Visual word form processing deficits driven by severity of reading impairments in children with developmental dyslexia.

The visual word form area (VWFA) in the left ventral occipito-temporal (vOT) cortex is key to fluent reading in children and adults. Diminished VWFA activation during print processing tasks is a common finding in subjects with severe reading problems. Here, we report fMRI data from a multicentre study with 140 children in primary school (7.9-12.2 years; 55 children with dyslexia, 73 typical readers, 12 intermediate readers). All performed a semantic task on visually presented words and a matched control task on symbol strings. With this large group of children, including the entire spectrum from severely impaired to highly fluent readers, we aimed to clarify the association of reading fluency and left vOT activation during visual word processing. The results of this study confirm reduced word-sensitive activation within the left vOT in children with dyslexia. Interestingly, the association of reading skills and left vOT activation was especially strong and spatially extended in children with dyslexia. Thus, deficits in basic visual word form processing increase with the severity of reading disability but seem only weakly associated with fluency within the typical reading range suggesting a linear dependence of reading scores with VFWA activation only in the poorest readers.

[Urethral stricture rate after prostate cancer radiotherapy : Five-year data of a certified prostate cancer center]. / Harnröhrenstrikturrate nach Bestrahlung eines Prostatakarzinoms : 5-Jahres-Daten eines zertifizierten Prostatakarzinomzentrums.

BACKGROUND: A urethral stricture is a scar of the urethral epithelium which can cause obstructive voiding dysfunction with consequential damage of the upper urinary tract. Almost 45% of all strictures are iatrogenic; they develop in 2-9% of patients after radical prostatectomy, but can also occur after prostate cancer radiotherapy. This study provides 5­year data of a certified prostate cancer center (PKZ) in terms of urethral strictures. MATERIALS AND METHODS: Between 01/2008 and 12/2012 a total of 519 men were irradiated for prostate cancer (LDR and HDR brachytherapy as well as external beam radiation). The entire cohort was followed-up prospectively according to a standardized protocol (by type of irradiation). Short segment urethral strictures were treated by urethrotomy, recurrent and long segment stenosis with buccal mucosa urethroplasty. RESULTS: A total of 18 of 519 (3.4%) patients developed a urethral stricture post-therapeutically, which recurred in 66% of cases after the first operative treatment. The largest risk for developing a urethral stricture is attributed to the HDR brachytherapy (8.9%). CONCLUSION: Urethral strictures after prostate cancer radiotherapy should be diagnosed and treated in time for long-term preservation of renal function. The rate of radiogenic urethral strictures (3.4%) is equivalent to those after radical prostatectomy. Due to a high rate of recurrences, urethrotomy has a limited importance after irradiation.

Evaluation of time, attendance of medical staff, and resources during interstitial brachytherapy for prostate cancer : DEGRO-QUIRO trial.

INTRODUCTION: The German Society of Radiation Oncology initiated a multicenter trial to evaluate core processes and subprocesses of radiotherapy by prospective evaluation of all important procedures in the most frequent malignancies treated by radiation therapy. The aim of this analysis was to assess the required resources for interstitial high-dose-rate (HDR) and low-dose-rate (LDR) prostate brachytherapy (BRT) based on actual time measurements regarding allocation of personnel and room occupation needed for specific procedures. PATIENTS AND METHODS: Two radiotherapy centers (community hospital of Offenbach am Main and community hospital of Eschweiler) participated in this prospective study. Working time of the different occupational groups and room occupancies for the workflow of prostate BRT were recorded and methodically assessed during a 3-month period. RESULTS: For HDR and LDR BRT, a total of 560 and 92 measurements, respectively, were documented. The time needed for treatment preplanning was median 24 min for HDR (n = 112 measurements) and 6 min for LDR BRT (n = 21). Catheter implantation with intraoperative HDR real-time planning (n = 112), postimplantation HDR treatment planning (n = 112), and remotely controlled HDR afterloading irradiation (n = 112) required median 25, 39, and 50 min, respectively. For LDR real-time planning (n = 39) and LDR treatment postplanning (n = 32), the assessed median duration was 91 and 11 min, respectively. Room occupancy and overall mean medical staff times were 194 and 910 min respectively, for HDR, and 113 and 371 min, respectively, for LDR BRT. CONCLUSION: In this prospective analysis, the resource requirements for the application of HDR and LDR BRT of prostate cancer were assessed methodically and are presented for first time.

