The phenotypic spectrum of congenital Zika syndrome.

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

Radiogenic responses of normal cells induced by fractionated irradiation--a simulation study. Part II. Late responses.

AIM: Based on controlled theory, a computed simulation model has been constructed which describes the time course of slowly responding normal cells after irradiation exposure. Subsequently, different clinical irradiation schemes are compared in regard to their delayed radiogenic responses referred to as late effects in radiological terminology. METHOD: A cybernetic model of a parenchymal tissue consisting of dominantly resting functional cells has been developed and transferred into a computer model. The radiation effects are considered by characteristic cell parameters as well as by the linear-quadratic model. RESULTS: Three kinds of tissue (brain and lung parenchyma of the mouse, liver parenchyma of rat) have been irradiated in the model according to standard-, super-, hyperfractionation and a single high dose per week. The simulation studies indicate that the late reaction of brain parenchyma to hyperfractionation (3 x 1.5 Gy per day) and of lung parenchyma tissue with regard to all fractionation schemes applied is particularly severe. In contrast to these observations the behavior of liver parenchyma is not unique: If Dtotal amounts to 60 Gy there is no evidence for compensation of radiation damages, but if Dtotal is restricted to 30 Gy the corresponding evidence can be expected for all schemes. In the case of a high single dose of 6 Gy a reduction of the recovery time from 1 week to 2...2 days yields also an indication of a severe damage, even if Dtotal amounts only to 30 Gy. CONCLUSIONS: A comparison of the simulation results basing to the survival of cell numbers with clinical experience and practice shows that the clinical reality can qualitatively be represented by the model. This opens the door for connecting side effects to normal tissue with the corresponding tumor efficacy (discussed in previous papers). The model is open to further refinement and to discussions referring to the phenomenon of late effects.

Radiogenic responses of normal tissue induced by fractionated irradiation--a simulation study. I. Acute effects.

AIM: Based on control theory, the attempt is made in this paper to construct a computer model which describes the time course of fast proliferating normal tissue after irradiation treatment. Subsequently, different clinical irradiation schemes are compared in regard to their radiogenic acute effects. MATERIAL AND METHODS: A cybernetic model of a cell renewal system consisting of stem-, transit- and functional cells has been developed and transferred into a computer model. The radiation effects are considered by characteristic cell parameters as well as by the linear-quadratic model. RESULTS: Three kinds of tissue (thick epidermis of man, thin epidermis of the mouse and jejunum of the mouse) have been irradiated in the model in accordance with different clinical irradiation schemes (standard-, super-, hyperfractionation and a single high dose per week). The simulation studies demonstrate that the acute reaction of normal tissue to hyperfractionation (3 times 1.5 Gy per day) is particularly severe. Furthermore, the radiation damage of the jejunum and of the thin epidermis of the mouse depends on the specific irradiation scheme and is only partially compensated. CONCLUSION: A comparison of the simulation results with clinical experience (and practice) demonstrates that the clinical reality can in quality be successfully represented by the model. This opens the door for connecting the side effects of irradiation to normal tissue with the corresponding tumor effectiveness (see our previous papers about irradiation of tumor spheroids.