Biomedical subjects

L Grimelius

Publications and source records attributed to L Grimelius.

At least 19 recordsLinked to original sources

PubMed1998

Identification of tryptophan hydroxylase as an intestinal autoantigen.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder with both endocrine and non-endocrine features. Periodic gastrointestinal dysfunction occurs in 25-30% of APS1 patients. We aimed to identify an intestinal autoantigen. METHODS: A human duodenal cDNA library was immunoscreened with serum samples from APS1 patients. A positive clone was identified and used for in-vitro transcription and translation, followed by immunoprecipitation with serum samples from 80 APS1 patients from Norway, Finland, and Sweden. Sections of normal and APS1-affected small intestine were immunostained with serum from APS1 patients and specific antibodies. An enzyme-inhibition assay was used to characterise the autoantibodies. FINDINGS: We isolated a cDNA clone coding for tryptophan hydroxylase. 48% (38/80) of APS1 patients had antibodies to tryptophan hydroxylase, whereas no reactivity to this antigen was detected in patients with other autoimmune diseases (n=372) or healthy blood donors (n=70). 89% (17/19) of APS1 patients with gastrointestinal dysfunction were positive for antibodies to tryptophan hydroxylase, compared with 34% (21/61) of patients with no gastrointestinal dysfunction (p<0.0001). Serum from antibody-positive APS1 patients specifically immunostained tryptophan-hydroxylase-containing enterochromaffin cells in normal duodenal mucosa. No serotonin-containing cells were seen in duodenal biopsy samples from APS1 patients. Serum from antibody-positive APS1 patients almost completely inhibited activity of tryptophan hydroxylase. INTERPRETATION: Tryptophan hydroxylase is an endogenous intestinal autoantigen in APS1, and there is an association between antibodies to the antigen and gastrointestinal dysfunction. Analysis of antibodies to tryptophan hydroxylase may be a valuable diagnostic tool to predict and monitor gastrointestinal dysfunction in APS1.

Adolescent↗

PubMed1998

Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period.

Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971-1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Adult↗

PubMed1998

A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.

OBJECTIVES: To characterize a family with hereditary paraganglioma, and to search for germline mutations in the von Hippel-Lindau disease (VHL) tumour suppressor gene and the ret proto-oncogene. DESIGN: Patient records and histopathological reports were reviewed. Available tumour samples were reinvestigated using immunohistochemical techniques. The VHL gene was investigated by single strand conformational polymorphism analysis of PCR products amplified from exons 1, 2 and 3 and the 3' untranslated region. The ret gene was analysed by amplifying and sequencing exons 10, 11 and 16. PATIENTS: A family with paragangliomas in three consecutive generations was investigated. RESULTS: The affected individuals were found to have multiple extra-adrenal paragangliomas. All three affected individuals had retroperitoneal tumours, and two also had paraganglioma in the neck. No mutations of the VHL or ret genes were detected. CONCLUSIONS: The described family may represent a novel dominantly inherited neuroendocrine tumour syndrome.

Adolescent↗

PubMed1998

Recovery from Marie-Bamberger's syndrome and diabetes insipidus after removal of a lung adenocarcinoma with neuroendocrine features.

A 44-year-old woman with Marie-Bamberger's syndrome and diabetes insipidus had a lung tumour with mediastinal metastases, but no signs of metastases to the hypothalamus or pituitary gland. A week after removal of the tumour, the joint pain, polyuria and polydipsia disappeared. The tumour was diagnosed histopathologically as a moderately differentiated adenocarcinoma with focal neuroendocrine cell differentiation and dispersed cells reacting with antisera against neurone-specific enolase, S-100 protein, neuropeptide Y, follicle-stimulating hormone, substance P, vasoactive polypeptide (VIP), adrenocorticotropic hormone and pancreatic polypeptide (PP) as well as to one of three tested antisera raised against antidiuretic hormone (ADH). It was suggested that Marie-Bamberger's syndrome might be caused by one of these immunoreactive substances or by a substance that shares an amino acid sequence with one of these neuroendocrine peptides. It was also suggested that the tumour might produce an ADH-like substance which might have an ADH-antagonist effect.

Adenocarcinoma↗

PubMed1998

Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families.

