LONG/TERM GENETIC AND EPIGENETIC DISORDERS IN PERSONS EXPOSED TO IONIZING RADIATION AND THEIR DESCENDANTS (review). / VIDDALENI GENETYChNI TA EPIGENETYChNI PORUShENNIa U OPROMINENYKh OSIB TA ÏKhNIKh NAShchADKIV (ogliad).

The review is devoted to long-term genetic and epigenetic disorders in exposed individuals and their descendants,namely to cytogenetic effects in the Chornobyl NPP accident clean-up workers and their children, DNA methylation as an epigenetic modification of human genome. Data presented in review expand the understanding of risk of the prolonged exposure for the present and future generations, which is one of key problems posed by fundamental radiation genetics and human radiobiology.

BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. PART III / FEATURES MORPHOMETRIC RETINAL PARAMETERS, AMPLITUDE AND LATENCY COMPONENTS OF VISUAL EVOKED POTENTIAL IN RADIATION EXPOSED IN UTERO. / GOLOVNYI MOZOK TA ORGAN ZORU IaK POTENTsIINI MIShENI DLIa VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa: ChASTYNA III ­ OSOBLYVOSTI MORFOMETRYChNYKh PARAMETRIV SITChASTOÏ OBOLONKY TA AMPLITUDA I LATENTNIST' KOMPONENTIV ZOROVYKh VYKLYKANYKh POTENTsIALIV U OPROMINENYKh VNUTRIShN'OUTROBNO OSIB.

One of the current problems of modern radiobiology is determine the characteristics of the manifestation of radiation-induced effects not only at different dose loads, but also at different stages of development of the organism. In previous reports, we have summarized available evidence that at certain ages there is a comparative acceleration of radiation-induced pathological changes in the eye and brain, and the study and assessment of the risk of possible ophthalmic and neurological pathology in remote periods after contamination of radioactive areas. Data of irradiated in utero individuals are possible on the basis of observation of the state of the visual analyzer in persons who underwent intrauterine irradiation in 1986. Therefore, a parallel study of retinal morphometric parameters, amplitude and latency of components of evoked visual potentials in irradiated in utero individuals was performed. OBJECTIVE: to evaluate the retinal morphometric parameters, amplitude and latency components of the evoked visual potentials in intrauterine irradiated persons. MATERIALS AND METHODS: The results of surveys of 16 people irradiated in utero in the aftermath of the Chornobyl disaster were used; the comparison group were residents of Kyiv of the corresponding age (25 people). Optical coherence tomography was performed on a Cirrus HD-OCT, Macular Cube 512x128 study technique was used. At the same time, the study of visual evoked potentials on the inverted pattern was performed, and occipital leads wereanalyzed. Visual evoked potentials were recorded on a reversible chess pattern (VEP) - an electrophysiological test, which is a visual response to a sharp change in image contrast when presenting a reversible image of a chessboard. RESULTS: In those irradiated in utero at the age of 22-25 years, there was a probable increase in retinal thickness in the fovea, there was a tendency to increase the thickness of the retina in the areas around the fovea. When recording visual evoked potentials on a reversible chess pattern in this group, there was a tendency to decrease the amplitudes of components (N75, P100, N145, P200) in the right and left parieto-occipital areas and asymmetric changes in latency of these components. CONCLUSIONS: Early changes of fovea recorded in OCT and decreasing amplitudes of components of visual evoked potentials on the reversible chess pattern at the age of 22 25 years may indicate a risk of development in patients irradiated in utero, early age-related macular degeneration, as well as increased risk and increased risk structures of the visual analyzer.

Prevalence and Characterization of Thyroid Hemiagenesis in Japan: The Fukushima Health Management Survey.

