Éva Csajbók

GABAergic Neurogliaform Cells Represent Local Sources of Insulin in the Cerebral Cortex

Concentrations of insulin in the brain are severalfold higher than blood plasma levels. Insulin in the brain regulates the metabolism, molecular composition, and cognitive performance of microcircuits and reduces food intake; cerebral insulin levels are altered in diabetes, aging, obesity, and Alzheimers disease. Released by pancreatic β cells, insulin passes the blood–brain barrier, but sources of locally released insulin still remain unclear. We find that insulin is strongly expressed in GABAergic neurogliaform cells in the cerebral cortex of the rat detected by single-cell digital PCR. Focal application of glucose or glibenclamide to neurogliaform cells mimics the excitation suppressing effect of external insulin on local microcircuits via insulin receptors. Thus, neurogliaform cells might link GABAergic and insulinergic action in cortical microcircuits.

Importance of Plasma Cells in the Infiltrate of Renal Allografts: An Immunohistochemical Study

The cellular infiltration in 42 needle and wedge biopsies of transplanted kidneys was investigated immunohistochemically. The percentages of helper/inducer (CD 4+) cells, suppressor/cytotoxic cells (CD 8+), B lymphocytes, macrophages, plasma cells (Pc) and granulocytes were determined. The proportions of the various inflammatory cell populations were established in acute interstitial rejection (AIR), acute vascular rejection (AVR), chronic rejection (CR) and cyclosporin A nephrotoxicity (CsAN). The most prominent differences were detected as regards the Pc, whose number was much higher in CR than in AIR, AVR or CsAN. The striking difference between CR and CsAN in the number of Pc may be of differential diagnostic importance: the presence of many Pc in the biopsies can be regarded as a sign of CR. Over 80% of the Pc in CR contained IgG, whereas in chronic interstitial nephritis (CIN) the IgA-positive Pc predominated. In AIR, AVR and CsAN, too, the majority of the Pc contained IgG, but the numbers of IgM and IgA-positive cells were also relatively high. The great number of IgG-positive Pc indicates an important role of a secondary type humoral immune response in CR.

Ulcerative colitis and primary sclerosing cholangitis as part of autoimmune polyglandular syndrome type III

To the Editor: Autoimmune polyglandular syndrome (APS) is an autoimmune disease affecting 2 or more endocrine organs; generally 4 types of APS are distinguished. APS type III as a subdivision of type II is characterized by autoimmune thyroid disease with other autoimmune disorders but without adrenal insufficiency.1 We report a case of a 37-year-old man initially diagnosed with ulcerative colitis (UC) who was found to have APS type III. In a 10-year period different clinical, laboratory, and radiological examinations revealed the presence of coexisting UC, primary sclerosing cholangitis (PSC), insulin-dependent diabetes mellitus (IDDM), Hashimoto’s thyroiditis, vitiligo, and rheumatoid arthritis (RA). The rare combination of these different, severe syndromes has not been reported before. Inflammatory bowel diseases are unusual as part of APS; however, celiac disease is the most commonly associated, immune-mediated enteral disease in APS type III.2 The presence of UC in any type of APS has not been documented before. The medical history of this 37year-old man started in 1994 when he was diagnosed with UC pancolitis accompanied by PSC involving both the extraand intrahepatic bile ducts. IDDM developed 2 years after the diagnosis of UC and PSC. After a long-lasting period with chronic mild activity, he had a flare-up of UC with 5–10 bloody stools daily in 2006. Control endocrine examinations performed in May 2007 revealed an elevated thyroid-stimulating hormone level of 199.5 mIU/L and an abnormal anti-thyroid peroxidase antibody level of 311.7 iu/mL, indicating Hashimoto’s thyroiditis. Therefore, Lthyroxin treatment was administered. In October 2007, because of the continuous endoscopic and clinical activity of UC despite the usual mesalazine and azathioprine treatment, cyclosporine was introduced but had to be discontinued because of the development of weakness and myalgia. In the same year, patchy vitiligo was observed affecting the whole body. In March 2008 the presence of a deforming polyarthritis involving both wrists, elbows, knees, and the small joints of the hands and feet was noted. The diagnosis of RA was established based on symmetric polyarthritis and the typical radiographic changes, including multiple juxta-articular erosions in the metacarpo-phalangeal, proximal interphalangeal, intercarpal, and radiocarpal joints and multiple ankyloses in the intercarpal joints (Fig. 1). IgM rheumatoid factor and antimutated citrullinated vimentin antibodies were negative; dehydroepiandrosterone sulfate, adrenocorticotropic hormone, and cortisol test were also within the normal range. Coexistence of UC, PSC, Hashimoto’s thyroiditis, IDDM, vitiligo, and RA indicated the diagnosis of APS type III. Gluten sensitive enteropathy was excluded by serological examinations and duodenal biopsy. Copyright

MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome.

OBJECTIVE: To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2. Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome. Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene. METHODS: Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals. Exons 10–16 of the rearranged during transfection proto-oncogene were analyzed by direct DNA sequencing, and all exons of the von Hippel-Lindau, succinate dehydrogenase B, and succinate dehydrogenase subunit D genes were tested by direct DNA sequencing and multiple ligation probe analysis. The G12S polymorphism of the succinate dehydrogenase subunit D gene was determined by restriction fragment length polymorphism. RESULTS: Of the 77 rearranged during transfection mutation carriers, 55 from 16 families had multiple endocrine neoplasia type 2A, three from three families had multiple endocrine neoplasia type 2B, and 19 from two families had familial medullary thyroid carcinoma. Eight of 55 (14.5%) patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, and sporadic pheochromocytoma groups, and its prevalence in controls was 1% (p<0.002 multiple endocrine neoplasia type 2A versus controls). No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed. CONCLUSION: The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established.

Increased short-term beat-to-beat variability of QT interval in patients with acromegaly

Cardiovascular diseases, including ventricular arrhythmias are responsible for increased mortality in patients with acromegaly. Acromegaly may cause repolarization abnormalities such as QT prolongation and impairment of repolarization reserve enhancing liability to arrhythmia. The aim of this study was to determine the short-term beat-to-beat QT variability in patients with acromegaly. Thirty acromegalic patients (23 women and 7 men, mean age±SD: 55.7±10.4 years) were compared with age- and sex-matched volunteers (mean age 51.3±7.6 years). Cardiac repolarization parameters including frequency corrected QT interval, PQ and QRS intervals, duration of terminal part of T waves (Tpeak-Tend) and short-term variability of QT interval were evaluated. All acromegalic patients and controls underwent transthoracic echocardiographic examination. Autonomic function was assessed by means of five standard cardiovascular reflex tests. Comparison of the two groups revealed no significant differences in the conventional ECG parameters of repolarization (QT: 401.1±30.6 ms vs 389.3±16.5 ms, corrected QT interval: 430.1±18.6 ms vs 425.6±17.3 ms, QT dispersion: 38.2±13.2 ms vs 36.6±10.2 ms; acromegaly vs control, respectively). However, short-term beat-to-beat QT variability was significantly increased in acromegalic patients (4.23±1.03 ms vs 3.02±0.80, P<0.0001). There were significant differences between the two groups in the echocardiographic dimensions (left ventricular end diastolic diameter: 52.6±5.4 mm vs 48.0±3.9 mm, left ventricular end systolic diameter: 32.3±5.2 mm vs 29.1±4.4 mm, interventricular septum: 11.1±2.2 mm vs 8.8±0.7 mm, posterior wall of left ventricle: 10.8±1.4 mm vs 8.9±0.7 mm, P<0.05, respectively). Short-term beat-to-beat QT variability was elevated in patients with acromegaly in spite of unchanged conventional parameters of ventricular repolarization. This enhanced temporal QT variability may be an early indicator of increased liability to arrhythmia.