Approximately 70 families with familial isolated hyperparathyroidism (FIHP) have been reported. Whether it is a separate entity or a variant of multiple endocrine neoplasia type 1 (MEN1 at 11q13) or hyperparathyroidism-jaw tumor (HPT-JT or HRPT2 at 1q21-32) syndrome is not known. We describe here 3 unreported families with familial primary hyperparathyroidism and evaluate their clinical, pathological, and genetic profiles. Biochemical and radiological screenings for MEN1 were negative for all families. In 2 families with a total of 10 affected cases and 3 female obligate carriers, there is no evidence of jaw or renal lesions despite careful radiological investigations. In both families the disease was linked to the 1q21-q32 region with the maximum logarithm of the odds (lod) scores of 3.10 and 3.43 for markers D1S222 and D1S249 respectively, at recombination fraction of 0. In 1 family 2 types of parathyroid pathology were found: 3 of chief cell type and 1 of oxyphil/oncocytic cell type. Two chief cell tumors and 1 oxyphil tumor were found to have loss of heterozygosity (LOH) involving loss of the wild-type alleles for chromosome 1q markers. In the third family, with 4 affected siblings, a parathyroid carcinoma and 2 cases of polycystic kidney disease were found. The parathyroid carcinoma also showed loss of heterozygosity in the 1q region. In conclusion, we found that the hyperparathyroidism traits in a subset of FIHP families are linked to the 1q21-32 markers in the HRPT2 region. We describe the spectrum of parathyroid disease in 1q-linked families involving 3 different types of pathology and demonstrate for the first time loss of wild-type alleles in these parathyroid tumors. Taken together, the results suggest that some of the FIHP are a variant of HPT-JT and that the gene involved is a tumor suppressor gene.

Adult↗

PubMed1998

Integrins in thyroid tissue: upregulation of alpha2beta1 in anaplastic thyroid carcinoma.

OBJECTIVE: To evaluate the integrin pattern in the normal thyroid gland and in different pathological disorders including malignant tumors, because the aggressiveness of several malignant tumors correlates with alterations in the expression of one or more integrins. DESIGN: We examined the expression of integrins and E-cadherin immunohistochemically in a large and well-defined sample of normal and pathological human thyroid tissue. METHODS: Cryosections of 58 thyroid tissue specimens from normal tissue, thyrotoxicosis, nodular goiter, oxyphilic adenoma, follicular adenoma, follicular carcinoma, papillary carcinoma and anaplastic carcinoma, and three lymph node metastases were investigated immunohistochemically using monoclonal antibodies specifically recognizing the integrin beta1-, beta4-, alpha1-, alpha2-, alpha3-, alpha5- and alpha6-subunits, or E-cadherin. RESULTS: All thyroid epithelial cells expressed integrin beta1- and alpha3-subunits. Immunostaining of the beta4-subunit and the alpha6-subunits was found only in tumors. The staining pattern in the three lymph node metastases from papillary carcinomas did not differ from that in their primaries. Anaplastic carcinomas demonstrated neoexpression of the integrin alpha2-subunit. E-cadherin was detected in all tissues except anaplastic carcinomas. CONCLUSIONS: Neoexpression of alpha6beta4 was seen in most malignant tumors, whereas alpha2 was exclusively found in anaplastic carcinomas. In the latter, a loss of E-cadherin expression was also seen. These changes in cell adhesion molecule expression strongly suggest an association with the acquisition of proliferative and invasive properties.

Cadherins↗

PubMed1998

Developmental gene expression of sympathetic nervous system tumors reflects their histogenesis.

Comparisons of the developing human sympathetic nervous system (SNS) to tumors presumed to derive from these cells may suggest tumor progenitors and predict tumor biologic behavior. Classic neuroblastoma (NB) and its more highly differentiated stroma-rich subtypes, extra-adrenal sympathetic paraganglioma, and pheochromocytoma were examined for the presence of the developmentally characterized gene products NSE, S-100, CD44, Bcl-2, HNK-1, PNMT, TrkA, IGF2, and tyrosine hydroxylase. The marker gene expression profiles of these tumors were compared with those similarly determined for a number of normal prenatal and postnatal human SNS cell types. Sympathetic paraganglioma, pheochromocytoma, and stroma-rich NB display marker expression profiles mimicking those of childhood sympathetic paraganglia, adrenal chromaffin cells, and sympathetic neurons, respectively. A selection of differentiating, extra-adrenal NB tumors with prognostically favorable features possess marker gene expression profiles paralleling that observed for fetal extra-adrenal sympathetic paraganglia/small intensely fluorescent cells. In contrast, undifferentiated, clinically aggressive NB tumors manifest characteristics mirroring that of embryonic/early fetal sympathetic neuroblasts of sympathetic ganglia and of the adrenal gland. These findings suggest that clinical features, such as primary tumor location and age at diagnosis, provide prognostic information for NB patients by virtue of the existence and biology of the presumed tumor progenitor cell type.

Adrenal Gland Neoplasms↗

PubMed1997

Diet and the risk of papillary and follicular thyroid carcinoma: a population-based case-control study in Sweden and Norway.