BACKGROUND: Thyroid hemiagenesis is a rare congenital variant characterized by the lack of development of one thyroid lobe with no clinical manifestations. METHODS: This study was performed to determine the prevalence and characteristics of thyroid hemiagenesis in a normal Japanese population. This cross-sectional study was performed from October 9, 2011, to April 30, 2015. In total, 299,908 children and young adults in the Fukushima Health Management Survey were examined to determine the presence of thyroid agenesis or hemiagenesis. Thyroid width, thickness, and length were measured in 292,452 of these subjects. RESULTS: Thyroid agenesis was diagnosed in 13 subjects, and hemiagenesis was detected in 67 subjects (0.02%; 22.3/100,000 individuals). Although there was no significant sex-related difference (p = 0.067), the female:male ratio was 1.67:1.00. Females were significantly dominant in right hemiagenesis, while there was no difference in left hemiagenesis between males and females. The thyroid volumes at the 2.5th and 97.5th percentiles for age and body surface area were determined for each sex. Multivariate regression analysis showed that a large hemithyroid volume was independently associated with the presence of contralateral hemiagenesis (p < 0.001). CONCLUSION: The prevalence of thyroid hemiagenesis in the present study is in agreement with that reported in other countries. The prevalence of right hemiagenesis was higher in females, and the larger contralateral lobe in patients with rather than without hemiagenesis may have been caused by a compensatory feedback mechanism to prevent hypothyroidism. In addition, the prevalence of hemiagenesis, especially right hemiagenesis, may be affected by sex-related factors similar to those in patients with an ectopic thyroid gland.

TREATMENT OF LOCAL RADIATION LESIONS IN BREAST CANCER PATIENTS.

The purpose of this paper is the demonstration and analysis of the effectiveness of spinal cord stimulation in treatment of chronic drug-resistant neuropathy pain in a patient with radiation-induced plexopathy. She underwent radiation therapy for cancer of the right breast in 2000. Ten years later she complained with pain and weakness her right arm. After physical examination and investigation right-side brachial plexopathy was diagnosed. Antidepressant and anticonvulsant had positive effect during one year but then pain appeared again. That is why the patient has been implanted the system of epidural electrostimulation of thickening of the cervical spinal cord. During the post-operative period significant improvement of pain relief was noted. The doses of analgesics were decreased. Spinal cord stimulation efficacy for treatment of chronic pain was repeatedly proved in clinical investigation and meta-analyses. Nevertheless spinal cord stimulation effects on radiation-induced neurological disorders and possible pathophysiological mechanisms are not enough examined. All these facts require further investigation.

Cerebrovascular Diseases in Workers at Mayak PA: The Difference in Radiation Risk between Incidence and Mortality.

A detailed analysis of cerebrovascular diseases (CeVD) for the cohort of workers at Mayak Production Association (PA) is presented. This cohort is especially suitable for the analysis of radiation induced circulatory diseases, due to the detailed medical surveillance and information on several risk factors. The risk after external, typically protracted, gamma exposure is analysed, accounting for potential additional internal alpha exposure. Three different endpoints have been investigated: incidence and mortality from all cerebrovascular diseases and incidence of stroke. Particular emphasis was given to the form of the dose-response relationship and the time dependence of the radiation induced risk. Young attained age was observed to be an important, aggravating modifier of radiation risk for incidence of CeVD and stroke. For incidence of CeVD, our analysis supports a dose response sub-linear for low doses. Finally, the excess relative risk per dose was confirmed to be significantly higher for incidence of CeVD compared to CeVD mortality and incidence of stroke. Arguments are presented for this difference to be based on a true biological effect.

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia.

Neuronal hyperexcitability plays an important role in epileptogenesis. Conditions of low extracellular calcium (Ca) or magnesium (Mg) can induce hyperexcitability and epileptiform activity with unclear mechanisms. Transient receptor potential canonical type 3 (TRPC3) channels play a pivotal role in neuronal excitability and are activated in low-Ca and/or low-Mg conditions to depolarize neurons. TRPC3 staining was highly enriched in immature, but very weak in mature, control cortex, whereas it was strong in dysplastic cortex at all ages. Depolarization and susceptibility to epileptiform activity increased with decreasing Ca and Mg. Combinations of low Ca and low Mg induced larger depolarization in pyramidal neurons and greater susceptibility to epileptiform activity in immature and dysplastic cortex than in mature and control cortex, respectively. Intracellular application of anti-TRPC3 antibody to block TRPC3 channels and bath application of the selective TRPC3 inhibitor Pyr3 greatly diminished depolarization in immature control and both immature and mature dysplastic cortex with strong TRPC3 expression. Epileptiform activity was initiated in low Ca and low Mg when synaptic activity was blocked, and Pyr3 completely suppressed this activity. In conclusion, TRPC3 primarily mediates low Ca- and low Mg-induced depolarization and epileptiform activity, and the enhanced expression of TRPC3 could make dysplastic and immature cortex more hyperexcitable and more susceptible to epileptiform activity.

