BARTH SYNDROME IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION IN THE TAZ GENE.

Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ) which lead to cardiolipin deficiency and mitochondrial dysfunction. Male patients have variable clinical findings, including cardiomyopathy, skeletal myopathy, prepubertal short stature, neutropenia and 3-methylglutaconic aciduria. Female carriers are usually asymptomatic. We report a novel TAZ gene mutation in male and female siblings with left ventricular noncompaction and hypotonia. Additionally, the brother presented an intermittent neutropenia and increased urinary levels of 3-methylglutaconic and 3-methylglutaric acid. The molecular genetic testing showed that both siblings carry the mutation: c.253insC, p.(Arg85Profs*54) in exon 3 of the TAZ gene. This article presents the first case of BTHS in a heterozygous female patient with normal karyotype.

[MENOPAUSE AND CARDIOVASCULAR RISK.]

Recently, in connection with the increased life expectancy; considerable interest in the problems of menopause has risen. The climax is a natural biological period of a woman's life during which a decrease in the production of sex hormones occurs. In response to the sharp decline in estrogen and altered hormonal environment characterizing menopause, a number of unfavourable changes in metabolism develop, increasing the risk of cardiovascular disease (CVD) and deterioration in the quality of life of menopausal women.

[PROBLEMS IN TEACHING STUDENTS ABOUT THE BEHAVIOR OF THE MIDWIFE IN EMERGENCY CONDITIONS].

As a result of reforms in the education of nurses and midwives in our country, their training is conducted in university structures bachelor's degree program. The purpose of this study is to determine the students' specialty "midwife" for emergencies in obstetrics and needs additional training in this field of obstetric care. Survey was carried out with 55 students in "midwife" who are trained in the Faculty of Public Health of the Medical University - Sofia. The study was conducted during the second semester of the academic year 2014/2015. The results show that students definitely have a need for training on the topic of emergencies in obstetrics, this training should be aimed at developing clinical thinking and skills to assess the condition of the patient.

A hominid tooth from Bulgaria: the last pre-human hominid of continental Europe.

A hominid upper premolar was discovered in the Azmaka quarry, near Chirpan (Bulgaria). The associated fauna, especially the co-occurrence of Choerolophodon and Anancus among the proboscideans, and Cremohipparion matthewi and Hippotherium brachypus among the hipparions, constrains the age of the locality to the second half of the middle Turolian (ca. 7 Ma), making it the latest pre-human hominid of continental Europe and Asia Minor. The available morphological and metric data are more similar to those of Ouranopithecus from the Vallesian of Greece than to those of the early to middle Turolian hominids of Turkey and Georgia, but the time gap speaks against a direct phyletic link, and Turolian migration from the east cannot be rejected.

Evidence for a motor and a non-motor domain in the human dentate nucleus--an fMRI study.

Dum and Strick (J. Neurophysiol. 2003; 89, 634-639) proposed a division of the cerebellar dentate nucleus into a "motor" and "non-motor" area based on anatomical data in the monkey. We asked the question whether motor and non-motor domains of the dentate can be found in humans using functional magnetic resonance imaging (fMRI). Therefore dentate activation was compared in motor and cognitive tasks. Young, healthy participants were tested in a 1.5 T MRI scanner. Data from 13 participants were included in the final analysis. A block design was used for the experimental conditions. Finger tapping of different complexities served as motor tasks, while cognitive testing included a verbal working memory and a visuospatial task. To further confirm motor-related dentate activation, a simple finger movement task was tested in a supplementary experiment using ultra-highfield (7 T) fMRI in 23 participants. For image processing, a recently developed region of interest (ROI) driven normalization method of the deep cerebellar nuclei was used. Dorso-rostral dentate nucleus activation was associated with motor function, whereas cognitive tasks led to prominent activation of the caudal nucleus. The visuospatial task evoked activity bilaterally in the caudal dentate nucleus, whereas verbal working memory led to activation predominantly in the right caudal dentate. These findings are consistent with Dum and Strick's anatomical findings in the monkey.

Radiation-induced defects in sucrose single crystals, revisited: a combined electron magnetic resonance and density functional theory study.

The results are presented of an electron magnetic resonance analysis at 110 K of radiation-induced defects in sucrose single crystals X-irradiated at room temperature, yielding a total of nine (1)H hyperfine coupling tensors assigned to three different radical species. Comparisons are made with results previously reported in the literature. By means of electron paramagnetic resonance and electron nuclear double resonance temperature variation scans, most of the discrepancies between the present 110 K study and a previous 295 K study by Sagstuen and co-workers are shown to originate from the temperature dependence of proton relaxation times and hyperfine coupling constants. Finally, radical models previously suggested in the literature are convincingly refuted by means of quantum chemical density functional theory calculations.