Increased leukocyte survival and accelerated onset of lymphoma in the absence of MCL-1 S159-phosphorylation.

The antiapoptotic BCL-2 protein MCL-1, which opposes mitochondrial outer membrane permeabilization, was shown to have a crucial role in the survival of hematopoietic cells. We have previously shown that, upon loss of phosphatidylinositol 3-kinase signaling, S159 of MCL-1 is phosphorylated by glycogen synthase kinase-3 (GSK-3), earmarking MCL-1 for enhanced ubiquitylation and degradation. In this study, we introduced MCL-1(wt) or the phosphorylation-deficient mutant MCL-1(S159A) in mouse BM cells, followed by adoptive transfer to recipient mice. Mice expressing MCL-1(S159A) exhibited significantly elevated white blood cell and lymphocyte counts, whereas no effect was observed on the distribution of T and B lymphocyte subsets or the numbers of monocytes, red blood cells or platelets. Expression of MCL-1(S159A) in Eµ-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with Eµ-Myc/MCL-1(wt) mice. Our data demonstrate that the absence of MCL-1 S159 phosphorylation provides a survival advantage for hematopoietic cells in vivo and facilitates oncogenesis.

Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK.

We previously reported that gliotoxin (GT), the major virulence factor of the mold Aspergillus fumigatus causing invasive aspergillosis (IA) in immunocompromised patients, induces apoptosis in a Bak-dependent manner. The signaling pathway leading to Bak activation and subsequent mitochondrial outer membrane permeabilization (MOMP) is elusive. Here, we show that GT and the supernatant of A. fumigatus (but not its GT-defective mutant) activate the JNK pathway and require a co-operative JNK-mediated BimEL phosphorylation at three sites (S100, T112 and S114) to induce apoptosis in mouse fibroblasts, human bronchial and mouse alveolar epithelial cells. Cells (i) treated with the JNK inhibitor SP600125, (ii) deleted or knocked down for JNK1/2 or Bim or (iii) carrying the BimEL triple phosphomutant S100A/T112A/S114A instead of wild-type BimEL are similarly resistant to GT-induced apoptosis. Triple-phosphorylated BimEL is more stable, redistributes from a cytoskeletal to a membrane fraction, better interacts with Bcl-2 and Bcl-xL and more effectively activates Bak than the unphosphorylated mutant. These data indicate that JNK-mediated BimEL phosphorylation at S100, T112 and S114 constitutes a novel regulatory mechanism to activate Bim in response to apoptotic stimuli.

Preterm twin and triplet pregnancies are at increased risk for the development of cystic periventricular leukomalacia.

BACKGROUND: An increased risk of cerebral palsy in multiples has been reported. AIMS: To determine the risk for the development of periventricular leukomalacia (PVL) of twin and triplet pregnancy. STUDY DESIGN: Retrospective single-centre study at a tertiary care university hospital. SUBJECTS: Infants ≤ 35 weeks gestational age born between 1988 and 2008. OUTCOME MEASURES: Risk of twin and triplet compared to singleton pregnancy regarding development of PVL in one offspring. RESULTS: Of 6195 infants 117 singletons and 39 multiples were diagnosed as having cystic PVL. Perinatal data did not differ as did not ultrasonographic findings and neurologic outcome. The relative risk (RR) of a twin pregnancy resulting in at least one infant with PVL when born prior to 36 weeks was 2.181 (CI 95% 1.474-3.228, p < .0001), and 6.793 (CI 95% 2.470-13.108, p < .0001) of a triplet pregnancy. In-vitro fertilisation was present in 3% of affected twins compared to 100% in triplets (p < .001). CONCLUSION: We found an increased risk for PVL in preterm twin and triplet pregnancies.

Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling.

Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case-control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant.

BACKGROUND: Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers. AIMS: To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. STUDY DESIGN: Retrospective single centre case-control study. SUBJECTS: Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. OUTCOME MEASURES: Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. RESULTS: Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p=.022 and .024, respectively). Lowest PaCO(2) values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p=.033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. CONCLUSION: We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.

The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCdelta and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCdelta downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.

Minor neurological dysfunction, cognitive development, and somatic development at the age of 3 to 7 years after dexamethasone treatment in very-low birth-weight infants.

The objective of this study was to assess minor neurological dysfunction, cognitive development, and somatic development after dexamethasone therapy in very-low-birthweight infants. Thirty-three children after dexamethasone treatment were matched to 33 children without dexamethasone treatment. Data were assessed at the age of 3-7 years. Dexamethasone was started between the 7th and the 28th day of life over 7 days with a total dose of 2.35 mg/kg/day. Exclusion criteria were asphyxia, malformations, major surgical interventions, small for gestational age, intraventricular haemorrhage grades III and IV, periventricular leukomalacia, and severe psychomotor retardation. Each child was examined by a neuropediatrician for minor neurological dysfunctions and tested by a psychologist for cognitive development with a Kaufman Assessment Battery for Children and a Draw-a-Man Test. There were no differences in demographic data, growth, and socio-economic status between the two groups. Fine motor skills and gross motor function were significantly better in the control group (p<0.01). In the Draw-a-Man Test, the control group showed better results (p<0.001). There were no differences in development of speech, social development, and the Kaufman Assessment Battery for Children. After dexamethasone treatment, children showed a higher rate of minor neurological dysfunctions. Neurological development was affected even without neurological diagnosis. Further long-term follow-up studies will be necessary to fully evaluate the impact of dexamethasone on neurological and cognitive development.

Preterm twin gestation and cystic periventricular leucomalacia.

OBJECTIVE: To identify risk factors for the development of cystic periventricular leucomalacia (PVL) in twin gestation. DESIGN: Retrospective case-control study. SETTING: Tertiary care university hospital, Department of Paediatrics, Division of Neonatology, Graz, Austria. PATIENTS: Preterm twin gestations with one sibling having developed cystic PVL, diagnosed by ultrasound scans, compared with their co-twins without PVL, in hospital between 1988 and 2000. MAIN OUTCOME MEASURES: Perinatal and postnatal risk factors for the development of PVL. RESULTS: Eighteen preterm twin gestations were included. Monochorionicity was evident in 47% of the pregnancies, and twin to twin transfusion syndrome occurred in two cases (11%). Fetal distress correlated inversely with PVL (15% v 53%, p = 0.019, relative risk (RR) = 2.057, 95% confidence interval (CI) = 1.067 to 3.968). Hypocarbia with Pco(2) levels below 30 mm Hg (4 kPa) was diagnosed in 29% of the cases compared with 6% of the controls (p = 0.038, RR = 1.944, 95% CI = 1.113 to 3.396). There were no significant differences between groups with regard to premature rupture of the membranes, early onset infection, respiratory distress syndrome, mechanical ventilation, arterial hypotension, persistent ductus arteriosus, and hyperbilirubinaemia. Asphyxia was only evident in three controls. Three infants died and another three were lost to follow up. None of the cases compared with 62% of the controls were diagnosed as having developed normally (p < 0.001), and 14 cases (82%) compared with two controls (15%) developed cerebral palsy (p < 0.001). CONCLUSION: Hypocarbia was the only risk factor strongly associated with cystic PVL. The general outcome of the infants was poor.

[Interstitial brachytherapy--a minimal invasive urological option for treatment of prostate cancer of increasing importance]. / Interstitielle Brachytherapie--eine minimal invasive urologische Therapieoption des Prostatakarzinoms mit zunehmender Bedeutung.

