Clinicopathological features and BRAFV600E mutations in patients with isolated hypothalamic-pituitary Langerhans cell histiocytosis.

BACKGROUND: Isolated hypothalamic-pituitary Langerhans cell histiocytosis (HPLCH) is very rare. We investigated the clinicopathological characteristics, endocrine function changes, BRAFV600E mutations and treatments of isolated HPLCH. METHODS: We identified seven patients with isolated HPLCH by reviewing the clinical and pathological files in our hospital from 2007 to 2015. The clinical characteristics of the seven patients were retrospectively reviewed, especially the endocrine function changes. Immunostaining and mutation profiling of BRAFV600E were performed. RESULTS: The seven HPLCH patients included three men and four women, aged 9-47 years. All patients presented with symptoms of central diabetes insipidus (CDI), and four displayed anterior pituitary hypofunction as well. Magnetic resonance imaging showed hypothalamic-pituitary axis involvement in all patients. There was no evidence for the involvement of other organs in all seven patients. Langerhans cell histiocytosis was confirmed by neuroendoscopic procedures, and immunohistochemical staining showed that all cases (7/7) were positive for CD68, CD1a, Langerin, and S-100. The BRAFV600E mutation was detected in three of the six cases (3/6). Six patients had follow-up information; all received desmopressin acetate and high-dose corticosteroid therapy, and two patients received radiotherapy. CONCLUSIONS: Our study indicated that all patients with isolated HPLCH had CDI as the earliest symptom, and more than half of the patients had anterior pituitary deficiencies. The BRAFV600E mutation is a common genetic change in HPLCH patients. Treatment of HPLCH patients is difficult, and the progressive loss of endocrine function is irreversible in most cases.

Peptidylgycine α-amidating monooxygenase and copper: a gene-nutrient interaction critical to nervous system function.

Peptidylgycine alpha-amidating monooxygenase (PAM), a highly conserved copper-dependent enzyme, is essential for the synthesis of all amidated neuropeptides. Biophysical studies revealed that the binding of copper to PAM affects its structure, and cell biological studies demonstrated that the endocytic trafficking of PAM was sensitive to copper. We review data indicating that genetic reduction of PAM expression and mild copper deficiency in mice cause similar alterations in several physiological functions known to be regulated by neuropeptides: thermal regulation, seizure sensitivity, and anxiety-like behavior.

Cell cycle control of pituitary development and disease.

The pituitary gland regulates diverse physiological functions, including growth, metabolism, reproduction, stress response, and ageing. Early genetic models in the mouse taught us that the pituitary is highly sensitive to genetic alteration of specific cell cycle regulators such as the retinoblastoma protein (pRB) or the cell cycle inhibitor p27(Kip1). The molecular analysis of human pituitary neoplasias has now corroborated that cell cycle deregulation is significantly implicated in pituitary tumorigenesis. In particular, proteins involved in cyclin-dependent kinase regulation or the pRB pathway are altered in nearly all human pituitary tumors. Additional cell cycle regulators such as PTTG1/securin may have critical roles in promoting genomic instability in pituitary neoplasias. Recent experimental data suggest that these cell cycle regulators may have significant implications in the biology of putative progenitor cells and pituitary homeostasis. Understanding how cell cycle regulation controls pituitary biology may provide us with new therapeutic approaches against pituitary diseases.

24-Hour rhythm in gene expression of nitric oxide synthase and heme-peroxidase in anterior pituitary of ethanol-fed rats.

