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Analog-Digital Conversion↗
Biomedical subjects
M Kaufman
Publications and source records attributed to M Kaufman.
Scleroderma-like skin indurations in a child with phenylketonuria: a clinicopathologic correlation and review of the literature.
Scleroderma-like skin lesions are one sequela of phenylketonuria. We describe a child with phenylketonuria and associated dermal connective tissue changes consistent with early inflammatory scleroderma. The severity of the skin lesions apparently waned with dietary restriction of phenylalanine.
Biopsy↗
Familial intracranial hypertension: report of a case and review of the literature.
A mother and daughter are presented who had intracranial hypertension 5 years apart. Possible contributing factors were the presence of obesity and occasional asthma in both. A review of the literature reveals three other families with intracranial hypertension occurring in successive generations (suggesting autosomal dominant transmission) and four families with intracranial hypertension occurring in siblings (suggesting autosomal recessive transmission). No reported cases of familial intracranial hypertension have revealed a contributing cause.
Adolescent↗
Suture closure versus stapling of bronchial stump in 304 lung cancer operations.
Suture closure of the bronchial stump was compared with staple closure after 304 operations for bronchogenic carcinoma over an 8-year period. In 154 cases (112 lobectomies and 42 pneumonectomies) the bronchial stump was closed with interrupted sutures of 000 polyester, and in 150 cases (120 lobectomies and 30 pneumonectomies) an autosuture stapler was used. The time for suture closure ranged from 5-15 minutes, whereas stapling was accomplished uniformly in c. 90 seconds. Bronchopleural fistula developed after suture closure in seven cases (4.5%), but in none after stapling closure. Stapling of the bronchial stump after lobectomy or pneumonectomy for lung cancer is safer and quicker than suture closure, and is recommended as the method of choice.
Bronchi↗
Androgen resistance due to mutation of the androgen receptor.
The androgen receptor (AR) is a 'one-stop' signal transduction system that is the core of the intracellular androgen-response apparatus. It is an androgen-regulated, DNA-binding protein that regulates the expression of certain target genes, primarily at the transcriptional level. Mutations at the X-linked AR locus cause deficient or defective AR activity and, thereby, an extraordinarily wide spectrum of clinical androgen resistance. At one extreme, the affected 46,XY person is an infertile phenotypic female; at the other, he is a phenotypic male who may even be fertile, yet have gynecomastia or other focal signs of postpubertal subvirilization. We have identified 32 proven or putatively pathogenic alterations in the AR gene of 38 androgen-resistant families. This permits heterozygote detection and prenatal diagnosis whenever relevant. Most of the mutations affect the AR's androgen-binding domain, partly because our search has been targetted on those whose genital skin fibroblasts have impaired androgen-binding activities. The AR is a prototypic member of a subfamily that includes the receptors for progesterone, glucocorticoid, and mineralocorticoid. Observations that correlate AR genotype with clinical and receptor phenotypes of androgen resistance will help to generate a fine structure-function map of the AR and its close relatives. Constitutional variation in androgen sensitivity, that may be restricted to an organ (or organ system), could contribute to the pathogenesis of certain diseases whose sex ratio departs significantly from one.
Amino Acid Sequence↗
Replacement of arginine 773 by cysteine or histidine in the human androgen receptor causes complete androgen insensitivity with different receptor phenotypes.
We have discovered two different point mutations in a single codon of the X-linked androgen-receptor (AR) gene in two pairs of unrelated families who have complete androgen insensitivity (resistance) associated with different AR phenotypes in their genital skin fibroblasts. One mutation is a C-to-T transition at a CpG sequence near the 5' terminus of exon 6; it changes the sense of codon 773 from arginine to cysteine, ablates specific androgen-binding activity at 37 degrees C, and eliminates a unique KpnI site at the intron-exon boundary. The other mutation is a G-to-A transition that changes amino acid 773 to histidine and eliminates an SphI site. This mutant AR has a normal androgen-binding capacity at 37 degrees C but has a reduced affinity for androgens and is thermolabile in their presence. Transient transfection of COS cells with cDNA expression vectors yielded little androgen-binding activity at 37 degrees C from Arg773Cys and abundant activity with abnormal properties from Arg773His, thereby providing the pathogenicity of both sequence alterations. This conclusion coincides with the following facts about evolutionary preservation of the position homologous to Arg773 in the AR: it is occupied by Arg or lysine in the progesterone, glucocorticoid, and mineralocorticoid receptors, and it is within a 14-amino-acid region of their steroid-binding domains that share approximately 85% amino acid identity.