As an alternative to a radical prostatectomy with complications reducing the quality of life because of incontinence of urine and erectile dysfunction, the insertion of radioactive sources into the prostate was established in the USA and evaluated by accompanying studies at the beginning of the eighties. The patient has the advantage of minimal-invasive character, the possibility of outpatient treatment and the lower operative morbidity as well as reduced complications. In the locally limited "low-risk" stage (pT1a - pT2c), the American Society for Urology judges it equieffective as a curative treatment as regards the survival period. Although there are long-term studies with a follow-up of 13 years, in Germany we are not able to give our opinion finally, but it can be assumed to be as equally good. Considering the demographic development, one has to expect an increase in this cancer, which today already has the highest cancer rate in men in Germany. The improved diagnosis will lead to an increase in treatments and younger men will be examined. As a result there will be more curable cases and an improvement or even prolongation of the survival period. The trend seen in the USA indicates a rise in this treatment in Germany as well. After a terminological definition of the expression and a presentation of the brachytherapy-technique, the range of actual therapeutical options of prostate cancer and the variations of brachytherapy are shown and compared as far as their efficiency is concerned. Uncertainties in the evaluation of medical necessity are discussed but also contradictions and diversities in the opinions on the mode of accounting.

[Transient periventricular echodensities (TPE) in preterm infants under 1500 gramms: an analysis of the outcome of the last 10 years]. / Transiente periventrikuläre Echodensitäten (TPE) bei Frühgeborenen unter 1500 Gramm: Eine Analyse des Outcome der letzten 10 Jahre.

BACKGROUND: The aim of our study was to analyze neurodevelopmental outcome in preterm infants with TPE. PATIENTS: 46 preterm infants with a birthweight (BW) < or = 1500 g were included in the study. They all had TPE in parieto-occipital location (some combined with frontal flares). Exclusion criteria were PVL II-IV, intraventricular hemorrhage, asphyxia and isolated frontal TPE. METHOD: We analyzed ultrasound scans (1992 - 2001) of patients with TPE (diameter > 1 cm, visible in both sagittal and coronal planes, duration > 7 days), and neurological follow-up visits (date of demission, corrected age of 4, 8, 12 months, and after that every 2 years until 6 years of age) regarding the neurodevelopmental outcome. We devided the patients in group 1 (duration of TPE 8 - 14 days) and group 2 (duration of TPE > 14 days) and then analyzed the groups regarding neurodevelopmental disorders and factors increasing the risk of occurrence of TPE. RESULTS: From 1992 - 2001 578 children < or = 1500 g were admitted at our department. 48 patients (8,3 %) fulfilled the entry criteria, 2 of them died, so 46 were included in the study. In group 1 (10 patients) the median gestational age (GA) was 28 weeks (range 25 - 31), median BW 1075 g (range 685 - 1430), 6 children were neurologically unimpaired, one developed a motor handicap, and 3 a psychomotor retardation. In group 2 (36 patients) the median GA was 28 weeks (range 25 - 35), median BW 1034,5 g (range 540 - 1470), 24 patients were neurologically unimpaired, 7 developed a motor handicap, and 5 a psychomotor retardation. No statistical difference was found between the groups neither in neurodevelopmental outcome nor factors increasing the risk of the occurrence of TPE. CONCLUSIONS: Obviously, the finding of TPE is of clinical relevance already at a duration of only 7 days regarding later neurological development.

p53 triggers apoptosis in oncogene-expressing fibroblasts by the induction of Noxa and mitochondrial Bax translocation.

