Increased basic fibroblast growth factor in plasma from multiple endocrine neoplasia type 1: relation to pituitary tumor.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. We previously reported a basic fibroblast growth factor (bFGF)-like substance in the plasma of subjects with MEN1. In the present study we used a novel sensitive specific 2-site immunoradiometric assay to test for bFGF in plasma. The assay employs immobilized affinity-purified N-terminal-specific anti-bFGF antibodies (antigen capture) and high affinity binding to radioiodinated heparin. bFGF-like immunoreactivity was undetectable (< 0.2 ng/mL) in normal subjects and in most unaffected relatives of MEN1 subjects. We found detectable bFGF ranging from 0.24-1.28 ng/mL in 21 of 50 subjects with MEN1. Seven of 8 MEN1 subjects with untreated pituitary tumors had detectable plasma bFGF-like immunoreactivity. Plasma bFGF-like immunoreactivity decreased after surgery for pituitary tumor in 4 patients and after initiation of bromocryptine therapy in 4 patients. bFGF was increased in the plasma of several subjects with sporadic endocrine disorders, including 3 with untreated or persistent acromegaly. We conclude that pituitary tumor is a possible source of high circulating bFGF immunoreactivity in MEN1 plasma.

Allelic loss from chromosome 11 in parathyroid tumors.

Parathyroid tumors may occur in a sporadic fashion or, more rarely, as part of a familial syndrome (such as familial multiple endocrine neoplasia type I). The MENI gene has been mapped by linkage analysis to chromosome 11 at band q11-q13, and presumably acts as a tumor suppressor gene. In the present study, which is an extension of our previous studies, we examined 41 parathyroid tumors from patients with familial multiple endocrine neoplasia type I and 61 sporadic parathyroid tumors with markers on chromosome 11, to assess the extent of allelic loss in those tumors. Twenty-four of the MENI-associated tumors (58%) and 16 of the sporadic parathyroid tumors (26%) displayed allelic loss from chromosome 11. The region of overlap of the allelic losses in the MENI-associated tumors enables us to place the MENI gene between PGA centromerically and INT2 telomerically, a region spanning about 7.5 cM. Taken together with locus ordering by linkage analysis, this clearly localizes the MENI gene telomeric to the PGA locus. Our inability to detect allelic loss on chromosome 11 in some parathyroid tumors suggests the existence of other genes involved in the development and/or progression of this subgroup of presumably monoclonal tumors; or that localized events involving the 11q tumor suppressor gene have occurred in some parathyroid tumors whose detection is beyond the sensitivity of our analysis; or that at least some of the specimens analyzed were in fact primarily hyperplastic parathyroid tissue.

[Evoked otoacoustic emissions in adults. Criteria for evaluation in clinical use]. / Evozierte otoakustische Emissionen bei Erwachsenen. Auswertekriterien für den klinischen Einsatz.

The work here presents the first part of a prospective study regarding the clinical use of evoked otoacoustic emissions (EOAE) in adults. Sixty subjects with normal hearing and 160 patients suffering from cochlear hearing loss were tested. The results were used to develop and optimize analysis criteria for the emissions, based on their physical properties. A short-time Fourier analysis was performed so that the EOAE intensity in time and frequency domains could be observed simultaneously. A comparison of this data with the individual thresholds of hearing showed the importance of the EOAE level. However, the bandwidth of the EOAE demonstrated an even steeper transition between normal and hearing-impaired subjects. These findings suggest that this bandwidth is a better criterion for the detection of an EOAE. On the other hand, both parameters correlated weakly with the hearing threshold and the differences between subjects were very large. A prediction of hearing loss based on EOAE results is impossible with the wideband click stimulation used here.

[Minimally invasive surgery of sinugenic orbital complications in childhood]. / Minimal invasive Chirurgie bei sinugener orbitaler Komplikation im Kindesalter.