Adolescent↗
Amber mutation creates a diagnostic MaeI site in the androgen receptor gene of a family with complete androgen insensitivity.
We have discovered in the X-linked androgen receptor gene a single nucleotide substitution that is the putative cause of complete androgen insensitivity (resistance) in a family with affected individuals in 2 generations. Earlier studies on the family indicated co-segregation of mutant phenotype and the RFLPs at the loci DXS1 and DXYS1. The mutation is an adenine-to-thymine transversion in exon 8 that changes the sense of codon 882 from lysine to an amber (UAG) translation termination signal. The substitution creates a recognition sequence for the restriction endonuclease MaeI: this permits ready recognition of hemizygotes and heterozygotes after amplification of genomic exon 8 by the polymerase chain reaction. The mutation predicts the synthesis of a truncated receptor that lacks 36 amino acids at the carboxy terminus of its 252-amino acid androgen-binding domain. The cultured genital skin fibroblasts of the one affected patient examined have normal levels of androgen receptor mRNA, but negligible androgen-receptor binding activity. These results accord with a variety of data from spontaneous and artificial mutations indicating that all portions of the steroid binding domain contribute to normal steroid binding by a steroid receptor.
Amino Acid Sequence↗
The 56 kDa androgen binding protein is an aldehyde dehydrogenase.
We have described a 56 kDa protein from genital skin fibroblasts that specifically binds androgen and that is generally not expressed in genital skin fibroblasts from patients with androgen insensitivity due to genetic defects of the androgen receptor. We have isolated a partial cDNA clone for the 56 kDa protein from an expression library of genital skin fibroblasts. In vitro translation of message selected with this clone faithfully produces the 56 kDa protein which can be immuneprecipitated with an anti-56 kDa antiserum. Northern blots probed with this clone show a 2.2 kb message, which parallels the expression of the 56 kDa protein. The sequence of this 998bp clone is identical to human liver aldehyde dehydrogenase 1, the cytoplasmic isoenzyme. On activity gels of genital skin fibroblast cytosol covalently labelled with androgen, aldehyde dehydrogenase activity comigrates with the single band labelled specifically with androgen. Thus, the 56 kDa androgen binding protein is an aldehyde dehydrogenase, which is prominently expressed in normal genital skin fibroblasts, but not in non-genital skin fibroblasts.
Alcohol Dehydrogenase↗
The 56/58 kDa androgen-binding protein in male genital skin fibroblasts with a deleted androgen receptor gene.
Human genital skin fibroblasts (GSF) make a relatively abundant 56/58 kDa protein that binds androgens. The protein shares many properties with the approximately 100 kDa androgen receptor that is encoded by a locus in the q12 region of the X chromosome. It does not appear to be androgen-induced, yet is absent in GSF of most patients with complete androgen insensitivity (CAI). A precursor-product relation with the androgen receptor (AR) protein has been largely excluded; that it may be an unorthodox product of the AR gene has not. The 56/58 kDa protein is made by the GSF of a mentally retarded subject who has CAI because of a complete deletion of the coding portion of the AR gene. Hence, the strong constitutional and statistical correlations that have been demonstrated between the two proteins cannot arise because they share the same gene. The subject's genomic DNA hybridizes normally with 11 single-copy probes from Xq11-Xq13. Therefore, we cannot attribute her mental retardation to a contiguous gene syndrome.
Androgen-Binding Protein↗
A cryoglobulin with cold agglutinin and erythroid stem cell suppressant properties.
