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Le gigantisme hypophysaire est une affection très rare qui se développe avant la fin de la période pubertaire suite à un excès d’hormone de croissance en général secrétée par un adénome de l’hypophyse. Cette maladie quoique parfois très impressionnante s’accompagne d’une réduction significative d’espérance de vie. Jusqu’à très récemment, peu d’études scientifiques avaient été consacrées aux géants, vraisemblablement en raison de leur rareté et de la difficulté d’en assembler de grandes séries. Suite aux travaux sur le FIPA et les mutations du gène AIP, il est devenu évident que les patients mutés pour le gène AIP présentent des adénomes hypophysaires secrétant préférentiellement l’hormone de croissance, plus agressifs et développent la maladie beaucoup plus tôt dans l’existence, fréquemment avant la fin de la puberté permettant alors l’accomplissement d’un gigantisme. Ces travaux ont stimulé la réalisation d’études scientifiques et notamment génétiques sur les géants. Plusieurs étiologies génétiques du gigantisme sont maintenant connues. La cause la plus fréquente est une mutation du gène AIP (environ 30 %). Dans 10 % la cause est une duplication du gène GPR101 responsable du syndrome X-LAG pour X-Linked AcroGigantism. Ce syndrome découvert très récemment comprend les formes les plus extrêmes de gigantisme humain (avec des tailles supérieures à 2m50), tel le géant Julius Koch alias le géant Constantin (2m59) mort à trente ans en 1902. Une étude soigneuse de son ADN a en effet permis le diagnostic. Ces travaux sur X-LAG ont permis de faire progresser notre compréhension sur la physiologie de la croissance et sur les mécanismes pathologiques hypothalamo-hypophysaires qui gouvernent la formation des adénomes somatotropes.

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIPmutations has not been reported. We studied two AIPmutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIPmutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIPlocus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIPmutation positive acromegaly patients that are resistant to first-generation SSA.

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.

AIPmutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIPmutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIPgene). These data support targeted genetic screening for AIPmutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities.

Gli adenomi ipofisari insorgono nel 5–6% dei casi in un contesto familiare, nell’ambito di sindromi come le Neoplasia Endocrine Multiple (MEN1, MEN4) o in forma isolata (Familial Isolated Pituitary Adenomas, FIPA). Negli ultimi anni sono state riconosciute nuove entità e nuovi geni di predisposizione tra cui, in particolare, il gene Aryl hydrocarbon receptor Interacting Protein(AIP). Il riconoscere una predisposizione genetica, anche in forme apparentemente sporadiche, è essenziale non solo per il caso indice ma anche per la sua famiglia.

AbstractFamilial pituitary adenomas account for approximately 5–8% of all pituitary adenomas. Besides the adenomas occurring as part of syndromic entities that group several endocrine or nonendocrine disorders (multiple endocrine neoplasia type 1 or 4, Carney complex and McCune–Albright syndrome), 2–3% of familial pituitary adenomas fit into the familial isolated pituitary adenomas (FIPA) syndrome, an autosomal dominant condition with incomplete penetrance. About 20% of FIPA cases are due to mutations in the AIP gene and have distinct clinical characteristics. Recent findings have isolated a new non-AIP FIPA syndrome called X-linked acrogigantism, resulting from a microduplication that always includes the GPR101 gene. These new advances in the field of pituitary disease are opening up a new challenging domain to both clinicians and researchers. This review will focus on these recent findings and their contribution to the diagnosis and the management of familial pituitary adenomas.

Familial pituitary adenomas account for approximately 5–8 of all pituitary adenomas. Besides the adenomas occurring as part of syndromic entities that group several endocrine or nonendocrine disorders (multiple endocrine neoplasia type 1 or 4, Carney complex and McCune–Albright syndrome), 2–3 of familial pituitary adenomas fit into the familial isolated pituitary adenomas (FIPA) syndrome, an autosomal dominant condition with incomplete penetrance. About 20 of FIPA cases are due to mutations in the AIP gene and have distinct clinical characteristics. Recent findings have isolated a new non-AIP FIPA syndrome called X-linked acrogigantism, resulting from a microduplication that always includes the GPR101 gene. These new advances in the field of pituitary disease are opening up a new challenging domain to both clinicians and researchers. This review will focus on these recent findings and their contribution to the diagnosis and the management of familial pituitary adenomas.

Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome.

