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Biomedical subjects

J L Miller

Publications and source records attributed to J L Miller.

At least 19 recordsLinked to original sources
PubMed1992

Monoclonal antibody AG-1 initiates platelet activation by a pathway dependent on glycoprotein IIb-IIIa and extracellular calcium.

The biochemical responses of intact human platelets to the monoclonal antibody (mAb) AG-1 were investigated. AG-1 is a murine IgG mAb that recognizes a series of platelet membrane glycoproteins (Gp) from M(r) 21,000 to 29,000, one of which is the M(r) 24,000 (p24) receptor for anti-CD9 mAbs. AG-1 causes platelet aggregation and secretion. Platelets binding AG-1 demonstrate a dose- and time-dependent breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2), production of diacylglycerol, and generation of phosphatidic acid (PA). These events are associated with the activation of protein kinase C (PKC), an increase in intracellular calcium, and fibrinogen binding. Platelet PA generation and PKC activation in response to AG-1 are inhibited by mAbs to platelet GpIIb-IIIa or by extracellular EGTA, but not by a mAb to platelet GpIb or by inhibiting platelet Na+/H+ exchange with 5-(N-ethyl-N-isopropyl)amiloride. Platelet cytoplasmic free calcium ([Ca2+]i) is elevated in response to AG-1, and this elevation is inhibited by mAbs to GpIIb-IIIa, an RGDS peptide or by chelating extracellular calcium. These results suggest that AG-1 binding to a unique platelet-surface glycoprotein initiates platelet responses through the activation of PIP2-specific phospholipase C, and that this occurs through a signal pathway that is dependent on GpIIb-IIIa and extracellular calcium.

Amino Acid Sequence↗
PubMed1992

Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease.

The primary sequences of the three individual glycoprotein (GP) chains, GPIb alpha, GPIb beta, and GPIX, comprising the normal platelet GPIb/IX receptor for von Willebrand factor (vWF) have recently been determined, opening the possibility for characterization of disorders of this receptor at the molecular level. The presence of a leucine tandem repeat in each of these chains is of particular interest, because such repeats may be involved in associations between polypeptide segments. We now report an autosomal dominant variant of Bernard-Soulier disease associated with the heterozygous substitution of phenylalanine for a highly conserved leucine residue within the GPIb alpha leucine tandem repeat. Affected individuals experienced a moderate bleeding tendency, thrombocytopenia, and an increased mean platelet volume. Platelet aggregation was decreased only in response to ristocetin or to asialo-vWF. The kd for 125I-vWF binding to patients platelets was significantly increased over control values at 0.5 mg/mL ristocetin, but was normal at 1.0 or 1.5 mg/mL ristocetin. While sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed an essentially normal complement of all components of the GPIb/IX complex, a minor amount of a putative proteolytic fragment was identified that migrated faster than GPIb and was immunoreactive with polyclonal anti-GPIb alpha antibody, but not with a monoclonal antibody directed against the 45-Kd amino-terminal region of GPIb alpha. However, because the great majority of patient GPIb alpha comigrates with normal GPIb alpha, the major functional abnormalities of the patient platelets are most likely a consequence of the altered structure of the nonproteolyzed protein. Full concordance within the studied family between phenotypic expression and a heterozygous single nucleotide substitution in genomic DNA coding for a phenylalanine in place of the wild-type leucine at residue 57 of the mature GPIb alpha, absence of this substitution in 266 alleles from the normal population, and the lack of any other abnormality of patient DNA throughout the entire coding sequence for GPIb alpha provide strong support that this substitution may constitute a pathologic point mutation responsible for the observed phenotypic abnormalities. While the roles that leucine tandem repeats may normally play within the GPIb/IX complex are not yet known, the perturbation of such a repeat in GPIb alpha may impair interaction with other components of the complex and/or with the binding of vWF.

Adolescent↗
PubMed1992

Neuromyoblastoma in the rat.

We report three tumours arising in the brain stem or adjacent cranial nerves of the Alderly Park rat. Light microscopy with special stains, immunocytochemistry and electron microscopy supported the conclusion that both neuronal and myoid differentiation occurred in all neoplasms. This was shown by the presence in neural cells of axon-like cell processes and in myoblastic cells of striated myofibrils. Although medulloblastomas occur in man and rats the tumours reported here were not related to the cerebellum. We have termed this tumour neuromyoblastoma.

Animals↗
PubMed1992

Serum androstanediol glucuronide in women with facial hirsutism.