Altered behavior in experimental cortical dysplasia.

PURPOSE: Developmental delay and cognitive impairment are common comorbidities in people with epilepsy associated with malformations of cortical development (MCDs). We studied cognition and behavior in an animal model of diffuse cortical dysplasia (CD), in utero irradiation, using a battery of behavioral tests for neuromuscular and cognitive function. METHODS: Fetal rats were exposed to 2.25 Gy external radiation on embryonic day 17 (E17). At 1 month of age they were tested using an open field task, a grip strength task, a grid walk task, inhibitory avoidance, an object recognition task, and the Morris water maze task. KEY FINDINGS: Rats with CD showed reduced nonlocomotor activity in the open field task and impaired motor coordination for grid walking but normal grip strength. They showed a reduced tendency to recognize novel objects and reduced retention in an inhibitory avoidance task. Water maze testing showed that learning and memory were impaired in irradiated rats for both cue discrimination and spatially oriented tasks. These results demonstrate significant deficits in cortex- and hippocampus-dependent cognitive functions associated with the diffuse abnormalities of cortical and hippocampal development that have been documented in this model. SIGNIFICANCE: This study documents multimodal cognitive deficits associated with CD and can serve as the foundation for future investigations into the mechanisms of and possible therapeutic interventions for this problem.

Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring.

It is now well accepted that parental whole body irradiation causes transgenerational genome and epigenome instability in the offspring. The majority of human exposures to radiation, such as therapeutic and diagnostic irradiation, are localized and focused. The potential of localized body-part exposures to affect the germline and thus induce deleterious changes in the progeny has not been studied. To investigate whether or not the paternal cranial irradiation can exert deleterious changes in the protected germline, we studied the accumulation of DNA damage in the shielded testes tissue. Here we report that the localized paternal cranial irradiation results in a significant accumulation of unrepaired DNA lesions in sperm cells and leads to a profound epigenetic dysregulation in the unexposed progeny conceived a week after paternal exposure.

Impaired developmental switch of short-term plasticity in pyramidal cells of dysplastic cortex.

PURPOSES: Human cortical dysplasia (CD) has a strong clinical association with intractable epilepsy. It is believed that neuronal networks of CD are hyperexcitable, which may initiate seizures. The underlying mechanisms are, however, still poorly understood. We have studied the alterations of synaptic properties in a rat model of CD, in utero irradiation. METHODS: Pregnant rats on E17 were exposed to 225 cGy of external gamma-irradiation and offspring were used for experiments. Coronal somatosensory brain slices were obtained from 13 - 60-day-old rats. Visualized whole-cell recordings were performed on pyramidal neurons in layer V of control neocortex and the middle region of dysplastic cortex. Short-term plasticity (STP) of evoked excitatory postsynaptic currents (EPSCs) was induced by 5-pulse (20 Hz or 50 Hz) train stimulations. RESULTS: STP of EPSCs in pyramidal cells of the normal cortex induced by 5-pulse train stimulation (20 Hz or 50 Hz) switched from depression at P13-15 to facilitation at P28-35 and P55-60. However, STP in CD at P28-35 and P 55-60 still showed depression. The failure rate of synaptic responses to the first pulse of the stimulation tested at P 28-35 was significantly lower in CD than in controls. The depression of STP in CD at P28-35 was altered neither by blocking the desensitization of glutamate receptors nor by blocking postsynaptic Ca(2+) rise. It was also not affected by an antagonist of mGluR2/3, LY341495. CONCLUSIONS: Our results indicate that, compared to control cortex, the presynaptic release probability of excitatory synapses in CD pyramidal cells at P28-35 and P55-60 remains abnormally high and reduced tonic activity of presynaptic mGluR2/3 may contribute to this elevated release probability.