[Gynalgin--one more opportunity in the treatment of bacterial vaginosis].

The data of 30 nonpregnant women in reproductive age BV treated with Gynalgin were presented. On clinical and microbiological indicator Gynalgin showed a good effect on BV-associated microorganisms (80%). Only one of the cases of BV was not affected (4%). With nixed infection of BV and Candida we established clinical improvement and recovery of Lactobacillus spp. In 66.6%, but in all cases on Candida is not effect. We consider that Gynalgin is still one more easily applicable and clinically effective opportunity for treatment of BV.

Verb generation in children and adolescents with acute cerebellar lesions.

The aim of the present study was to examine verb generation in a larger group of children and adolescents with acute focal lesions of the cerebellum. Nine children and adolescents with cerebellar tumours participated. Subjects were tested a few days after tumour surgery. For comparison, a subgroup was tested also 1 or 2 days before surgery. None of the children had received radiation or chemotherapy at or before the time of testing. Eleven age- and education-matched control subjects participated. Subjects had to generate verbs to blocked presentations of photographs of objects. As control condition, the objects had to be named. Furthermore, dysarthria was quantified by means of a sentence production and syllable repetition task. Detailed analysis of individual 3D-MR images revealed that lesions affected cerebellar hemispheres in all children and adolescents. The right cerebellar hemisphere was affected in four and the left hemisphere in five subjects. In the present study, naming and verb generation accuracy were preserved in the majority of subjects with cerebellar lesions. No significant signs of learning deficits were observed, as reduction of reaction times over blocks was not different compared to controls. There was a trend of children and adolescents with right-hemispheric lesions to perform worse compared to controls. In this group, however, significant signs of dysarthria were present. In sum, no significant signs of disordered verb generation were observed in children and adolescents with acute cerebellar lesions. Findings suggest that the role of the cerebellum in verb generation may be less pronounced than previously suggested. Findings need to be confirmed in a larger group of subjects with acute focal lesions.

Activation of cerebellar nuclei comparing finger, foot and tongue movements as revealed by fMRI.

The aim of the present study was to compare possible activation of the interposed and dentate cerebellar nuclei during finger, foot and tongue movements using functional magnetic resonance imaging (fMRI). Nineteen healthy control subjects performed sequential finger and repetitive tongue and foot movement tasks. Thin slices (2.5mm) were acquired of the cerebellar region containing the cerebellar nuclei with high spatial resolution (matrix size 128 x 128 x 10) using a Siemens 1.5T Sonata system. Use of an eight channel head coil provided better signal-to-noise-ratio compared to standard head coils. Only data of those 12 subjects were included in final statistical analysis, who showed significant activation of the cerebellar nuclei at least in one task. Cortical activations of the superior cerebellum were found in accordance to the known somatotopy of the human cerebellar cortex. Nuclear activations were most significant in the sequential finger movement task. Both interposed nuclei and ipsilateral dentate nucleus were activated. Dentate activation was present in the more caudal parts of both the dorsal and ventral nucleus. Activation overlapped with motor and non-motor domains of the dentate nucleus described by Dum and Strick [R.P. Dum, P.L. Strick, An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex, J. Neurophysiol. 89 (2003) 634-639] based on anatomical data in monkey. Tongue movement related activations were less extensive and overlapped with activations of caudal parts of the dentate nucleus in the finger movement task. No nuclear activation was seen following foot movements. The present findings show that both interposed and dentate nuclei are involved in sequential finger movements in humans. Interposed nucleus likely contributes to movement performance. Although no direct conclusions could be drawn based on the present data, different parts of the dentate nucleus may contribute to movement performance, planning and possible non-motor parts of the task.

Trace eyeblink conditioning in human subjects with cerebellar lesions.