BACKGROUND: Measurement of serum 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-diolG) has been proposed as a useful biochemical marker of peripheral androgen metabolism. Is 3 alpha-diol G a useful biochemical marker of peripheral androgen metabolism and does it correlate with degree of facial hirsutism? OBJECTIVE: Our purpose was to assess possible correlation between serum 3 alpha-diol G and degree of facial hirsutism and to compare serum 3 alpha-diol G levels with levels of other commonly measured serum androgens. METHODS: Twenty-three consecutive women with facial hirsutism were studied, and serum concentrations of 3 alpha-diol G, testosterone (total, free, and biologically active portions), dehydroepiandrosterone sulfate, and androstenedione were measured. RESULTS: There was no correlation between serum 3 alpha-diol G levels and degree of facial hirsutism. There was a correlation between levels of 3 alpha-diol G and dehydroepiandrosterone sulfate (p less than 0.01), biologically active testosterone (p = 0.01), free free testosterone (p less than 0.02), and androstenedione (p less than 0.05). CONCLUSION: Serum 3 alpha-diol G concentrations have no correlation with degree of facial hirsutism and do not provide additional information over the commonly measured androgens.

Adolescent↗
PubMed1992

Serum androgens and depression in women with facial hirsutism.

BACKGROUND: Studies on the psychopathologic aspects of hirsutism are sparse. Attempts to correlate these aspects with either the extent of the facial hirsutism and/or circulating serum androgens are virtually nonexistent. This study evaluates the psychopathologic aspects of hirsutism and correlates these findings with the extent of the facial hirsutism as well as with the circulating serum androgens. OBJECTIVE: Our purpose was to assess the psychopathologic aspects of facial hirsutism and to determine whether any correlation exists between these findings and either the extent of the facial hirsutism or the circulating serum androgens. METHODS: Twenty consecutive women with facial hirsutism were studied by administration of psychologic tests (DeRogatis Symptom Inventory and the Affects Balance Scale). The results of these tests were correlated with the grade of facial hirsutism as well as serum levels of total testosterone (T), biologically active testosterone (BT), free testosterone (FT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A-dione). RESULTS: Significant levels of depression were found. No correlation was found between the psychopathologic measurements and the extent of facial hirsutism or serum levels of T, DHEA, DHEA-S, and A-dione. Significant correlations were found between depression and serum levels of FT and BT. CONCLUSION: There is an increased incidence of depression in facially hirsute women and this correlates with their circulating active testosterone levels and not with the extent of their facial hirsutism.

Adolescent↗
PubMed1992

In vitro effects of substance P analogue [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P on human tumour and normal cell growth.

Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50 microM. There was dose dependent inhibition of colony forming efficiency (CFE) in 3/3 SCLC and 1/1 N-SCLC CL, IC50s of 0.5-6.5 microM in 5% serum. Exposure of SCLC CL HC12 to 100 microM D-Phe5SP for 1-4 h caused a progressive fall in viable cell number; surviving cells, grown in the absence of peptide, showed a decreased growth rate. During 1 week's exposure of two SCLC CLs to 20 microM D-Ph5SP, growth was slower than control cultures, while 50-100 microM completely inhibited growth. These inhibitory effects were partially reversed by increasing serum concentration from 5 to 20%, but not by SP, vasopressin, bombesin or insulin-like growth factor 1. There was some inhibition of CFE by 3/3 normal human bone marrows, IC50s of 30-80 microM, compared with 8 microM for HC12 in 20% FCS. Therefore D-Phe5SP appears to have more potent antiproliferative effects in tumour cells than normal cells, suggesting a role for this analogue in tumour treatment.

Analysis of Variance↗
PubMed1992

Phonetic prototypes: influence of place of articulation and speaking rate on the internal structure of voicing categories.

In this investigation, the effects of context on the perception of voicing contrasts specified by voice-onset-time (VOT) in syllable-initial stop consonants were examined. In an earlier paper [J.L. Miller and L.E. Volaitis, Percept. Psychophys. 46, 505-512 (1989)], it was reported that the listener's adjustment for one contextual variable, speaking rate, was not confined to the region of the phonetic category boundary, but extended throughout the phonetic category. The current investigation examines whether this type of perceptual remapping also occurs for another contextual variable, the place of articulation of the syllable-initial consonant. In a preliminary experiment that involved acoustic measurement of natural speech, it was confirmed that as place of articulation moves from labial to velar, VOT increases, and it was established that this occurs across a range of speaking rates (syllable durations). In the main experiments, which focused on the voiceless category, it was found that this acoustic change was reflected in perception not only as a shift in the location of the voiced-voiceless category boundary, but also a change in both the specific range of stimuli identified as members of the voiceless category and the set of stimuli judged to be the best exemplars, or prototypes, of the category. These findings extend earlier research by showing that a change in place of articulation, like a change in speaking rate, systematically alters the internal perceptual structure of voicing categories.