A population-based case-control study was conducted in two regions of Sweden and Norway to investigate the association between dietary habits and the risk of thyroid cancer. The consumption of selected foods was reported in a self-completed food-frequency questionnaire by 246 cases with histologically confirmed papillary (n = 209) and follicular (n = 37) thyroid carcinoma, and 440 age- and gender-matched controls. Odds ratios (OR) and their 95 percent confidence interval (CI) were calculated as estimates of the relative risk using conditional logistic regression. High consumption of butter (OR = 1.6, CI = 1.1-2.5) and cheese (OR = 1.5, CI = 1.0-2.4) was associated with increased risks. Residence in areas of endemic goiter in Sweden was associated with an elevated risk, especially among women (OR = 2.5, CI = 1.3-4.9). High consumption of cruciferous vegetables was associated with increased risk only in persons who ever lived in such areas. A decreased risk was associated with consumption of iodized salt in northern Norway, and with use of iodized salt during adolescence among women (OR = 0.6, CI = 0.6-1.0). The results of this study suggest a role of diet and environment in the risk of thyroid cancer.

Adolescent↗

PubMed1997

Effects of adrenalectomy on serotonin-, somatostatin-, and gastrin-immunoreactive cells in rat gastrointestinal tract.

The effects of bilateral adrenalectomy on the serotonin-, somatostatin-, and gastrin-immunoreactive cells in the rat gastrointestinal tract were studied four weeks after surgery. Body weight was reduced and the small intestine shorter in adrenalectomized animals compared with controls, while no changes were found in the histology of the mucosa. In the adrenalectomized animals the number of serotonin-immunoreactive cells was increased in the cecum and large intestine, while the somatostatin-immunoreactive cells were decreased in number in the antrum and increased in the corpus, cecum, and large intestine. The gastrin-immunoreactive cells in the antrum were not affected in number, but their nuclear size was enlarged, possibly indicating increased cellular activity.

Adrenal Glands↗

PubMed1997

Parental cancer and risk of papillary and follicular thyroid carcinoma.

In a population-based case-control study in the Uppsala-Orebro Health Care Region of Sweden, the histories of cancer among parents of 517 histologically confirmed cases of papillary and follicular carcinoma and of a similar number of sex- and age-matched controls were compared. The parental history of cancer was compiled through information from death certificates and from the nationwide Cancer Register. The incidence of malignancies in a cohort of parents of cases of thyroid cancer was also compared with the incidence in the whole Swedish population. A maternal history of cancer was more common among women with follicular carcinoma than among their controls (OR 2.11, 95% CI 0.96-4.67). Parents of probands with papillary carcinoma had an increased risk of thyroid cancer (OR 4.25, 95% CI 1.16-10.89), and mothers of probands with follicular carcinoma had an increased risk of stomach cancer (OR 3.65, 95% CI 0.99-9.35) compared with the general population. Cancer of the lung, breast, and pancreas were less common than in the general population. Familial cases of thyroid cancer were not limited to the papillary type. An inheritable pattern of carcinogenesis is possible for certain differentiated non-medullary thyroid cancers, but shared environmental exposures may also explain the parent-child associations of cancer in this study.

Adenocarcinoma, Follicular↗

PubMed1997

Colonic endocrine cells in inflammatory bowel disease.

OBJECTIVES: To study colonic endocrine cell types in patients with ulcerative colitis (UC) and Crohn's disease (CD). SETTING: Departments of Medicine and Pathology, University Hospitals, Umeå and Uppsala, Sweden. SUBJECTS: Seventeen patients with UC (seven females and 10 males) and 11 patients with CD (five females and six males). Twenty-two patients (eight females and 14 males) operated on for colon carcinoma and without signs of inflammatory bowel disease were used as controls. MEASUREMENTS: The colonic endocrine cell types were identified by immunohistochemical methods and quantified by computed image analysis. RESULTS: The areas of the argyrophil cells as well as those immunoreactive to chromogranin A and serotonin were significantly increased in patients with both UC and CD, compared with those in the controls. In patients with CD, the areas of polypeptide YY(PYY)- and pancreatic polypeptide (PP)-immunoreactive cells were significantly reduced, whilst the area of enteroglucagon-immunoreactive cells was increased. There was no statistical difference in endocrine cell area between specimens with slight versus severe inflammation, except for PYY and enteroglucagon cell areas in patients with CD. Whilst the former cell area decreased, the latter increased in specimens with severe inflammation. The mean cellular area for each endocrine cell type did not differ between the controls and patients with UC or CD. CONCLUSIONS: The increase in the serotonin-immunoreactive cell area in patients with both UC and CD might be one of the factors causing reduced colonic contraction and increased intraluminal pressure observed in patients with inflammatory bowel disease. Furthermore, in patients with CD, the decreased PYY-immunoreactive cell area may explain the decreased absorption and increased secretion found in these patients.

