Phaeochromocytoma in multiple endocrine neoplasia type 2: RET codon-specific penetrance and changes in management during the last four decades.

OBJECTIVES: We describe phaeochromocytoma (phaeo) penetrance in multiple endocrine neoplasia type 2 (MEN2) according to RET protooncogene-specific mutations and report changes in phaeo diagnosis and management from 1968 to 2015. DESIGN: This retrospective chart review included 309 MEN2 patients from one specialized ambulatory care centre. Phaeo patients were categorized by diagnosis date: early, 1968-1996, n=40, and recent, 1997-2015, n=45. RESULTS: Phaeochromocytoma was diagnosed in 85/309 patients with RET mutations in the following exons (phaeos/all carriers, %): exon 11 (56/120, 46.6%); exon 16 (7/17, 41.2%), exon 10 (14/47, 29.8%), and exon 13-15 (2/116, 1.7%). Age at phaeo diagnosis differed according to affected exon: 21.9±1.5 years, exon 16; 34.1±11.6 years, exon 11; and 41.8±8.8 years, exon 10. Age-related phaeo penetrance differed among five amino acid substitutions at codon 634 and was highest for Cys634Arg and Cys634Tyr. Age at diagnosis was 34.4±11.6 years in the early and recent groups. Phaeochromocytoma and medullary thyroid carcinoma (MTC) were diagnosed synchronously in 21/40 (early) vs 8/45 (recent) and metachronously in 19/40 vs 37/45 cases. Diagnostic methods significantly changed from clinical (22/40 vs 4/45) to biochemical and/or imaging based (14/40 vs 35/45). Phaeochromocytoma diameter at diagnosis was 4.6 vs 2.6 cm. CONCLUSION: Phaeochromocytoma penetrance and age of diagnosis are highly correlated with MTC aggressiveness based on RET mutation status, with higher penetrance and younger age of diagnosis associated with more aggressive MTC. Penetrance steadily increases with age. At-risk patients require lifelong follow-up.

Long-Term Follow-Up and Treatment of Postoperative Permanent Hypoparathyroidism in Patients with Medullary Thyroid Carcinoma: Differences in Complete and Partial Disease.

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or >10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p<0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0-2.3 mmol/l) in 63% of visits, decreased (<2.0 mmol/l) in 20.4%, high-normal (2.4-2.6 mmol/l) in 15.8%, and increased (>2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 µg/day and 0.47±0.20 µg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=-0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification.

[Endocrine tumors: clinical overview]. / Endokrine Tumoren : Klinische Übersicht.

The term endocrine tumor incorporates all neoplasms which originate from the various endocrine organs. Endocrine tumors can be characterized by different criteria: localization, endocrine function, dignity (i.e. tumorigenesis, sporadic or hereditary). These characteristics also determine the clinical outcome. The clinical history, symptoms and physical examination findings (e.g. amenorrhea, skin alterations, striae, virilization, increased blood pressure and flush) direct the diagnostic process of functioning endocrine tumors. Laboratory findings (endocrine parameters) are needed to establish a diagnosis supplemented by imaging for localization and special investigations (ophthalmological examination). In hereditary tumor syndromes, the familial history and molecular genetic testing and screening of family members are essential for establishing the diagnosis and achieve optimal and early treatment. Ideally, affected family members can be treated before clinical symptoms or metastatic disease occurs, improving outcome and prognosis. Incidentalomas are increasingly found due to widespread use of imaging techniques, especially in the thyroid, adrenal glands, pancreas and pituitary gland. In incidentalomas the functional status and risk of malignancy has to be evaluated as both parameters determine therapy decisions. The aim of this introductory article is to give an overview about particular features of endocrine tumors, clinical and related aspects for the diagnostic and therapeutic approach. The clinical features of tumors of the pituitary, parathyroid and adrenal glands and the gastroenteropancreatic system are summarized according to localization.

Perineuronal and perisynaptic extracellular matrix in the human spinal cord.