Trace eyeblink conditioning was investigated in 31 patients with focal cerebellar lesions and 19 age-matched controls. Twelve patients presented with lesions including the territory of the superior cerebellar artery (SCA). In 19 patients lesions were restricted to the territory of the posterior inferior cerebellar artery (PICA). A 3D magnetic resonance imaging was used to determine the extent of the cortical lesion and possible involvement of cerebellar nuclei. Eyeblink conditioning was performed using a 40 ms tone as conditioned stimulus (CS) followed by a stimulus free trace-interval of 400 ms and a 100 ms air-puff as unconditioned stimulus (US). In SCA patients with lesions including parts of the cerebellar interposed nucleus trace eyeblink conditioning was significantly impaired. Pure cortical lesions of the superior cerebellum were not sufficient to reduce acquisition of trace conditioned eyeblink responses. PICA patients were not impaired in trace eyeblink conditioning. Consistent with animal studies the findings of the present human lesion study suggest that, in addition to forebrain areas, the interposed nucleus is of importance in trace eyeblink conditioning. Although cortical cerebellar areas appear less important in trace compared with delay eyeblink conditioning, the present data strengthen the view that cerebellar structures contribute to different forms of eyeblink conditioning paradigms.

Probabilistic 3D MRI atlas of the human cerebellar dentate/interposed nuclei.

In a previous study, a three-dimensional (3D) MRI atlas of the human cerebellar nuclei was introduced based on findings in one healthy human subject [Dimitrova, A., Weber, J., Redies, C., Kindsvater, K., Maschke, M., Kolb, F.P., Forsting, M., Diener, H.C., Timmann, D., 2002. MRI atlas of the human cerebellar nuclei. NeuroImage 17, 240-255]. The present MRI investigation was designed to study variability of the anatomy of the dentate/interposed nuclei in a larger group of healthy subjects. Similar to our previous study, iron-induced susceptibility artifacts were used to visualize the cerebellar nuclei as hypointensities on MR images. Data of 63 healthy subjects (27 female, 36 male; mean age 45.3+/-13.4 years, age range 22--71 years) were included. A 3D axial volume of the cerebellum was acquired using a T2*-weighted FLASH sequence on a Siemens Sonata 1.5 T MR scanner. Each volume was registered, re-sampled to 1.00 x 1.00 x 1.00 mm(3) voxel size and spatially normalized into a standard proportional stereotaxic space using SPM99. Dentate/interposed nuclei were traced on axial images and saved as regions of interest using MRIcro-software by two independent examiners. A probabilistic 3D MRI atlas of the cerebellar dentate/interposed nuclei is presented based on findings in all subjects.

Functional localization in the human cerebellum based on voxelwise statistical analysis: a study of 90 patients.

The aim of the present study was to examine somatotopy in the cerebellar cortex and a possible differential role of the cerebellar cortex and nuclei in functional outcome. Clinical findings and 3D MRI-based cerebellar lesions site were compared in a group of 90 patients with focal cerebellar lesion using International Cooperative Ataxia Rating Scale (ICARS) and voxel-based lesion-symptom mapping (VLSM). Separate analysis was performed in patients with acute and chronic ischemic lesions (n=43) and patients with acute and chronic surgical lesions (n=47). Thirty-eight patients were included after resection of a cerebellar tumor in childhood or adolescence. The most significant lesion symptom correlations were observed in the subgroup with acute ischemic lesions. Limb ataxia was significantly correlated with lesions of the interposed (NI) and part of the dentate nuclei (ND), ataxia of posture and gait with lesions of the fastigial nuclei (NF) including NI. Correlations with cortical lesions were less significant and present in the superior cerebellum only. Upper limb ataxia was correlated with lesions of vermal, paravermal and hemispheral lobules IV-V and VI, lower limb ataxia with lesions of vermal, paravermal and hemispheral lobules III and VI, dysarthria with lesions of paravermal and hemispheral lobules V and VI and ataxia of posture and gait with lesions of vermal and paravermal lobules II, III and IV. In the subgroups with chronic focal lesions, similar correlations were observed with lesions of the cerebellar nuclei, but significantly less correlations with lesions of the cerebellar cortex. Functional localization based on VLSM backs findings in previous animal and functional brain images studies in healthy human subjects. The lesion site appears to be critical for motor recovery. Lesions affecting the cerebellar nuclei are not fully compensated at any age and independent of the pathology in humans.

Impact of surgery and adjuvant therapy on balance function in children and adolescents with cerebellar tumors.

OBJECTIVES: This study examined the effects of posterior fossa tumor surgery and concomitant irradiation and/or chemotherapy on the long-term recovery of balance function in children and adolescent patients. SUBJECTS AND METHODS: 22 patients, treated during childhood for a benign (n = 14) or malignant cerebellar tumor (n = 8), were examined in chronic state (mean latency between surgery and testing: 7.7 years, range 3 - 17 years). Postural impairments were assessed with static and dynamic posturography. All cerebellar lesions were documented by standardized and normalized MRI data. Healthy age- and gender-matched subjects served as a control group. RESULTS: Comparing the balance function of (i) children with or without affected cerebellar nuclei and (ii) children with and without adjuvant chemotherapy and/or radiotherapy revealed that damage to the cerebellar nuclei had more impact on neurological impairment than concomitant tumor therapy. Balance abnormalities were most pronounced when a lesion affected the fastigial nucleus. Chemotherapy with its neurological side effect was associated with enhanced postural sway in only two children with malignant tumors. CONCLUSIONS: The study results indicate that the sparing of the deep cerebellar nuclei had the greatest impact on the recovery of balance function in pediatric patients treated for both a benign or malignant cerebellar tumor.

