[Kalmann syndrome in monozygous twins as an isolated manifestation of the SOX10 gene defect].

More than 30 genes are known to take part in hypothalamic-pituitary-gonadal axis development at the date and role of more than 10 other genes is studied. Despite it about 50% of isolated hypogonadotropic hypogonadism cases still have no molecular genetic explanation.A number of specific associations between iHH and different not-reproductive manifestations called syndromic forms are distinguished in general group of iHH. For example, the combination of Kalmann syndrome with sensorineural hearing loss is known as manifestation for defects of some genes encoding factors of neuronal migration; in patients with this phenotype CHD7, SOX10 genes defects are most frequent. However, defects in the genes of neuronal migration factors are characterized by a wide variability of phenotype, which is explained by the epigenetic mechanisms influence. Carriers of the mutation within the same family may lack some non-reproductive manifestations as well as hypogonadism.Here we present a case of Kalmann syndrome in monozygous twins, caused by a previously not described heterozygous mutation c.462C> G: p.I154M in the SOX10 gene in the absence of sensorineural hearing loss. The mutation was inherited from a father who has only isolated anosmia in the phenotype. This mutation was identified during full exome sequencing. This unique observation for Russia shows on the one hand expediency to check SOX10 sequence in addition to the other factors of neuronal migration and differentiation and, on the other hand, the prospect of full exome sequencing in a group of patients with undifferentiated iHH.

[A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics].

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450-42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

[Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects].

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

[Clinical and molecular genetic features of cases of isolated hypogonadotropic hypogonadism, associated with defects in GNRHR genes].

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Clinically, there are variants of CHH with hypo-/anosmia (Kalman syndrome) and normosmic hypogonadotropic hypogonadism. Given a  growing list of gene mutations accounting for CHH, the application of next generation sequencing (NGS) comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. Biallelic mutations in GNRHR gene lead to the development of hypogonadotropic hypogonadism with normosmia. In this paper, we describe 16 patients with proven GnRH resistance and estimate the frequency of pathogenic variants in the GNRHR gene in the Russian population.

[Familial case of hypogonadotropic hypogonadism as the CHARGE syndrome manifestation].

CHARGE syndrome is a rare autosomal dominant disease caused by CHD7 gene mutations. Individuals with CHARGE display a wide spectrum of clinical features. It might be presented only as a delay puberty, which does not require any hormone replacement therapy to severe CHARGE phenotype, requiring a multidisciplinary therapeutic approach. Wild spectrum of clinical presentation can be seen even among the patients with identical mutation. Diagnosis might be suspected by a combination of major and minor clinical criteria of this disorder, but molecular genetic analysis is mandatory for final verification. Accurate diagnosis is essential to informing patients about all possible clinical features, reproductive status and choosing the correct treatment approach. The most common endocrine abnormality in patients with CHARGE syndrome is the disturbance in gonadotropins function ranged from delay puberty to persistent hypogonadotropic hypogonadism with different olfactory phenotypes, resulted by specific role of CHD7 in GnRH neuronal embryogenesis.We describe a familial case of CHARGE syndrome with significant intrafamilial clinical heterogeneity due to CHD7 gene mutation.

Contributi scientifici in memoria di Antonio Fusco.