Adult↗
PubMed1992

Finasteride for benign prostatic hyperplasia.

The pathogenesis of benign prostatic hyperplasia is related to the action of 5 alpha-dihydrotestosterone (DHT), the physiologically active form of testosterone. The conversion of testosterone to DHT is catalyzed intracellularly in prostatic tissue by the enzyme 5 alpha-reductase. Finasteride blocks the action of 5 alpha-reductase by competitively inhibiting the binding of testosterone to 5 alpha-reductase. The maximum effect of finasteride on reducing prostatic volume occurs after three months of oral therapy. Most patients experience improvement in urine flow rates, and side effects are minimal. However, following discontinuation of treatment, serum DHT levels return to baseline within two weeks.

5-alpha Reductase Inhibitors↗
PubMed1991

Conformational energy analysis of the substitution of Val for Gly 233 in a functional region of platelet GPIb alpha in platelet-type von Willebrand disease.

Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder in which patient platelets exhibit an abnormally increased binding of circulating von Willebrand factor (vWF). We have recently shown that this abnormality is associated with a point mutation resulting in substitution of Val for Gly 233 in platelet membrane glycoprotein Ib alpha (GPIb alpha), a major component of the platelet GPIb/IX receptor for vWF. To investigate the effect of this substitution on the three-dimensional structure of this region of the protein, we have generated the allowed (low energy) conformations of the region of the GPI alpha protein containing residues 228-238 (with 5 residues on either side of the critical residue 233) with Gly 233 (wild type) and Val 233 (PT-vWD) using the computer program ECEPP (Empirical Conformational Energies of Peptides Program). The wild-type sequence is Tyr-Val-Trp-Lys-Gln-Gly-Val-Asp-Val-Lys-Ala. We find that the Gly 233-containing peptide can exist in two low energy conformers. The lowest energy conformer is a structure containing a beta-turn at Gln 232-Gly 233 while the alternative conformation is an amphipathic helical structure. Only the amphipathic helical structure is allowed for the Val 233-containing peptide which contains a hydrophobic 'face' consisting of Val 229, Val 233 and Val 236 and another hydrophilic surface composed of such residues as Lys 231 and Asp 235. No such surfaces exist for the lowest energy bend conformer for the Gly 233-containing peptide, but do exist in the higher energy helical structure. The amphipathic surfaces in the 228-238 region of the Val 233-containing GPIb alpha protein may associate strongly with complementary surfaces during vWF binding to the GPIb/IX receptor complex and may help explain heightened association of vWF with this receptor in PT-vWD.

Amino Acid Sequence↗
PubMed1991

Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease.

Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor (vWF) by patient platelets. Although the platelet glycoprotein (GP) Ib/IX complex is known to constitute the platelet's ristocetin-dependent receptor for vWF, a unique structural abnormality within this complex has not previously been identified in PT-vWD. Using the polymerase chain reaction to amplify genomic DNA coding for the alpha chain of GP Ib (GP Ib alpha) and then sequencing the amplified DNA following cloning into M13mp18 and M13mp19 phage vectors, we have found a single point mutation in the GP Ib alpha coding region of PT-vWD DNA resulting in the substitution of valine for glycine at residue 233. This substitution within the vWF-binding region of GP Ib alpha is likely to exert a significant influence on the conformation of the resulting protein. Competitive oligonucleotide primer assay for this mutation showed a homozygous wild-type pattern in genomic DNA from the 161 normal volunteers studied and from 6 phenotypically normal members of a PT-vWD family. All 7 affected members of this family studied were heterozygous for the mutant allele. Platelet GP Ib alpha mRNA reverse-transcribed and studied by competitive oligonucleotide primer assay showed similar expression of the mutant and wild-type alleles in the affected PT-vWD patients. Absence in the normal population, tight linkage with phenotypic expression of disease, and absence of any additional abnormality of GP Ib alpha in these patients identify the glycine-to-valine substitution as a point mutation underlying functional abnormality of the vWF receptor in PT-vWD.

Alleles↗
PubMed1991

A living systems analysis of organizational pathology.

Organizations have essentially the same subsystem processes as living systems at other levels. All of them adjust subsystem variables to changing environmental and internal circumstances. Pathology exists in any system when a subsystem variable remains out of its steady-state range for an extended period. The same classes of pathology can be found at all levels. This article analyzes the various forms of pathology that exist in living systems at the level of organizations and describes living systems process analysis. Studies of several types of organizations including U.S. Army battalions, a corporation, a hospital, and a possible space station or lunar base, are discussed.