Two new versions of four-block monolithic Ge X-ray resonators with closed-loop cycling of the beam are presented. These resonators present new geometries for entrance and exit of the beam. In the first version the X-ray resonator operates in the spatially defocusing mode and in the second version, in the spatially focusing mode.

Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL.We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors.Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes.From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHBin two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHDand three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients.This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHBdeletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHxgenes.

X-ray cyclic monochromators, which are particular cases of X-ray resonators, are considered. Conditions for the existence of a resonance wavelength in the Co-Kα1 line spectral interval in monolithic cyclic monochromators and polylithic tunable cyclic monochromators are discussed. Maximum reflectivity for a four-reflection monolithic monochromator is achieved when each reflection is symmetric. For a two-monolith four-reflection polylithic monochromator, maximum reflectivity is achieved when the asymmetry of one reflection in one monolith is the inverse of the other reflection in the same monolith.

The evolution of initial perturbations in a plasma-filled system with a high current relativistic electron beam is considered. The beam current is assumed to be comparable or higher than the limiting vacuum current. The approach is based on equation for slowly varying amplitude of the induced waveform, which enable us to separate out the most intrinsic peculiarities of the overlimiting electron beam instabilities. An equation for slowly varying amplitude is derived and solved. An analytical expression describing space structure and development dynamics of the fields is obtained and analyzed. The well-known maximal growth rate of beam instability is actually the growth rate in the peak of induced wave train. Results are valid both for instability due to aperiodic modulation of the beam density in medium with negative dielectric constant and for instability due to excitation of beam wave with negative energy. Comparison with the case of a sublimiting beam is carried out.

The evolution of initial perturbations in a plasma-filled system with a high current relativistic electron beam is considered. The beam current is assumed to be comparable or higher than the limiting vacuum current. The approach is based on equation for slowly varying amplitude of the induced waveform, which enable us to separate out the most intrinsic peculiarities of the overlimiting electron beam instabilities. An equation for slowly varying amplitude is derived and solved. An analytical expression describing space structure and development dynamics of the fields is obtained and analyzed. The well-known maximal growth rate of beam instability is actually the growth rate in the peak of induced wave train. Results are valid both for instability due to aperiodic modulation of the beam density in medium with negative dielectric constant and for instability due to excitation of beam wave with negative energy. Comparison with the case of a sublimiting beam is carried out.

A special arrangement of Bonse–Hart X‐ray interferometers, which uses the Bragg geometry of X‐ray diffraction for the beam splitter, mirrors and the analyser (so‐called BBB interferometers), has been designed and characterized both computationally and experimentally in different versions. The design includes wavelength‐dependent optimization of transmission through the lamella, which is used both for beam splitting and for recombination. For characterization of the function of the instrument, interference patterns were evaluated from BBB interferograms, as well as from LLL (employing the Laue geometry for coherent beam splitting, reflecting and analysing) topograms and from interferograms resulting from a new combined geometrical layout. The influence of gravitation on the horizontally running diffraction planes was visible as a system of fringes in the interferograms, resulting from bending of the lamella under its own weight.

Evoked potentials in the hippocampus to stimulation of the pallidum and vice versa were studied in unanesthetized and anesthetized (pentobarbital 40 mg/kg) cats with permanently implanted electrodes. Hippocampal and pallidal evoked potentials in waking cats consisted of an initial positive deflection (latent period 15–20 msec) followed by a positive-negative wave (latent period 40–50 msec) both of considerable amplitude and duration. Under pentobarbital anesthesia the fast initial short-latency components of the evoked potentials remained unchanged, subsequent long-latency components of the responses were modified, and thresholds of onset of the responses also became appreciably higher. These results suggest a functional connection between the globus pallidus and hippo-campus in cats.

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Conclusions Reconstruction of the Gyumush HES into a HES-PSS will make it possible to additionally obtain a peak capacity of 160 MW, which has great significance both from the viewpoint of the effective use of existing structures and equipment and an increase of prompt flexibility of the power system.

Étudier la prévalence de mutations ponctuelles et de grands réarrangements du gène AIPdans une population de patients atteints d’adénome hypophysaire (à prolactine, GH, mixte, non sécrétant, ACTH ou TSH).

Le but de cette étude est de comparer la réponse des adénomes hypophysaires à GH au traitement en première ligne par analogues de la somatostatine(SSA) en fonction de l’intensité du signal IRM des adénomes en séquence T2.

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