Orbital complications of acute sinusitis are classified into inflammatory edema, orbital cellulitis, subperiostal abscess and orbital abscess. The diagnosis is based on endoscopy of the nose, computed tomography of sinuses and orbit and an ophthalmological examination. Endonasal sinus surgery improves drainage and ventilation of sinuses and is free of long-term complications as observed with previous surgical techniques. Thus, the early surgical treatment of orbital complications is indicated even in children. Inflammatory edema and orbital cellulitis will still be treated conservatively. Subperiostal abscess and orbital abscess are treated surgically.

Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism.

Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of 49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 less than 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (p2 less than 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, p2 less than 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar long-term control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographically identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation.

A prospective study of hyperlipidemia as a pathogenic factor in sudden hearing loss.

The pathogenic role of hyperlipidemia in sudden hearing loss (SHL) was examined in a prospective study. Twenty-five patients (14 males, 11 females; age range, 23-59 years) with a first event of SHL (group I) were compared with 9 patients (4 males, 5 females; age range, 28-86 years) with a repeated event of SHL (group II). Audiological examination revealed different types of SHL in group I vs group II: high-frequency loss, 76% vs 22%; low-frequency loss, 12% vs 22%; pancochlear hearing loss, 12% vs 56%. Serum lipid patterns and atherogenic risk factors in both groups were not different and corresponded to lipid patterns in the average population. These findings indicate that both hyperlipidemia and atherogenic risk factors are not of major pathological importance in SHL.

[Surgical anatomy of the optic nerve and the internal carotid artery in the lateral wall of the sphenoid sinus. An anatomic study of the cranial base]. / Chirurgische Anatomie des Nervus opticus und der Arteria carotis interna in der lateralen Keilbeinhöhlenwand. Eine anatomische Studie am Schädelbasispräparat.

The optic nerve and the internal carotid artery lying in the cavernous sinus contact the bony wall of the sphenoid sinus, and can easily be injured during surgery. The maxillary sinus, the sphenoid sinus and the ethmoid cells were opened on both sides during ten resections of the skull base. After removing the bony part of the lateral wall of the sphenoid sinus the following measurements were performed: the distance between the optic nerve and the frontal dura; the distance between the optic nerve and the internal carotid artery; the length and width of the optic nerve and the internal carotid artery in the area contacting the bony wall of the sphenoid sinus. This study illustrates the regularity of the structures of the posterior nasal wall. Landmarks are offered for finding the orbital aperture of the optic canal. The necessity of orientation by landmarks is emphasized.

Heterogeneous size of the parathyroid glands in familial multiple endocrine neoplasia type 1.

OBJECTIVE: We wished to determine whether there was size heterogeneity of the parathyroid glands in patients with familial multiple endocrine neoplasia type 1 (FMEN1) and primary hyperparathyroidism. DESIGN: At the National Institutes of Health we performed a retrospective analysis of parathyroid gland volume either from initial or repeat parathyroid exploration. PATIENTS: We studied subjects with FMEN1 and primary hyperparathyroidism. MEASUREMENTS: The parathyroid gland volume was estimated from recorded orthogonal diameters. Volume could also be estimated conservatively in many glands for which one or more diameters were not recorded. Reproducibility of volume measurements was tested with a series of clay gland models. Indices of variability (among glands at an operation or among replicate measurements of a clay model) were the ratio of maximum volume/minimum volume and the average standard deviation of the log volume. RESULTS: The most complete data were from eight initial operations with three dimensions recorded for all four glands. Volume heterogeneity was indicated by the average ratio of 9.6 for the maximum/minimum gland volume within an operation. The size heterogeneity was even greater among other subgroups. For example, the average ratio of maximum/minimum gland volume within an operation was 17 among five initial operations with four glands removed, but lacking measurements of three dimensions for some glands. Little of this size heterogeneity could be attributed to measurement error since eight replicate measurements on a model gland yielded a maximum/minimum volume ratio of 1.45. CONCLUSIONS: There is a wide heterogeneity in size of the parathyroid glands in the patients with FMEN1 and primary hyperparathyroidism.