Animals↗
PubMed1991

Clear-cell change in follicular adenoma mimicking Hürthle-cell tumor on thyroid aspiration biopsy cytology.

We present a case of follicular adenoma with clear-cell change, which on fine-needle aspiration biopsy mimicked a Hürthle-cell tumor. Papanicolaou-stained smears revealed a monomorphic pattern of loosely cohesive groups of cells with abundant cytoplasm and centrally placed round nuclei with single prominent nucleoli. The cytoplasm was granular or finely vacuolated with occasional intracytoplasmic brown pigment. Subsequent surgical histology of the partial thyroidectomy specimen revealed a follicular adenoma composed of macro- and microfollicles. The microfollicular areas showed clear-cell change: these cells appeared identical to those seen on cytology. No Hürthle-cell change was present in the surgical specimen. Follicular cells with clear-cell change of the granular type must be added to the list of differential diagnoses when cells with Hürthle-like features are seen on aspiration biopsy of the thyroid.

Adenoma↗
PubMed1991

Androgens and oligomenorrhea in hirsute women.

A recent study demonstrated that hirsute women with irregular menses had higher levels of serum androgens that hirsute women with regular menses. To investigate this finding, we measured total testosterone, biologically active testosterone, free testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate in 51 hirsute women with regular menses and compared the levels found to those found in 28 hirsute women with oligomenorrhea. There was no significant difference in the degree of facial hirsutism between the two groups. Oligomenorrheic women had significantly higher levels of free testosterone (p less than 0.02) and biologically active testosterone (p less than 0.05). The other androgens did not differ significantly between the two groups. The free fractions of testosterone are the metabolically active forms of the hormone and their levels are a function of the rates of production and clearance of testosterone that are elevated in states of hyperandrogenism. This study confirms that hirsute women with oligomenorrhea have higher levels of free and biologically active testosterone than those with regular menses.

Androgens↗
PubMed1991

Cloning and nucleotide sequence of the anaerobically regulated pepT gene of Salmonella typhimurium.

The anaerobically regulated pepT gene of Salmonella typhimurium has been cloned in pBR328. Strains carrying the pepT plasmid, pJG17, overproduce peptidase T by approximately 70-fold. The nucleotide sequence of a 2.5-kb region including pepT has been determined. The sequence codes for a protein of 44,855 Da, consistent with a molecular weight of approximately 46,000 for peptidase T (as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration). The N-terminal amino acid sequence of peptidase T purified from a pJG17-containing strain matches that predicted by the nucleotide sequence. A plasmid carrying an anaerobically regulated pepT::lacZ transcriptional fusion contains only 165 bp 5' to the start of translation. This region contains a sequence highly homologous to that identified in Escherichia coli as the site of action of the FNR protein, a positive regulator of anaerobic gene expression. A region of the deduced amino acid sequence of peptidase T is similar to segments of Pseudomonas carboxypeptidase G2, the E. coli peptidase encoded by the iap gene, and E. coli peptidase D.

Amino Acid Sequence↗
PubMed1991

GnRH agonists: gonadorelin, leuprolide and nafarelin.

Gonadotropin-releasing hormone (GnRH), a decapeptide synthesized and released by the hypothalamus, regulates production and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the adenohypophysis. Parenterally administered GnRH was initially used diagnostically as a test of adenohypophyseal reserve of LH and FSH. Subsequently, native GnRH was used therapeutically to treat hypothalamic hypogonadal and infertility states in both men and women. Because of the low potency and short half-life of native GnRH, long-acting, potent analogs have been developed that suppress secretion of native pituitary gonadotropins, resulting in medical gonadectomy. When administered parenterally and, more recently, intranasally, these compounds are useful in the management of prostate and breast carcinoma, endometriosis and uterine leiomyomata, precocious puberty and nontumorous ovarian hyperandrogenic syndromes.

Endometriosis↗
PubMed1991

Etidronate for hypercalcemia of malignancy and osteoporosis.

The biphosphonates are becoming well established as effective agents for the treatment of metabolic bone diseases. Etidronate disodium is the only biphosphonate approved by the U.S. Food and Drug Administration. Accepted indications for etidronate therapy are symptomatic Paget's disease, heterotopic ossification and hypercalcemia of malignancy. An unapproved, but apparently successful use is treatment of postmenopausal osteoporosis. Both oral and intravenous preparations are available. Newer biphosphonates, which may be more efficacious and less toxic than etidronate, are being studied.

Etidronic Acid↗