Adolescent↗

PubMed1997

Effect of hypophysectomy on endocrine cell types in rat gastrointestinal mucosa.

The effect of hypophysectomy on the gastrointestinal tract was studied in the rat 8 wk after operation, particularly regarding the frequency and distribution of serotonin, somatostatin and gastrin-immunoreactive cells. Body weight, the length of the intestine and the thickness of the mucosa of the antrum and small intestine were all reduced in the hypophysectomised rats compared with sham-operated and untreated controls. In the hypophysectomised animals the serotonin-immunoreactive cells were fewer in the antrum and caecum, whereas they were more numerous in the proximal large intestine. There were fewer gastrin-immunoreactive cells in the antrum, while the somatostatin-immunoreactive cells were more numerous in the antrum and caecum. The significant influence of hypophysectomy on the gastrointestinal tract could be direct, but could also be associated with the marked effect of pituitary deficiency on endocrine cells, known to exert both trophic and antitrophic actions. However, it could also be an indirect effect on metabolism, resulting in lower food intake, other endocrine cell systems, and growth factors.

Animals↗

PubMed1997

Apoptosis and growth factors in parathyroid adenomas.

Detection of apoptotic cells and of immunoreactivity to transforming growth factor alpha (TGF-alpha) and to its ligand, epidermal growth factor receptor (EGFR), was studied in 20 cases of parathyroid adenoma. The DNA nick-end labelling method revealed that 85% of these adenomas contained apoptotic cells. Detection rates of TGF-alpha and EGFR were very high, but neither TGF-alpha nor EGFR was correlated to apoptosis. As TGF-alpha exerts its effect via EGFR, the concomitant demonstration of the two factors occurring in both the adenomatous tissue and the surrounding rim of normal tissue may reflect a significant mutual association. The markers were located mainly within the cytoplasm, indicating their important role in growth regulation, cell differentiation and cell function. The synchronous expression of TGF-alpha and EGFR in both parathyroid adenomas and normal glandular parenchyma suggests that these functions may be mediated by an autocrine mechanism.

Adenoma↗

PubMed1997

Complex co-localization of chromogranins and neurohormones in the human gastrointestinal tract.

Co-localization of chromogranin (Cg) A, B, and C has been studied in different neuroendocrine cell types in histologically normal mucosa from human gastrointestinal tract (corpus, antrum, duodenum, ileum, and colon) using single-, double-, and triple-immunofluorescence stainings. Virtually all enterochromaffin (EC) cells contained CgA, and those in the luminal two thirds of the antral mucosa and villi of small intestine often also contained CgB. A few EC cells in the duodenal crypts contained CgC. Most gastrin cells harbored both CgB and CgA, although rather more CgB than CgA, but some gastrin cells contained all three types, i.e., also CgC. Some CCK cells also contained all three chromogranins. Enteroglucagon cells in the duodenal villi contained CgA and some CgB. CgA (but not B or C) was found in some secretin, GIP, enteroglucagon/peptide YY, and neurotensin cells. A few somatostatin cells contained CgA but neither CgB nor CgC. CgA and C were found mainly in the basal cell region, whereas CgB occurred more diffusely throughout the cytoplasm. This varying distribution suggests that not all secretory granules contain CgA, or that CgB may occur in a nongranular form. The varying composition of the different chromogranins may reflect their complex functional roles in the widespread neuroendocrine system.

Cholecystokinin↗

PubMed1997

Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism.

Secretion of PTH is regulated by extracellular calcium via calcium receptors (CaR) on the parathyroid cell surface. Recent studies have shown a decreased expression of CaR messenger RNA (mRNA) and CaR protein in pathological parathyroids. We studied the expression of CaR mRNA in pairs of adenoma and adenoma-associated normal gland from the same patients (n = 17) and in biopsies of normal parathyroid glands of normocalcemic subjects (n = 4) using in situ hybridization with oligonucleotide probes on frozen sections. No down-regulation of CaR mRNA caused by hypercalcemia could be demonstrated in the normal adenoma-associated parathyroids when compared with the normal parathyroids of normocalcemic subjects. In contrast, CaR mRNA in the adenomas was significantly reduced to 64% (median; range 41-98) of the corresponding normal adenoma-associated glands. No correlation was seen between CaR mRNA in the adenoma and preoperative serum calcium, PTH, or weight of the adenoma. Loss of heterozygosity studies were performed on adenomas using markers for the locus of the CaR gene on chromosome 3q. No allelic loss was demonstrated, excluding allelic loss as the cause for decreased CaR mRNA expression in the adenomas. It is concluded that the lowered levels of CaR mRNA in parathyroid adenomas may contribute to the increased set point of PTH secretion. In large adenomas the increased cell mass seems to be more important for the increased secretion of PTH.