A 93-year-old woman presented with profound anemia (hematocrit 23% [0.23]); there was clumping of her red cells in test tubes and on peripheral blood smears. There was also a marked decrease in erythroid precursors in the bone marrow and reticulocytopenia in the peripheral blood. An IgM kappa monoclonal gammopathy was found in low concentration (approximately 1%) in her serum, and the cold agglutinins had a titer of 2560. However, the cold agglutinin titer of the supernatant after cryoglobulin precipitation was 40. Redissolving the cryoglobulin in the supernatant resulted in a cold agglutinin titer of 1280. Moreover, the addition of the patient's whole serum inhibited erythroid colony formation in culture. The inhibition was removed by cryoprecipitation of the cryoglobulin. The patient was given steroid therapy, to which she responded with reticulocytosis and an elevation of hematocrit. By 3 months, the cold agglutinin titer had fallen to 10. She remained well 4 years later. Whereas reports of cryoprecipitable cold agglutinins are rare, this case is unique because there have been no previous reports that these cold active proteins also have erythroid stem cell-suppressant properties.
Aged↗
Induction of long-term but reversible unresponsiveness after activation of murine T cell hybridomas.
T cell receptor (TCR)-mediated stimulation of murine T cell hybridomas induces cell activation and lymphokine production. We have observed that following productive activation, T cell hybridomas become refractory to a subsequent stimulation. Hyporesponsiveness is long-lasting but reversible, and is not due to reduced receptor expression. It is noteworthy that hyporesponsiveness is cell autonomous, persists in spite of cell division and does not require continuous exposure to ligands. Hyporesponsive cells retain the ability to produce lymphokines in response to pharmacological agents bypassing receptor triggering, indicating that they possess a functional enzymatic machinery for interleukin 2 synthesis and secretion. Reduced phosphatidylinositol hydrolysis was observed in these cells in response to TCR stimulation, suggesting that hyporesponsiveness result from defective transduction of activation signals. The development of unresponsiveness following receptor stimulation resembles desensitization, and may thus play an important role in the regulation of an immune response and in the induction of immune tolerance.
Animals↗
Strain differences in mouse brain weight gain and spatial-location scores during postnatal development.
Brain weight and performance on a spatial-location test were measured from birth to weaning on mouse strains CD1, Balb/c, and their F1 cross. For CD1, onsets of both the last rapid-brain-growth stage and nonzero scores on the spatial-location test were around age 17 days; asymptotes of both were reached about age 23 days. Balb/c and F1 had at least 5- to 6-day delays of both onsets and asymptotes. For the strains studied, onset of nonzero performance on the spatial-location test may be a provisional indicator of onset of significant and rapid brain growth after age 15 days. The delayed F1 brain growth stage could indicate that control of brain growth about age 20 days resides in an inhibitory factor present in Balb/c but not in CD1.
Animals↗
Substitution of aspartic acid-686 by histidine or asparagine in the human androgen receptor leads to a functionally inactive protein with altered hormone-binding characteristics.
We have identified two different single nucleotide alterations in codon 686 (GAC; aspartic acid) in exon 4 of the human androgen receptor gene in three unrelated families with the complete form of androgen insensitivity. One mutation (G----C) results in an aspartic acid----histidine substitution (with 15-20% of wild-type androgen-binding capacity), whereas the other mutation (G----A) leads to an aspartic acid----asparagine substitution (with normal androgen-binding capacity, but a rapidly dissociating ligand-receptor complex). The mutations eliminate a Hinfl restriction site. Screening for the loss of the Hinfl site in both families with the Asp----Asn mutation resulted in the recognition of heterozygous carriers in successive generations of each. Both mutant androgen receptors were generated in vitro and transiently expressed in COS and HeLa cells. The receptor proteins produced had the same altered binding characteristics as those measured in fibroblasts from the affected subjects. R1881-activated transcription of a GRE-tk-CAT reporter gene construct was strongly diminished by both mutant receptors and was only partially restored using a 100-fold higher concentration of ligand compared with wild-type receptor. Thus, aspartic acid-686 appears essential for normal androgen receptor function. Substitution of this amino acid residue, by either histidine or asparagine, results in androgen insensitivity and lack of androgen-dependent male sexual differentiation.
Adult↗
Post-Tarasoff legal developments and the mental health literature.