Prognostic significance of aortic stiffness index in acromegaly-Results from a 4-year follow-up

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Physical Training-Induced Weight Reduction Is Associated With Improved Aortic Distensibility

To the editor We read with great interest paper of Miyaki et al entitled ‘‘Effect of weight reduction with dietary intervention on arterial distensibility and endothelial function in obese men.’’ This study investigated whether low-calorie diet-induced weight reduction affects central arterial distensibility and endothelial function in middle-aged obese men. The authors found that weight reduction by low-calorie diet in obese men increases central arterial distensibility, which may contribute to the improvement in endothelial function. We feel that these results are very important, but some additional comments may be useful. Obesity is associated with structural (altered aortic size) and functional (decreased aortic elasticity) vascular abnormalities. We aimed to investigate additive effects of physical training over low-calorie diet on aortic elasticity in obese middle-aged participants. Our preliminary study included 16 consecutive obese participants (mean age: 48 + 13 years, 6 males, mean body mass index [BMI]: 39.2 + 10.1 kg/m). All of them were on low-calorie diet (base metabolism – 600 kcal). In all cases, a routine physical, echocardiographic and blood pressure measurement was performed before and after a physical training program: a professional trainer guided aquafitness or physical training 3 times 1 hour per week for 4 months. Aortic stiffness index (b) was evaluated from echocardiography-derived systolic and diastolic aortic diameter and blood pressure data. At the end of this program, reduction in BMI (39.2 + 10.1 vs. 35.5 + 11.0 kg/m, P < .17) and improvement in b index was observed (10.5 + 9.7 vs. 4.5 + 4.9, P < .02). It has been described that high physical activity or aerobic exercise training increases central arterial distensibility in older humans. Associations between weight change and progression/regression of arterial stiffness were seen even among non-obese individuals. According to the literature and our results, it could be stated that weight reduction by different methods (diet, physical training program, etc) are associated with improved aortic elasticity. Moreover, further improvement in aortic elasticity could be observed after physical training over diet suggesting additive effects. However, further studies are warranted to confirm these results in larger populations. Moreover, further studies are necessary to evaluate the effect of different drugs on weight loss and aortic stiffness.

In the labyrinth of calcium metabolism

The authors present the case of a 27-year-old male patient. In 2010, he suffered from a bone fracture of the pelvis. As imaging techniques showed multiple osseal lytic lesions, diagnostic investigations were performed for multiple myeloma. Later, a mass lesion measuring 37 mm in size was removed from the left side of his mandible. Histology revealed a giant-cell tumour of the bone and oncologic therapy was considered. However, before this planned treatment a PET-CT was performed, which showed numerous distinct lesions with enhanced glucose metabolism in the skeleton as well as in soft tissue behind the right lobe of the thyroid. Hence, the patient was referred to endocrinologists. On the basis of severe hypercalcemia (serum calcium 3.66 mmol/l) and high serum parathyroid hormone level (162.5 pmol/l) the diagnosis of a right sided parathyroid tumour was established. After surgical excision of the parathyroid tumour, high levels of serum calcium and parathyroid hormone returned to normal. Histology failed to show malignancy and the patient recovered soon. This case report may shed some light on the importance of serum calcium measurements and the differential diagnostic significance of primary hyperparathyroidism.