The mechanism of p53-dependent apoptosis is still only partly defined. Using early-passage embryonic fibroblasts (MEF) from wild-type (wt), p53(-/-) and bax(-/-) mice, we observe a p53-dependent translocation of Bax to the mitochondria and a release of mitochondrial Cytochrome c during stress-induced apoptosis. These events proceed independent of zVAD-inhibitable caspase activation, are not prevented by dominant negative FADD (DN-FADD), but are negatively regulated by Mdm-2. Bcl-x(L) expression prevents the release of mitochondrial Cytochrome c and apoptosis, but not Bax translocation. At a single-cell level, enforced expression of p53 is sufficient to induce Bax translocation and Cytochrome c release. Real-time RT-PCR analysis reveals a significant induction of RNA expression of Noxa and Bax in p53(+/+), but not in p53(-/-) MEF. Noxa protein expression becomes detectable prior to Bax translocation, and downregulation of endogenous Noxa by RNA interference protects wt MEF against p53-dependent apoptosis. Hence, in oncogene-expressing MEF p53 induces apoptosis by BH3 protein-dependent caspase activation.

Absent or reversed end-diastolic blood flow in the umbilical artery and abnormal Doppler cerebroplacental ratio--cognitive, neurological and somatic development at 3 to 6 years.

UNLABELLED: The objective of this study was to examine the cognitive, neurological and somatic developments of children who had in utero an absent or reversed end-diastolic blood flow (ARED) in the umbilical artery or an abnormal cerebroplacental ratio (ABF). METHODS: 16 children with ARED blood flow and 15 children with ABF were each matched to children with the same gestational age, appropriate for gestational age, the same sex and born within 4 months. Data were assessed at the age of 3-6 years. Children with asphyxia, neonatal infection, malformation or major surgical interventions in the neonatal period were excluded. Each child underwent a neuropediatrical examination; furthermore, a Kaufman Assessment Battery for Children, a Snijders-Oomen Intelligence Scale for Children and a Man-Drawing Test were used to evaluate cognitive development. The socioeconomic status was also assessed. RESULTS: Children in the ARED group remained lighter and had a higher frequency of microcephaly. In the Kaufman Assessment Battery for Children and the Snijders-Oomen Intelligence Scale for Young Children, cognitive development was impaired in the ARED and the ABF groups compared to the control group. The ARED and the ABF groups, however, showed no differences. The Man-Drawing Test and the Denver Development Test did not show any differences. DISCUSSION: ARED blood flow and ABF showed impaired cognitive development. The degree of impairment was the same in the ARED and the ABF groups. Long-term follow-up studies until adulthood are necessary to see if impaired cognitive development remains significant in these groups of patients.

The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia.

The Wilms tumor gene wt1 and the protooncogene bcl-2 are upregulated in acute myeloid leukemia (AML) and are known to regulate or to inhibit the onset of apoptosis. Since wt1 has been shown to regulate the expression of bcl-2, we investigated the association of the expression of these genes and their prognostic relevance in AML. Leukemic blasts from the bone marrow of 152 patients with newly diagnosed AML were analyzed for bcl-2 and wt1 mRNA expression using RT-PCR and quantitative PCR. Therapy outcome was correlated with the level of bcl-2 and wt1 transcripts. Bcl-2-specific mRNA was detectable in 127/152 (84%) patients and wt1 mRNA in 113/152 (74%) patients with AML. In monocytic subtypes the frequency of bcl-2 and wt1 transcripts was significantly lower. The expression of bcl-2 mRNA was correlated significantly with that of wt1 mRNA (P < 0.0001). In AML patients <60 years, high expression of bcl-2 and wt1 was associated with a reduced rate of continuing complete remission (CCR, P = 0.002 and P = 0.005, respectively) and increased death rate (P = 0.0002 and P = 0.04, respectively) in contrast to patients >60 years, where the expression of bcl-2 or wt1 had no prognostic impact. Based on the coexpression of bcl-2 and wt1, we established a prognostic model defining three risk groups with significant differences in CCR rate (P = 0.01), overall survival (P < 0.04) and disease-free survival (P < 0.03). Thus, bcl-2 and wt1 mRNA expression are associated with response and long-term outcome in AMLs. The coexpression of these genes allows determination of prognostic groups with high predictive value for overall and disease-free survival.