Extracellular matrix (ECM) forms an active interface around neurons of the central nervous system (CNS). Whilst the components, chemical heterogeneity and cellular recruitment of this intercellular assembly in various parts of the brain have been discussed in detail, the spinal cord received limited attention in this context. This is in sharp contrast to its clinical relevance since the overall role of ECM especially that of its chondroitin sulphate-based proteoglycan components (CSPGs) was repeatedly addressed in neuropathology, regeneration, CNS repair and therapy models. Based on two post-mortem human specimen, this study gives the first and detailed description of major ECM components of the human spinal cord. Immunohistochemical investigations were restricted to the systematic mapping of aggrecan, brevican, proteoglycan link-protein as well as tenascin-R and hyaluronan containing matrices in the whole cranio-caudal dimension of the human spinal cord. Other proteoglycans like versican, neurocan and NG2 were exemplarily investigated in restricted areas. We show the overall presence of tenascin-R and hyaluronan in both white and grey matters whereas aggrecan, proteoglycan link-protein and brevican were restricted to the grey matter. In the grey matter, the ECM formed aggrecan-based perineuronal nets in the ventral and lateral horns but established single perisynaptic assemblies, axonal coats (ACs), containing link-protein and brevican in all regions except of the Lissauer's zone. Intersegmental differences were reflected in the appearance of segment-specific nuclei but not in overall matrix distribution pattern or chemical heterogeneity. Perineuronal nets were typically associated with long-range projection neurons including cholinergic ventral horn motorneurons or dorsal spinocerebellar tract neurons of the Clarke-Stilling nuclei. Multiple immunolabelling revealed that nociceptive afferents were devoid of individual matrix assemblies unlike glycinergic or GABAergic synapses. The detailed description of ECM distribution in the human spinal cord shall support clinical approaches in injury and regenerative therapy.

Unique features of extracellular matrix in the mouse medial nucleus of trapezoid body--implications for physiological functions.

The medial nucleus of the trapezoid body (MNTB) is a vital structure of sound localization circuits in the auditory brainstem. Each principal cell of MNTB is contacted by a very large presynaptic glutamatergic terminal, the calyx of Held. The MNTB principal cells themselves are surrounded by extracellular matrix components forming prominent perineuronal nets (PNs). Throughout the CNS, PNs, which form lattice-like structures around the somata and proximal dendrites, are associated with distinct types of neurons. PNs are highly enriched in hyaluronan and chondroitin sulfate proteoglycans therefore providing a charged surface structure surrounding the cell body and proximal neurites of these neurons. The localization and composition of PNs have lead investigators to a number of hypotheses about their functions including: creating a specific extracellular ionic milieu around these neurons, stabilizing synapses, and influencing the outgrowth of axons. However, presently the precise functions of PNs are still quite unclear primarily due to the lack of an ideal experimental model system that is highly enriched in PNs and in which the synaptic transmission properties can be precisely measured. The MNTB principal cells could offer such a model, since they have been extensively characterized electrophysiologically. However, extracellular matrix (ECM) in these neurons has not yet been precisely detailed. The present study gives a detailed examination of the ECM organization and structural differences in PNs of the mouse MNTB. The different PN components and their distribution pattern are scrutinized throughout the MNTB. The data are complemented by electron microscopic investigations of the unique ultrastructural localization of PN-components and their interrelation with distinct pre- and postsynaptic MNTB cell structures. Therefore, we believe this work identifies the MNTB as an ideal system for studying PN function.

Aggrecan: Beyond cartilage and into the brain.

Aggrecan is well-studied in cartilage but its expression and function in the central nervous system has only recently begun to be appreciated. Aggrecan plays an important role in the organization of the neural extracellular space by binding and organizing hyaluronan to the cell surface through interactions with link protein and tenascins forming a large aggregated quaternary complex. While all members of the lectican family to which aggrecan belongs are thought to mediate similar roles in organizing the neural matrix, aggrecan is unique in that it is the only family member found almost exclusively in an enigmatic matrix substructure called the perineuronal net. Current work has established a critical role for perineuronal nets and aggrecan in regulating developmental neural plasticity and in the recover from injury. In this review we focus on the structure, expression and function of aggrecan in the central nervous system.

[Secondary osteoporosis - relevant clinical characteristics in diagnosis and therapy]. / Sekundäre Osteoporose - praxisrelevante Besonderheiten bei der Diagnostik und Therapie.

Osteoporosis is a systemic skeletal disease causing increased fracture risk. According to pathogenesis, primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) are distinguished. Secondary osteoporosis comprises all entities in which osteoporosis is predominantly and causally associated with certain diseases or conditions. The aim of this review article is to put attention to special features in diagnosis, prophylaxis and treatment of secondary osteoporosis in general and to demonstrate some forms of secondary osteoporosis which seem particularly important during clinical practice. The manuscript refers to the guidelines of the DVO 2009 for prevention, diagnosis and therapy of osteoporosis and selective original papers considering the special types of secondary osteoporosis. History, clinical examination and basic laboratory tests are indicative for the diagnosis of secondary osteoporosis. Its clinical presentation is frequently characterized by rapid development and multiple fractures. Therefore, early diagnosis, prophylaxis and causal treatment is decisive. If causal treatment is impossible, risk adaption of bone mineral density (BMD) for osteoporosis specific treatment is essential. Common causes are medications, endocrine, gastrointestinal and hematologic diseases. Glucocorticoid induced osteoporosis, antihormonal therapy (aromatase inhibitor in women with breast cancer, androgen deprivation therapy in men with prostate cancer) and vitamin D deficiency causing secondary hyperparathyroidism are presented in detail. History and basic laboratory testing are decisive to identify possible causes for secondary osteoporosis and to initiate early diagnostic procedures. The risk of severe osteoporosis can be reduced by early and causal treatment or by risk stratified early bone specific medication if causal therapy is impossible.