[Endonasal, endoscopic-microscopic control of the decompression of the optic nerve. An anatomic endoscopic presentation of the operation]. / Die endonasale, endoskopisch-mikroskopisch kontrollierte Dekompression des N. opticus. Eine anatomisch-endoskopische Darstellung der Operation.

The indication for decompression of the optic nerve after indirect trauma is made both by the ophthalmologist and the ENT-surgeon. The ENT-surgeon usually reaches and decompresses the optic canal by a transethmoidal-transsphenoidal route. The majority of authors prefer the transfacial approach to the ethmoid including resection of the crossing plane comprising the frontal process of the maxilla, the ethmoid, the lacrimal and the frontal bone. Hitherto we have knowledge of only one author utilising an endonasal approach to decompress the optic nerve. At the university hospital of Göttingen, the ENT-surgeons gathered experience with the endonasal, endoscopically and microscopically controlled operation method, which is less traumatic to the patient and avoids postoperative mucoceles of the frontal sinus. This surgical procedure is described by surgical-anatomical specimens.

Natriuretic peptide receptors regulate endothelin synthesis and release from parathyroid cells.

Cloned rat parathyroid cells (PTr cell line) that produce parathyroid hormone-related peptide plus endothelin 1 and primary cultures of human parathyroid cells were tested for growth and differentiation responses to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). High- and low-affinity binding sites for ANP were found on PTr cells; BNP appeared to bind to the same receptors with similar affinities. Either ANP or BNP stimulated production of cGMP and caused a 30% decrease in Na(+)-K(+)-Cl- cotransport. Each peptide increased synthesis and secretion of endothelin 1 by PTr cells in a dose-dependent fashion, but cell growth was not affected. Human parathyroid cells (normal and pathological) also responded to ANP or BNP with an increase in cGMP production. The finding of receptors for natriuretic hormones on parathyroid cells with consequent effects on release of endothelin 1 might be of relevance in understanding the clinical association between hyperparathyroidism and hypertension.

[Pseudotumor of the hypopharynx and other primary diseases in the head and neck region in HIV infections. A case report and review of the literature]. / Pseudotumor des Hypopharynx und andere Primärerkrankungen in der Kopf-Hals-Region bei HIV-Infektion. Fallbeschreibung und Literatur-Ubersicht.

The present article describes a pseudotumor of the hypopharynx, and deteriorating breathing and swallowing in a 72-year-old man. The pseudotumor was due to advanced HIV-infection and is the first such case to be described. Additionally, the article reviews the literature concerning otorhinolaryngeal diseases as primary manifestations of HIV infection.

Endothelin as an autocrine factor in the regulation of parathyroid cells.

Endothelin, originally purified from porcine aortic endothelial cells, is widely distributed in tissues and is recognized as a product of epithelial cells, glial cells, and neurons in addition to endothelial cells. We found evidence by mRNA content and immunoreactivity that this peptide is synthesized in rat parathyroid epithelial cells (PT-r cells) and bovine parathyroid chief cells. The peptide synthesized by PT-r cells comigrated with synthetic endothelin 1 in reverse-phase HPLC and was diluted out in radioimmunoassay in parallel with the synthetic peptide. Bovine parathyroid endothelial cells (BPE-1 cells) did not express this peptide. Preproendothelin 1 mRNA expression by PT-r cells and endothelin 1 peptide production were regulated by calcium. Shifts in extracellular calcium either from high to low concentrations or vice versa elicited similar evanescent increases in expression of mRNA with a peak at 1 h. Synthesis of the peptide seems to be controlled by mRNA expression, and peptide in the medium appears to be continuously degraded or taken up by cells because its concentration in the medium showed a time course similar to that of mRNA expression. PT-r cells also bear a single class of receptors highly specific for endothelin 1, suggesting an autocrine regulation by endothelin 1 of the parathyroid. The facile regulation of endothelin concentrations in the medium by shifts in extracellular calcium concentration and possible autocrine regulation by endothelin 1 suggest that this peptide may mediate, at least in part, effects of calcium on the parathyroid system.