Pathophysiology of radiation-induced growth hormone deficiency: efficacy and safety of GH replacement.

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced. Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80-90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.

The Sun determines human longevity: teratogenic effects of chaotic solar radiation.

An association between fertility and longevity has been known for many years, and considerable research has been focused on the mechanisms of ageing that ultimately determine longevity, which has remained essentially unchanged despite a near doubling of human life expectancy in the past 200 years. In this paper, the authors present evidence that the Sun determines the limits of longevity for the longest-living complex organisms. The Sun is a dynamical system and although solar cycles occur every 8-14 years (averaging approximately 11.1 years), the authors show that 28% of these cycles exhibit chaotic features and irregularly release up to 300% more ultraviolet radiation than usual. These chaotic solar cycles create an environment mutagenic to DNA that must be largely avoided in order to pass uncorrupted genes to the next generation. This requirement determines the limits of fertility, e.g., menarche and menopause in humans, and sets longevity to approximately 100 years.

Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis.

To evaluate human placental extract in the treatment of radiation mucositis involving the oral/oropharyngeal region, a prospective randomized study was carried out in 120 patients with squamous cell carcinoma of the head and neck from August 1997 to March 1999. The study was conducted in patients receiving radical external radiation therapy, planned for = > 60 Gy/30 F/6 weeks, who developed grade 2 radiation mucositis (patchy mucositis) during radiation treatment. The patients were randomized in two groups of 60 patients each to receive either placentrex treatment (placentrex group) or conventional treatment (control group). Placentrex treatment was given as Inj Placentrex 2 ml by deep intramuscular injection 5 days a week for 15 injections. Conventional treatment given in the control group was disprin gargles and betamethasone oral drops. A subjective decrease in pain was observed in 48/60 (80%) of patients in the placentrex group compared with 22/60 (36.7%) in the control group. The progression to grade 3 radiation mucositis was 24/60 (40%) in the placentrex group compared with 52/60 (86.7%) in the control group. The subjective improvement in difficulty in swallowing was seen in 56/60 (93%) of patients in the placentrex group compared with 9/60 (15%) of patients in the control group. Only one patient in the placentrex group compared with three in the control group required interruption of radiation therapy because of severe radiation reactions. Human placental extract appears to be effective in the management of radiation-induced oral/oropharyngeal mucositis and especially in controlling subjective symptoms.

Moyamoya syndrome after radiation therapy for optic pathway glioma: case report.

We present a 4-year-old girl with neurofibromatosis-1 who developed moyamoya syndrome characterized by bilateral stenosis or occlusion of the distal internal carotid arteries and their branches, leading to the development of an abnormal vascular network. In light of a literature review, the postradiation vasculopathy of the moyamoya type and its relationship with neurofibromatosis-1 are discussed.

The accelerated occurrence of age-related changes of organism in Chernobyl workers: a radiation-induced progeroid syndrome?

The rate of aging was studied in 306 persons working at Chernobyl Atomic Power Station after the accident by means of integral and partial biological age assessment. An accelerated rate of aging was found in 81% of men and in 77% of women in comparison with a control random population sample of Kiev. Persons younger than 45 years appeared to be more vulnerable to radiation. The biological age of persons who worked in the contaminated zone immediately after the disaster exceeded the biological age in those who arrived in Chernobyl 4 months later. The biological age in the investigated persons exceeded its average populational value for 5 years (the integral biological and partial cardiopulmonary age) and for 11 years for the partial psychological age. These data may underlie the concept of radiation progeroid syndrome as the form of accelerated aging.

Reduced inhibition in an animal model of cortical dysplasia.

