptor and thereby cause certain types of partial of complete AI.

Androgen-Insensitivity Syndrome↗
PubMed1982

Sodium thiocyanate: a probe for the conformations of the androgen-receptor complex.

In the presence of sodium thiocyanate (NaCNS), partially purified 5 alpha-dihydrotestosterone-receptor (DHT-R) complexes extracted from normal genital skin fibroblasts (GSF) dissociate with complex (biphasic) kinetics. The rate constant of the 'fast' component and the magnitude of the 'slow' component vary with temperature (29-37 degrees C) and NaCNS concentration (0.1-0.4 M). Equimolar sodium bromide is much less effective; potassium chloride up to 1 M has no effect. DHT-R complexes from the GSF of a subject with partial androgen insensitivity (PAI) yield biphasic dissociation profiles that differ from normal and are influenced by NaCNS. Together with the temperature-dependent, first-order (monophasic) dissociative behavior of normal DHT-R complexes in the absence of NaCNS (Kaufman et al., 1982), the foregoing data have been used to construct a kinetic model involving the dissociation of DHT from 3 conformationally related forms of the androgen-receptor complex: (1) dysactivated; (2) preactivated; (3) activated.

Dihydrotestosterone↗