Identification of heparan sulfate proteoglycan as a high affinity receptor for acidic fibroblast growth factor (aFGF) in a parathyroid cell line.

We have characterized two high affinity acidic fibroblast growth factor (aFGF) receptors in a rat parathyroid cell line (PT-r). Affinity labeling with 125I-aFGF showed that these two receptors, apparent molecular masses, 150 and 130 kDa, respectively, display higher affinity for aFGF than for bFGF. The 150-kDa receptor bears a heparan sulfate chain(s), demonstrated by a decrease in size of 15-20 kDa with heparitinase digestion after affinity labeling. Heparitinase digestion before affinity labeling markedly reduced the intensity of the 150 kDa species. Scatchard analysis showed two different high affinity binding sites (Kd of 3.9 pM with 180 sites/cell and Kd of 110 pM with 5800 sites/cell). The higher affinity site was completely eliminated by digestion with heparitinase before adding labeled aFGF; the lower affinity site was unaffected. In ion exchange chromatography after metabolic labeling of the cells with [3H]glucosamine and affinity labeling with 125I-aFGF, the larger receptor-ligand complex, 165 kDa, eluted with approximately 0.5 M NaCl, typical eluting conditions for heparan sulfate proteoglycans. Both of the receptor-ligand complexes were smaller on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than two major heparan sulfate proteoglycans, HSPG I and II, which we characterized in this cell line previously (Yanagishita, M., Brandi, M. L., and Sakaguchi, K. (1989) J. Biol. Chem. 264, 15714-15720). Both receptors have similar N-linked oligosaccharide and sialic acid contents, shown by analysis of affinity-labeled receptors upon digestion with glycopeptidase F and with neuraminidase. All together, these results suggest that PT-r cells bear two distinct high affinity receptors for aFGF, a 150-kDa receptor which is a heparan sulfate proteoglycan and another that is a glycoprotein. The heparan sulfate glycosaminoglycan moiety of the 150- kDa receptor is critical for high affinity binding of aFGF. These findings contrast with current concepts derived from other systems, suggesting that heparan sulfate glycosaminoglycans/proteoglycans function as a reservoir source for FGF or as a group of low affinity binding sites.

Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, pancreatic islets, and anterior pituitary. The gene for this disease maps to chromosome 11q12-11q13, and allelic loss in this region has been shown in both sporadic and FMEN1-related parathyroid tumors. FMEN1-related pancreatic islet tumors, and rarely in sporadic anterior pituitary tumors. We tested for allelic loss at 7 loci on chromosome 11 in 17 tumors outside the parathyroid. We found loss of heterozygosity in 2 of 2 FMEN1-related benign pancreatic islet tumors but in none of 8 informative sporadic islet tumors (P = 0.02) including 5 malignant gastrinomas. Of 3 islet tumors from patients who had some but not all features of FMEN1, one showed allelic loss for 5 of 5 informative restriction fragment length polymorphisms, and the other 2 retained heterozygosity for all informative markers. A bronchial carcinoid from an FMEN1 patient and 3 sporadic anterior pituitary tumors showed no allelic loss. These data provide new evidence that many sporadic pancreatic islet neoplasms, even when malignant, do not develop through homozygous inactivation of the MEN1 gene.

Locally recurrent parathyroid neoplasms as a cause for recurrent and persistent primary hyperparathyroidism.