Cortical dysplasia has a strong association with epilepsy in humans, but the underlying mechanisms for this are poorly understood. In utero irradiation of rats produces diffuse cortical dysplasia and neuronal heterotopia in the neocortex and hippocampus. Using in vitro neocortical slices, whole-cell patch-clamp recordings were obtained from pyramidal neurons in dysplastic cortex and control neocortex. Spontaneous IPSCs were reduced in amplitude (35%) and frequency (70%) in pyramidal cells from dysplastic cortex. Miniature IPSCs were reduced in frequency (66%) in dysplastic cortex. Two additional measures of cortical inhibition, monosynaptic evoked IPSCs and paired pulse depression of evoked EPSCs, were also impaired in dysplastic cortex. Spontaneous EPSCs were increased in amplitude (42%) and frequency (77%) in dysplastic cortex, but miniature EPSCs were not different between the two groups. These data demonstrate significant physiological impairment in inhibitory synaptic transmission in experimental cortical dysplasia. This supports previous immunohistochemical findings in this model and observations in humans of a reduction in the density of inhibitory interneurons in dysplastic cortex.

Análisis del gen del activador de plasminógeno tipo urocinasa para la identificación de elementos de respuesta a la radiación ultravioleta / Analysis of the gene activator of plasminogen urokinase type for the identification of alements of response to ultraviolet radiation

La exposición de las células a la radiación ultravioleta dispara una respuesta de inducción transcripcional. El activador de plasminógeno es una enzima que se incrementa su actividad por efecto de la radiación ultravioleta. Nosotros mostramos que la radiación ultravioleta induce al activador del plasminógeno tanto en células normales (HeLa) como en células con mecanismo de reparación de ADN deficientes (XPC2096); sin embargo, estas últimas mostraron una mayor inducción con una menor dosis de radiación. El análisis del gen del activador del plasminógeno mostró una ausencia de elementos de respuesta en el fragmento con 500 pb, en ambas líneas celulares. La inducción de la actividad de luciferas en los fragmentos que contenían 2500 pb (UPA= y 1500 pb (PSTI) fue indicativa de la inducción del gen del activador del plasminógeno debido a la presencia de elementos de respuesta presentes en ellos. La adición de antiinterleucina-6 al medio de cultivo de células radiadas inhibió la actividad del activador del plasminógeno en un 100 por ciento de las células HeLa y en un 70 por ciento en las células XPC2096. Con base en los resultados, se propone que el gen de activador del plasminógeno presenta secuencias reguladoras específicas para la interleucina-6, que funcionan independientemente de los mecanismo de reparación del ADN

Resultados a longo prazo da radioterapia nos hemangiomas da mama näo desenvolvida / Long term results of radiotherapy for hemangioma in underveloped breasts

Os autores examinaram 48 mulheres irradiadas na regiäo mamária no período infantil a fim de estabelecer os efeitos dos tipos de radiaçöes e suas doses sobre o desenvolvimento da mama e da aréola, e as mudanças cutâneas devidas à irradiaçäo. Foram encontradas leves e graves disparidades de crescimento em mais de 50//dos casos, assim como mudanças cutâneas. Esses resultados parecem ser principalmente relacionados à posiçäo do hemangioma, ao tipo de irradiaçäo e dose total recebida. No entanto, a idade na época do tratamento e o tipo de hemangioma näo parecem influenciar o resultado sucessivo

Potentiating effects of caffeine on teratogenicity of alkylating agents in mice.

Teratogenic to subteratogenic doses of x-ray, mitomycin C, MNNG, thio-TEPA, cyclophosphamide, and chlorambucil were administered to pregnant ICR mice together with caffeine at doses of 12.5, 25, or 50 mg/kg on day 11 of gestation. Fetuses were examined for gross malformations on day 18 of gestation. The teratogenicity of mitomycin C was significantly potentiated by caffeine at a dose as low as 12.5 mg/kg. The teratogenicity of chlorambucil was also significantly potentiated by caffeine at 50 mg/kg, but similar potentiation was not observed for x-ray, MNNG, thio-TEPA, and cyclophosphamide.