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J M Alexander

Publications and source records attributed to J M Alexander.

At least 73 records · Page 4Linked to original sources
PubMed1992

Glycoprotein hormone alpha-subunit production in somatotroph adenomas with and without Gs alpha mutations.

Activating mutations of the Gs alpha subunit have been identified in a subset of somatotroph adenomas. The mutant form of the Gs alpha subunit causes persistent activation of adenylyl cyclase and consequently results in high intracellular levels of cAMP. Because cAMP is known to stimulate the synthesis of the glycoprotein hormone (GPH) alpha-subunit as well as GH, we examined somatotroph tumors with and without Gs alpha mutations for GPH alpha-subunit production. GPH alpha-subunit production was assessed in vivo by measuring serum hormone levels and in vitro by analyzing hormone secretion by cultured pituitary tumor cells. DNA was extracted from the pituitary tumors of 26 acromegalic patients. The Gs alpha gene was amplified by the polymerase chain reaction and screened for mutations at codons 201 and 227 using oligonucleotide specific hybridization. Nine of the 26 tumors (35%) had point mutations at Arg 201. Seven of these tumors contained a CGT to TGT mutation (Arg to Cys) and 2 contained a CGT to CAT mutation (Arg to His). No mutations were detected at codon 227. There were no significant differences in age, sex distribution, tumor size, or serum levels of GH or insulin-like growth factor-1 between the groups of patients with or was Gs alpha mutations. The mean serum level of the free GPH alpha-subunit was 1.9-fold higher in the group with Gs alpha mutations (0.48 +/- 0.37 micrograms/L) than in patients without mutations (0.25 +/- 0.17) (P less than 0.05). In pituitary tumor cell culture, 75% of somatotroph tumors with Gs alpha mutations secreted free GPH alpha-subunit into the media compared with 45% of tumors without Gs alpha mutations. The amount of GPH alpha-subunit secretion was 12-fold greater in the group of tumors containing the Gs alpha mutation (P less than 0.05). Immunocytochemical detection of the free GPH alpha-subunit was similar in the two groups of patients with 75% positive for the GPH alpha-subunit in tumors with Gs alpha mutations and 67% positive in tumors without mutations (P = 0.69). We conclude that GPH alpha-subunit production occurs in somatotroph tumors with and without Gs alpha mutations. The increased levels of GPH alpha-subunit secretion in vivo and in vitro suggest that the Gs alpha mutation may increase the amount of preexisting GPH alpha-subunit biosynthesis in the tumors, perhaps via activation of the cAMP pathway.

Adenoma↗
PubMed1992

Clonal origins of adrenocorticotropin-secreting pituitary tissue in Cushing's disease.

It is unclear whether Cushing's disease results from a primary pituitary disorder or arises in response to abnormal hypothalamic control of the pituitary gland. Clonal analysis can provide information as to whether neoplastic tissue is derived from a monoclonal proliferation of a genetically altered cell or from a polyclonal expansion of a group of cells affected by a common stimulus. We used X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase, hypoxanthine phosphoribosyltransferase, and DXS255 loci in 11 women with biochemically and pathologically confirmed Cushing's disease to determine the clonal origins of corticotroph adenomas and corticotroph hyperplasia. Tumor tissue from all 10 women with morphologically and immunohistochemically confirmed ACTH-secreting pituitary microadenomas demonstrated a monoclonal pattern. Pathologically confirmed corticotroph hyperplasia in a patient with a CRH-secreting bronchial carcinoid was found to be polyclonal. We conclude that corticotroph microadenomas in Cushing's disease are monoclonal, supporting the theory that a spontaneous somatic mutation is the primary pathogenetic mechanism in this disorder. In addition, the demonstration of polyclonality in corticotroph hyperplasia implies that excess of hypothalamic hormones is an etiologic mechanism in cases of Cushing's syndrome associated with ectopic CRH-secreting tumors.

Adrenocorticotropic Hormone↗
PubMed1991

The effects of activin on follicle-stimulating hormone secretion and biosynthesis in human glycoprotein hormone-producing pituitary adenomas.