Perisynaptic aggrecan-based extracellular matrix coats in the human lateral geniculate body devoid of perineuronal nets.

The extracellular matrix surrounds different neuronal compartments in the mature nervous system. In a variety of vertebrates, most brain regions are loaded with a distinct type of extracellular matrix around the somatodendritic part of neurons, termed perineuronal nets. The present study reports that chondrotin sulfate proteoglycan-based matrix is structured differently in the human lateral geniculate body. Using various chondrotin sulfate proteoglycan-based extracellular matrix antibodies, we show that perisomatic matrix labeling is rather weak or absent, whereas dendrites are contacted by axonal coats appearing as small, oval structures. Confocal laser scanning microscopy and electron microscopy demonstrated that these typical structures are associated with synaptic loci on dendrites. Using multiple labelings, we show that different chondrotin sulfate proteoglycan components of the extracellular matrix do not associate exclusively with neuronal structures but possibly associate with glial structures as well. Finally, we confirm and extend previous findings in primates that intensity differences of various extracellular matrix markers between magno- and parvocellular layers reflect functional segregation between these layers in the human lateral geniculate body.

Veterinary service missions and good governance.

The rationale for the existence of official Veterinary Services (VS) has seldom been under such intensive public scrutiny as over the past two decades when the world has been confronted with outbreaks of major animal diseases that have posed a potential threat not only to human health but also to animal health and national food security. The mere existence of VS is not enough. The mission statement of the VS can no longer be cast in stone but needs to adapt and be amended continually to cope with new demands. The ability to ensure not only acceptance but also sustainability of the delivery of VS as a global public good, thereby demonstrating good governance, is becoming and will remain a challenge in terms of keeping it a non-rivalrous and non-excludable service to a demanding public clientele. Mission statements to improve the health and welfare of animals will, however, remain no more than noble normative statements of intent if further refinement on how this should be done and governed is not encompassed in the strategic plans, vision and goals of the Veterinary Authority. They will also remain but noble statements if cognisance is not taken of the increased sensitivity, nationally and internationally, around animal welfare issues during transport, movement, housing, treatment and slaughter of animals and if this sensitivity is not reflected or addressed in national animal health and veterinary public health legislation. The author describes some of the ways in which currently accepted critical functions of the VS need to change to demonstrate good governance and respond to the challenges of new or amended missions in order to meet the demands of an ever-changing VS environment.

[Hereditary variants of primary hyperparathyroidism--MEN1, MEN2, HPT-JT, FHH, FIHPT]. / Hereditäre Formen des primären Hyperparathyreoidismus. MEN1, MEN2, HPT-JT, FHH, FIHPT.

OBJECTIVE: The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS: 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS: 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION: Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Managing the risks of disease transmission through trade: a commodities-based approach?

Since its founding in 1924, the World Organisation for Animal Health (OIE) has facilitated safe trade in animals and animal products by developing effective standards to prevent the spread of animal diseases across the globe. A protocol for recognising the disease-free status of countries is an integral part of this process and has been adopted and advanced through the years to assist OIE Member Countries in placing disease-free animals and their products on the international market. Options such as trade from disease-free zones and disease-free compartments are now available to Members and have proven to be a positive mechanism for facilitating trade. A further option is trading in safe commodities, i.e. animals and animal products that have been identified as safe to trade even in the presence of disease, either with or without applying risk mitigation measures before export. Although most Members have incorporated the acceptance of disease-free countries or zones into their animal health policies and sanitary measures, there still appears to be a reluctance to trade in commodities from infected countries, despite clear, scientifically based risk management standards that can be applied if needed. This paper offers some examples reflecting the apparent reluctance to trade in commodities and discusses how the standards in the OIE's Terrestrial Animal Health Code could be used to apply scientifically based risk management practices to review outdated policies.