Come si leggerà nell'Introduzione della sezione propriamente scientifica del Volume, il presente testo nasce dalla volontà e, soprattutto, dall'esigenza culturale di omaggiare il fu Prof. Antonio Fusco. Un debito scientifico ed umano che trova il suo locus naturale in questa prima parte del testo stesso, cui farà poi seguito la parte propriamente scientifica. In siffatta parentesi dovuta per le ragioni appena menzionate, il lettore, l'amico o l'allievo dell'opera del Prof. Fusco potranno trovare un suo sintetico Curriculum Vitae, correlato da una specifica ed accurata prosa, svolta dal già Magnifico Rettore Carlo Cipolli; il quale, oltre che evidenziare, ricordando, i meriti del collega oramai scomparso, aggiunge alsuo scritto un elemento che sarebbe imprescindibile a non trasformare lo stesso in una mera sequenza di parole: l'amicizia e l'affetto per un amico che, oramai, non c'è più. A fine lettura, evidente risuonerà il fatto che la vita di ognuno, se mossa dalla passione per ciò per cui si è predisposti cognitivamente e psicologicamente, può essere ricca di riconoscimenti, riconoscenze e soddisfazioni che, lungi dal divenire un cuscino di allori su cui adagiarsi, per una mente creativa come quella del Prof. Fusco hanno funto solo da motivazioni ad agire instancabilmente guardando sempre al futuro. Il lavoro di una vita che, materialmente, è sancito da un supporto poco più di cm 25x15: una targa. Una materialità evidente che, con grande commozione e riconoscenza, è stata affissa il 25 ottobre 2019 sull'aula fronte l'Aula Magna del Campus "La Folcara", a testimonianza che quello spirito creativo in continua evoluzione non si ferma; non si arresta neppure con la fine biologica di chi lo ha "posseduto". Rimangono le opere ed il pensiero del Prof. Fusco e restano gli affetti. A tal proposito, il lettore troverà una breve e sentita sezione su Testimonianze; coloro i quali hanno avuto modo, nell'arco della vita accademica ed umana, personale, di Fusco di conoscerlo. Ecco, allora, che i ricordi saranno i veri protagonisti di questa parentesi. Dopo di ciò, prima dei contributi prettamente scientifici dei lavori, tenutisi in occasione del Convegno Internazionale Psicologia, Arte, Letteratura. Antiche e Nuove Tendenze, seguiranno i saluti delle autorità che in quei due giorni si sono succedute a rappresentare non solo l'istituzione affiliata, ma anche la relazione di stima e di affetto che le legava al compianto Professore. Si passerà, infine, al volume tradizionalmente inteso.

Reflectance of graphene-coated dielectric plates in the framework of Dirac model: joint action of energy gap and chemical potential.

We investigate the reflectance of a dielectric plate coated with a graphene sheet which possesses the nonzero energy gap and chemical potential at any temperature. The general formalism for the reflectance using the polarization tensor is presented in the framework of Dirac model. It allows calculation of the reflectivity properties for any material plate coated with real graphene sheet on the basis of first principles of quantum electrodynamics. Numerical computations of the reflectance are performed for the graphene-coated SiO2 plate at room, liquid-nitrogen, and liquid-helium temperatures. We demonstrate that there is a nontrivial interplay between the chemical potential, energy gap, frequency, and temperature in their joint action on the reflectance of a graphene-coated plate. Specifically, it is shown that at the fixed frequency of an incident light an increase of the chemical potential and the energy gap affect the reflectance in opposite directions by increasing and decreasing it, respectively. According to our results, the reflectance approaches unity at sufficiently low frequencies and drops to that of an uncoated plate at high frequencies for any values of the chemical potential and energy gap. The impact of temperature on the reflectance is found to be more pronounced for graphene coatings with smaller chemical potentials. The obtained results could be applied for optimization of optical detectors and other devices exploiting graphene coatings.

[Hereditary Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia].

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

[Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome].

Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

[Issues of biomedical support of explorations missions].

Sine qua non for piloted exploration missions is a system of biomedical support. The future system will be considerably different from the analogous systems applied in current orbital missions. The reason is the challenging conditions in expeditions to remote space. In a mission to Mars, specifically, these are high levels of radiation, hypomagnetic environment, alternation of micro- and hypogravity, very long mission duration and autonomy. The paper scrutinizes the major issues of medical support to future explorers of space.

[Rates of aberrant lymphocytes elimination in various bio-objects].