The effects of activin on pituitary FSH biosynthesis have been previously characterized using primary rat pituitary cultures; however, little is known of the effects of activin on FSH biosynthesis and secretion in human pituitary tissue. Production of intact glycoprotein hormones and free subunits is increasingly recognized in pituitary tumors; however, the regulation of gonadotropins in such tumors has not been addressed. We have investigated the effects of human recombinant activin on glycoprotein hormone biosynthesis and secretion in primary cultures of 12 human glycoprotein hormone-producing pituitary adenomas and compared this with the effects of activin in normal rat anterior pituitary cells. In 33% of the human pituitary tumors studied, significant (P less than 0.05) increases in FSH beta secretion occurred in response to incubation with 20 ng/mL activin for 24 h (19-287% stimulation), without changes in the production of intact FSH. A Northern analysis performed on cells derived from one tumor indicated that FSH beta mRNA levels increased 350% after activin treatments; however, FSH secretion did not parallel the mRNA changes. None of the human glycoprotein hormone-producing tumors significantly increased FSH secretion in response to activin. To validate the biological activity of recombinant human activin-A and to confirm time and dose conditions for the human tumor cultures, we also examined its ability to stimulate FSH production in rat pituitary cultures. Activin (20 ng/mL) added to the culture medium significantly increased FSH secretion and steady state levels of FSH beta mRNA after 24 h. These data indicate that some glycoprotein hormone-producing pituitary tumors treated with purified activin have discordant responses of intact gonadotropins and free subunit responses. In contrast to responses in normal rat gonadotrophs, FSH beta biosynthetic pathways may be uncoupled from intact FSH secretion in a subset of glycoprotein hormone-producing pituitary adenomas.

Activins↗
PubMed1991

Somatostatin regulation of glycoprotein hormone and free subunit secretion in clinically nonfunctioning and somatotroph adenomas in vitro.

There is increasing evidence that clinically nonfunctioning pituitary tumors produce and secrete glycoprotein hormone and/or free alpha- and beta-subunits. In addition, hypersecretion of free alpha-subunit occurs in up to 37% of patients with somatotroph adenomas. An understanding of glycoprotein hormone regulation is important in developing effective therapeutic strategies for patients with tumors associated with intact glycoprotein hormone and free subunit hypersecretion. We investigated glycoprotein hormone and free subunit secretion by somatostatin in primary dispersed cultures of pituitary tumor cells from 23 patients with pituitary adenomas. Fifteen tumors from patients with clinically nonfunctioning adenomas (group 1) and 8 tumors from patients with somatotroph adenomas and cosecretion of alpha-subunit (group 2) were studied. Cultures were incubated with control or somatostatin-supplemented media for 24 h. Media samples from group 1 tumors were assayed for intact glycoprotein hormones and free alpha- and beta-subunits secretion levels, while media samples from group 2 cultures were assayed for alpha-subunit and GH secretion levels. Significant (P less than 0.05-0.001) inhibition of secretion of 1 or more intact hormones and/or free subunits was found in 10 of the 15 group 1 tumors. SRIF[10(-7) M] suppressed intact gonadotropin secretion in 60% of FSH-producing tumors and 30% of LH-producing tumors. Media concentrations of FSH beta and LH beta were decreased in 31% and 50% of group 1 tumors, respectively, following somatostatin treatment in those tumors which secreted free beta-subunits. alpha-Subunit was secreted by 12 of the 15 tumors, but significant (P less than 0.02-0.01) inhibition by somatostatin was observed in only 2 tumors. In contrast, significant (P less than 0.05-0.001) inhibition of alpha-subunit in the somatotroph adenomas was found in 6 of the 8 tumors. Significant decreases in alpha-subunit were observed only in those tumors where GH was also significantly inhibited by somatostatin. We conclude that 1) somatostatin inhibits intact glycoprotein or free subunit secretion in the majority of clinically nonfunctioning pituitary tumors in vitro and 2) alpha-subunit secretion is suppressed in 17% and 69% of clinically nonfunctioning and somatotroph adenomas, respectively, consistent with a differential regulation of alpha-subunit by somatostatin in these two tumor types.

Adenoma↗
PubMed1990

Clinically nonfunctioning pituitary tumors are monoclonal in origin.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

Adenoma↗
PubMed1989

Cell-specific and developmental regulation of a nerve growth factor-human growth hormone fusion gene in transgenic mice.

We recently showed that a nerve growth factor-human growth hormone (NGF-hGH) fusion gene containing the promoter and 750 bp of 5' flanking region is transcriptionally active in the NGF-secreting L929 mouse fibroblast cell line. For the present experiments, we extended the 5' flank by 5 kb and constructed transgenic mice. These mice began to secrete hGH into saliva at puberty. hGH was detected immunocytochemically in the granulated convoluted tubular cells of the submandibular gland (SMG). SMG levels of hGH mRNA were 10-fold higher in adult males than in females. hGH mRNA was very abundant in SMG, moderately abundant in heart, brain, and kidney, rare in skin and adrenal gland, and undetectable in lung, liver, and spleen. Thus, the NGF-hGH gene reflects NGF gene expression. We conclude that basal NGF gene transcription is regulated by sequences in the cloned NGF gene fragment.

Animals↗
PubMed1985

Patient perceptions of orthognathic surgery.