Ensuring safe international trade: how are the roles and responsibilities evolving and what will the situation be in ten years' time?

The roles of the international standard-setting bodies that are mandated to facilitate safe trade, such as the World Organisation for Animal Health (OIE), the Codex Alimentarius Commission, the International Plant Protection Convention and the World Trade Organization, are well documented, as are the roles of the international organisations responsible for global health issues: the OIE, the World Health Organization and the Food and Agriculture Organization of the United Nations. However, developments in international trade, such as accelerating globalisation and the frequent emergence and re-emergence of diseases affecting both humans and animals, have brought new challenges and the need to reconsider the future roles of such organisations. New participants and new demands have also emerged to challenge these mandates, leading to potential areas of conflict. The need for countries to establish themselves as new trade partners, or to strengthen their positions while still maintaining safe trade, poses a challenge to standard-setting organisations, which must meet these demands while still remaining sensitive to the needs of developing countries. In this paper, the author describes and discusses some of these challenges and suggests how international organisations could evolve to confront such issues.

Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels--an observational study during clinical practice conditions.

UNLABELLED: Vitamin D deficiency is associated with increased fracture risk. The observational study aimed to investigate vitamin D status and supplementation in ambulatory patients. Only 20% of patients had optimal serum 25-hydroxyvitamin D [25(OH)D] levels. Commonly recommended dosages were insufficient to achieve clinically relevant increase of 25(OH)D levels. Higher dosages were safe and effective under clinical practice conditions. INTRODUCTION: Vitamin D deficiency is associated with adverse health outcome. The study aimed to investigate vitamin D status and supplementation in ambulatory patients. METHODS: Nine hundred seventy-five women and 188 men were evaluated for bone status from January 2008 to August 2008 within an observational study; 104 patients (n = 70 osteoporosis) received follow-up after 3 months. Dosage of vitamin D supplementation was documented and serum 25(OH)D and parathyroid hormone (PTH) determined. RESULTS: In all patients (age, 60.4 ± 14.1 years), distribution of 25(OH)D was 56.3 ± 22.3 nmol/L (normal range, 52-182 nmol/L) and PTH 53.8 ± 67.5 ng/L (normal range, 11-43 ng/L). The proportion of patients with 25(OH)D < 25, 25 to <50, 50 to <75, ≥75 nmol/L was 7.5%, 33.3%, 38.9% and 20.2% in the total group and 20.1%, 38.5%, 30.8%, 10.6% at baseline in the follow-up group, respectively. After 3 months, 3.9% had still 25(OH)D < 25 nmol/L; only 12.5% achieved 25(OH)D ≥ 75 nmol/L. In osteoporosis patients, 25(OH)D increased more in those taking ≥1,500 (median, 3,000) IU vitamin D per day (33.1 ± 14.7 nmol/L) compared with ≤1,000 (median, 800) IU/day (10.6 ± 20.0 nmol/L) (p < 0.0008). PTH decreased more in patients taking ≥1,500 IU/day (-13.2 ± 15.2 ng/L) compared with ≤1,000 IU/day (-7.6 ± 19.2 ng/L; p = 0.29). 25(OH)D was negatively correlated to PTH (r = -0.49, p < 0.0001). An increase of 25(OH)D ≥ 75 nmol/L resulted in normalised PTH. CONCLUSION: Supplementation with higher vitamin D dosages (2,000-3,000 IU/day) is required to achieve a relevant increase of 25(OH)D and normalisation of PTH.

Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer's disease.

The biological basis for the selective vulnerability of neurons in Alzheimer's disease (AD) is elusive. Aggrecan-based perineuronal nets (PNs) of the extracellular matrix have been considered to contribute to neuroprotection in the cerebral cortex. In the present study, we investigated the organization of the aggrecan-based extracellular matrix in subcortical regions known to be preferentially affected by tau pathology in AD. Immunocytochemistry of aggrecan core protein was combined with detection of neurofibrillary degeneration. The results show that many regions affected by tau pathology in AD, such as the basal nucleus of Meynert, the dorsal thalamus, hypothalamic nuclei, raphe nuclei, and the locus coeruleus were devoid of a characteristic aggrecan-based extracellular matrix. Regions composed of nuclei with clearly different intensity of tau pathology, such as the amygdala, the thalamus and the oculomotor complex, showed largely complementary distribution patterns of neurofibrillary tangles and PNs. Quantification in the rostral interstitial nucleus of the longitudinal fascicle potentially affected by tau pathology in AD revealed that tau pathology was not accompanied by loss of aggrecan-based PNs. Neuro-fibrillary tangles in net-associated neurons extremely rarely occurred in the pontine reticular formation. We conclude that the low vulnerability of neurons ensheathed by PNs previously described for cortical areas in AD represents a more general phenomenon that also applies to subcortical regions. The aggrecan-based extracellular matrix of PNs may thus, be involved in neuroprotection.