Between 1982 and 1989, 145 patients underwent operations for persistent or recurrent primary hyperparathyroidism (HPT). At re-exploration, 15 patients (10.3%) were found to have locally recurrent parathyroid tumors (11 patients with adenoma and 4 with carcinoma). These 15 patients had 28 previous operations at outside institutions for HPT. Patients with locally recurrent HPT secondary to adenoma had a longer disease-free interval than patients with locally recurrent carcinoma. At the time of evaluation at the National Institutes of Health (NIH) for recurrent or persistent HPT, each patient was symptomatic and patients with carcinoma had significantly more symptoms and higher serum levels of calcium and parathyroid hormone than patients with adenoma. Locally recurrent parathyroid neoplasm was correctly localized by preoperative testing in 14 of 15 patients. These 15 patients underwent 18 reoperations at NIH for excision of locally recurrent parathyroid tumors. Following the final reoperation (two patients had more than one procedure), each patient had normal serum levels of calcium. In addition each patient remains biochemically cured (based on normal serum calcium level), with a median follow-up interval of 21 months. Local recurrence of parathyroid adenoma comprises a small but significant proportion of cases of recurrent or persistent HPT and can be indistinguishable from parathyroid carcinoma. Findings suggestive of carcinoma include shorter disease-free interval, higher serum levels of calcium and parathyroid hormone, and histologic appearance. Whether the locally recurrent parathyroid neoplasm is benign or malignant, aggressive surgery can control serum levels of calcium in these patients with acceptable rates of morbidity.

Topographical anatomy of the internal auditory canal. Implications for functional surgery in the cerebello-pontine angle.

For exposure of the cerebello-pontine angle by an enlarged middle-fossa approach without destruction of the inner ear, bone removal anterior and posterior to the internal auditory meatus (c.a.i.) can be performed with orientation at landmarks. Based on the experience of more than 300 interventions and documented by a series of 10 temporal bone micro-dissections, rules have been established for reliable localization of the following structures: geniculate ganglion, Fallopian canal, vertical crest at the fundus of the c.a.i., basal coil of the cochlea, and ampulla of the superior semicircular canal. The surgical technique has enabled the authors to remove acoustic neurinomas of up to 3.5 cm with preservation of hearing in 51%.

[Therapy of ozena]. / Zur Therapie der Ozaena.

This paper reports on surgical therapy of ozena. Hydroxylapatite was implanted under the mucosa of the nasal septum and the floor of the nasal cavity in four patients with ozena. In five patients the nostrils were totally closed by the method of Young. After a period of 2 to 5 years, the clinical results in both groups enable us to recommend both surgical procedures.

Establishment and characterization of a clonal line of parathyroid endothelial cells.

We have isolated endothelial cells derived from bovine parathyroid tissue. These cells have been cloned and maintained by serial passage for more than 40 months without showing signs of senescence. Prolonged culture was accomplished by using a medium favoring endothelial cell growth and methods for enriching endothelial cells in primary culture. The cloned parathyroid endothelial cells contained factor VIII-related antigen, took up acetylated low-density lipoproteins and parathyroid hormone, and showed morphological features comparable to other endothelial cells. Bovine parathyroid endothelial cells replicated with a mean doubling time of 65 h. Fibroblast growth factors, platelet-derived growth factor, and calcium acted as mitogens for parathyroid endothelial cells, whereas transforming growth factor beta inhibited proliferation.

Genetic abnormalities in sporadic parathyroid adenomas.

We analyzed genomic DNA from 43 sporadic benign parathyroid adenomas for rearrangements of the PTH gene, and for point mutations of the H-ras (codons 12, 13, and 61), N-ras (codons 12, 13, and 61), and K-ras (codons 12 and 13) genes. One of 43 parathyroid adenomas showed a chromosome 11 rearrangement involving both the PTH gene on the short arm of chromosome 11 (at band p15) and a locus on the long arm (11q13). This rearrangement was indistinguishable from one that was previously described in a parathyroid adenoma by Arnold et al., indicating that this may be an important contributor to tumorigenesis in a small subset of patients with parathyroid adenoma. H-ras, K-ras, and N-ras oncogene activation by point mutation at codons 12, 13, or 61, known to occur in many tumors, could not be detected in any parathyroid adenoma.