A retrospective study of ninety orthognathic surgery patients was conducted to investigate (1) their presurgical concerns and motivations, (2) their preoperative preparation for surgery, and (3) their perceptions of the postsurgical outcome. All subjects completed a twenty-three-item questionnaire and Rotter's Locus of Control Inventory. Statistical date analyses were performed by means of frequency distributions, chi-square, Spearman's r, and Fisher's exact probability tests. The results are presented as thirteen tentative conclusions categorized into three broad areas: motivations and concerns, presurgical preparation, and postsurgical outcome. In the area of motivations and concerns, those with primarily esthetic motivations have less initial reticence toward having orthognathic surgery and less difficulty adjusting to their new appearance than those with strong functional incentives. Younger patients and those patients with strong cosmetic motivations are less concerned about surgical risks. Under the category of presurgical preparation, more females than males desire to speak to a previous orthognathic surgery patient. Patients who receive inadequate explanation of the surgical procedure are more likely to be emotionally unprepared. One of the leading factors in patient dissatisfaction with surgery is the patient's experience of postoperative "surprises." In the area of postsurgical outcome, two-jaw operations precipitate more pain complaints than single-arch procedures. With time, however, patients tend to forget the degree of postoperative pain. Maxillary surgical procedures lead to less severe pain complaints than mandibular procedures, but there are more initial complaints of breathing difficulties and sinus problems following maxillary procedures. Surgical goal fulfillment does not guarantee that a patient would re-elect to have the treatment.

Adolescent↗
PubMed1985

Dosage of tobramycin in cystic fibrosis--a short report.

A 15 kg, 7-year-old girl with cystic fibrosis was admitted with a chest infection. It was found that a tobramycin, 12 mg/kg/day (standard recommended dose 6-7.5 mg/kg/day), was required to obtain acceptable plasma levels and that the volume of distribution varied in line with the patient's weight changes.

Child↗
PubMed1984

Psychological factors in adjustment to orthognathic surgery.

The psychological adjustment of 30 orthognathic surgery patients was evaluated before and on three occasions after surgery. Results of preoperative testing showed the group to be well adjusted, and there were no major changes in psychological functioning as a result of surgery. Motivation for surgery included both functional and esthetic goals, and the majority of patients were satisfied with the results of surgery. The patient's perception of the surgeon was significantly related to pre- and postoperative adjustment. Two of the measures used, the Health Opinion Survey and the Impact Message Inventory, have potential as brief early screening devices to identify patients who may experience problems in psychological adjustment to orthognathic surgery.

Adolescent↗
PubMed1983

Temporomandibular joint arthrography: negative pressure, nontomographic techniques.

The injection of contrast material through a catheter under direct fluoroscopic vision seems to be more informative than blind injection technique. Injection of a controlled amount of Renografin can diminish the likelihood of overfill and allow more complete opening of the mouth. If overfilling is suspected, after waiting approximately 15 minutes for absorption, the patient will then be able to move his condyle more freely. The use of a 100 mm. camera will provide good films and eliminate the need for tomograms. A catheter is preferred over a steel needle, and its position is more accurately assessed by using the negative pressure technique. Catheterization of the superior joint space is not done if the lower compartment injection shows obvious anterior subluxation of the meniscus. In certain borderline cases, the upper compartment filling may yield more positive diagnotic information. It is within the scope of this article to present a technique, not to indicate the usefulness or necessity of TMJ arthrography or tomography. The role of arthrography in the diagnosis and subsequent decision as to whether surgical or nonsurgical modalities should be performed will become evident only when the state of the art is defined.

Adult↗
PubMed1983

Patient responses to the orthognathic surgical experience: factors leading to dissatisfaction.

The authors surveyed 93 orthognathic surgery patients about presurgical concerns, preparation for the surgical experience, and postsurgical outcomes. Nine of the 90 respondents indicated they would not re-elect the surgical treatment. Reasons for dissatisfaction varied, although all had in common the occurrence of unanticipated postsurgical events. The importance of effective preoperative preparation of patients cannot be overestimated. The authors have written an information brochure to reinforce verbal orientation for the orthognathic surgery patient and family.

Adolescent↗
PubMed1981

Influence of Turgor Pressure Manipulation on Plasmalemma Transport of HCO(3) and OH in Chara corallina.

A modified version of the osmotic shock technique was used to investigate HCO(3) (-) and OH(-) transport in the alga Chara corallina. Cell turgor was brought close to zero and then restored. When turgor was reduced to near the plasmolytic point using an osmoticum, little effect was observed on H(14)CO(3) (-) assimilation and OH(-) transport. However, when turgor was recovered in these cells, there was a large reduction in HCO(3) (-) and OH(-) transport activity. In contrast, when cells were air-dried to zero turgor, and rewetted to restore turgor, no significant effect on OH(-) transport was observed.The effect of plasmolysis was also studied. When Chara cells were plasmolyzed, in most cases, all OH(-) transport activity was lost and acidification was observed along the cell surface.None of the above treatments had any long term effect on cyclosis. These results are discussed with respect to present concepts of turgorinduced changes in membrane functions.

Journal Article↗