Since Tarasoff first established the duty of psychotherapists to warn or otherwise protect third parties when a patient is considered dangerous, the mental health literature has continued to address the two most controversial issues in that case: the questionable ability of clinicians to predict violent behavior, and the role of confidentiality in psychotherapy. The author examines recent trends in the law in light of this research and concludes that so-called anti-Tarasoff statutes recently passed by some states appropriately take into account the mental health literature and effectively balance competing public policy concerns.
Confidentiality↗
Compressed air injury to the esophagus: case report.
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Adult↗
Acute pseudo-obstruction of the colon.
Fourteen patients with acute pseudo-obstruction of the colon (Ogilvie's syndrome) were treated over a 16-year period. Ten patients (71.4%) had a recent history of mental illness and were treated with hypnotic and sedative drugs uninterruptedly for many months. The clinical picture and abdominal radiographs on admission to hospital were typical of acute mechanical obstruction of the colon; 1 patient had a perforation of the transverse colon. Obstruction was ruled out by barium enema in 9 patients, by colonoscopy in 3 and by immediate laparotomy in 2. Twelve patients were treated conservatively by nasogastric tube, correction of fluid and electrolyte imbalance, enemas, cessation of all hypnotic and sedative drugs, and decompression of the colon using a rigid rectoscope and rectal tube. There were no complications and no deaths. Ogilvie's syndrome should be suspected in patients with symptoms of large-bowel obstruction whose history discloses intake of hypnotic and sedative drugs. After mechanical obstruction is ruled out, conservative management is indicated. It should include cessation of all psychopharmacological agents and decompression of the colon by rectal intubation or colonoscopy. If conservative measures fail and the caecum increases in size, operative decompression by transverse colostomy rather than cecostomy is indicated.
Acute Disease↗
The state transitions of normal and mutant androgen-receptor complexes in human genital skin fibroblasts.
We have incubated cells from controls and subjects with receptor-defective androgen resistance with 3H-labelled testosterone (T), methyltrienolone (MT), dihydrotestosterone (DHT) or mibolerone (MB) and studied the temperature dependence of the dissociation rate constants of these various androgen-receptor (A-R) complexes both within cells and after they were extracted from them. In control cells, Arrhenius plots for T-, MT-, DHT- and MB-R complexes were linear and formed a hierarchy of dissociation states with energies of state IV greater than III greater than II, greater than I, respectively. Relative to this hierarchy, the dissociation states of the MB-, DHT- and MT-R complexes in mutant cells were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. When extracted from cells control or mutant T- or MT-R complexes, and mutant (but not control) DHT- or MB-R complexes lowered their respective dissociation rates by undergoing state transitions in conformity with the hierarchy. Hence we propose that different A-R complexes reach different dissociative states by undergoing sequential transitions along a common pathway, and that these transitions are co-regulated both by the chemical characteristics of the bound androgen and by other cellular non-receptor factors.
Cells, Cultured↗
The 56 kDa androgen-binding protein in human genital skin fibroblasts: its relation to the human androgen receptor.
We have recently described in genital skin fibroblasts (GSF) a relatively abundant 56 kDa protein with androgen-binding activity. This protein is missing in GSF of most patients with complete androgen insensitivity syndrome (CAI). The protein has many characteristics compatible with the androgen receptor; it has in fact been tentatively considered as a precursor or degradation form of the prototypic (approximately 100 kDa) human androgen receptor. We have prepared an antiserum to this protein, which allowed us to detect it as a direct product by in vitro translation of mRNA from GSF. It is thus very unlikely to be a degradation product of a larger precursor. Furthermore, covalent photolytic labeling of this protein with the androgen analogue [3H]mibolerone revealed a much lower affinity for this protein than is known for the androgen receptor. Finally, the GSF of two exceptional patients with complete androgen insensitivity syndrome due to negligible androgen receptor-binding activity express this protein normally, as determined on two-dimensional gels by Western blot analysis with the antiserum and by photolytic covalent labeling with androgen analogues. These data indicate that the protein is not a precursor or a degradation product of the receptor; nor is it androgen-induced. They are more compatible with the idea that the protein is another member of the steroid/thyroid/retinoic acid receptor supergene family, perhaps as an unorthodox product of the human androgen receptor gene.
Androgen-Binding Protein↗