Chronic exposure of rats to ethanol results in significant changes in pituitary hormone secretion. However, identification of the site(s) and mechanism of action of ethanol to induce these effects remains elusive. Free radical damage at the adenohypophyseal level may play a role in the decline in serum gonadotropin levels in ethanol-fed rats. Since 24-h changes in redox state occurred, we analyzed the 24-h changes in pituitary gene expression of the prooxidant enzymes nitric oxide synthase (NOS) 1 and 2, and of heme oxygenase-1 (HO-1) enzyme, and in plasma NO(2)(-) and NO(3)(-) (NO(x)) levels, in ethanol and control rats. Male rats, 35-day-old, received a liquid diet for 4 weeks. The ethanol-fed group received a similar diet to controls except for that maltose was isocalorically replaced by ethanol. Animals were killed at six time intervals during a 24-h cycle. Anterior pituitary mRNA levels encoding NOS1, NOS2 and HO-1 were measured by real-time PCR analysis. Plasma NO(x) concentration was determined by the Griess reaction. Ethanol feeding of prepubertal rats changed significantly the 24-h pattern of expression of NOS1, NOS2 and HO-1 in the adenohypophysis and augmented NOS2 and HO-1 mRNA levels. Peak values for the three enzymes in ethanol-fed rats occurred at the beginning of the scotophase (i.e., at 21:00 h). Ethanol feeding augmented mean values plasma NO(x) levels with a maximum at 13:00 h while in controls a biphasic pattern was observed, with peaks at 09:00 h and 17:00-21:00 h. One of the mechanisms by which ethanol augments oxidative damage in the adenohypophysis may include overproduction of nitric oxide and carbon monoxide.

Anti-alpha-enolase antibodies in pituitary disease.

A previous study reported a high prevalence of autoantibodies to alpha-enolase in lymphocytic hypophysitis and these antibodies efficiently distinguished lymphocytic hypophysitis from pituitary tumors. To confirm this, we examined autoantibodies to alpha-enolase in patients with lymphocytic hypophysitis (n = 17), pituitary non-functioning adenoma (n = 13), other pituitary diseases (n = 17) and other autoimmune diseases (n = 30), and compared to healthy controls (n = 46). Autoantibodies were found in 41.2%, 46.2%, 23.5%, 20.0% and 4.3%, respectively. Our findings indicate that detection of anti-alpha-enolase antibodies is not suitable for specific diagnosis of lymphocytic hypophysitis.

Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain.

P35 or its truncated fragment p25 is required for cyclin dependent kinase (Cdk)5 activation. It has been reported that p25 is accumulated in the brain of Alzheimer's disease (AD) patients and that p25/Cdk5 induces high phosphorylation of tau and apoptosis in cultured neurons (Nature 402 (1999) 615). Our investigation of AD brain did not show specific accumulation of p25. Exposure to Ca ionophore (A23187) at 10(-6) M induced p25 accumulation in rat primary hippocampal neurons, causing neuronal death without showing hyperphosphorylation of tau. Transgenic mice expressing p25 showed the accumulation of p25 but neither hyperphosphorylation of tau nor neuronal death was shown in these mice. The feature of these mice was the progression of cell growth in pituitary gland. These results suggest that overexpression of p25 lead to the activation of cell cycle but not to the direct phosphorylation of tau.

Immunocytochemical demonstration of the expression and induction of manganese-superoxide dismutase in the adenohypophysis.

Immunocytochemistry for manganese-superoxide dismutase (Mn-SOD) was studied in 12 normal adenohypophyses and 38 various pituitary lesions. The proportions of cells with granular immunoreactivity for Mn-SOD in normal adenohypophysis ranged from 9.8% to 29.6% (mean +/- SD; 18.4+/-6.2%). Some positive cells tended to accumulate in clusters, distribution of which corresponded well with those immunopositive for mitochondrial protein and cytochrome oxidase. The number of Mn-SOD-positive cells increased in adjacent residual adenohypophysis in eight of nine recent infarcts, in two of five old infarcts, in all four cases of lymphocytic hypophysitis, in two of four abscess cases and in one of three metastatic tumour cases, whereas the immunoreactivities of mitochondrial protein- and cytochrome oxidase-positive cells either did not vary or decreased. The intensity of the histological inflammatory reactions showed a positive correlation with reactivity for Mn-SOD in these lesions. Of eight adenomas, the surrounding area of compressed adenohypophysis showed increased numbers of Mn-SOD- and mitochondrial protein-/cytochrome oxidase-positive cells in four and six cases respectively. It is suggested that positivity for Mn-SOD may be related to some functional activity of mitochondria. It is further suggested that adenohypophysial cells have a high potential to induce Mn-SOD by inflammatory and ischaemic stress and, in addition, by enhanced mitochondrial activity.