Summary Background Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma–paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma–paraganglioma syndrome is often unrecognised, although 10–30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma–paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. Methods Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. Findings SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel–Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87–100) and 84% (60–97), respectively. Interpretation Phaeochromocytoma–paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma–paraganglioma syndrome.

Various pathologic conditions, such as hemorrhage, hemolysis and cell injury, are characterized by the release of large amounts of heme. Recently, it was demonstrated that heme oxygenase (HO), the heme-degrading enzyme, and heme are able to modulate adhesion molecule expression in vitro. In the present study, the effects of heme and HO on inflammation in mice were analyzed by monitoring the biodistribution of radiolabeled liposomes and leukocytes in conjunction with immunohistochemistry. Small liposomes accumulate in inflamed tissues by diffusion because of locally enhanced vascular permeability, whereas leukocytes actively migrate into inflammatory areas through specific adhesive interactions with the endothelium and chemotaxis. Exposure to heme resulted in a dramatic increase in liposome accumulation in the pancreas, but also intestines, liver, and spleen exhibited significantly increased vascular permeability. Similarly, intravenously administered heme caused an enhanced influx of radiolabeled leukocytes into these organs. Immunohistochemical analysis showed differential up-regulation of the adhesion molecules ICAM-1, P-selectin, and fibronectin in liver and pancreas in heme-treated animals. Heme-induced adhesive properties were accompanied by a massive influx of granulocytes into these inflamed tissues, suggesting an important contribution to the pathogenesis of inflammatory processes. Moreover, inhibition of HO activity exacerbated hemeinduced granulocyte infiltration. Here it is demonstrated for the first time that heme induces increased vascular permeability, adhesion molecule expression, and leukocyte recruitment in vivo, whereas HO antagonizes heme-induced inflammation possibly through the down-modulation of adhesion molecules. IntroductionThe inflammatory response consists of a complex cascade of orchestrated signals resulting in increased permeability of blood vessels, changes in blood flow, and migration of leukocytes from blood to affected tissues. 1 Vascular permeability results from the partial retraction of endothelial cells of small venules in the vicinity of inflammation, leaving small intercellular gaps (approximately 0.1-0.4 m). This so-called vascular leakage results in slower blood flow by allowing the passage of water, salts, and small proteins from the plasma into the damaged area, whereas blood cells are retained within the vessels. 1 In normal circumstances the endothelial layer is nonadhesive for leukocytes. However, during inflammation, activated endothelial cells increase the surface expression of specific adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), endothelial leukocyte adhesion molecule (E-selectin), and P-selectin. 2 This increased cell surface adhesion enables circulating activated leukocytes to specifically interact with their ligands on the endothelium. 2 Although the inflammatory response of the host is considered essential in the protection against pathogens, activated leukocytes and endothelial cells ma...

The coexistence of galanin (GAL)-like immunoreactivity (LI) with markers for catecholamines, 5-hydroxytryptamine (5-HT), GABA, or some neuropeptides was mapped in the rat CNS by using adjacent sections, as well as by elution-restaining and double-labeling immunocytochemistry. Many instances of coexistence were observed, but there were also numerous GAL-positive cell body populations displaying distributions similar to those of these markers but without apparent coexistence. In the hypothalamic arcuate nucleus GAL-LI was found in a large proportion of tyrosine hydroxylase (TH)-positive cell bodies (A12 cells), both in the dorsomedial and ventrolateral subdivisions, with a higher number in the latter. GAL-LI coexisted in glutamic acid decarboxylase (GAD)-positive somata in the posterior aspects of the arcuate nucleus and at all rostrocaudal levels in fibers in the external layer of the median eminence. In the anterior hypothalamus, a large population of the cells of the parvocellular and magnocellular paraventricular nuclei contained both GAL-LI and vasopressin-LI. Moreover, somata containing both GAD- and GAL-LI were seen lateral to the mammillary recess in the tuberal and caudal magnocellular nuclei. Some of the neurons of the caudal group were shown to project to the occipital cortex using combined retrograde tracing and immunofluorescence. With regard to mesencephalic and medullary catecholamine neurons, GAL-LI coexisted in a large proportion of the noradrenergic locus coeruleus somata (A6 cell group) and in the A4 group dorsolateral to the fourth ventricle, as well as in the caudal parts of the A2 group in the dorsal vagal complex. However, in more rostral parts of the latter, especially in the medial subdivision of the solitary tract nucleus, a very large population of GAL-IR small cell bodies was seen intermingling with catecholamine neurons, but they did not contain TH-LI. Furthermore, GAL-IR cell bodies coextensive with, but not coexisting in, TH-IR somata were seen in the C1 (epinephrine) horea in the ventrolateral medulla at the level of area postrema and in the most rostral aspects of the C1 group. Finally, 5-HT-positive cell bodies of the mesencephalic and medullary raphe nuclei and a subpopulation of coarse 5-HT nerve fibers in the hippocampus co-contained GAL-LI. The present results demonstrate that a GAL-like peptide is present in many systems containing other neuroactive compounds, including dopamine, norepinephrine, 5-HT, GABA, and vasopressin.(ABSTRACT TRUNCATED AT 400 WORDS)

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