Rate of damaged cells elimination in mammals after prolonged irradiation modifies frequency of chromosomal aberrations (CAF) significantly. Hence, CAF is unlikely to be identical in a bio-object exposed to equal doses with varying dose rate for the reason of different periods of ionizing irradiation. This should be taken into account by designers of bio-dosimeters. Main time characteristics of chromosomal aberrations in mammals can be calculated from the experimentally evidenced CAF growth in the course of irradiation and decline afterwards. This assumption was tested using the data about disaster fighters at the Chernobyl nuclear power station and of experiments with chronic and fractionated exposure of rhesus macaques to 2.5 Gy (Cs137). The experimental doses ranged from 25 cGy to 250 cGy; dose rate made up 1.4 and 20 cGy/hr. Therapeutic doses were within the interval of 1.2 to 9.8 Gy. Rate of aberrant cells elimination was determined for two objects, i.e. humans and rhesus macaques. The follow-up period was approx. 6 years (61 to 2174 days). Elimination rate in the experiment was estimated using a proposed mathematical description of CAF dynamics in peripheral blood lymphocytes of monkeys. Elimination rates of aberrant peripheral lymphocytes in two bio-species were compared. The parameter is equal to (2 +/- 0.5).10(-3) d(-1) and (16 +/- 3) x 10(-3) d(-1) for the human and rhesus macaque, respectively.

[Radiation lesion formation and character of repair processes in the hematopoietic system of primates exposed to continuous and fractionated gamma-irradiation by equally effective doses].

The article is dedicated to comparison of the biological effectiveness of continuous and fractionated gamma-irradiation of rhesus macaques by equally effective doses. These radiation conditions are broadly used in radiobiological experiments. Specifically, they are applied in modeling radiation effects on cosmonauts during extended exploration mission. A model of radiation damage and repair on the cell, tissue and organism levels, i.e., a model of effective residual dose responsible for change in mammals' resistance to irradiation of varying duration was used to calculate equally effective doses in the experiment with primates subject to continuous and fractionated exposure. The authors publish data related to formation of radiation lesion and rate of ensuing hemopoiesis reparation. Two groups of animals were compared in resistance modification followed after testing by acute irradiation. The test was to reproduce a radiation situation for cosmonauts in the event of a cannonade of powerful solar proton events resulting in an effective residual dose of 1 Sv total The experiment evidenced close resemblance of the hemopoietic effects in primates exposed to the compared radiation conditions.

[Problems of ensuring human radiation safety during interplanetary flights].

The work contains the analyses and discussion of the main sources of space radiation specified for interplanetary flights, the dosimetric functionals used for describing the processes of radiation lesions and reparation of the organism in the conditions of the complex radiation impact with a broad charge composition of cosmic rays and a peculiar spatial and temporal dose behavior. It represents the results of calculations of the radiation risks during the flight and the total lifelong radiation risk with taking into account all the delayed unfavorable biological consequences. The main uncertainties in the calculated values of radiation risk leading to its undervaluation are analyzed. In addition, also provided is the range of theoretical and experimental investigations necessary for the adjustment of coefficient values used in the algorithm of radiation risk calculations, as well as in the nomenclature of experiments for estimating the individual resistance of man to the extreme influence and investigations aimed at estimating and increasing the reliability of the operator activity of cosmonauts.

[Results of measuring neutron dose inside the Russian segment of the International Space Station using bubble detectors in experiment Matreshka-R].

Distribution of neutron equivalent dose both inside and outside the spherical phantom (experiment Matryeshka-R) was determined with the help of dedicated research equipment "Bubble-dosimeter". Equipment is built up from an automatic bubbles counter and 8 bubble detectors of neutrons with energy ranging from approximately 200 keV to 15 MeV. Measurements inside the ISS were made in several 7-day sessions in the period from April 2006 till October 2007 (ISS increments 13-15). According to the bubble detectors on the outside of the phantom, ambient neutron dose H*(10) was equal to 0.1 mSv/d or approximately 20% of the dose from charged particles inside the ISS. In the tissue-equivalent phantom, neutron dose was 1.2 +/- 0.2 times less as compared with the phantom surface which characterized the degree of dose attenuation in cosmonaut's body.

[Dose loads on and radiation risk values for cosmonauts on a mission to Mars estimated from actual Martian vehicle engineering development].

