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Biomedical subjects

M D Katz

Publications and source records attributed to M D Katz.

At least 19 recordsLinked to original sources
PubMed1999

A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred.

Complete androgen insensitivity syndrome (CAIS) is an X-linked inherited disease caused by mutations in the androgen receptor (AR) gene. We have previously reported the largest kindred of CAIS, with 17 46,XY psychosexual and phenotypic females who lack secondary sexual hair. Analysis of AR binding indicated a receptor-negative form of complete androgen insensitivity, and DNA linkage analysis indicated that the absent binding was not caused by a large AR gene deletion. Using PCR-single-strand DNA conformational polymorphism, PCR-denaturing gradient gel electrophoresis, and DNA sequencing, we have identified a novel mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single adenine is inserted, or equivalently, a GC-dinucleotide is deleted at this region of the gene. The mutation results in a frameshift at amino acid 60 and a premature termination of the receptor downstream of the mutation. This predicts a mutant AR with only 79 amino acids in the amino-terminal of AR protein, prohibiting binding to the ligand, as well as the cognate DNA. The rest of the encoding regions of the AR gene in the affected subjects are normal. These results are consistent with previous ligand binding and DNA linkage analysis studies. This new mutation in the CAG trinucleotide area of exon 1 of the AR gene represents the first example of a defect in a CAG repeat causing CAIS in this large kindred. All previous reported variants in this region are changes in the number of triplet repeats.

Androgen-Insensitivity Syndrome↗
PubMed1998

Natural potent androgens: lessons from human genetic models.

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase-3 (17 beta-HSD-3) deficiency and 5 alpha-reductase-2 (5 alpha-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17 beta-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17 beta-HSD-3 gene are responsible for male pseudohermaphroditism due to 17 beta-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17 beta-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17 beta-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio. Two 5 alpha-reductase (5 alpha-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5 alpha-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5 alpha-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

The identification of 5 alpha-reductase-2 and 17 beta-hydroxysteroid dehydrogenase-3 gene defects in male pseudohermaphrodites from a Turkish kindred.

Male pseudohermaphroditism (MPH) is characterized by incomplete differentiation of male genitalia in the presence of testicular tissue. Enzymatic defects involving androgen synthesis or action are causes of MPH. We studied the molecular genetics of a large isolated inbred Turkish kindred with MPH due to either 5 alpha-reductase-2 (SRD5A2) or 17 beta-hydroxysteroid dehydrogenase-3 (17 beta HSD3) gene defects. Using single strand DNA conformational polymorphism analysis and DNA sequencing, a new mutation in exon 5 of SRD5A2 gene was detected in certain male pseudohermaphrodites from this kindred. This single base deletion (adenine) resulted in a frame shift at amino acid position 251 resulting in the addition of 23 amino acids at the carboxyl-terminal of this 254-amino acid isozyme. Transfection expression of the mutant isozyme in CV1 cells showed a complete loss of enzymatic activity in the conversion of [14C]testosterone to dihydrotestosterone, without a change in the messenger ribonucleic acid level compared to that of the wild-type isozyme. Analysis of the 17 beta HSD3 gene in other male pseudohermaphrodites from this kindred revealed a single point mutation (G-->A) at the boundary between intron 8 and exon 9, disrupting the splice acceptor site of exon 9. In this kindred, in addition to the identification of male pseudohermaphrodites with either a homozygous SRD5A2 or 17 beta HSD3 gene defect, other male pseudohermaphrodites were found to be genetically more complex: e.g. homozygous for the SRD5A2 defect and heterozygous for the 17 beta HSD3 defect, or homozygous for the 17 beta HSD3 defect and heterozygous for the SRD5A2 defect. Also, phenotypically normal carriers were identified with either one or both gene defects. Homozygous male pseudohermaphrodites with SRD5A2 or 17 beta HSD3 gene defects were phenotypically distinguishable by the presence of mild gynecomastia in the latter. Hormone data were consistent with the particular homozygous gene defect. In summary, we show 1) the novel existence of two gene defects, SRD5A2 and 17 beta HSD3, each causing MPH within a large isolated Turkish kindred; 2) that the two defects segregate independently and may be inherited from two different progenitors; and 3) analysis of a new mutation in exon 5 of SRD5A2 gene, supporting the functional importance of the carboxyl-terminal of 5 alpha-reductase-2 isozyme.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

A novel mutation of the human luteinizing hormone receptor in 46XY and 46XX sisters.