Adenoma↗

PubMed1997

Expression of islet amyloid polypeptide in fetal and adult porcine and human pancreatic islet cells.

The synthesis and intracellular localization of the putative hormone islet amyloid polypeptide (IAPP) and its relation to insulin and glucagon during ontogenesis was investigated in fetal and adult porcine and human pancreatic islets. By means of ultrastructural immunogold immunocytochemistry, it was revealed that IAPP is produced by the hormonally pluripotent endocrine stem cells from the earliest time point studied. IAPP was colocalized with insulin and glucagon in the immature and nondifferentiated cell granules in both species. In adult man, highly intense IAPP immunoreactivity was found in beta-cell granules and, at lower intensity, in delta-cell granules. Some alpha-cells also contained a small amount of IAPP in their granules, and among these occasional granules displayed an intense immunoreactivity. In adult pig, IAPP was stored in quantity in beta-cell granules and in small amounts in granules of alpha- and delta-cells. It was difficult to determine the presence of IAPP in pancreatic polypeptide cells, because they were so seldom seen in this material. It is concluded that, in both man and pig, fetal pancreatic islet stem cells synthesize and store IAPP together with insulin and glucagon. The storage in different types of cells and granules was not as predictable as that of the classical islet hormones. The substance is more widely distributed within the pancreatic islet cell types than are any of the other islet hormones, which presumably has functional implications.

Adult↗

PubMed1996

Decreased growth rate and tumour formation of human anaplastic thyroid carcinoma cells transfected with a human thyrotropin receptor cDNA in NMRI nude mice treated with propylthiouracil.

The effect of the human TSH-receptor (TSHR) on the growth of human anaplastic thyroid carcinoma cells lacking the endogenous expression of TSHR, was studied both in vitro and in vivo in NMRI nude mice. Cells from a human anaplastic thyroid carcinoma cell line (C643) were transfected with a TSHR cDNA, and clones were isolated after neomycin selection. The expression of a functional receptor protein was ensured by analysis of the specific binding of 125I-TSH and measurement of TSH-induced cAMP. Incorporation of [3H]thymidine and increase in cell number was slightly inhibited by TSH in TSHR-expressing cells in vitro. In order to investigate whether the regained expression of a functional TSHR protein in C643 cells could influence the in vivo growth, cells were injected subcutaneously into NMRI nude mice. To manipulate the endogenous level of TSH, animals were given 6n-propyl-2-thiouracil (PTU; resulting in a high TSH level), T4 (a low TSH level) or no treatment (as a control). There seemed to be a TSH induced inhibition of tumour growth, since tumours in mice treated with PTU grew after a longer take rate and with a slower growth rate. The present results suggest a TSH-mediated growth inhibition in the TSHR-transfected C 643 anaplastic thyroid carcinoma cells.

Animals↗

PubMed1996

X-ray microanalysis of elemental changes in human parathyroid glands in primary and secondary hyperparathyroidism.

The elemental composition of chief cells of parathyroid glands from patients with adenomatous primary hyperparathyroidism (HPT) and uremic secondary HPT was studied by X-ray microanalysis. Glands histologically deemed normal were used as controls. The analyses were also carried out on tissue specimens incubated in hypo-, normo- and hypercalcemic media (0.5, 1.25, and 3.0 mM calcium concentration). Analysis of chief cells from normal glands did not reveal any significant differences in ionic composition after exposure to the different calcium concentrations. In chief cells from adenomatous and uremic hyperplastic glands, elemental changes were noted. In comparison with specimens incubated in 1.25 mM calcium medium, cells in 0.5 mM calcium medium had a lower content of potassium and phosphorus. After stimulation with increasing extracellular concentration, an increase in the K/Na ratio was observed, due to a marked decrease of sodium and an increase of potassium; the calcium concentration was almost unchanged. Our findings indicate that in HPT an increase in serum calcium concentration might exert a stimulatory effect on the Na/K pump (sodium pump) and on the calcium-activated potassium channels. Either of these mechanisms might contribute to a lowering of cytoplasmic calcium. Our observations suggest that changes in ionic content of the parathyroid cells may be of importance for the stimulus secretion process in the cells.

Adult↗