The current design philosophy of a Mars orbiting vehicle, takeoff and landing systems and the transport return vehicle was taken into consideration for calculating the equivalent doses imparted to cosmonaut's organs and tissues by galactic cosmic rays, solar rays and the Earth's radiation belts, values of the total radiation risk over the lifespan following the mission and over the whole career period, and possible shortening of life expectancy. There are a number of uncertainties that should be evaluated, and radiation limits specified before setting off to Mars.

[Space radiation doses in the anthropomorphous phantom in space experiment "Matryeshka-R" and spacesuit "Orlan-M" during extravehicular activity].

Russian space experiment "Matryeshka-R" was conducted in 2004-2005 to study dose distribution in the body of anthropomorphous phantom inserted in a spacesuit imitating container mounted on outer surface of the ISS Service module (experiment "Matryeshka"). The objective was to compare doses inside the phantom in the container to human body donned in spacesuit "Orlan-M" during extravehicular activity (EVA). The shielding function was calculated using the geometric model, specification of the phantom shielded by the container, "Orlan-M" description, and results of ground-based estimation of shielding effectiveness by gamma-raying. Doses were calculated from the dose attenuation curves obtained for galactic cosmic rays, and the AE-8/AP-8 models of electron and proton flows in Earth's radiation belt. Calculated ratios of equivalent doses in representative points of the body critical organs to analogous doses in phantom "Matryeshka" H(ORLAN-M)/H(Matryeshka) for identical radiation conditions vary with organs and solar activity in the range from 0.1 to 1.8 with organs and solar activity. These observations should be taken into account when applying Matryeshka data to the EVA conditions.

[Results of sociological interview of physicians of military-medical committees].

Was effectuated an interview of 95 physicians of regional military-medical committees of Kirovskaya area. For the question, whether military-medical expertise (MME) was given in IHE, affirmative answer gave 10.9% of respondents. A rather low (16.4%) was percent of physicians, got education in MME during postgraduate courses. Analyze has shown that nowdays the education of physicians on the topic of MME is effectuated predominantly in the course of work, conversance of judicial consequences of expertise is insufficient. It is found that physicians underestimate value of MME and don't perceive it as a self direction.

[The dynamics of chromosomal aberration frequency in lymphocytes of the human peripheral blood after an acute irradiation].

Biodosimetrical estimation of radiation body burden is based on the counting of chromosomal aberration frequency in lymphocytes of the peripheral blood. This counting was made during a period of time after radiation. However, this frequency differs from counterpart, measured immediately after irradiation. This change caused by elimination of aberrant cells. In order to avoid consistent error in evaluation of dosage it is necessary to know the process generality of elimination temporally. The article contains the results of investigation of aberration frequency dynamics in lymphocytes of 41 patients' peripheral blood. The patients were observed in hospital after Chernobyl accident. The dosage of patients' irradiation varied in the range from 1.2 Gr to 9.8 Gr. Observations had been made during six years or so (from 61 to 2174 days). The results of these observations were used for the research of aberrant cells elimination rate. At the end of the analysis regularities of chromosomal aberration (dicentric and centrical rings) frequency change were obtained. The regularities comply with the exponential law of decreasing with the rate index of elimination (parameter b), which is equal (2.0 +/- 0.5) x 10(3) day(-1) in the range to 10(3) days after radiation. In some cases beyond this interval there was the change of the elimination rate. This fact should be researched additionally. The article contains a model for chromosomal aberration frequency dynamics expression. In analyzed range the b parameter can be constant, but for the extrapolation it in the area of less dosage it is essential to carry on additional investigations.

[Radiation safety provisions in a piloted mission to Mars based on calculated risks of overdose behind shielding].

The article deals with the prime sources of radiation hazard in a mission to Mars, compares the radiation risk values in flight and over the life span with consideration for various shielding thicknesses in habitable compartments and radiation shelter, and estimates possible life shortening. Given the stochastic nature of solar cosmic rays effects in a two-year mission and probability of powerful solar proton events, calculated were not only the mean tissue-equivalent doses behind various thickness of the shelter but also probability of their violation, risks of immediate and delayed radiation consequences and conceivable approaches to risk mitigation.