We report a novel homozygous mutation of the LH receptor (LHR) gene in three siblings: two 46XY and one 46XX. The 46XY siblings presented with female external genitalia, primary amenorrhea, and lack of breast development. Hormonal evaluation revealed a markedly elevated LH level with a low testosterone level, which failed to increase after human CG stimulation. Enzymatic deficiencies of testosterone biosynthesis were eliminated as possible etiologies. Histologic analysis of the inguinal gonads in a 46XY sibling revealed no Leydig cells; Sertoli cells, spermatogonia, and primary spermatocytes were seen. The 46XX sibling had female external genitalia, normal breast development, and primary amenorrhea. Hormonal analyses showed markedly elevated LH levels and low plasma 17 beta-estradiol levels. Genetic analysis of the LHR revealed a homozygous missense mutation at exon 11 of the LHR gene. Guanine was replaced by adenine (GAA-->AAA), resulting in a substitution of lysine for glutamic acid (glu) at amino acid position 354 of the receptor. This mutation is located in the extracellular domain adjacent to the first transmembrane helix of the LHR. Glutamic acid at position 354 of the LHR has been highly conserved throughout evolution. Functional analysis of the LHR mutation, using an in vitro mutagenesis-transfection assay, demonstrated complete loss of function, indicated by the lack of cAMP production after human CG stimulation in transfected human embryonic kidney 293 cells. Screening of family members demonstrated heterozygosity for the mutation, indicating autosomal recessive inheritance. Delineation of the specific genetic defect in this family confirms recent reports that a single mutation in the LHR gene causes male pseudohermaphroditism in 46XY subjects and primary amenorrhea in 46XX subjects. More importantly, it also defines a new region of the LHR molecule that is critical for biologic activity.

Adolescent↗
PubMed1996

5 alpha-reductase-2 gene mutations in the Dominican Republic.

Male pseudohermaphroditism due to 5 alpha-reductase deficiency was clinically and biochemically described in a large Dominican kindred of 23 families with 38 affected subjects in 1974. Recently, the 5 alpha-reductase-2 gene defect in the large Dominican kindred was found to be due to a single base substitution of thymidine (TGG) for cytosine (CGG) on exon 5 of the 5 alpha-reductase-2 gene, causing a tryptophan replacement of arginine at amino acid 246 (R246W) of the enzyme. In the present report, affected subjects from four additional Dominican families were studied to determine whether they carried the same 5 alpha-reductase-2 gene defect as the large kindred, suggesting a common ancestry for the gene defect within this small country. Using single strand conformational polymorphism and DNA sequencing, two other mutations of the 5 alpha-reductase-2 gene were found in affected subjects from two of the four families. A point mutation on exon 2 of the 5 alpha-reductase-2 gene, in which substitution of adenine (GAC) for guanine (GGC) caused an aspartic acid replacement of glycine at amino acid 115 (G115D), was demonstrated in one of these families, and a substitution of adenine (AGT) for guanine (GGT) on exon 3 causing a serine replacement for glycine at amino acid 183 (G183S) was detected in the other family. Affected subjects from the two remaining families demonstrated the same exon 5 mutation of the 5 alpha-reductase-2 gene as previously detected in the large Dominican kindred. The phenotypic and biochemical characteristics of the male pseudohermaphrodites were similar regardless of the genetic defect, except that one affected subject (C-VI-2) with the same exon 5 mutation as the large Dominican kindred had much more facial and body hair. Thus, the identification of multiple mutations in the 5 alpha-reductase-2 gene in male pseudohermaphrodites from the Dominican Republic demonstrates a lack of common ancestry, as had been previously postulated.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

HIV infection and AIDS: attitudes and knowledge of Arizona pharmacists.

