Background. Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are found in familial isolated pituitary adenoma syndrome (FIPA) families and in a small number of sporadic pituitary adenoma (PA) patients. Although the tumorigenic mechanisms of AIP mutations are unclear, truncating mutations are considered pathogenic, but missense mutations are difficult to evaluate. p.R16H (c.47G>A) is a controversial AIP variant of unknown significance. Aim. To describe a new PA case associated with AIP p.R16H. Patients and methods. One AIP p.R16H non-functioning pituitary adenoma (NFPA) case identified by mutation sequencing screening of sporadic PA patients; 108 controls were screened for p.R16H. Results. The 38 yrs old male NFPA patient had no family history of PA and harboured a heterozygous p.R16H variant. The proband and two brothers presented severe intellectual disability. Severe visual impairment was the initial symptom and clinical, biochemical and imaging examination demonstrated a large NFPA invading the right cavernous sinus. After transsphenoidal debulking, the remaining tumor continued growth. One of proband's sisters was negative for p.R16H. Among controls, we identified one heterozygous p.R16H carrier, presenting a thyroid follicular neoplasm. Loss of heterozygosity analysis of the pituitary and thyroid tumors was not performed. Conclusions. We report two new occurrences of AIP p.R16H, associated with a NFPA and with a thyroid tumor. The NFPA patient was young and presented an invasive macroadenoma, features typical of AIP-mutated patients. Because the association between p.R16H and PAs has not been conclusively established, further research of p.R16H is warranted, in view of its implications for AIP genetic testing.

Reference EPFL-CONF-196873View record in Web of Science Record created on 2014-02-17, modified on 2017-05-25

The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O(2)). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes.

SummaryBackground The long‐acting depot somatostatin analogues [octreotide LAR (LAR) and lanreotide (LAN)] are among the most effective available medical therapies for acromegaly. However, published data on a biochemical test suitable for predicting the responsiveness to these depot agents are lacking.Aim To investigate the value of an acute octreotide suppression test (OST) in predicting the responses to treatment with long‐acting somatostatin analogues in patients with active acromegaly.Patients and Methods Thirty patients with active acromegaly [mean GH in GH day curve (GHDC) > 5 mU/l] were subjected to an OST [hourly GH measurements for 6 h following 100 µg subcutaneous (s.c.) octreotide]. Subsequently, 14 patients were treated with LAR, 10 with LAN and 6 received both drugs at different times. The final response to treatment was evaluated when the subjects had achieved ‘safe’ GH levels (mean GH < 5 mU/l) or after receiving the maximal dose of each drug (maximum duration of treatment 6 months).Results The nadir GH values during the OST were 2·6 ± 2·5 mU/l (mean ± SD, range 0·2–8·7) with a percentage fall of 84·8 ± 15·7% (mean ± SD, range 26–99%) from the baseline levels (26·2 ± 31·5 mU/l, mean ± SD). All the patients except one showed a decrease of greater than 50%. The mean time to achieve the nadir GH value was 3·8 ± 1·6 h (mean ± SD, range 1–6). The nadir GH levels showed a positive correlation with both pre‐treatment (i.e. before commencing LAN or LAR) GH values during the GHDC (r = 0·63, P < 0·01) and IGF‐I levels (r = 0·56, P < 0·05). The nadir GH values during the OST showed a positive correlation with the achieved mean GH levels in patients treated with LAR (r = 0·66, P < 0·01) but not in the ones treated with LAN. The criterion of GH < 5·25 mU/l during the OST had sensitivity 100%, specificity 80%, positive predictive value (PPV) 94% and negative predictive value (NPV) 100% in predicting achievement of ‘safe’ GH levels in patients treated with LAR. A less optimal prognostic profile was obtained for subjects treated with LAN with the criterion of GH < 6·05 mU/l during the OST providing sensitivity 92%, specificity 67%, PPV 92% and NPV 67%. The above cut‐off GH levels had a PPV of only 77% and 60% in predicting normalization of IGF‐I on treatment with LAR or LAN, respectively.Conclusions The OST is a reliable tool for the selection of patients with active acromegaly who will achieve ‘safe’ GH levels on therapy with LAR. Its prognostic profile is less optimal for patients treated with LAN. If GH values during the test fall < 5·25 mU/l (in case of LAR treatment) or < 6·05 mU/l (in case of LAN treatment), there is a 92–94% chance of subsequently achieving ‘safe’ GH levels after up to 6 months treatment with either of these agents.

Introduction: There is a large agreement that the music has a neuromodulator effect. One of the most famous composers, Johann Sebastian Bach, dedicated a musical masterpiece (Goldberg Variations) for treating the insomnia. The aim of the study was to investigate the effect of music compared to placebo (isomorphic sounds) on human sleep in relation with estrogens. Subjects and methods: We made complete polisomnographic recordings in 9 adult females and divided them in three groups: 3 menstruating women, 6 menopausal women before any hormone replacement therapy (HRT) and 5 menopausal women after at least 2 weeks of estrogen treatment. They slept at least 2 nights, one with Bach's music and one with waves isomorphic sounds (placebo), at the beginning of the night (22.00) and three hours later. We used Bio-logic equipment together with Sleepscan II software. Results: Bach's music has a positive effect on sleep efficiency in estrogenized women and a negative one in untreated menopausal women. The latency of sleep onset is not influenced. Also Bach's music increases REM sleep duration in menstruating and menopausal women with HRT but show no effect in menopausal women without any therapy. Compensatory changes are registered for stages I and II. Conclusions: Music influences human sleep, exerting benefic effects only on estrogenized brains. This indicates that music is an exogenous neuromodulator and could be used as a no side-effect therapy for poor sleep.