Children and adolescents with chronic cerebellar lesions show no clinically relevant signs of aphasia or neglect.

We studied language and visuospatial functions of 12 children and adolescents who had undergone surgery for cerebellar astrocytoma without subsequent radiation or chemotherapy and compared them with 27 age-, gender-, and education-matched healthy control subjects. To study possible lateralization of the functions of the left and right cerebellar hemispheres, subjects performed several language tasks including a verb-generation task as well as standard neglect and extinction tests. Three-dimensional-MR images confirmed that lesions affected cerebellar hemispheres in all children but one who had a pure vermal lesion. The right cerebellar hemisphere was affected in six, the left hemisphere in four children, and both hemispheres in one child. There were no signs of aphasia in the children or adolescents with cerebellar lesions. Language abilities did not differ between cerebellar patients and control subjects except for small increases in reaction times in verb generation in patients with left-sided lesions. Visuospatial functions were also intact in cerebellar subjects except for minor group differences in neglect tasks. In sum, chronic focal cerebellar lesions acquired in childhood or youth do not result in persistent language disorders or clinically significant signs of spatial neglect or extinction.

Cerebellar agenesis II: motor and language functions.

In a former study of a patient with cerebellar agenesis (HK) mild motor deficits, problems in delay eyeblink conditioning and mild to moderate deficits in IQ, planning behavior, visuospatial abilities, visual memory, and attention were found. The present study reports additional findings in the same patient. In the motor domain, impairments in fine motor manipulations, trace eyeblink conditioning and motor imagination in a functional magnetic resonance (fMRI) study were found. Based on fMRI findings; however, cortical areas involved in a tapping task did not significantly differ from a healthy control group. In the cognitive domain, deficits in speech comprehension as well as verbal learning and declarative memory were present. No significant affective symptoms were observed. Although problems in executive, visuospatial and language tasks are in agreement with the so-called cerebellar cognitive affective syndrome-other possibilities remain. Non-motor impairments in HK might also be a consequence of lacking motor abilities in development and motor deficits may interfere with the performance of parts of the cognitive tasks. In addition, lack of promotion and learning opportunities in childhood may contribute and mental retardation based on extracerebellar dysfunction cannot be excluded.

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment.

Lithium is the most effective mood-stabilizing drug in the therapy of bipolar affective disorder (BP). It is thought to exert its effect via the phosphatidylinositol signalling system. Myo-inositol monophosphatase 2 (IMPA2) codes for an enzyme in this system that is inhibited by lithium. It is located on 18p11.2, a region implicated as a BP susceptibility locus. We examined eight single-nucleotide polymorphisms (SNPs) identified within this gene for association with BP, using 237 parents-offspring trios and in 174 cases and 170 controls. No SNP showed association with BP. When good responders to lithium treatment were compared with the poor responders, some statistically significant differences emerged for two SNPs; however, the sample became too small to draw definitive conclusions. We cannot find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation.

Preserved verb generation in patients with cerebellar atrophy.

A role of the right cerebellar hemisphere has been suggested in linguistic functions. Nevertheless, studies of verb generation in cerebellar patients provide inconsistent results. The aim of the present study was to examine verb generation in a larger group of cerebellar patients with well-defined lesions. Ten subjects with degenerative cerebellar disorders and ten healthy matched controls participated. Subjects had to generate verbs to the blocked presentation of photographs of objects (i.e. four blocks of sixteen objects). As control condition, the objects had to be named. Furthermore, dysarthria was quantified by means of a sentence production and syllable repetition task. Volumetric analysis of individual 3D-MR scans was performed to quantify cerebellar atrophy. Cerebellar patients were slower in the sentence production and syllable repetition tasks, and cerebellar volume was decreased compared to controls. Despite cerebellar atrophy and dysarthria, the answers produced did not differ between patients and controls. In addition, both groups revealed the same amount of decrease in verbal reaction time over blocks (i.e. learning). The results suggest that the role of the cerebellum in verb generation is less pronounced than previously suggested.