OBJECTIVE: To assess Arizona pharmacists' attitudes and knowledge regarding HIV infection and AIDS. METHODS: Mailing of a 7-page survey, which included demographic and attitudinal items, as well as preparedness, comfort, and knowledge scales. SETTING: Randomly selected pharmacists registered and residing in Arizona. PARTICIPANTS: Of the 479 pharmacists surveyed, 41 were removed from the sample because they had moved with no forwarding address, were retired or not practicing, or had died. The response rate was 46% for the remaining 438 pharmacists. A final sample size of 199 was obtained. RESULTS: The respondents had a high level of preparedness and comfort in addition to positive attitudes. Overall, their knowledge level was low. Inpatient pharmacists had a higher level of therapeutic knowledge (p < 0.0001) and were more willing to work with a person infected with HIV than were outpatient pharmacists (p = 0.05). Pharmacists who had attended at least 1 HIV/AIDS-related continuing education (CE) program had higher levels of preparedness (p < 0.0001), comfort (p = 0.01), and knowledge (p < 0.0001) than those who had not. The majority of respondents believed that an HIV/AIDS CE program should be mandatory. CONCLUSIONS: Although Arizona pharmacists feel prepared, are comfortable, and have positive attitudes regarding patients with HIV/AIDS, their level of knowledge is low. The results of this study may be used by CE providers to design programs to meet the educational needs of pharmacists.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The biochemical and phenotypic characterization of females homozygous for 5 alpha-reductase-2 deficiency.

The biochemical and physiologic manifestations of decreased 5 alpha-dihydrotestosterone (DHT) in females are characterized. Three females from the large Dominican kindred with 5 alpha-reductase-2 deficiency were identified as homozygous for a point mutation (R246W, C-->T) on exon 5 of the 5 alpha-reductase-2 gene by single strand DNA conformational polymorphism analysis and DNA sequence analysis. Body hair was decreased; there was no history of acne. Despite delayed menarche, all were fertile, and two had twins. Urinary 5 beta/5 alpha C19 and C21 steroid metabolite ratios were elevated. Plasma testosterone was normal to elevated, with low DHT, resulting in an increased testosterone/DHT ratio. 3 alpha,5 alpha-Androstanediol glucuronide was low. Menstrual cycle profiling performed in two subjects showed ovulatory gonadotropin peaks. Sebum production was normal. 5 alpha-Reductase-2-deficient homozygotic females demonstrate the importance of DHT in the physiology and pathophysiology of body hair growth. Normal sebum implies regulation by the 5 alpha-reductase-1 isoenzyme. Delayed puberty suggests involvement of 5 alpha-reductase-2 in menarche at the hypothalamic/pituitary and/or ovarian level. As two had nonidentical twins, DHT and/or the DHT/estradiol ratio may regulate follicular development, with lower levels permitting more than one dominant follicle per cycle and higher levels impairing follicular development and ovulation. Thus, females with 5 alpha-reductase-2 deficiency highlight a role for DHT in hirsutism and/or menstrual disorders.

Adult↗
PubMed1994

Hemodialysis graft salvage with endoluminal stents.

The most common cause of failure of hemodialysis access sites is stenosis within the site. The stenoses have traditionally been corrected surgically, but endovascular techniques may be an alternative method to treat these flow-limiting lesions and maintain graft patency. Over a recent 17-month period, endoluminal stents to relieve stenoses resistant to balloon dilatation alone were placed in 14 access sites. All sites were located on the upper extremity (13 PTFE bridge grafts and 1 A-V fistula). A total of 20 stents were placed: seven at the venous anastomosis, 12 in the venous outflow tract (including 3 in the subclavian vein), and one within the graft. Nine patients had placement of a single stent, four patients had two stents placed, and one patient had three. An additional eight stenotic lesions within these 14 sites were successfully dilated without need of a stent. After stent placement, these 14 sites have remained functional for a mean of 6.2 months. Four were functioning without further intervention at a mean of 8.5 months. Nine sites occluded at a mean of 4.7 months. The remaining site remained functional until death of the patient 10 months after stent placement. Of the nine failed sites, four developed restenosis at the site of stent placement, four developed stenoses at other sites, and the other site was abandoned. Three stents were placed in subclavian vein stenoses, and none of these has failed. Further study is necessary to determine whether endovascular stenting of dialysis access site stenoses will prove to be a durable, cost-effective alternative to surgical revision.

Angioplasty, Balloon↗
PubMed1992

Uncomplicated amebic liver abscess: prospective evaluation of percutaneous therapeutic aspiration.