Xanthomatous hypophysitis as a cause of cluster headache: a case report

Our case: We report a 23-year-old man with XH who presented with cluster type headache, diabetes insipidus and MRI-proven pituitary intrasellar mass. Since 2009 our patient suffered from recurrent headache. CT scan, ophthalmological, neurological investigations revealed no obvious cause of the symptoms. In April 2011, polyuria-polydipsia occurred and endrocrine investigations revealed diabetes insipidus. Anterior pituitary hormone levels were normal: TSH: 1.3 mIU/l, FSH: 2.4 IU/l, LH: 3.7 IU/l, PR L: 197 mIU/l, ACTH: 7.78 pm/l, cortisol 08 h: 444 nm/l. After initialization of ddAVP treatment, diuresis returned to normal. The pituitary MRI scan revealed a 14x10x17 mm inhomogenous lesion with the disappearance of the hyperintense signal of the neurohypophysis. In July 2011, transsphenoideal surgery was performed and histology proved xanthomatous hypophysitis. We could stop the glucocorticoid (GC) treatment without having any perioperative complication. The headache resolved but the diabetes insipidus persisted. The anterior pituitary function after the surgery was normal: serum cortisol 08 h: 404-445 nm/l, ACTH:6.49 pm/l, FSH:3.1 mIU/l, LH:4.2 mIU/l, TSH:1.61 mIU/l. 2 months later severe cluster type headache occurred. Endocrine investigations revealed hypadrenia, hypothyroidism and peripheral hypogonadism: serum cortisol 08 h: 96 nm/l, TSH: 1.32 mIU/l, ft4: 10.5 pm/l, testosterone: 3.44 nm/l, FSH: 3.3 mIU/l, LH: 2.8 mIU/l, ACTH: 3.38pm/l. LHRH test results: FSH: 0 min: 2.8, 30 min: 4.7, 60 min: 5.1 mIU/l, LH: 0 min: 2.9, 30 min:13.5, 60 min:13.8 mIU/l. The postopreative pituitary MRI scan proved the persistent presence of the inhomogenous mass. After initialization of glucocorticoid replacement the headache disappeared. With levothyroxin, testosterone supplementation and gradually lowered dosage of GC and all symptomps disappeared with the exception of diabetes insipidus. Despite of low IGF 1 (92 ng/ml,age matched reference rate:117-329 ng/ml) and hGH (0.08 ng/ml) levels GH therapy was not introduced. Autoimmune screen: ANA, antiCL, antib2GP, antitransglutaminase, antiTPO and antiparietal cell antibody was negative. Regularly performed sella MRI scans showed no change in tumor size and appearance after the surgery and after the introduction of hormone replacement therapy. The patient requires GC supplementation only in case of recurrent cluster type headache, but no persistent replacement is needed. Conclusion: Typical cluster type headache and diabetes insipidus were the two main syndromes of the XH In our case. The patient requires GC supplementation only in case of recurrent cluster type headache, but no persistent replacement is needed. The cause of the XH is still unknown, but the regular endocrine check-up can reveal disturbances in the pituitary function and, as in our case, glucocorticoid replacement seems to be effective in the treatment of the disease. ABSTRACT Introduction: Hypophysitis is an inflammatory disease of the pituitary gland that may mimic pituitary tumors clinically and radiologically. Primary hypophysitis has traditionally been classified as lymphocytic (LH), granulomatous (GH), and xanthomatous (XH). Case description: We report on a case of a xanthomatous hypophysitis initially diagnosed as pituitary adenoma. A 23-year-old men suffered from typical cluster type headache. Two years after the first symptoms, we confirmed diabetes insipidus. All the anterior pituitary hormone levels were normal. Sella MRI scan depicted a 14x10x17 mm inhomogenous mass. Transphenoidal surgery was performed; the removed tissue showed accumulation of foamy cells and xanthomatous epithelioid cells. Following an uneventful postoperative recovery, severe cluster type headache returned after stopping the hydrocortisone therapy. The endrocrine work-up revealed hypadrenia (morning cortisol: 96 nm/l, ACTH:3.38 pm/l), hypothyroidism ( ft4:10.5 pm/l), hypogonadism (testosterone: 3.44 nm/l) with normal FSH and LH (FSH:3,3 mIU/l,LH:2,8 mIU/l). We restarted hormonal therapy: hydrocortisone, levothyroxine and testosterone were stepwise reintroduced. During the followup period we could stop the hydrocortisone and levothyroxine supplementations, whereas the patient has permanently required desmopressin and testosterone substitution. Control sella MRI scans revealed no progression of the intitially seen pituitary mass. Conclusion: We describe an unusual case of xanthomatous hypophysitis causing cluster type headache and permanenty requiring ddAVP (desmopressine) and testosterone supplementation without requiring maintenance medication with hydrocortisone and levothyroxin.