Aggrecan-based extracellular matrix shows unique cortical features and conserved subcortical principles of mammalian brain organization in the Madagascan lesser hedgehog tenrec (Echinops telfairi Martin, 1838).

The Madagascan tenrecs (Afrotheria), an ancient mammalian clade, are characterized by unique brain anatomy. Striking features are an expanded paleocortex but a small and poorly differentiated neocortex devoid of a distinct granular layer IV. To investigate the organization of cortical areas we analyzed extracellular matrix components in perineuronal nets (PNs) using antibodies to aggrecan, lectin staining and hyaluronan-binding protein. Selected subcortical regions were studied to correlate the cortical patterns with features in evolutionary conserved systems. In the neocortex, paleocortex and hippocampus PNs were associated with nonpyramidal neurons. Quantitative analysis in the cerebral cortex revealed area-specific proportions and laminar distribution patterns of neurons ensheathed by PNs. Cortical PNs showed divergent structural phenotypes. Diffuse PNs forming a cotton wool-like perisomatic rim were characteristic of the paleocortex. These PNs were associated with a dense pericellular plexus of calretinin-immunoreactive fibres. Clearly contoured PNs were devoid of a calretinin-positive plexus and predominated in the neocortex and hippocampus. The organization of the extracellular matrix in subcortical nuclei followed the widely distributed mammalian type. We conclude that molecular properties of the aggrecan-based extracellular matrix are conserved during evolution of mammals; however, the matrix scaffold is adapted to specific wiring patterns of cortical and subcortical neuronal networks.

New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour.

UNLABELLED: Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers. FAMILY 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed. FAMILY 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin. CONCLUSION: Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.

The role of the World Organisation for Animal Health (OIE) to facilitate the international trade in animals and animal products.

The international trade in animals and animal products has become a sensitive issue for both developed and developing countries by posing an important risk for the international spread of animal and human pathogens whilst at the same time being an essential activity to ensure world-wide food security and food safety. The OIE has since its founding in 1924, applied a democratic and transparent decision-making process to continuously develop and review international standards for animal health and zoonoses to facilitate trade in animals and animal products. The role of the OIE is also mandated by the World Trade Organization (WTO) as international reference point for standards related to animal health. In support of its overall objective of promoting animal health world-wide, the OIE has also launched several other initiatives such as the improvement of the governance of veterinary services within its member countries and territories and to enhance the availability of diagnostic and scientific expertise on a more even global geographical distribution. Several trade facilitating concepts such as country, zonal and compartment freedom from disease as well the trade in disease free commodities has been introduced to enhance the trade in animals and animal products for all its members including those from developing and transitional countries who are still in the process of enhancing to full compliance with international sanitary standards.

Aggrecan-based extracellular matrix is an integral part of the human basal ganglia circuit.

The extracellular matrix is known to be involved in neuronal communication and the regulation of plastic changes, and also considered to protect neurons and synapses against damage. The goal of this study was to investigate how major extracellular matrix components (aggrecan, link protein, hyaluronan) constitute the pathways of the nigral system in the human basal ganglia circuit affected by neurodegeneration in Parkinson's disease. Here we show that aggrecan- and link protein-related components form clear regional distribution patterns, whereas hyaluronan is widely distributed in gray and white matter. Two predominant phenotypes of the aggrecan-based matrix can be discriminated: (1) perineuronal nets (PNs) and (2) axonal coats (ACs) encapsulating preterminal fibers and synaptic boutons. Clearly contoured PNs are associated with GABAergic projection neurons in the external and internal division of the globus pallidus, the lateral and reticular part of the substantia nigra, as well as subpopulations of striatal and thalamic inhibitory interneurons. Dopaminergic nigral neurons are devoid of PNs but are contacted to a different extent by matrix-coated boutons forming subnucleus-specific patterns. A very dense network of ACs is characteristic especially of the posterior lateral cell groups of the compact substantia nigra (nigrosome 1). In the subthalamic nucleus and the lateral thalamic nuclei numerous AC-associated axons were attached to principal neurons devoid of PNs. We conclude from the region-specific patterns that the aggrecan-based extracellular matrix is adapted to the fast processing of sensorimotor activities which are the therapeutic target of surgery and deep brain stimulation in the treatment of advanced stages of Parkinson's disease.