The performance of therapeutic aspiration in the treatment of amebic liver abscess, advocated and practiced in many centers, is controversial. Previously, this practice has been evaluated in retrospective analyses. To test the potential benefit of therapeutic aspiration, the authors undertook a prospective randomized trial in 57 patients admitted for suspected amebic liver abscess during a 15-month period. Sixteen patients were excluded from the trial. The remaining 41 patients were randomly included in one of two study groups to receive amebicidal therapy alone or amebicidal therapy coupled with image-guided percutaneous therapeutic aspiration. All patients in the trial recovered. No statistically significant benefit was demonstrated in the aspiration group for the two objective parameters evaluated: length of hospitalization and duration of time to becoming afebrile. Subjective improvement in symptoms after aspiration was greater in the aspiration group at a marginally statistically significant level. These data do not support the adjunctive performance of percutaneous therapeutic aspiration in the treatment of uncomplicated amebic liver abscess. Amebicidals alone were equally efficacious in treating the group studied.

Humans↗
PubMed1992

Danazol increases the anticoagulant effect of warfarin.

OBJECTIVE: To report two cases demonstrating an interaction between danazol and warfarin, resulting in the potentiation of warfarin's effect and bleeding complications. DATA SOURCES: Case reports, review articles, and studies identified by MEDLINE. STUDY SELECTION: All published English-language reports involving danazol and warfarin interactions were reviewed. DATA SYNTHESIS: Danazol, a synthetic testosterone derivative, is used in the treatment of endometriosis, fibrocystic breast disease, menorrhagia protein C deficiency, and hemophilia. We describe two cases including an interaction between danazol and warfarin, resulting in bleeding complications. There are at least two other reported cases of this interaction. This interaction may be attributable to several mechanisms. Danazol may inhibit the metabolism of warfarin and/or it may have a direct effect on the coagulation and fibrinolytic systems. CONCLUSIONS: Based on this report and other published cases, clinicians must be aware that danazol may increase the anticoagulant effect of warfarin. Patients receiving warfarin who are prescribed danazol must be monitored closely to prevent excessive anticoagulation and subsequent bleeding. Studies are needed to determine the frequency of this interaction and its underlying mechanisms.

Adult↗
PubMed1989

Effects of passive smoking on theophylline clearance.

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.

Adult↗
PubMed1989

Octreotide, a new somatostatin analogue.

The chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects and drug interactions, dosage, availability and cost, and indications for use of octreotide, a new synthetic analogue of the peptide hormone somatostatin (SS), are reviewed. Like SS, octreotide suppresses secretion of pituitary growth hormone (GH) and thyrotropin and decreases release of a variety of pancreatic islet cell hormones including insulin, glucagon, and vasoactive intestinal peptide (VIP). Octreotide also reduces splanchnic blood flow, gastric acid secretion, GI motility, and pancreatic exocrine function and alters the absorption of water, electrolytes, and nutrients from the GI tract. The elimination half-life of i.v. octreotide is 72-98 minutes, compared with 2-3 minutes for i.v. SS. Usual administration of octreotide is by the i.v. or s.c. route. Octreotide has been studied in the treatment of hormone-secreting pituitary tumors and pancreatic islet cell tumors. Octreotide therapy lowers GH secretion and improves clinical symptoms in patients with acromegaly and may suppress clinical symptoms to a greater degree than bromocriptine. Patients with carcinoid syndrome and VIP-secreting tumors (vipomas) have had substantial improvement in clinical symptoms with administration of octreotide. This agent does not appear to be effective in the treatment of nonvariceal upper GI bleeding and acute pancreatitis; its relative usefulness in the treatment of variceal bleeding is not established. Adverse effects associated with octreotide therapy generally have been mild, including pain or burning at the injection site, abdominal pain, and diarrhea. Octreotide has been shown to interfere with absorption of oral cyclosporine. Standard initial therapy is octreotide acetate 50-100 micrograms s.c. every 8-12 hours, with titration based on clinical and biochemical effects. Up to 3000 micrograms/day of octreotide acetate has been administered to patients with acromegaly without serious adverse effect. Octreotide is marketed under the brand name Sandostatin and is available in 1-mL ampuls containing 50, 100, and 500 micrograms of octreotide acetate. Because the conditions for which octreotide appears to be most effective are uncommon, the drug should be considered for addition to the formulary in tertiary-care institutions only; addition of octreotide to the formulary of a community hospital is probably unnecessary. The synthetic analogue octreotide is longer acting and more specific in pharmacologic action than SS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